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  • Published: 12 February 2024

The double burden: type 1 diabetes and heart failure—a comprehensive review

  • María Teresa Julián 1 , 2   na1 ,
  • Alejandra Pérez-Montes de Oca 1 , 2   na1 ,
  • Josep Julve 3 , 4 &
  • Nuria Alonso 1 , 2 , 4  

Cardiovascular Diabetology volume  23 , Article number:  65 ( 2024 ) Cite this article

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Heart failure (HF) is increasing at an alarming rate, primary due to the rising in aging, obesity and diabetes. Notably, individuals with type 1 diabetes (T1D) face a significantly elevated risk of HF, leading to more hospitalizations and increased case fatality rates. Several risk factors contribute to HF in T1D, including poor glycemic control, female gender, smoking, hypertension, elevated BMI, and albuminuria. However, early and intensive glycemic control can mitigate the long-term risk of HF in individuals with T1D. The pathophysiology of diabetes-associated HF is complex and multifactorial, and the underlying mechanisms in T1D remain incompletely elucidated. In terms of treatment, much of the evidence comes from type 2 diabetes (T2D) populations, so applying it to T1D requires caution. Sodium-glucose cotransporter 2 inhibitors have shown benefits in HF outcomes, even in non-diabetic populations. However, most of the information about HF and the evidence from cardiovascular safety trials related to glucose lowering medications refer to T2D. Glycemic control is key, but the link between hypoglycemia and HF hospitalization risk requires further study. Glycemic variability, common in T1D, is an independent HF risk factor. Technological advances offer the potential to improve glycemic control, including glycemic variability, and may play a role in preventing HF. In summary, HF in T1D is a complex challenge with unique dimensions. This review focuses on HF in individuals with T1D, exploring its epidemiology, risk factors, pathophysiology, diagnosis and treatment, which is crucial for developing tailored prevention and management strategies for this population.

Introduction

Heart failure (HF) currently represents a global health problem due to the significant levels of morbidity and mortality associated with it [ 1 , 2 ]. Although the treatment of HF has improved in recent years, its prevalence and incidence have increased, leading to a substantial number of hospital admissions, progressive deterioration in the quality of life, and increased mortality. It is well established that diabetes mellitus (DM) is a significant risk factor for the development of heart disease, including HF [ 3 ]. Numerous epidemiological studies have established that diabetes is independently associated with the risk of developing HF [ 3 , 4 , 5 ]. Importantly, recent findings have revealed that among individuals with DM, especially those with type 2 diabetes (T2D), HF is increasingly becoming the primary manifestation of cardiovascular conditions, overtaking atherosclerotic diseases in this regard [ 6 ]. Indeed, the rising prevalence of DM worldwide and the aging of the world’s population have led to the emergence of a significant problem associated with diabetes-related HF [ 7 , 8 ]. The relationship between DM and HF is complex and multifactorial, and several mechanisms have been implicated. Diabetes increases the risk of HF regardless of classical cardiovascular risk factors such as hypertension or coronary heart disease. While the existence of distinct diabetic cardiomyopathy (DCM) remains a subject of debate, numerous experimental and preclinical studies have shown that hyperglycemia results in structural, functional, metabolic, and hemodynamic alterations in the myocardium [ 9 , 10 ].

In recent years, there has been growing interest in HF due to the development of new therapies, including glucose-lowering medications, such as sodium-glucose cotransporter 2 inhibitors (SGLT2), which have demonstrated significant cardioprotective effects, leading to notable improvements in HF symptoms, reduced hospitalizations rates, and decreased mortality [ 11 ]. Nonetheless, most of the knowledge concerning HF and the evidence from cardiovascular safety trials involving antidiabetic drugs refer to T2D.

Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by the destruction of insulin-producing beta cells in the pancreas. Similar to what occurs in T2D, cardiovascular disease, which includes HF, emerges as a long-term complication in T1D [ 12 ]. Recent epidemiological findings have shown an increasing prevalence of HF in individuals with T1D, potentially linked to a growing population of older individuals with long-standing T1D. However, HF in patients with T1D has not been studied as comprehensively as in patients with T2D. Understanding the complex mechanisms that link T1D and HF is crucial for the development of effective strategies for prevention and management. In this review, our primary focus will be on examining the evidence regarding heart failure in individuals with T1D, with particular attention paid to aspects such as epidemiology, risk factors, pathophysiology, and treatment options.

Methodology

We conducted a systematic search on the electronic database PubMed to look for relevant articles based on the research question. Papers were selected for inclusion in the present review according to their relevance, as judged by the authors. As a literature review, no ethics committee approval was needed.

Epidemiology, risk factors and prognosis

In developed countries, HF affects approximately 1–2% of the adult population [ 6 , 13 ], and in elderly individuals, the prevalence can rise to more than 10% [ 14 ]. Data from observational [ 15 ] and systematic studies [ 16 ] suggest a significant increase in the incidence rate of HF in subjects with T1D (Table  1 ) and a high risk of hospitalization due to HF among individuals with T1D, a risk that may quadruple that of the general population [ 17 , 18 ]. A 10-year retrospective study by McAllister et al. [ 17 ] found 1313 occurrences of HF among patients with T1D of more than 3.25 million adults without DM, T2D, and T1D. The crude incidence rate of HF hospitalization in the T1D group was 5.6 per 1000 person-years, compared with 2.4 cases in individuals without DM and 12.4 cases in those with T2D. Patients with T1D had a higher case fatality rate than people without DM and the difference was bigger in men (OR, 1.91; 95% CI, 1.68–2.18) than in women (OR, 1.31; 95% CI, 1.05–1.65) [ 17 ].

Furthermore, a recent meta-analysis investigated the risk of HF in individuals with T1D compared to those without DM. They reviewed four studies, with follow-up periods ranging from 1 to 12 years, and found that there had been a total of 1378 HF events among individuals with T1D, 3993 among those with T2D, and 18,945 among the controls. The incidence rate of HF per 1000 person-years was 5.8 for T1D, 10.0 for T2D, and 2.3 for controls. T1D patients had a three-fold higher risk of HF compared to controls (RR 3.4) and this risk was approximately five times higher in women with T1D (RR 4.9) compared to men (RR 3.0) [ 16 ]. Moreover, a separate systematic review that analyzed six observational studies, found that the HF incidence rate in T1D patients was also three times higher than in healthy controls ( p  < 0.001). The analysis indicated a correlation between HF risk and the age of T1D patients, suggesting that careful monitoring of HF risk factors is crucial, mainly since early diabetes onset may be a significant factor in reducing HF risk in this population. For every 10 years of disease duration, there was a slight increase of 0.003 in the Incidence Rate (IR) of HF, although this trend did not reach statistical significance ( p value = 0.07) [ 15 ]. Additionally, this elevated risk of developing HF for T1D individuals was found to be even higher, approximately four times so, in a meta-analysis aimed at investigating the association between T1D and cardiovascular disease (CVD) (Table  1 ). The study also noted an elevated risk of HF among females with T1D [ 19 ].

Regarding the different phenotypes based on left ventricular ejection fraction (LVEF) (heart failure with reduced ejection fraction [HFrEF], heart failure with mid-range ejection fraction [HFmrEF], heart failure with preserved ejection fraction [HFpEF], the available data is very limited. In a 7-year prospective study involving individuals with long-standing T1D, the overall prevalence of HF at the end of the follow-up period was 3.7%. Among the patients with HF, 85% exhibited HFpEF (defined by LVEF ≥ 50%), while the remaining 15% had HFrEF (defined by LVEF < 50%) [ 20 ]. Similar to other conditions, there is a lack of data regarding the prevalence of HFmrEF (defined as LVEF 40–49%) because most epidemiological studies, including the aforementioned one, have categorized HF patients into two groups using an LVEF cutoff value of 50%. Moreover, a recent study included 154 patients with T1D and myocardial dysfunction from the Thousand & 1 study as a comparison subgroup. Although this study assessed LVEF in individuals with T1D, it primarily focused on subjects without known heart disease. Notably, the study only reported the mean ejection fraction (55.8 ± 7.58) [ 21 ]. The specific analysis of different phenotypes based on LVEF within the context of HF and T1D, remains insufficiently documented, presenting an area that warrants further research.

Regarding risk factors, in a study of 33,402 patients with T1D over a mean follow-up period of 7.9 years, Rosegren et al. found that, besides female gender, worse glycemic control and the presence of albuminuria were associated with an increased risk of HF. Interestingly, even well-controlled diabetes and normoalbuminuria were linked to an elevated risk of HF, though it was not as pronounced in those with both well-controlled diabetes and normoalbuminuria [ 18 ]. Furthermore, a Danish cohort of T1D subjects with either diastolic or systolic subclinical myocardial dysfunction, when compared to a control group, had a longer history of diabetes (35.1 ± 14.9 vs. 30.1 ± 15.5 years; p  = 0.005), a higher body mass index (BMI) (26.1 ± 3.9 vs. 25.0 ± 3.7 kg/m 2 ; p  = 0.013), higher systolic blood pressure (143 vs. 136 mmHg; p  < 0.001), and lower kidney function (eGFR 75.4 ± 26.2 vs. 83.7 ± 21.0 mL/min/1.73m 2 ; p  = 0.003). Additionally, they were more likely to be on statin ( p  = 0.039) and antihypertensive medications ( p  < 0.001), and showed a higher prevalence of advanced retinopathy and albuminuria stages ( p  < 0.001 for both comparisons) [ 21 ] (Table 2 ).

The DCCT/EDIC study revealed that glycemic control, measured by glycated hemoglobin (HbA1c) was the most significant modifiable risk factor for congestive HF in 1441 patients with T1D over 29 years. For every 1% increase in HbA1c, there was a 3.15-fold higher risk of HF. Early intensive therapy appeared to reduce the long-term risk of HF five fold compared to conventional treatment; however, the 30-year analysis included relatively few HF events, preventing a definitive conclusion [ 22 ]. In line with these results, Lind et al. found that patients with elevated HbA1c levels (≥ 10.5%) experienced a > tenfold increased risk of morbidity and mortality from CVD, particularly HF. This risk escalated with age and the duration of diabetes and was further exacerbated by modifiable factors such as smoking, high systolic blood pressure, and elevated BMI. Additionally, a history of acute myocardial infarction contributed to an increased risk of HF. On the other hand, higher levels of HDL cholesterol (HDL-c) were associated with a reduced risk of HF, while LDL cholesterol levels showed no significant correlation [ 23 ].

Moreover, in a study of 78 adolescents with a 6-year history of T1D, despite normal cholesterol and lipid levels, a significant number had microalbuminuria and diastolic dysfunction. Female patients with diastolic dysfunction had lower HDL-c levels (OR 0.93; 95% CI 0.88–0.99; p  = 0.029) and higher total cholesterol (TC)/HDL-c (OR 2.55; 95% CI 1.9–5.45; p  = 0.016) and triglyceride (TG)/HDL-c (OR 2.74; 95% CI 1.12–6.71; p  = 0.028) ratios, which were linked to diastolic complications. The cutoff values for predicting diastolic dysfunction were 49 mg/dL for HDL, 3.0 for TC/HDL-c, and 1.85 for TG/HDL. These findings suggest that these ratios may help predict diastolic dysfunction in young female patients with poorly controlled T1D [ 24 ].

Regarding mortality, a UK study examined the impact of DM on mortality and the occurrence of HF, with a focus on gender differences. Results showed that individuals with DM had nearly twice the risk of mortality and HF compared to those without. Notably, women with DM, especially T1D, had a significantly higher risk of HF than men with DM, independent of other risk factors. This gender-diabetes interaction was more pronounced in T1D [ 25 ]. Furthermore, in a Swedish study involving 27,195 individuals with T1D and 135,178 controls with a median follow-up period of 10 years, 924 T1D patients and 1405 controls died. The findings showed that individuals who developed T1D between 0 and 10 years of age had significantly higher hazard ratios for various outcomes compared to controls, including a 4.11-fold risk of death, a 7.38-fold risk of cardiovascular death, an 11.44-fold risk of CVD, a 30.50-fold risk of coronary heart disease, a 30.95-fold risk of acute myocardial infarction, a 6.45-fold risk of stroke, a 12.90-fold risk of HF, and a 1.17-fold risk of atrial fibrillation. For those who developed T1D between the ages of 26 and 30, the risks were lower but still high. The overall incidence rate for all-cause mortality in T1D patients was 1.9 per 100,000 person-years. Developing T1D before 10 years of age resulted in a greater loss of life-years compared to diagnosis between 26 and 30 years of age, with women losing 17.7 and men losing 14.2 life-years in the former group and 10.1 and 9.4 life-years in the latter group, respectively. The study underscores the substantial impact of age at T1D onset on mortality and cardiovascular risks [ 26 ].

On diabetes onset, a recent study comparing Latent Autoimmune Diabetes in Adults (LADA) to T2D revealed similar risks of death (HR 1.44; 95% CI 1.03, 2.02 vs. 1.31,95% CI, 1.03, 1.67) and CVD, including HF (HR 1.22; 95% CI 0.82, 1.62 vs. 1.53, 95% CI, 1.17, 2.00). However, LADA individuals exhibited a higher risk of diabetic retinopathy and poorer glycemic control. Two LADA subgroups emerged based on autoantibody levels: lower GADA levels were more likely to have CVD at the time of diagnosis and linked to higher risks of recurrent CVD and mortality, while higher GADA levels were associated with poor glycemic control and increased risk of CVD after diagnosis [ 27 ]. The main result of this study aligns with the findings of the UKPDS and other research studies [ 28 , 29 ].

Moreover, a cohort study that evaluated the significance of risk factors and previous CVD, HF, and chronic kidney disease (CKD) for mortality in 36,303 T1D patients, revealed that older age (> 60 years), male gender, high HbA1c (> 7.8%), high blood pressure, a history of CVD, albuminuria, and advanced CKD were all associated with an increased risk of death. Subjects with a combination of CKD, CVD, and HF, exhibited a markedly increased risk of dying prematurely. The highest mortality rates were seen in people with the lowest renal function (eGFR stages G4–G5), or with a history of CVD, but especially in those with a history of HF. This underscores the importance of managing risk factors and addressing cardiovascular and renal complications in people with T1D [ 30 ].

Pathophysiology of diabetes-associated HF

The mechanisms responsible for the association between DM and HF are complex and not fully understood. It is known that the primary contributors to HF in patients with DM include coronary artery disease (CAD) as well as arterial hypertension. However, numerous experimental and clinical studies have reported a direct harmful impact of DM on the myocardium. The presence of myocardial dysfunction in the absence of overt clinical CAD, valvular disease, and other conventional cardiovascular risk factors such as hypertension has led to the use of the term diabetic cardiomyopathy (DCM) [ 10 ]. The existence of this specific form of cardiomyopathy was first proposed in 1972 after post-mortem studies [ 31 ], based on the discovery of HF in individuals with DM who showed no signs of detectable CAD. Further investigations subsequently yielded more conclusive evidence of DCM in diabetic subjects without CAD [ 32 ]. This entity is based on the concept that diabetes itself is the key factor that induces structural and/or functional changes leading to the development of progressive left ventricular (LV) dysfunction. However, the existence of a cardiomyopathy as a distinct clinical entity is still uncertain and continues to be a subject of controversy. Indeed, it is reasonable to expect that this form of cardiomyopathy may also be present in diabetics who have concomitant CAD and/or hypertension. Nevertheless, assessing the specific impact of DCM on overall ventricular dysfunction in such cases is a significant challenge.

On the other hand, DCM is frequently an unrecognized pathological process and the exact prevalence remains uncertain because the disease follows a subclinical and asymptomatic course during its initial stage. The presence of LV dysfunction in diabetic subjects is estimated to be around 15–20%, but diastolic dysfunction, an early functional alteration in the diabetic myocardium, can be detected in up to 25–60% using conventional and Doppler ultrasound [ 33 ]. Although the concept of DCM is often considered in subjects affected by T2D, a metabolically-induced cardiomyopathy is also evident in subjects with T1D. In T1D, the presence of diastolic dysfunction has been demonstrated even in adolescents and young adults, as a potential early marker of HF [ 18 , 34 , 35 ].

DCM is characterized by cardiac hypertrophy, interstitial fibrosis, cardiomyocyte apoptosis and associated diastolic and/or systolic myocardial dysfunction, and eventually by clinical HF [ 36 , 37 , 38 ]. Pathogenic mechanisms implicated in the development and progression of DCM are likely to be complex and multifactorial, from altered myocardial metabolism (hyperglycemia, hyperinsulinemia, lipotoxicity) to inflammation and oxidative stress, renin–angiotensin–aldosterone activation, microvascular dysfunction, cardiac autonomic neuropathy, or cardiac autoimmunity, among other things [ 39 ]. Most of these mechanisms are closely interrelated. Diabetic cardiomyopathy has been extensively studied in T2D, while its mechanisms in T1D are not fully understood. Although T1D and T2D differ in etiology and metabolic profiles, the two types share many features of cardiomyopathy [ 37 ]. However, specific mechanisms have been documented only in T1D. Figure  1 schematically represents the common and differential potential pathophysiological mechanisms involved in the onset and progression of DCM in both types of diabetes. Next, we will provide a concise overview of the main primary pathways associated with myocardial dysfunction, with a particular focus on findings related to T1D.

figure 1

Potential mechanisms implicated in the pathophysiology of diabetic cardiomyopathy, and differential features in both types of diabetes. AGE Advanced glycation end products, T2D , Type 2 diabetes mellitus, T1D Type 1 diabetes mellitus

Molecular and cellular mechanisms contributing to diabetes-associated HF in type 1 diabetes

Hyperglycemia and advanced glycation end products (ages).

One of the most well established mechanisms linking DM, including T1D, to HF is chronic hyperglycemia. Both preclinical and clinical evidence strongly suggests that hyperglycemia plays a causal role in diabetes-related HF, including in T1D [ 19 , 23 , 40 , 41 ]. In experimental models of T1D diabetic cardiomyopathy, the improvement of hyperglycemia mitigates diabetes-associated diastolic dysfunction [ 42 ]. Chronic hyperglycemia results in the exacerbation of two potentially pathological molecular processes: non-enzymatic glycation with the formation of advanced glycation end products (AGEs) and oxidative stress, both intricately linked. AGEs may play a pivotal role in the development and progression of DCM by stimulating collagen expression and accumulation, contributing to myocardial fibrosis and stiffness, and diastolic dysfunction [ 43 , 44 ].

Oxidative stress and mitochondrial dysfunction

Additionally, chronic hyperglycemia increases mitochondrial activity, promoting the production of reactive oxygen species (ROS) and elevated oxidative stress. These effects trigger an inflammatory process in the myocardium, leading to fibrosis and cardiac remodeling, disruption of calcium homeostasis, endothelial dysfunction, and ultimately a reduction in cardiac contractility and relaxation [ 36 , 39 ]. In several mouse models of T1D, therapeutic targeting focused on oxidative stress was associated with suppressed high glucose-induced superoxide generation and enhanced mitochondrial function, with an effect in preventing cardiac remodeling and dysfunction in a setting of DM [ 45 , 46 , 47 ].

Mitochondrial dysfunction plays a pivotal role in DCM and is usually found in cardiac tissue in T1D [ 37 , 48 , 49 ]. Decreased mitochondrial oxidative capacity is caused by altered mitochondrial ultrastructure, proteomic remodeling, and oxidative damage to proteins and mitochondrial DNA [ 47 , 50 ]. Additional mechanisms for mitochondrial dysfunction comprise perturbed mitochondrial Ca2+dynamics, mitochondrial uncoupling in T2D, and decreased cardiac insulin signaling in T1D [ 48 , 49 ].

Inflammation

On the other hand, chronic inflammation plays a key role in the pathogenesis of HF in diabetes, especially in HF with preserved ejection fraction [ 49 , 51 , 52 , 53 ]. It is well established that DM is a pro-inflammatory state [ 54 ]. This inflammatory milieu can cause direct damage to cardiac myocytes, leading to myocardial dysfunction. Additionally, inflammation contributes to the formation and progression of atherosclerosis, a key factor in HF development. Several systemic inflammatory biomarkers have been described as being associated with CVD, including HF [ 55 ]. In particular, in a study by Puig et al., the systemic pro-inflammatory molecule GlycA, a novel biomarker of protein glycan N‐acetyl groups, was associated with the presence of myocardial dysfunction in T1D subjects [ 21 ].

In relation to cardiac inflammation, studies using experimental models of diabetes have identified a critical role for increased myocardial inflammation in the progression of DCM [ 56 ]. Hearts from T1D mice and rats showed increased infiltration by leukocytes, such as macrophages, which raised levels of pro-inflammatory cytokines (TNFα, IL-1β, IL-6), increased the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, and decreased the activity of the collagen-degrading matrix metalloproteinase (MMP), leading to profibrotic responses and cardiac remodeling [ 51 , 57 ]. Therapies that target proinflammatory signaling have been shown to attenuate the development of experimental diabetic cardiomyopathy associated with a reduction in myocardial inflammation and cardiac fibrosis [ 56 , 57 , 58 ]. Nevertheless, clinical trials of anti-inflammatory and anti-cytokine therapies have shown limited cardioprotective benefits, in some cases even inducing adverse effects [ 52 ]. Moreover, studies in mouse models of T1D have detected higher T-cell infiltration in the myocardium, and certain efforts to mitigate cardiac fibrosis by reducing T-cell movement have proven effective [ 59 , 60 ].

Lipotoxicity

Lipotoxicity and cardiac lipid accumulation in the heart have also been implicated in the development of DCM [ 61 , 62 , 63 ]. Studies on myocardial metabolism have demonstrated reduced glucose uptake and increased fatty acid (FA) uptake in individuals with T1D. In T1D, the deficiency of insulin promotes the release of FAs from adipose tissue, leading to a heightened presence of excess FAs in various tissues, including the myocardium. Under physiological conditions, the myocardium can utilize fatty acids and glucose as energy substrates, being able to switch energy sources depending on their relative availability, a condition known as metabolic flexibility. When an excessive amount of FAs exceeds the cell’s oxidative capacity, the FAs will accumulate, leading to a rise in metabolic stress and a significant reduction in cardiac efficiency and function. Additionally, the accumulation of FAs stimulates the production of intermediate products (ceramides, diacylglycerol, and ROS) which accumulate in the cardiomyocyte’s cytoplasm and lead to its apoptosis [ 64 , 65 , 66 ].

Endothelial and microvascular dysfunction

Microangiopathy has been shown to be present in the myocardium of diabetic patients. Autopsy samples of ventricular myocardium analyzed through traditional histological methods have revealed signs such as capillary basement membrane thickening, arteriole medial thickening, and perivascular fibrosis [ 37 , 67 , 68 ]. The possible mechanisms promoting microangiopathy in DCM are hyperglycemia, hyperlipidemia, and activation of the neurohormonal system. These factors may act either independently or synergistically, giving rise to oxidative stress, alterations in cellular signaling, and gene transcription. The microvascular changes result in reduced myocardial perfusion, subsequently compromising energy levels and leading to alterations in calcium handling, apoptosis, and diminished cardiac contractile strength [ 69 ].

Impaired endothelial function is a typical finding in DCM. In subjects with T1D hyperglycemia and oxidative stress impair endothelial function [ 70 ]. This endothelial dysfunction results in reduced bioavailability of nitric oxide, a molecule responsible for vasodilation and maintaining blood vessel health. With compromised endothelial function, there is an increased risk of hypertension and atherosclerosis, both of which are risk factors for HF. In the clinical settings, a link between coronary microvascular dysfunction and concurrent albuminuria has been reported. In T1D patients without a known history of heart disease, both microalbuminuria and macroalbuminuria have been associated with the presence of subclinical myocardial dysfunction [ 71 ].

Neurohormonal dysregulation and cardiovascular autonomic neuropathy

Activation of the renin–angiotensin–aldosterone system (RAAS) contributes to myocardial dysfunction [ 72 , 73 , 74 ]. Therefore, significantly more impaired cardiac sympathetic nervous system activity has been reported in HF patients with DM compared with HF patients without [ 75 ], and this is associated with adverse outcomes [ 76 , 77 ]. Activation of the adrenergic system increases β-adrenergic expression and signaling, promoting myocyte hypertrophy, interstitial fibrosis, myocyte apoptosis, and contractile dysfunction [ 78 ]. In experimental models of T1D, an elevation in angiotensin-II receptor density and synthesis has been observed [ 57 , 79 ] .

On the other hand, although cardiovascular autonomic neuropathy (CAN) is one of the least understood of all serious complications of diabetes, cardiac sympathetic signals play an important role in the perfusion of myocardial injury [ 80 ]. CAN is associated with imbalance between sympathetic and parasympathetic components of the autonomic nervous system. For instance, heightened cardiac sympathetic tone may lead to a decrease in myocardial vascularity, induce vascular hyperreactivity, heighten mitochondrial production of reactive oxygen species, disrupt intracellular signaling, trigger myocardial apoptosis, and encourage myocardial remodeling [ 39 , 81 ]. Clinically it is associated with rest tachycardia, exercise intolerance, orthostatic hypotension and silent myocardial ischemia.

CAN is known to occur in individuals with T1D, correlating with increased CVD and mortality [ 79 , 80 ]. It is suggested that cardiac neuropathy may affect up to 40% of individuals with T1D [ 82 , 83 ]. However, CAN is more commonly associated with T2D, and it has been independently associated with LV diastolic dysfunction, even in asymptomatic T2D patients without any history of CVD [ 82 ]. In the study conducted by Maddaloni et al., it was observed that the prevalence of CAN is significantly higher in individuals with T2D compared to those with autoimmune diabetes (LADA and T1D) (64% vs. 40% vs. 26%; p < 0.001) [ 84 ]. Moreover, the study showed that individuals with LADA are 2.7 times less likely to develop CAN than those with T2D, even with a similar disease duration, irrespective of age and gender [ 84 ]. Conversely, after adjusting for pre-specified confounders and age, the risk of CAN in LADA was found to be similar to that in T1D. Long-standing diabetes and poor glycemic control are considered the main risk factors for the development of CAN in T1D [ 81 , 85 ]. Strict glycemic control can prevent the development or delay the progression of CAN in subjects with T1D [ 86 ]. Some observational studies suggest that the presence of CAN is associated with the impairment of systolic and diastolic LV function [ 87 ].

Cardiac autoimmunity

A role for autoimmune mechanisms in the development of DCM is another point of recent interest. In observational studies, the presence of autoantibodies against heart muscle proteins is associated with subclinical myocardial dysfunction in subjects with T1D, independent of traditional CV risks. A study published by Sousa et al. involving 892 subjects with T1D being followed in the DCCT observed higher levels of cardiac autoantibodies in those who had inadequate glycemic control. Subjects who tested positive for two cardiac autoantibodies were more likely to have subclinical myocardial dysfunction and had an increased risk of higher cardiovascular disease. Using cardiac magnetic resonance indices, subjects with ≥ 2 autoantibodies were shown to have markedly greater LV end-diastolic volume (EDV), end-systolic volume (ESV), and LV mass, as well as a lower LVEF [ 88 ]. Chronic hyperglycemia causes myocardial damage and is associated with the release of myocardial proteins into the circulation. This could potentially result in the exposure of previously sequestered cardiac antigens, including α-myosin, to the immune system. Previous experimental studies have shown that the immune system is normally enriched in autoreactive CD4 + T cells specific for cardiac myosin due to loss of immunological tolerance [ 89 ].

A newly identified pathway in the development of DCM is the concept of autophagy [ 46 ]. Autophagy is a highly conserved cellular process that recycles long-lived proteins and organelles to uphold cellular equilibrium. Dysregulated autophagy has been linked to the pathogenesis of numerous ailments, including infectious diseases, cancer, obesity, and various cardiac conditions, such as DCM [ 90 , 91 , 92 ].

Several investigations have explored the potential connection between disrupted autophagy and the onset of DCM [ 91 ]. Within heart tissue, the elimination of damaged mitochondria through autophagy plays a vital role in preserving the well-being of cardiomyocytes. Damaged mitochondria resulting from cardiac injuries can generate ROS and release factors that induce cell death, thereby exacerbating cardiac harm. Nevertheless, excessive or prolonged autophagy can prove detrimental if it leads to cardiac atrophy [ 91 ]. Research findings in the context of DCM have yielded contradictory results. There is sufficient evidence from rodent model studies to indicate that cardiac autophagy is reduced in T1D [ 90 , 93 , 94 , 95 ]. However, the functional consequence of this reduction in autophagy remains unclear. One suggested hypothesis is that impaired autophagy plays a role in causing cardiac damage by reducing the removal of dysfunctional organelles and protein aggregates. It is believed that enhancing autophagy could potentially mitigate damage in the hearts of subjects with T1D. On the contrary, Xu et al. have proposed that the reduced cardiac autophagy observed in T1D mice is actually an adaptive response aimed at preventing excessive autophagic degradation of cellular components [ 90 ]. However, autophagy may play a different role in T2D. Results from experimental T2D studies involving animals are less consistent, showing that cardiac autophagy can be either unchanged [ 96 ], reduced [ 97 , 98 ], or even increased [ 99 , 100 ]. Additional research is required to explore the underlying mechanisms responsible for the differences in autophagy observed in T1D compared to T2D.

Diabetes-related comorbidities

T1D often coexists with other metabolic disorders, such as dyslipidemia and obesity. These comorbidities further increase the risk of HF. Dyslipidemia can lead to the development of atherosclerosis, while obesity contributes to insulin resistance and exacerbates hyperglycemia, augmenting the cardiovascular burden.

T1D patients show significant qualitative and functional abnormalities of lipoproteins that are likely to be implicated in the development of atherosclerosis and premature CVD. Subjects with T1D, particularly women with suboptimal glycemic control, exhibit an altered lipid profile characterized by elevated triglyceride levels and reduced HDL concentrations (HDL-c). Improving glycemic control has been shown to normalize most of these changes, with the exception of HDL-c [ 101 ]. In relation to lipoprotein quality, intensive diabetes therapy has been linked to potentially beneficial alterations in circulating LDL-c and HDL-c subclasses in T1D [ 102 ].

Relationship between advanced metabolic profile and atherosclerotic CVD in T1D has been reported [ 21 ]. On the other hand, the presence of diabetic dyslipidemia may also contribute to diabetic myocardial dysfunction. In particular because the excess flux of mobilized FAs to the liver promotes overproduction of TG-rich lipoproteins (TGRLs) and their remnants. Higher numbers of circulating TGRLs are frequently associated with increased concentrations of remnant cholesterol and with reduced HDL-c, and all contribute to the development of ischemic heart disease [ 103 ]. However, their contribution, if any, on non-ischemic cardiomyopathy remains poorly explored. In a recent study involving 1093 T1D subjects without known heart disease, TGRLs, such as VLDL (total VLDL particles, large VLDL subclass, and VLDL-TG content) and IDL were associated with the presence of subclinical myocardial dysfunction [ 21 ].

In summary, numerous mechanisms have been identified that can contribute to myocardial remodeling and LV dysfunction in DM, including T1D. Diabetic cardiomyopathy was initially described as a phenotype of dilated cardiomyopathy with systolic LV dysfunction [ 31 ]. However, in recent years, the presence of diastolic dysfunction is regarded as the first manifestation of DCM. Traditionally, two stages have been identified: an initial phase characterized by LV hypertrophy, increased myocardial stiffness, increased atrial filling pressure, and altered diastolic function (restrictive phenotype/HFpEF), and a later stage characterized by increased cardiac fibrosis, further deterioration in diastolic function, and the onset of systolic dysfunction (dilated phenotype/HFrEF) [ 104 , 105 ]. Nevertheless, there is controversy regarding whether these two phenotypes are successive stages or instead independent phenotypes. The evaluation of myocardial dysfunction using more advanced techniques for assessing systolic/diastolic function in the preclinical stage of DCM has shown the presence of systolic dysfunction in the course of normal diastolic function. Employing these techniques, Seferovic et al., have recently found evidence favoring the notion of two independent clinical phenotypes rather than successive stages of the same disease [ 106 ]. Whereas both phenotypes are characterized by disparities in structural and functional aspects, they differ in their underlying pathophysiological mechanisms. In the restrictive phenotype, hyperglycemia, lipotoxicity, and insulin resistance are the primary mechanisms that induce left ventricular remodeling with myocardial and interstitial fibrosis. In the dilated phenotype, the loss of cardiomyocytes is a consequence of oxidative stress generated by microvascular damage and autoimmune-related inflammatory cells, with a possible role for hyperglycemia and lipotoxicity as well. Distinguishing between these two forms could have important prognostic and therapeutic implications.

Screening and diagnosis of HF

The diagnosis of HF requires the presence of symptoms and/or signs of HF and objective evidence of cardiac dysfunction [ 107 ]. According to the recent recommendations of the 2023 ESC Guidelines for the management of CVD in diabetes, in order to identify the shift from being at risk of HF to actually developing it, healthcare providers should routinely assess for HF symptoms in clinical practice [ 108 ]. There are no specific recommendations regarding the diagnosis and screening of HF in patients with T1D. If one or more of the symptoms or signs is present and/or the patient has an abnormal electrocardiogram, HF can be suspected, and the measurement of natriuretic peptides (NPs; BNP, B-type natriuretic peptide; NT-proBNP, N-terminal pro-B-type natriuretic peptide) is recommended. A value of NT-proBNP or BNP below the cut-off point has a high negative predictive value and indicates a low probability of HF. On the other hand, elevated levels of NPs support a diagnosis of HF, and echocardiography is then recommended to assess cardiac function and markers of diastolic dysfunction (Fig.  2 ) [ 107 , 108 ].

figure 2

Diagnostic and screening algorithm for heart failure in individuals with diabetes. Adapted from the European Society of Cardiology Guidelines for the management of cardiovascular disease in diabetes 2023 [108]. BNP B-type natriuretic peptide, ECG electrocardiogram, HF heart failure, HFmrEF heart failure with mildly reduced ejection fraction, HFpEF heart failure with preserved ejection fraction, HFrEF heart failure with reduced ejection fraction, LVEF left ventricular ejection fraction; NT-proBNP N-terminal pro-B-type natriuretic peptide, PN natriuretic peptide

Screening for HF is a priority in individuals with DM since, as we have noted, HF constitutes an early, highly prevalent, and often undiagnosed complication. As we have seen in this review, a non-negligible proportion of patients with DM, including adolescents or young adults with T1D, have subclinical diastolic dysfunction. Therefore, these individuals are at higher risk of developing symptomatic HF. The 2022 AHA/ACC/HFSA guidelines classify DM as a preclinical state of HF and recommend the periodic measurement of NPs, even in individuals who have not developed symptoms. The use of NPs to rule out HF in DM is well validated [ 109 ]. A recent study found that elevated NT-ProBNP levels were independently linked to HF in a cohort of 664 individuals with T1D [HR 1.7 (95% CI 1.1–2.4), p  = 0.01] [ 110 ].

On the other hand, the best approach to the diagnosis of DCM is the detection of functional and structural changes in the LV and the exclusion of other heart diseases [ 37 ]. For diastolic dysfunction in young individuals with T1D, the general guidelines provided by the American Society of Echocardiography and the European Association of Cardiovascular Imaging recommend using various indices such as pulse Doppler transmitral inflow velocities (E and A waves), tissue Doppler early and late mitral annular diastolic velocities (e0 and a0), measuring atrial size, and evaluating pulmonary venous flow [ 111 ]. Recent advances in ultrasound techniques have allowed for the detection of subtle cardiac abnormalities that conventional methods may miss, such as ventricular deformation and desynchrony indices. Other techniques such as cardiac magnetic resonance can increase the detection of subclinical myocardial dysfunction [ 112 ]. In a recent study, Kaushik et al., identified preclinical ventricular dysfunction with echocardiographic abnormalities in individuals with T1D [ 113 ]. Specifically, they observed lower LV strain indices in children and adolescents with T1D compared to non-diabetic controls, even though these individuals did not display overt HF and had normal LVEFs. These myocardial abnormalities were found to be correlated with HbA1c levels. Although LV diastolic dysfunction is the earliest sign of HF in individuals with DM, recent research has highlighted the role of left atrial dysfunction as a contributing factor. A study by Ifuku et al. observed left atrial dysfunction, particularly left atrial phasic strain, in adolescents and young people with T1D but not in non-diabetic controls [ 35 ]. The authors suggest that this could serve as an early and sensitive marker of diastolic dysfunction in T1D. Therefore, identifying cardiac dysfunction in asymptomatic individuals with T1D may support the development of effective therapeutic approaches for diabetic cardiomyopathy. This could enhance treatment for these patients and ultimately improve their prognosis.

Therapeutic strategies for type 1 diabetes-associated HF

The optimal management of HF involves utilizing pharmacological and device-based treatments but also implementing lifestyle changes. The current pharmacological treatment of HF is based on the use of drugs that have been demonstrated scientifically to reduce the risk of hospitalization for HF and cardiovascular mortality. It is important to note that, except in the case of SGLT2 inhibitors, clinical trials in HF have not been conducted exclusively in patients with DM, so the available evidence is derived from subanalyses of mixed populations. The occurrence of DM among study participants ranged from 20% to nearly 50%, with most of them having T2D. Overall, all pharmacological and device-based therapies available for HF were similarly effective, regardless of the presence of DM [ 114 ]. Current guidelines for the treatment of acute and chronic HF published by the ESC (2021), AHA/ACC/HFSA (2022) and, more recently, ESC Guidelines for the management of CVD in diabetes (2023), do not recommend specific treatment approaches for patients with DM and HF, and treatments vary depending on LVEF [ 107 , 108 , 115 ]. Pharmacological and non-pharmacological treatments for HF according to LVEF are summarized in Table  3 . The main goals of medical treatment for patients with HF include preventing recurrent hospitalization due to worsening heart failure, reducing mortality, and improving the quality of life and functional capacity [ 107 , 108 , 116 ].

Lifestyle interventions

Lifestyle changes play a crucial role in the management of heart failure and diabetes, and are listed in Table  3 . Regular medical follow-up, preferably within multidisciplinary units, patient education, and active participation in disease self-management are key aspects for improving clinical outcomes and patients’ quality of life.

Pharmacological treatment of HF

Type 2 diabetes mellitus.

Pharmacological treatment is the cornerstone of HF management and should be implemented concurrently with other non-pharmacological interventions. Classically, therapies in HF focused on the renin–angiotensin and sympathetic nervous system. Regarding HFrEF, large well-designed randomized controlled clinical trials have shown that angiotensin-converting enzyme inhibitors (ACEI) [ 117 ], angiotensin II receptor blockers (ARBs) [ 118 ], β-blockers [ 119 , 120 ], mineralocorticoid receptor antagonists (MRAs) [ 121 , 122 ], and, more recently sacubitril/valsartan (a neprilysin inhibitor/ARBs) [ 123 ] and ivabradine [ 124 ] have all resulted in significant reductions in CV events in terms of mortality and hospitalizations.

A significant breakthrough in contemporary management of HF was the finding that treatment with SGLT2 inhibitors was associated with a lower risk of HF hospitalization in patients with T2D and CV disease or at high risk thereof. A meta-analysis of six CV and renal outcome trials of four SGLT2 inhibitors (empagliflozin [ 125 ], canagliflozin [ 126 ], dapagliflozin [ 127 ] and ertugliflozin [ 128 ]) in patients with T2D (EMPA-REG OUTCOME, CANVAS Programme, DECLARE-TIMI-58, CREDENCE, VERTIS CV) demonstrated a 32% reduction in HF hospitalization [ 129 ]. These results indicated a potential benefit of SGLT2 inhibitors in treating individuals with established HF, although it should be noted that HF-related outcomes were not the primary focus of the study. Taking into account these findings, recent randomized clinical trials (RCTs) have been conducted involving patients with HFrEF (DAPA-HF [ 130 ] and EMPEROR-Reduced trials [ 131 ]) and HFpEF (EMPEROR-Preserved and DELIVER trials [ 130 , 132 ]), in which HF outcomes were the primary objective, and including patients both with and without DM (almost 50% had T2D). In these large trials, treatment with SGLT2 inhibitors in combination with optimal medical therapy (ACEI/ARNI, β-blockers, and MRAs) in patients with symptomatic chronic HF is associated with a reduction in the risk of hospitalization for HF and cardiovascular mortality, regardless of the presence of DM and across all LVEF. Furthermore, there have also been reported improvements in symptoms and quality of life among patients with HF. Recent trials with SGLT2 inhibitors have also shown benefits concerning HF-related hospitalization and CV mortality in subjects admitted to the hospital due to acute decompensated HF (SOLOIST-WHF trial: sotagliflozin and EMPULSE trial: empagliflozin) [ 133 , 134 ]. This positive effect was also observed regardless of LVEF or the presence of DM. Thus, based on strong evidence, the SGLT2 inhibitors dapagliflozin, empagliflozin, and more recently sotagliflozin (currently approved for the treatment of HF in the United States but not in the European Union) are recommended as first line therapy in patients with T2D and HF to reduce CV death and HF hospitalization [ 108 ].

Another pharmacological group of interest in terms of cardioprotective effects is the glucagon-like peptide 1 agonists (GLP1-RAs). Despite positive outcomes in reducing major cardiovascular events, studies have shown most GLP-RAs having a neutral effect on the risk of HF hospitalization in patients with T2D who had, or were at high risk of, CVD [ 135 , 136 ]. Future studies are needed to investigate the effects of GLP1-RAs in HF and T2D as primary outcomes and as well as its benefits in certain populations such as non-diabetic or T1D subjects. Recently, treatment with a GLP1-RA (semaglutide) was associated with improved symptoms and exercise capacity in patients with HFpEF and obesity [ 137 ]. Moreover, in patients with preexisting cardiovascular disease and overweight or obesity, treatment with semaglutide resulted in a 20% reduction in the risk of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (HR 0.80; 95% CI, 0.72 to 0.90). Noteworthy, an 18% reduction for the HF composite endpoint (HR 0.82; 95% CI, 0.71 to 0.96) and a 21% reduction in hospitalization or urgent medical visit for HF (HR 0.79; 95% CI, 0.60 to 1.03) were observed [ 138 ].

Type 1 diabetes mellitus

In relation to T1D, it is worth noting that most large-scale trials involving medications (ACEI, ARBS, β-blockers, MRAs and sacubitril/valsartan) and medical devices for HF have had limited participation from individuals with T1D, often excluding them or lacking detailed information about this specific subgroup. As a result, the choice of treatment for individuals with T1D is primarily extrapolation from results observed in individuals with T2D. Thus, though the therapies employed for preventing and managing HF in T1D are similar, there is no strong evidence to support this approach [ 4 , 114 ].

Moreover, it is important to note that in all of the large RCTs with SGLT2 inhibitors, patients with HF and T1D were consistently excluded. To our knowledge, there are no studies that have assessed the effects of SGLT2 inhibitor treatment in patients with T1D and HF, resulting in a lack of evidence and specific recommendations for this subgroup. In experimental models of T1D, treatment with dapagliflozin prevents intimal thickening, cardiac inflammation, and fibrosis [ 139 ]. Regarding glycemic control, several clinical trials have evaluated the efficacy and safety of the use of SGLT2 inhibitors in T1D [ 140 , 141 , 142 , 143 ]. Treatment with SGLT2 inhibitors added to adjunctive therapy with basal-bolus regimen insulin have demonstrated reduced HbA1c and lower glucose variability with increased time in optimal glucose range as well as additional benefits in terms of reductions in weight and insulin dose without increasing the incidence of hypoglycemia. Based on these positive results, dapagliflozin was the first SGLT2 inhibitor to have its marketing authorization extended to T1D with a BMI ≥ 27 kg/m 2 . However, ‘euglycemic ketoacidosis’ has been reported in 2–3% of patients with T1D taking SGLT2 inhibitors. The careful selection of individuals with T1D for SGLT2 inhibitor treatment is crucial for minimizing the risk of diabetic ketoacidosis (DKA). This treatment may be considered for subjects between the ages of 18 and 74 who are overweight or obese, have been on stable and optimized insulin therapy (not recently diagnosed), require a high dose of insulin (i.e., > 0.5 units/kg per day), presentation with ketone levels < 0.6 nmol/L, and have demonstrated adherence to their insulin regimen as well as the ability to understand and apply relevant education regarding the risk of DKA [ 140 ]. In our opinion, when weighing the use of SGLT2 inhibitors in T1D for the treatment of asymptomatic HF, it is essential to establish strategies to reduce the risk of DKA, ideally with the involvement of specialized multidisciplinary units. This entails providing comprehensive education to both individuals with T1D and healthcare professionals about the potential risk of DKA and, if it arises, the methods by which it can be mitigated. It is crucial to closely monitor ketone levels and consider recommendations for temporary suspension in specific circumstances (such as during fasting, vigorous physical activity, concurrent medical illness, recurrent vomiting, alcoholism, etc.).

Stage-based treatment of HF

According to the severity of symptoms and the presence of structural heart disease, the ACC/AHA/HFSA classified HF into four distinct stages. Stage A includes individuals at high risk of developing HF, such as patients with diabetes, and focuses on preventive measures, including lifestyle changes and management of risk factors. Stage B targets patients with structural heart disease but no symptoms, utilizing medications such as ACEI, ARBs and β-blockers to delay the onset of HF symptoms. In Stage C, for patients with structural disease and symptoms, medications include diuretics, ACEI or ARBs, -blockers, MRAs, sacubitril/valsartan, ivabradine, implantable cardioverter-defibrillators, and cardiac resynchronization therapy-defibrillators, to manage symptoms and improve quality of life. Stage D, the most advanced stage, focuses on managing symptoms and prolonging life in patients with refractory HF, utilizing specialized interventions such as mechanical circulatory support devices, and, in some cases, heart transplantation. For patients with diabetes, SGLT2 inhibitors are recommended from stage B, but thiazolidinediones and DPP4i saxagliptin, should be avoided due to the increased risk of HF admission linked to their use [ 117 , 144 ].

Glycemic control

In addition to the monitoring of blood pressure and body weight as well as lipid control, a holistic approach to HF management in subjects with DM should also include glycemic control. The effect of chronic hyperglycemia on micro and macrovascular complications has been firmly established in longitudinal studies involving both subjects with T2D and subjects with T1D [ 145 , 146 , 147 ]. It is also known that reducing HbA1c decreases microvascular complications [ 148 ]. However, the influence of glycemic optimization on the risk of cardiovascular events is more complex, and its impact in HF has not been clearly established. In T2D, more intensive glycemic control reduces the risk of microvascular disease but has not been proven to reduce the risk of macrovascular complications [ 149 , 150 , 151 , 152 ]. A meta-analysis that included 8 randomized trials (37,229 subjects) showed that more intensive glycemic control in patients with T2D did not reduce the occurrence of HF events [ 153 ]. Moreover, findings regarding optimization of glycemic control and its effects on diastolic dysfunction in patients with T2D have been conflicting [ 154 , 155 ]. A large prospective study to assess long-term LVEF trajectory (up to 15 years) in T2D and HD did not find a significant relationship between the degree of glycemic control and recurrent HF admissions [ 156 ]. In contrast to what occurs in T2D, achieving near-normal HbA1c levels has demonstrated long-term beneficial effects on the incidence of CVD in T1D [ 22 , 147 , 149 ]. In the 30-year follow-up of the DCCT/EDIC trial, intensive glucose control led to a 30% reduction in the incidence of overall CVD, including CV death. Although HF was uncommon in this trial, the group that received intensive treatment showed a notable long-term reduction in the risk of HF.

The usual treatment for T1D is basal-bolus insulin therapy, and, as demonstrated, early intensive therapy seems to be crucial for reducing the long-term risk of HF. However, intensive diabetes therapy is associated with an increased risk of hypoglycemia. This adverse effect continues to be a significant challenge for subjects with T1D throughout their life span [ 147 ]. On the other hand, it is well established that hypoglycemia is associated with an increased risk of vascular events, especially in those with high CV risk. Evidence linking hypoglycemia to CVD comes predominantly from studies involving T2D patients. Severe hypoglycemia was associated with higher HF hospitalization in most of these studies. Although severe hypoglycemic events were associated with higher HF hospitalization [ 157 , 158 , 159 , 160 ], recent analyses have revealed a bi-directional association between hypoglycemia and CV outcomes, including HF. This suggests that causality is not straightforward, and hypoglycemia may be indicative of underlying frailty, or vice versa [ 157 , 158 ]. Several observational studies have found a U-shaped relationship between HbA1c and all-cause mortality in patients with T2D and chronic HF. Consequently, patients with either very low or very high HbA1c levels were at a higher risk [ 161 ]. The lowest risk was found in those with modest glycemic control (HbA1c 7.1–8.0%) [ 162 ]. In T1D, despite the even greater risk of hypoglycemia, very few studies have investigated whether hypoglycemia may also increase the risk of CVD or death in this population. In most studies, severe hypoglycemic events have been associated with an increased risk of CVD and all-cause mortality, but data regarding HFoutcomes has not usually been reported [ 163 , 164 , 165 , 166 , 167 ].

In addition to hypoglycemia, glycemic variability (GV), measured as glucose oscillations intra- and interday, is emerging as an independent risk factor and predictor of worse CV outcomes. Recent clinical data indicate that GV is associated with increased risk of hypoglycemia, microvascular and macrovascular complications, and mortality in patients with DM, independently of HbA1c level [ 168 , 169 , 170 , 171 ]. Interestingly, greater GV has been observed in individuals with T1D compared to those with T2D. While some studies have associated GV with the risk of CAN in T1D, the substantial heterogeneity in the methodologies employed across various studies hinders any assertion of a causal relationship [ 172 ]. Experimental studies suggest that GV may contribute to CV complications through mechanisms such as oxidative stress, increased [ 170 , 173 ]. Nevertheless, there remains a lack of substantial evidence supporting the beneficial impact of treating high GV to improve CV outcomes.

The technology applied to T1D has advanced significantly in recent years. Improvements in technological devices for diabetes management, such as continuous and intermittent glucose monitoring and hybrid closed-loop systems have improved glycemic control and resulted in overall decreases in the rates of hypoglycemia and as well as improved GV [ 116 , 174 ]. Thus, device use may be associated with long-term prevention of T1D complications. However, there is still limited research on the direct effects of these devices on chronic complications in T1D [ 175 ]. Longitudinal studies indicate that using insulin pumps may help offset CV risk factors like hypertension and dyslipidemia [ 176 , 177 ]. Additionally, pump users have been shown to have less arterial stiffness and better myocardial function. Data derived from registries and case–control studies have established an association between insulin pump use and a decreased incidence of CV events, including HF, and overall mortality rates [ 177 , 178 ].

Individuals with T1D face a significantly elevated risk of HF compared to those without DM. Despite the clear association between T1D and HF, the exact mechanisms are still not fully understood. Studies are needed to elucidate the underlying processes, pinpoint specific risk factors, and establish precise diagnostic biomarkers. On the other hand, evaluating comprehensive cardioprotection strategies and exploring adjunctive therapies are crucial. While certain therapeutic groups, such as SGLT2 inhibitors in T2D, show promise, their effectiveness and safety in T1D patients with HF remain uncertain and require further investigation.

Availability of data and materials

Not applicable. No new datasets were generated for this review article.

Abbreviations

Angiotensin-converting enzyme inhibitors

Advanced glycation end products

American Heart Association/American College of Cardiology/Heart Failure Society of America

Body mass index

Coronary artery disease

Cardiovascular autonomic neuropathy

Cardiovascular disease

Diabetes Control and Complications Trial

  • Diabetic cardiomyopathy

Diabetic ketoacidosis

  • Diabetes mellitus

Estimated glomerular filtration rate

End-diastolic volume

End-systolic volume

European society of cardiology

Glycemic variability

Glucagon-like peptides 1 agonists

Glycated hemoglobin

  • Heart failure

Heart failure with reduced ejection fraction

Heart failure with mildly reduced ejection fraction

Heart failure with preserved ejection fraction

High-density lipoprotein

Incidence rate

Low-density lipoprotein

Left ventricular

Left ventricular ejection fraction

Matrix metalloproteinase

Mineralocorticoid receptor antagonists

N-terminal pro-B-type natriuretic peptide

Natriuretic peptides

Renin–angiotensin–aldosterone system

Randomized clinical trials

Sodium-glucose cotransporter 2 inhibitors

Type 2 diabetes

  • Type 1 diabetes

Total cholesterol

Triglycerides

Chronic kidney disease

TG-rich lipoproteins

Savarese G, Lund LH. Global public health burden of heart failure. Card Fail Rev. 2017;3:7.

Article   PubMed   PubMed Central   Google Scholar  

Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93:1137.

Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: The Framingham study. Am J Cardiol. 1974;34:29–34.

Article   CAS   PubMed   Google Scholar  

Shaw JA, Cooper ME. Contemporary management of heart failure in patients with diabetes. Diabetes Care. 2020;43:2895–903.

Packer M. Heart failure: the most important, preventable, and treatable cardiovascular complication of type 2 diabetes. Diabetes Care. 2018;41:11–3.

Conrad N, Judge A, Tran J, Mohseni H, Hedgecott D, Crespillo AP, et al. Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals. Lancet. 2018;391:572.

Dauriz M, Mantovani A, Bonapace S, Verlato G, Zoppini G, Bonora E, et al. Prognostic impact of diabetes on long-term survival outcomes in patients with heart failure: a meta-analysis. Diabetes Care. 2017;40:1597–605.

Article   PubMed   Google Scholar  

MacDonald MR, Petrie MC, Varyani F, Östergren J, Michelson EL, Young JB, et al. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) programme. Eur Heart J. 2008;29:1377–85.

Ritchie RH, Abel ED. Basic mechanisms of diabetic heart disease. Circ Res. 2020;126:1501.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Alonso N, Moliner P, Mauricio D. Pathogenesis, clinical features and treatment of diabetic cardiomyopathy. Adv Exp Med Biol. 2018;1067:197–217.

Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-reduced and DAPA-HF trials. Lancet. 2020;396:819–29.

De Ferranti SD, De Boer IH, Fonseca V, Fox CS, Golden SH, Lavie CJ, et al. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the american heart association and american diabetes association. Diabetes Care. 2014;37:2843–63.

Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med. 2015;372:1333.

Van Riet EES, Hoes AW, Wagenaar KP, Limburg A, Landman MAJ, Rutten FH. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. a systematic review. Eur J Heart Fail. 2016;18:242–52.

Avogaro A, Azzolina D, Fadini GP, Baldi I. Incidence of heart failure in patients with type 1 diabetes: a systematic review of observational studies. J Endocrinol Invest. 2021;44:745–53.

Haji M, Erqou S, Fonarow GC, Echouffo-Tcheugui JB. Type 1 diabetes and risk of heart failure: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2023;202: 110805.

McAllister DA, Read SH, Kerssens J, Livingstone S, McGurnaghan S, Jhund P, et al. Incidence of hospitalization for heart failure and case-fatality among 3.25 million people with and without diabetes mellitus. Circulation. 2018;138:2774–86.

Rosengren A, Vestberg D, Svensson AM, Kosiborod M, Clements M, Rawshani A, et al. Long–term excess risk of heart failure in people with type 1 diabetes: a prospective case-control study. Lancet Diabetes Endocrinol. 2015;3:876–85.

Cai X, Li J, Cai W, Chen C, Ma J, Xie Z, et al. Meta-analysis of type 1 diabetes mellitus and risk of cardiovascular disease. J Diabet Complicat. 2021. https://doi.org/10.1016/j.jdiacomp.2020.107833 .

Article   Google Scholar  

Konduracka E, Cieslik G, Galicka-Latala D, Rostoff P, Pietrucha A, Latacz P, et al. Myocardial dysfunction and chronic heart failure in patients with long-lasting type 1 diabetes: a 7-year prospective cohort study. Acta Diabetol. 2013;50:597–606.

Puig-Jové C, Julve J, Castelblanco E, Julián MT, Amigó N, Andersen HU, et al. The novel inflammatory biomarker GlycA and triglyceride-rich lipoproteins are associated with the presence of subclinical myocardial dysfunction in subjects with type 1 diabetes mellitus. Cardiovasc Diabetol. 2022. https://doi.org/10.1186/s12933-022-01652-z .

Gubitosi-Klug RA, Lachin JM, Backlund JYC, Lorenzi GM, Brillon DJ, Orchard TJ. Intensive diabetes treatment and cardiovascular outcomes in Type 1 diabetes: the DCCT/EDIC study 30-year follow-up. Diabetes Care. 2016;39:686–93.

Lind M, Bounias I, Olsson M, Gudbjörnsdottir S, Svensson AM, Rosengren A. Glycaemic control and incidence of heart failure in 20,985 patients with type 1 diabetes: an observational study. Lancet. 2011;378:140–6.

Khedr D, Hafez M, Lumpuy-Castillo J, Emam S, Abdel-Massih A, Elmougy F, et al. Lipid biomarkers as predictors of diastolic dysfunction in diabetes with poor glycemic control. Int J Mol Sci. 2020;21:1–15.

Chadalavada S, Jensen MT, Aung N, Cooper J, Lekadir K, Munroe PB, et al. Women with diabetes are at increased relative risk of heart failure compared to men: insights from UK biobank. Front Cardiovasc Med. 2021;8: 658726.

Rawshani A, Sattar N, Franzén S, Rawshani A, Hattersley AT, Svensson AM, et al. Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset: a nationwide, register-based cohort study. Lancet. 2018;392:477–86.

Wei Y, Herzog K, Ahlqvist E, Andersson T, Nystrom T, Zhan Y, et al. All-cause mortality and cardiovascular and microvascular diseases in latent autoimmune diabetes in adults. Diabetes Care. 2023;46:1857–65.

Maddaloni E, Coleman RL, Pozzilli P, Holman RR. Long-term risk of cardiovascular disease in individuals with latent autoimmune diabetes in adults (UKPDS 85). Diabetes Obes Metab. 2019;21:2115–22.

Luk AOY, Lau ESH, Lim C, Kong APS, Chow E, Ma RCW, et al. Diabetes-related complications and mortality in patients with young-onset latent autoimmune diabetes: a 14-year analysis of the prospective Hong Kong diabetes register. Diabetes Care. 2019;42:1042–50.

Eliasson B, Lyngfelt L, Strömblad SO, Franzén S, Eeg-Olofsson K. The significance of chronic kidney disease, heart failure and cardiovascular disease for mortality in type 1 diabetes: nationwide observational study. Sci Rep. 2022. https://doi.org/10.1038/s41598-022-22932-4 .

Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972;30:595–602.

Tj R, Mm L, Ss A, Ge L, Ha O, Mr A, et al. Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest. 1977;60:885–99.

Boyer JK, Thanigaraj S, Schechtman KB, Pérez JE. Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus. Am J Cardiol. 2004;93:870–5.

Gøtzsche O, Darwish A, Gøtzsche L, Hansen L, Sørensen K. Incipient cardiomyopathy in young insulin-dependent diabetic patients: a seven-year prospective doppler echocardiographic study. Diabet Med. 1996;13:834–40.

Ifuku M, Takahashi K, Hosono Y, Iso T, Ishikawa A, Haruna H, et al. Left atrial dysfunction and stiffness in pediatric and adult patients with type 1 diabetes mellitus assessed with speckle tracking echocardiography. Pediatr Diabet. 2021;22:303–19.

Huynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther. 2014;142:375–415.

Miki T, Yuda S, Kouzu H, Miura T. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail Rev. 2013;18:149–66.

Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ Res. 2018;122:624–38.

Marwick TH, Ritchie R, Shaw JE, Kaye D. Implications of underlying mechanisms for the recognition and management of diabetic cardiomyopathy. J Am Coll Cardiol. 2018;71:339–51.

Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, et al. Glycemic control and heart failure among adult patients with diabetes. Circulation. 2001;103:2668–73.

Erqou S, Lee CTC, Suffoletto M, Echouffo-Tcheugui JB, De Boer RA, Van Melle JP, et al. Association between glycated haemoglobin and the risk of congestive heart failure in diabetes mellitus: systematic review and meta-analysis. Eur J Heart Fail. 2013;15:185–93.

Tate M, Deo M, Cao AH, Hood SG, Huynh K, Kiriazis H, et al. Insulin replacement limits progression of diabetic cardiomyopathy in the low-dose streptozotocin-induced diabetic rat. Diab Vasc Dis Res. 2017;14:423–33.

Ahmed N. Advanced glycation endproducts–role in pathology of diabetic complications. Diabetes Res Clin Pract. 2005;67:3–21.

Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol. 2014;18:1–14.

Ritchie RH, Love JE, Huynh K, Bernardo BC, Henstridge DC, Kiriazis H, et al. Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes. Diabetologia. 2012;55:3369–81.

De Blasio MJ, Huynh K, Qin C, Rosli S, Kiriazis H, Ayer A, et al. Therapeutic targeting of oxidative stress with coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of diabetes with diminished PI3K(p110α) signaling. Free Radic Biol Med. 2015;87:137–47.

Huynh K, Kiriazis H, Du XJ, Love JE, Gray SP, Jandeleit-Dahm KA, et al. Targeting the upregulation of reactive oxygen species subsequent to hyperglycemia prevents type 1 diabetic cardiomyopathy in mice. Free Radic Biol Med. 2013;60:307–17.

Bugger H, Abel ED. Mitochondria in the diabetic heart. Cardiovasc Res. 2010;88:229.

Riehle C, Bauersachs J. Of mice and men: models and mechanisms of diabetic cardiomyopathy. Basic Res Cardiol. 2019. https://doi.org/10.1007/s00395-018-0711-0 .

Wallace DC. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science. 1992;256:628–32.

Riehle C, Bauersachs J. Key inflammatory mechanisms underlying heart failure. Herz. 2019;44:96–106.

Murphy SP, Kakkar R, McCarthy CP, Januzzi JL. Inflammation in heart failure: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75:1324–40.

Paulus WJ, Zile MR. From systemic inflammation to myocardial fibrosis: the heart failure with preserved ejection fraction paradigm revisited. Circ Res. 2021;128:1451–67.

Diamant M, Lamb HJ, Smit JWA, De Roos A, Heine RJ. Diabetic cardiomyopathy in uncomplicated type 2 diabetes is associated with the metabolic syndrome and systemic inflammation. Diabetologia. 2005;48:1669–70.

Akinkuolie AO, Buring JE, Ridker PM, Mora S. A novel protein glycan biomarker and future cardiovascular disease events. J Am Heart Assoc. 2014. https://doi.org/10.1161/JAHA.114.001221 .

Jadhav A, Tiwari S, Lee P, Ndisang JF. The heme oxygenase system selectively enhances the anti-inflammatory macrophage-m2 phenotype, reduces pericardial adiposity, and ameliorated cardiac injury in diabetic cardiomyopathy in zucker diabetic fatty rats. J Pharmacol Exp Ther. 2013. https://doi.org/10.1124/jpet.112.200808 .

Westermann D, Rutschow S, Jäger S, Linderer A, Anker S, Riad A, et al. Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism. Diabetes. 2007;56:641–6.

Tschöpe C, Walther T, Escher F, Spillmann F, Du J, Altmann C, et al. Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction and oxidative stress in experimental diabetic cardiomyopathy. FASEB J. 2005;19:2057–9.

Lin Y, Tang Y, Wang F. The protective effect of HIF-1α in T lymphocytes on cardiac damage in diabetic mice. Ann Clin Lab Sci. 2016;46:32–43.

CAS   PubMed   Google Scholar  

Abdullah CS, Li Z, Wang X, Jin ZQ. Depletion of T lymphocytes ameliorates cardiac fibrosis in streptozotocin-induced diabetic cardiomyopathy. Int Immunopharmacol. 2016;39:251–64.

Van De Weijer T, Schrauwen-Hinderling VB, Schrauwen P. Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovasc Res. 2011;92:10–8.

Ussher JR. The role of cardiac lipotoxicity in the pathogenesis of diabetic cardiomyopathy. Expert Rev Cardiovasc Ther. 2014;12:345–58.

Bayeva M, Sawicki KT, Ardehali H. Taking diabetes to heart—deregulation of myocardial lipid metabolism in diabetic cardiomyopathy. J Am Heart Assoc. 2013. https://doi.org/10.1161/JAHA.113.000433 .

Ritchie RH, Zerenturk EJ, Prakoso D, Calkin AC. Lipid metabolism and its implications for type 1 diabetes-associated cardiomyopathy. J Mol Endocrinol. 2017;58:R225–40.

Herrero P, Peterson LR, McGill JB, Matthew S, Lesniak D, Dence C, et al. Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus. J Am Coll Cardiol. 2006;47:598–604.

Diarte-Añazco EMG, Méndez-Lara KA, Pérez A, Alonso N, Blanco-Vaca F, Julve J. Novel insights into the role of HDL-associated sphingosine-1-phosphate in cardiometabolic diseases. Int J Mol Sci. 2019. https://doi.org/10.3390/ijms20246273 .

Kawaguchi M, Techigawara M, Ishihata T, Asakura T, Saito F, Maehara K, et al. A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with diabetes mellitus with and without hypertension. Heart Vessel. 1997;12:267–74.

Article   CAS   Google Scholar  

Factor SM, Okun EM, Minase T. Capillary microaneurysms in the human diabetic heart. N Engl J Med. 1980;302:384–8.

Adameova A, Dhalla NS. Role of microangiopathy in diabetic cardiomyopathy. Heart Fail Rev. 2014;19:25–33.

Llauradó G, Ceperuelo-Mallafré V, Vilardell C, Simó R, Albert L, Berlanga E, et al. Impaired endothelial function is not associated with arterial stiffness in adults with type 1 diabetes. Diabet Metab. 2013;39:355–62.

Jensen MT, Sogaard P, Andersen HU, Bech J, Hansen TF, Galatius S, et al. Prevalence of systolic and diastolic dysfunction in patients with type 1 diabetes without known heart disease: the thousand & 1 study. Diabetologia. 2014;57:672–80.

Khatter JC, Sadri P, Zhang M, Hoeschen RJ. Myocardial angiotensin II (Ang II) receptors in diabetic rats. Ann N Y Acad Sci. 1996;793:466–72.

Sechi LA, Griffin CA, Schambelan M. The cardiac renin–angiotensin system in STZ-induced diabetes. Diabetes. 1994;43:1180–4.

Ka C, Aj B, Dj K. Angiotensin II and the cardiac complications of diabetes mellitus. Curr Pharm Des. 2007;13:2721–9.

Paolillo S, Rengo G, Pagano G, Pellegrino T, Savarese G, Femminella GD, et al. Impact of diabetes on cardiac sympathetic innervation in patients with heart failure: a 123I meta-iodobenzylguanidine (123I MIBG) scintigraphic study. Diabet Care. 2013;36:2395.

Gargiulo P, Acampa W, Asile G, Abbate V, Nardi E, Marzano F, et al. 123I-MIBG imaging in heart failure: impact of comorbidities on cardiac sympathetic innervation. Eur J Nucl Med Mol Imaging. 2023;50:813–24.

Jacobson AF, Senior R, Cerqueira MD, Wong ND, Thomas GS, Lopez VA, et al. Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. results of the prospective ADMIRE-HF (adreview myocardial imaging for risk evaluation in heart failure) study. J Am Coll Cardiol. 2010;55:2212–21.

Falcão-Pires I, Leite-Moreira AF. Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment. Heart Fail Rev. 2012;17:325–44.

Singh VP, Le B, Khode R, Baker KM, Kumar R. Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis. Diabetes. 2008;57:3297.

Di Carli MF, Bianco-Batlles D, Landa ME, Kazmers A, Groehn H, Muzik O, et al. Effects of autonomic neuropathy on coronary blood flow in patients with diabetes mellitus. Circulation. 1999;100:813–9.

Torry RJ, Connell PM, O’Brien DM, Chilian WM, Tomanek RJ. Sympathectomy stimulates capillary but not precapillary growth in hypertrophic hearts. Am J physiol. 1991. https://doi.org/10.1152/ajpheart.1991.260.5.H1515 .

Voulgari C, Psallas M, Kokkinos A, Argiana V, Katsilambros N, Tentolouris N. The association between cardiac autonomic neuropathy with metabolic and other factors in subjects with type 1 and type 2 diabetes. J Diabet Complicat. 2011;25:159–67.

Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007;115:387–97.

Du Maddaloni E, Moretti C, Del Toro R, Sterpetti S, Ievolella MV, Arnesano G, et al. Risk of cardiac autonomic neuropathy in latent autoimmune diabetes in adults is similar to type 1 diabetes and lower compared to type 2 diabetes: a cross-sectional study. Diabet Med. 2021;38: e14455.

Debono M, Cachia E. The impact of cardiovascular autonomic neuropathy in diabetes: is it associated with left ventricular dysfunction? Auton Neurosci. 2007;132:1–7.

Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86.

Pop-Busui R, Kirkwood I, Schmid H, Marinescu V, Schroeder J, Larkin D, et al. Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial blood flow reserve and diastolic dysfunction. J Am Coll Cardiol. 2004;44:2368–74.

Sousa GR, Pober D, Galderisi A, Lv HJ, Yu L, Pereira AC, et al. Glycemic control, cardiac autoimmunity, and long-term risk of cardiovascular disease in type 1 diabetes mellitus. Circulation. 2019;139:730–43.

Lv HJ, Havari E, Pinto S, Gottumukkala RVSRK, Cornivelli L, Raddassi K, et al. Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans. J Clin Investig. 2011;121:1561–73.

Xu X, Kobayashi S, Chen K, Timm D, Volden P, Huang Y, et al. Diminished autophagy limits cardiac injury in mouse models of type 1 diabetes. J Biol Chem. 2013;288:18077.

Kubli DA, Gustafsson ÅB. Unbreak my heart: targeting mitochondrial autophagy in diabetic cardiomyopathy. Antioxid Redox Signal. 2015;22:1527–44.

Riehle C, Abel ED. Insulin regulation of myocardial autophagy. Circ J. 2014;78:2569.

Xie Z, Lau K, Eby B, Lozano P, He C, Pennington B, et al. Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes. 2011;60:1770–8.

Ikeda Y, Shirakabe A, Maejima Y, Zhai P, Sciarretta S, Toli J, et al. Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ Res. 2015;116:264–78.

Zhao Y, Zhang L, Qiao Y, Zhou X, Wu G, Wang L, et al. Heme oxygenase-1 prevents cardiac dysfunction in streptozotocin-diabetic mice by reducing inflammation, oxidative stress. Apoptosis Enhanc Autophagy PLoS ONE. 2013;8:75927.

Google Scholar  

Lancel S, Montaigne D, Marechal X, Marciniak C, Hassoun SM, Decoster B, et al. Carbon monoxide improves cardiac function and mitochondrial population quality in a mouse model of metabolic syndrome. PLoS ONE. 2012. https://doi.org/10.1371/journal.pone.0041836 .

Guo R, Zhang Y, Turdi S, Ren J. Adiponectin knockout accentuates high fat diet-induced obesity and cardiac dysfunction: role of autophagy. Biochem Biophys Acta. 2013;1832:1136–48.

Cui M, Yu H, Wang J, Gao J, Li J. Chronic caloric restriction and exercise improve metabolic conditions of dietary-induced obese mice in autophagy correlated manner without involving AMPK. J Diabet Res. 2013. https://doi.org/10.1155/2013/852754 .

Mellor KM, Bell JR, Young MJ, Ritchie RH, Delbridge LMD. Myocardial autophagy activation and suppressed survival signaling is associated with insulin resistance in fructose-fed mice. J Mol Cell Cardiol. 2011;50:1035–43.

Russo SB, Baicu CF, Van Laer A, Geng T, Kasiganesan H, Zile MR, et al. Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes. J Clin Investig. 2012;122:3919–30.

Pérez A, Wägner AM, Carreras G, Giménez G, Sánchez-Quesada JL, Rigla M, et al. Prevalence and phenotypic distribution of dyslipidemia in type 1 diabetes mellitus: effect of glycemic control. Arch Intern Med. 2000;160:2756–62.

Vinagre I, Sánchez-Quesada JL, Sánchez-Hernández J, Santos D, Ordoñez-Llanos J, De Leiva A, et al. Inflammatory biomarkers in type 2 diabetic patients: effect of glycemic control and impact of LDL subfraction phenotype. Cardiovasc Diabetol. 2014. https://doi.org/10.1186/1475-2840-13-34 .

Varbo A, Benn M, Nordestgaard BG. Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment. Pharmacol Ther. 2014;141:358–67.

Velez M, Kohli S, Sabbah HN. Animal models of insulin resistance and heart failure. Heart Fail Rev. 2014;19:1–13.

Dunlay SM, Roger VL, Weston SA, Jiang R, Redfield MM. Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction. Circ Heart Fail. 2012;5:720–6.

Seferović PM, Paulus WJ. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes. Eur Heart J. 2015;36:1718–27.

McDonagh TA, Metra M, Adamo M, Baumbach A, Böhm M, Burri H, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–726.

Marx N, Federici M, Schütt K, Müller-Wieland D, Ajjan RA, Antunes MJ, et al. ESC guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023. https://doi.org/10.1007/s00059-023-05218-x .

Alonso N, Lupón J, Barallat J, de Antonio M, Domingo M, Zamora E, et al. Impact of diabetes on the predictive value of heart failure biomarkers. Cardiovasc Diabetol. 2016. https://doi.org/10.1186/s12933-016-0470-x .

Tofte N, Theilade S, Winther SA, Birkelund S, Goetze JP, Hansen TW, et al. Comparison of natriuretic peptides as risk markers for all-cause mortality and cardiovascular and renal complications in individuals with type 1 diabetes. Diabet Care. 2021;44:595–603.

Nagueh SF, Smiseth OA, Appleton CP, Byrd BF, Dokainish H, Edvardsen T, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the american society of echocardiography and the european association of cardiovascular imaging. J Am Soc Echocardiogr. 2016. https://doi.org/10.1016/j.echo.2016.01.011 .

Murtaza G, Virk HUH, Khalid M, Lavie CJ, Ventura H, Mukherjee D, et al. Diabetic cardiomyopathy—a comprehensive updated review. Prog Cardiovasc Dis. 2019;62:315–26.

Kaushik A, Kapoor A, Dabadghao P, Khanna R, Kumar S, Garg N, et al. Use of strain, strain rate, tissue velocity imaging, and endothelial function for early detection of cardiovascular involvement in young diabetics. Ann Pediatr Cardiol. 2021. https://doi.org/10.4103/apc.APC_158_19 .

Seferović PM, Petrie MC, Filippatos GS, Anker SD, Rosano G, Bauersachs J, et al. Type 2 diabetes mellitus and heart failure: a position statement from the heart failure association of the european society of cardiology. Eur J Heart Fail. 2018;20:853–72.

Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. Circulation. 2022;145:E895-1032.

PubMed   Google Scholar  

Elsayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. Introduction and methodology: standards of care in diabetes—2023. Diabet Care. 2023;46:S1-4.

Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J med. 1991. https://doi.org/10.1056/NEJM199108013250501 .

Young JB, Dunlap ME, Pfeffer MA, Probstfield JL, Cohen-Solal A, Dietz R, et al. Mortality and morbidity reduction with Candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials. Circulation. 2004;110:2618–26.

MacMahon S, Sharpe N. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet. 1997;349:375–80.

Hjalmarson Å, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the metoprolol CR/XL randomized Intervention trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group JAMA. 2000;283:1295–302.

CAS   Google Scholar  

Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. randomized aldactone evaluation study investigators. N Engl J med. 1999;341:709–17.

Zannad F, McMurray JJV, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21.

McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Eng J med. 2014;371:132–3.

Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet (London, Eng). 2010;376:875–85.

Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2016; 374:1094. https://doi.org/10.1056/NEJMc1600827 .

Rajagopalan S, Brook R. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:2098–9.

Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019. https://doi.org/10.1056/NEJMoa1812389 .

Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383:1425–35.

McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZI, Dagogo-Jack S, et al. Association of sglt2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021;6:148–58.

Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387:1089–98.

Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–24.

Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385:1451–61.

Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384:117–28.

Voors AA, Angermann CE, Teerlink JR, Collins SP, Kosiborod M, Biegus J, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022;28:568–74.

Bethel MA, Patel RA, Merrill P, Lokhnygina Y, Buse JB, Mentz RJ, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabet Endocrinol. 2018;6:105–13.

Kristensen SL, Rørth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabet Endocrinol. 2019;7:776–85.

Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J med. 2023;389:1069–84.

Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389:2221–32.

Hodrea J, Saeed A, Molnar A, Fintha A, Barczi A, Wagner LJ, et al. SGLT2 inhibitor dapagliflozin prevents atherosclerotic and cardiac complications in experimental type 1 diabetes. PLoS ONE. 2022. https://doi.org/10.1371/journal.pone.0263285 .

Evans M, Hicks D, Patel D, Patel V, McEwan P, Dashora U. Optimising the benefits of sglt2 inhibitors for type 1 diabetes. Diabet Therapy. 2020;11:37.

Dandona P, Mathieu C, Phillip M, Hansen L, Tschöpe D, Thorén F, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: the DEPICT-1 52-week study. Diabet Care. 2018;41:2552–9.

Buse JB, Garg SK, Rosenstock J, Bailey TS, Banks P, Bode BW, et al. Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: the North American Intandem1 study. Diabet Care. 2018;41:1970–80.

Danne T, Cariou B, Banks P, Brandle M, Brath H, Franek E, et al. HbA1c and hypoglycemia reductions at 24 and 52 weeks with sotagliflozin in combination with insulin in adults with type 1 diabetes: the European Intandem2 study. Diabet Care. 2018;41:1981–90.

Cavallari I, Maddaloni E, Pieralice S, Mulè MT, Buzzetti R, Ussia GP, et al. The vicious circle of left ventricular dysfunction and diabetes: from pathophysiology to emerging treatments. J Clin Endocrinol Metab. 2020;105:e3075–89.

Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.

The Diabetes Control and Complications Trial (DCCT) Research Group. Effect of intensive diabetes management on macrovascular events and risk factors in the diabetes control and complications trial. Am J cardiol. 1995;75:894–903.

Nathan DM, Bayless M, Cleary P, Genuth S, Gubitosi-Klug R, Lachin JM, et al. Diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: advances and contributions. Diabetes. 2013;62:3976–86.

Turner R. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–65.

Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. Engl J Med. 1993;329:977–86.

Turner R. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–53.

Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.

Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet (London, England). 2010;376:419–30.

Castagno D, Baird-Gunning J, Jhund PS, Biondi-Zoccai G, MacDonald MR, Petrie MC, et al. Intensive glycemic control has no impact on the risk of heart failure in type 2 diabetic patients: evidence from a 37,229 patient meta-analysis. Am Heart J. 2011. https://doi.org/10.1016/j.ahj.2011.07.030 .

Jarnert C, Landstedt-Hallin L, Malmberg K, Melcher A, Ohrvik J, Persson H, et al. A randomized trial of the impact of strict glycaemic control on myocardial diastolic function and perfusion reserve: a report from the DADD (diabetes mellitus and diastolic dysfunction) study. Eur J Heart Fail. 2009;11:39–47.

Von Bibra H, Hansen A, Dounis V, Bystedt T, Malmberg K, Rydén L. Augmented metabolic control improves myocardial diastolic function and perfusion in patients with non-insulin dependent diabetes. Heart (British Cardiac Soc). 2004;90:1483–4.

Julián MT, Alonso N, Lupón J, Gavidia-Bovadilla G, Ferrer E, De Antonio M, et al. Long-term LVEF trajectories in patients with type 2 diabetes and heart failure: diabetic cardiomyopathy may underlie functional decline. Cardiovasc Diabetol. 2020. https://doi.org/10.1186/s12933-020-01011-w .

Standl E, Stevens SR, Lokhnygina Y, Angelyn Bethel M, Buse JB, Gustavson SM, et al. Confirming the bidirectional nature of the association between severe hypoglycemic and cardiovascular events in type 2 diabetes: insights from EXSCEL. Diabet Care. 2020;43:643–52.

Standl E, Stevens SR, Armstrong PW, Buse JB, Chan JCN, Green JB, et al. Increased risk of severe hypoglycemic events before and after cardiovascular outcomes in TECOS suggests an at-risk type 2 diabetes frail patient phenotype. Diabet Care. 2018;41:596–603.

Pratley RE, Husain M, Lingvay I, Pieber TR, Mark T, Saevereid HA, et al. Heart failure with insulin degludec versus glargine U100 in patients with type 2 diabetes at high risk of cardiovascular disease: DEVOTE 14. Cardiovasc Diabetol. 2019. https://doi.org/10.1186/s12933-019-0960-8 .

Fitchett D, Inzucchi SE, Wanner C, Mattheus M, George JT, Vedin O, et al. Relationship between hypoglycaemia, cardiovascular outcomes, and empagliflozin treatment in the EMPA-REG OUTCOME ® trial. Eur Heart J. 2020;41:209.

Das SR, Drazner MH, Yancy CW, Stevenson LW, Gersh BJ, Dries DL. Effects of diabetes mellitus and ischemic heart disease on the progression from asymptomatic left ventricular dysfunction to symptomatic heart failure: a retrospective analysis from the studies of left ventricular dysfunction (SOLVD) prevention trial. Am Heart J. 2004;148:883–8.

Elder DHJ, Singh JSS, Levin D, Donnelly LA, Choy AM, George J, et al. Mean HbA1c and mortality in diabetic individuals with heart failure: a population cohort study. Eur J Heart Fail. 2016;18:94–102.

Gruden G, Barutta F, Chaturvedi N, Schalkwijk C, Stehouwer CD, Witte DR, et al. Severe hypoglycemia and cardiovascular disease incidence in type 1 diabetes: the EURODIAB prospective complications study. Diabet Care. 2012. https://doi.org/10.2337/dc11-1531 .

Lu CL, Shen HN, Hu SC, Der WJ, Li CY. A population-based study of all-cause mortality and cardiovascular disease in association with prior history of hypoglycemia among patients with type 1 diabetes. Diabet Care. 2016. https://doi.org/10.2337/dc15-2418 .

Giménez M, López JJ, Castell C, Conget I. Hypoglycaemia and cardiovascular disease in type 1 diabetes results from the catalan national public health registry on insulin pump therapy. Diabet Res Clin Pract. 2012. https://doi.org/10.1016/j.diabres.2012.01.014 .

Khunti K, Davies M, Majeed A, Thorsted BL, Wolden ML, Paul SK. Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study. Diabet Care. 2015;38:316–22.

McCoy RG, Shah ND, Van Houten HK, Wermers RA, Ziegenfuss JY, Smith SA. Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabet Care. 2012. https://doi.org/10.2337/dc11-2054 .

Colette C, Monnier L. Acute glucose fluctuations and chronic sustained hyperglycemia as risk factors for cardiovascular diseases in patients with type 2 diabetes. Horm Metab Res. 2007;39:683–6.

Xia J, Hu S, Xu J, Hao H, Yin C, Xu D. The correlation between glucose fluctuation from self-monitored blood glucose and the major adverse cardiac events in diabetic patients with acute coronary syndrome during a 6-month follow-up by wechat application. Clin Chem Lab Med. 2018;56:2119–24.

Saisho Y. Glycemic variability and oxidative stress: a link between diabetes and cardiovascular disease? Int J Mol Sci. 2014;15:18381.

Martinez M, Santamarina J, Pavesi A, Musso C, Umpierrez GE. Glycemic variability and cardiovascular disease in patients with type 2 diabetes. BMJ Open Diabet Res Care. 2021. https://doi.org/10.1136/bmjdrc-2020-002032 .

Helleputte S, De Backer T, Lapauw B, Shadid S, Celie B, Van Eetvelde B, et al. The relationship between glycaemic variability and cardiovascular autonomic dysfunction in patients with type 1 diabetes: a systematic review. Diabetes/metabolism Res Rev. 2020. https://doi.org/10.1002/dmrr.3301 .

Alfieri V, Myasoedova VA, Vinci MC, Rondinelli M, Songia P, Massaiu I, et al. The role of glycemic variability in cardiovascular disorders. Int J mol sci. 2021. https://doi.org/10.3390/ijms22168393 .

Phillip M, Nimri R, Bergenstal RM, Barnard-Kelly K, Danne T, Hovorka R, et al. Consensus recommendations for the use of automated insulin delivery technologies in clinical practice. Endocr Rev. 2023;44:254.

Pauley ME, Tommerdahl KL, Snell-Bergeon JK, Forlenza GP. Continuous glucose monitor, insulin pump, and automated insulin delivery therapies for type 1 diabetes: an update on potential for cardiovascular benefits. Curr Cardiol Rep. 2022;24:2043–56.

Kamrath C, Tittel SR, Kapellen TM, von dem Berge T, Heidtmann B, Nagl K, et al. Early versus delayed insulin pump therapy in children with newly diagnosed type 1 diabetes: results from the multicentre, prospective diabetes follow-up DPV registry. Lancet Child Adolesc Health. 2021;5:17–25.

Derosa G, Catena G, Scelsi L, D’Angelo A, Raddino R, Cosentino E, et al. Glyco-metabolic control, inflammation markers, and cardiovascular outcomes in type 1 and type 2 diabetic patients on insulin pump or multiple daily injection (italico study). Diabetes/metabolism Res Rev. 2020. https://doi.org/10.1002/dmrr.3219 .

Steineck I, Cederholm J, Eliasson B, Rawshani A, Eeg-Olofsson K, Svensson AM, et al. Insulin pump therapy, multiple daily injections, and cardiovascular mortality in 18,168 people with type 1 diabetes: observational study. BMJ (Clin Research Ed). 2015. https://doi.org/10.1136/bmj.h3234 .

Giménez-Pérez G, Viñals C, Mata-Cases M, Vlacho B, Real J, Franch-Nadal J, et al. Epidemiology of the first-ever cardiovascular event in people with type 1 diabetes: a retrospective cohort population-based study in catalonia. Cardiovasc Diabetol. 2023. https://doi.org/10.1186/s12933-023-01917-1 .

Larsson SC, Wallin A, Håkansson N, Stackelberg O, Bäck M, Wolk A. Type 1 and type 2 diabetes mellitus and incidence of seven cardiovascular diseases. Int J Cardiol. 2018;262:66–70.

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Acknowledgements

Not applicable.

This work was support by research grants from the Carlos III Institute of Health, Spain (PI17/01362/PI21/00817) and from la Fundació Marató TV3 (Grant number 201602.30.31), Spain. Also, this research was supported by CIBER-Consorcio Centro de Investigación Biomédica en Red-CIBERDEM (CB15/00071, D.M.), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación. Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau is accredited by the Generalitat de Catalunya as Centre de Recerca de Catalunya (CERCA).

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María Teresa Julián and Alejandra Pérez-Montes de Oca have contributed equally.

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María Teresa Julián, Alejandra Pérez-Montes de Oca & Nuria Alonso

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Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain

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Center for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain

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Julián, M.T., Pérez-Montes de Oca, A., Julve, J. et al. The double burden: type 1 diabetes and heart failure—a comprehensive review. Cardiovasc Diabetol 23 , 65 (2024). https://doi.org/10.1186/s12933-024-02136-y

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Cardiovascular Diabetology

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literature review on hypertension and diabetes

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Published on 16.2.2024 in Vol 10 (2024)

Understanding Gaps in the Hypertension and Diabetes Care Cascade: Systematic Scoping Review

Authors of this article:

Author Orcid Image

  • Jie Wang 1 * , BMed   ; 
  • Fangqin Tan 1 * , BMed   ; 
  • Zhenzhong Wang 1 , BM   ; 
  • Yiwen Yu 1 , MPH   ; 
  • Jingsong Yang 1 , BMed   ; 
  • Yueqing Wang 1 , MPH   ; 
  • Ruitai Shao 1 , PhD   ; 
  • Xuejun Yin 1, 2 , PhD  

1 School of Population Medicine and Public Health, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2 The George Institute for Global Health, University of New South Wales, Sydney, Australia

*these authors contributed equally

Corresponding Author:

Xuejun Yin, PhD

School of Population Medicine and Public Health

Chinese Academy of Medical Sciences & Peking Union Medical College

31 Beijige San Tiao

Dongcheng District

Beijing, 100005

Phone: 86 18600988138

Email: [email protected]

Background: Hypertension and diabetes are global health challenges requiring effective management to mitigate their considerable burden. The successful management of hypertension and diabetes requires the completion of a sequence of stages, which are collectively termed the care cascade.

Objective: This scoping review aimed to describe the characteristics of studies on the hypertension and diabetes care cascade and identify potential interventions as well as factors that impact each stage of the care cascade.

Methods: The method of this scoping review has been guided by the framework by Arksey and O’Malley. We systematically searched MEDLINE, Embase, and Web of Science using terms pertinent to hypertension, diabetes, and specific stages of the care cascade. Articles published after 2011 were considered, and we included all studies that described the completion of at least one stage of the care cascade of hypertension and diabetes. Study selection was independently performed by 2 paired authors. Descriptive statistics were used to elucidate key patterns and trends. Inductive content analysis was performed to generate themes regarding the barriers and facilitators for improving the care cascade in hypertension and diabetes management.

Results: A total of 128 studies were included, with 42.2% (54/128) conducted in high-income countries. Of them, 47 (36.7%) focused on hypertension care, 63 (49.2%) focused on diabetes care, and only 18 (14.1%) reported on the care of both diseases. The majority (96/128, 75.0%) were observational in design. Cascade stages documented in the literature were awareness, screening, diagnosis, linkage to care, treatment, adherence to medication, and control. Most studies focused on the stages of treatment and control, while a relative paucity of studies examined the stages before treatment initiation (76/128, 59.4% vs 52/128, 40.6%). There was a wide spectrum of interventions aimed at enhancing the hypertension and diabetes care cascade. The analysis unveiled a multitude of individual-level and system-level factors influencing the successful completion of cascade sequences in both high-income and low- and middle-income settings.

Conclusions: This review offers a comprehensive understanding of hypertension and diabetes management, emphasizing the pivotal factors that impact each stage of care. Future research should focus on upstream cascade stages and context-specific interventions to optimize patient retention and care outcomes.

Introduction

Noncommunicable diseases (NCDs) constitute a formidable global health challenge, accounting for approximately 80% of NCD-related deaths, and they include cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes [ 1 ]. Hypertension is the most pivotal risk factor for cardiovascular diseases [ 2 ]. The prevalence of hypertension among adults aged 30-79 years worldwide is estimated to be 1.28 billion, with an alarming 700 million individuals unaware of their condition. Less than half of adults with hypertension are diagnosed and treated. Only approximately 1 in 5 adults with hypertension have their blood pressure controlled [ 3 ]. Similarly, the global prevalence of diabetes among adults has surged to 537 million in 2021, with nearly half of these cases (240 million) remaining undiagnosed. Moreover, the treatment rate for diabetes is suboptimal, with only 32.9% of patients receiving appropriate care and a mere 16.5% attaining treatment goals [ 4 ]. Evidence suggests that a substantial proportion of patients with hypertension and diabetes reside in low- and middle-income countries (LMICs), wherein the management of these conditions remains persistently low [ 3 , 5 ].

Hypertension and diabetes are often approached differently by distinct clinical subspecialties owing to their clinical complexities. However, it is essential to recognize that the management of these 2 conditions together can be highly beneficial owing to their shared risk factors and bidirectional interaction. The management of hypertension and diabetes also shares the same pathway, which includes early detection, appropriate treatment, and continuous monitoring. The health care systems and implementation strategies designed to ensure the continuity of care exhibit significant overlap and can be harnessed efficiently and effectively to support both hypertension and diabetes patients. The care cascade is a model for evaluating patient retention across sequential stages of care required to achieve a successful treatment outcome [ 6 ]. This model has sequential stages, including awareness, screening, diagnosis, appropriate management, and disease control, that patients navigate while accessing health care services. Acknowledging potential lapses at each stage, the care cascade model identifies critical stages where patients may disengage, hindering them from attaining disease control [ 7 ]. The care cascade model was originally conceived for HIV care [ 8 ]. It has since been extended to monitor and manage infectious diseases, such as hepatitis C [ 9 ] and tuberculosis [ 6 ], and has been more recently applied to NCDs [ 10 ].

The utility of studying the care cascade of hypertension and diabetes goes beyond the mere exploration of their clinical pathways. It encompasses a broader holistic perspective that includes not only clinical aspects but also the impact on health systems, the quality of life of affected individuals, and the efficiency of health care delivery. Cascade analysis for hypertension and diabetes can help understand the common factors that affect the care model in order to identify appropriate strategies to improve health care for these 2 conditions. However, there is limited evidence synthesis regarding the care cascade of hypertension and diabetes. Therefore, we performed a systematic scoping review with the goal of mapping and describing the current state of evidence on a global scale. We sought to understand the process of hypertension and diabetes management, identify the factors that influence each stage of the care cascade, and explore potential interventions that hold promise for improving care continuity. By synthesizing existing evidence, our findings seek to inform future research endeavors, propelling the advancement of management strategies for hypertension and diabetes.

Study Design

This scoping review was conducted following the stages of a scoping review by Arksey and O’Malley [ 11 ] and was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) [ 12 ].

Identifying the Research Questions

This scoping review focused on mapping the existing evidence on the care cascade of hypertension and diabetes. The specific research questions were as follows:

  • How the care cascade model has been applied in hypertension and diabetes research?
  • Which stage of the hypertension and diabetes care cascade has the current research in high-income countries (HICs) and LMICs primarily focused on?
  • What are the barriers and facilitators of hypertension and diabetes care cascade completion?
  • What strategies have been employed to improve retention in the hypertension and diabetes care cascade?
  • What are the key knowledge gaps that remain in the literature about the hypertension and diabetes care cascade?

Identifying Relevant Studies

To identify relevant studies, a systematic search was conducted in MEDLINE, Embase, and Web of Science, using terms pertinent to hypertension, diabetes, and the specific stages of the care cascade. The framework of population, concept, and context was used to identify core concepts related to the research question and inform the search strategy [ 13 ]. A complete overview of the search terms for each database is provided in Multimedia Appendix 1 . The population of interest in this review was adults aged 18 years or older who had been screened for or diagnosed with hypertension or type 2 diabetes, as well as patients with hypertension or type 2 diabetes undergoing treatment or management. The key concept of the review was the hypertension and diabetes care cascade, with a focus on studies explicitly applying the cascade care model to one or more stages of screening, diagnosis, treatment, and control. Articles describing interventions targeting specific stages of the cascade or factors influencing interventions or outcomes of at least one stage of the care cascade were included. The review aimed to explore a broad range of influencing factors involving both barriers and facilitators, with all pertinent descriptions included, regardless of statistical associations. The contextual scope of this review was in both HICs and LMICs, where hypertension and diabetes care was provided. The timeframe for database searches spanned from January 2011 to January 2023 since the concept of the care cascade was introduced in 2011 [ 8 ]. There was no restriction on publication language, allowing for an inclusive evaluation of relevant studies worldwide. The eligibility criteria are shown in Textbox 1 .

  • Population: Adults aged 18 years or older who had been screened for or diagnosed with hypertension or type 2 diabetes and patients with known hypertension or type 2 diabetes currently undergoing treatment or management.
  • Concept: Hypertension and diabetes care cascade, with a focus on studies explicitly applying the cascade care model to one or more stages from awareness to control. Interventions that impact patient outcomes and factors that influence implementation outcomes and service outcomes within at least one stage of the care cascade.
  • Context: No limitation. All clinical and primary care settings.
  • Language: No limitation.
  • Published between January 1, 2011, and January 17, 2023.
  • Article type: Original articles and protocol papers, including cross-sectional studies, cohort studies, trials, and implementation studies published in peer-reviewed journals.

Study Selection

All identified articles were imported into Covidence, and duplicates were removed. Screening proceeded through 2 distinct stages, where titles and abstracts were assessed independently by 4 researchers (JW, FT, XY, and ZW) in pairs, adhering to predefined inclusion and exclusion criteria to determine potential eligibility. In the event of disagreements, a collaborative discussion within the research team swiftly resolved any discrepancies. Subsequently, full-text screening followed a similar process, again involving 4 researchers (JW, FT, YY, and ZW) in pairs. Articles were excluded if they were (1) observing outcomes unrelated to hypertension and type 2 diabetes health care; (2) case reports, conference abstracts, editorials, commentaries, or reviews; and (3) unavailable in full text. Any unresolved discrepancies in article eligibility were resolved by group discussion until a consensus was reached. Notably, to glean insights into ongoing or planned projects and to identify potential interventions and relevant factors, study protocols were intentionally retained and not excluded in the scoping review.

Charting the Data

A data-charting form was created in Microsoft Excel and pilot tested with 15 articles to establish clarity and consistency in data extraction variables across reviewers. Data extraction was performed by 4 researchers (JW, FT, YY, and ZW). The extracted variables included title, author names, year of publication, study countries, disease of interest (hypertension, diabetes, or both), study method (quantitative, qualitative, or mixed method), study design (cross-sectional study, cohort study, trial, or implementation study), sample size, mean age of participants, stages of the care cascade involved, interventions aimed at improving retention, factors associated with stage completion, and reported outcomes. The care of hypertension and diabetes was divided into multiple stages of the cascade, including awareness, screening, diagnosis, linkage to care, treatment, medication adherence, and ultimately, disease control. The world’s economies were classified based on the World Bank classification as follows: low income, lower-middle income, upper-middle income, and high income [ 14 ]. The outcomes were categorized into implementation outcomes, service outcomes, and client outcomes. Implementation outcomes encompassed aspects pertaining to the process of implementing interventions and services for hypertension and diabetes care. This included factors such as acceptability, adoption, appropriateness, cost, feasibility, fidelity, and sustainability of interventions to health care providers or patients. Service outcomes were those related to the quality and effectiveness of the health care services provided to patients with hypertension and diabetes, such as access to health care services, continuity of care, appropriateness of care, equity of service, and health care provider adherence to clinical guidelines. Client outcomes, on the other hand, delved into the impact of health services on patients’ health and clinical conditions, such as blood pressure and blood glucose control, reductions in cardiovascular risk factors, and improvements in overall quality of life. To ensure data accuracy and consistency, a senior researcher (XY) reviewed all extracted data. Any disagreements were resolved by consensus.

Collating, Summarizing, and Reporting the Results

Interventions and influencing factors were analyzed by cascade stages and focused diseases. Studies that reported multiple stages of the care cascade were included in the synthesis of each relevant stage. The resulting information was subjected to rigorous quantitative analysis, employing frequencies and percentages to elucidate key patterns and trends. Inductive content analysis was performed to generate themes regarding the barriers and facilitators for improving the care cascade in hypertension and diabetes management. The initial list of codes was grouped into categories and then themes against the supporting evidence. Throughout this process, subthemes and themes were discussed and refined within the research team.

Ethical Considerations

This review does not involve human subject information, primary data collection, or any form of experimentation on individuals.

Characteristics of the Included Studies

Of the 1321 unique articles identified for the title and abstract screening, 222 were retrieved for full-text review. Of these, 128 were included in the analysis after excluding 94 articles for various reasons ( Figure 1 ).

The 128 studies originated from 40 countries, with 42.2% (54/128) conducted in HICs ( Figure 2 ). Of the 128 studies, 47 (36.7%) focused on hypertension care, 63 (49.2%) focused on diabetes care, and 18 (14.1%) reported on the care of both diseases. Most studies (104/128, 81.3%) employed quantitative methods. The majority were cross-sectional studies (70/128, 54.7%), followed by cohort studies (26/128, 20.3%). There were 24 (18.8%) trials evaluating interventions to promote retention in at least one cascade stage. Only 8 (6.3%) were implementation studies designed to systematically assess service delivery gaps and identify contextually appropriate solutions to address these bottlenecks. A total of 116 (90.6%) studies reported health receivers’ perspectives, and only 8 (6.3%) studies had health system perspectives. Most studies (83/128, 64.8%) reported client outcomes as primary outcomes, and they mainly focused on the measure of the effectiveness of disease control. Moreover, 16 (12.5%) studies reported service outcomes, and they mainly focused on the measure of satisfaction. Furthermore, 29 (22.7%) studies reported implementation outcomes, such as feasibility, cost, and adoption ( Table 1 ). Detailed characteristics of the 128 included studies are summarized in Multimedia Appendix 2 [ 10 , 15 - 131 ].

literature review on hypertension and diabetes

Completion of the Hypertension and Diabetes Care Cascade

Only 3 studies documented all 7 cascade stages, with 2 of them focusing on hypertension management and 1 addressing both hypertension and diabetes [ 15 , 16 , 132 ]. They were all population-based cross-sectional surveys aimed to describe disease prevalence and quantify the unmet need for hypertension and diabetes care. The remaining studies included in our analysis examined specific stages of the care cascade. Among the studies focusing on hypertension, 13 highlighted increasing awareness and knowledge related to hypertension, 8 addressed the importance of screening through blood pressure measurements, 14 focused on the diagnosis of hypertension, 13 explored the linkage to care, 34 discussed the initiation of treatment, 16 emphasized medication adherence, and 26 explored blood pressure management and control. For diabetes care, 8 studies addressed the critical aspect of awareness, 16 concentrated on screening, 20 discussed the diagnosis of diabetes, 21 explored the linkage to care, 38 focused on treatment interventions, 23 examined medication adherence, and 37 investigated the factors impacting diabetes control. In addition, 18 studies adopted an integrated approach, encompassing care for both hypertension and diabetes. Among these studies, 6 addressed awareness, 1 addressed screening, 4 addressed diagnosis, 10 addressed linkage to care, 9 addressed treatment, 2 addressed medication adherence, and 10 addressed control ( Table 2 ).

Interventions of the Hypertension and Diabetes Care Cascade

Various interventions were identified to enhance the knowledge of disease prevention. Health education programs for hypertension and diabetes were emphasized as continuous efforts to support ongoing management and care [ 17 ]. The provision of comprehensive education was achieved through training classes and consulting at nutrition-based shared medical appointments [ 17 - 19 ]. Automated outreach call services with the integration of electronic health records emerged as effective approaches [ 20 ]. Out-of-hospital continuous nursing interventions and community awareness campaigns were used to augment the awareness [ 21 ]. Dissemination of awareness campaign information occurred through various channels, including the internet, public awareness events, and targeted home visits [ 22 ].

In the pursuit of enhancing the screening process for hypertension and diabetes, a diverse array of interventions has emerged. The Sustainable East Africa Research in Community Health (SEARCH) study implemented a community health campaign that offered universal adult screening, rendering screening services widely accessible [ 23 ]. Moreover, innovative approaches like home-based screening interventions empowered individuals by providing convenience and ease of access to early detection services [ 24 ]. Early diabetes detection was prioritized through specialized medical check-ups, facilitating timely intervention [ 22 ]. The Integrated Tracking, Referral, and Electronic Decision Support and Care Coordination (I-TREC) program incorporated cutting-edge technologies, including electronic case record forms and clinical decision support systems, streamlining patient information and offering guideline-based screening. Enhanced training for health care providers in NCD management and lifestyle interventions further fortified the screening process [ 25 ]. Lastly, efforts were made to strengthen health education and outreach services, particularly targeting individuals without symptoms, to foster a proactive approach to screening [ 26 ].

Effective interventions have been deployed to enhance the diagnosis of hypertension and diabetes. Continuous and coordinated care among multi-level health institutions was emphasized to enable timely diagnosis and consistent follow-up for hypertension and diabetes. Telephone peer coaching provided personalized support through weekly calls, aiding in timely diagnosis and empowering patients to engage in self-care [ 27 ]. Patient-centered integrated care with advanced technologies, such as electronic case record forms and clinical decision support systems, streamlined patient information and referrals to deliver tailored guideline-based care. Enhanced training for primary health care providers further strengthened timely diagnosis among patients [ 25 ].

Linkage to Care

Follow-up within 6 weeks at NCD clinics for participants with hypertension, coupled with the use of diabetes self-management record sheets and telephone reinforcement, has shown positive outcomes [ 133 ]. Additionally, 8-week training classes encompassing diverse self-care aspects have demonstrated effectiveness [ 18 ]. Mobile health applications [ 28 ], shared medical appointments [ 29 ], telephone peer coaching [ 27 ], and regular general practitioner contact [ 30 ] have proven to be successful strategies for ensuring a smooth connection to care. Furthermore, providing training in communication skills and self-care education to health providers, along with reduced workload and increased availability of competent diabetes specialist nurses, has contributed to enhancing the linkage to care [ 31 ]. Educational group programs, decision support tools, and feedback reports for primary care professionals further reinforced the process [ 32 ]. Institution-level continuity of ambulatory care [ 33 ], standardized “self-care” programs [ 22 ], and patient-held health records [ 34 ] have also played pivotal roles in promoting seamless linkage to essential health care services among patients diagnosed with hypertension and diabetes.

Various interventions have been explored to improve the treatment process for patients with hypertension and diabetes. Lifestyle interventions, including physical activity promotion and heart-healthy diets, have shown promise in improving treatment outcomes [ 35 ]. Collaborative care models involving pharmacists and physicians demonstrated positive effects on medication therapy management and overall patient care [ 36 ]. Self-monitoring of blood pressure is vital for facilitating appropriate treatment [ 37 ]. Additionally, interventions targeting medication affordability [ 38 ] and continuity of care [ 39 - 41 , 134 ] play crucial roles in ensuring optimal treatment adherence. Telehealth and digital interventions, such as continuous remote care and mobile health applications, are being explored for improved treatment accessibility and engagement [ 28 , 135 ]. Integrated care models, employing multidisciplinary teams and decision support tools, have yielded promising outcomes in coordinating comprehensive patient care [ 20 , 136 ]. Targeted education for patients and health care providers can effectively enhance communication and self-care skills [ 31 , 32 ]. Moreover, financial incentive programs, like pay-for-performance schemes, have encouraged optimal health care delivery and reimbursement [ 42 ].

Medication Adherence

A range of interventions has been investigated to optimize medication adherence in patients with hypertension and diabetes. Community-based interventions with patient education, recall services, and reduced out-of-pocket payments have shown promise in promoting adherence [ 43 ]. Self-measured blood pressure monitoring and chronic disease management programs in primary care settings facilitated continuous and comprehensive patient care [ 38 , 44 ]. Telephone peer coaching [ 27 ], regular general practitioner contact [ 30 ], and continuity of care initiatives [ 39 , 40 , 45 , 46 , 134 ] have also demonstrated positive effects on medication adherence. Collaborative care models, which involve patient-centered coordinated care, referral systems, and diabetes education, have yielded favorable results [ 47 ]. Additionally, interventions, such as medication co-payment schemes, enhanced counseling, and training for health care providers in communication skills, have reinforced medication adherence efforts [ 31 , 48 ]. Patient and provider engagement programs, along with pay-for-performance initiatives, have also incentivized optimal medication adherence [ 32 , 42 ]. Integrating pharmacists into multidisciplinary care teams has enhanced medication management and adherence [ 136 ].

Interventions, including multidisciplinary collaboration, patient education, and technology integration, were adopted to enhance hypertension and diabetes control. The integration of pharmacists into care teams and the transition to specialized diabetes physicians can optimize disease management [ 49 , 50 , 136 ]. For instance, pharmacist-physician collaborative practice models have shown promise through features like shared medical records, defined interprofessional roles, frequent follow-ups, and collaborative practice agreements [ 50 ]. Structured educational programs, both for patients and primary care professionals, offer essential knowledge and support, such as tailored SMS text message communication and telephone peer coaching [ 27 , 51 ]. Patient health records and electronic decision support were used to improve the continuity of care and enable tailored interventions [ 34 ]. Additionally, integrated interventions like the EMPOWER-PAR program, grounded in the Chronic Care Model, made contributions to advancing disease control, even in the face of challenges related to health care system constraints [ 137 ].

Barriers and Facilitators of Completing Different Stages of the Care Cascade

In the completion of the hypertension and diabetes care cascade, several barriers and facilitators were identified, encompassing patient-level and system-level factors ( Table 3 ). Patient-level barriers included factors like low socioeconomic status, unhealthy lifestyle choices, and limited health literacy, hindering effective management. Misconceptions about disease and treatment, high treatment costs, and fear of diagnosis also impeded the care progress. At the system level, inadequate resources, heavy workloads, limited capacity in primary care, and a fragmented health system were identified as significant obstacles to effective care.

a HIC: high-income country.

b LMIC: low- and middle-income country.

Conversely, various patient-level facilitators positively impacted the cascade. At the patient level, characteristics like high socioeconomic status, positive health behaviors, and strong belief in treatment efficacy played vital roles. Furthermore, timely monitoring of blood pressure and glucose levels, engagement in health programs, and partner involvement were found to be associated with improved outcomes. System-level facilitators included a well-trained health workforce, existing chronic disease management programs, and improved access to medications.

Notably, certain barriers and facilitators were context-specific, with diverse prominence in HICs and LMICs. For instance, lack of understanding and misconceptions were more prevalent in LMICs, while the influence of cultural beliefs and minority status was more pronounced in HICs. Physician density and adequate resources were often noted as facilitators in HICs, while social support and tailored diabetes education were emphasized in LMICs.

This scoping review identified a substantial body of literature investigating the hypertension and diabetes care cascade in both HICs and LMICs. While most studies provided descriptive snapshots of each cascade stage, only a limited number of studies applied implementation cascade analysis to explore the barriers and facilitators of patient retention. Furthermore, there was a paucity of studies evaluating the effects of interventions to bridge gaps between cascade stages. In addition to analyzing the characteristics of the included studies, this scoping review comprehensively summarized key interventions, facilitators, and barriers associated with completing cascade stages. These findings provide critical insights into the existing evidence on hypertension and diabetes management, offering valuable directions for enhancing health care delivery for these chronic conditions.

The results of this scoping review have revealed a notable gap in the existing literature concerning the entire continuum of all stages in the hypertension and diabetes care cascade. The majority of studies predominantly focused on treatment and control for both hypertension and diabetes care. There was a relative paucity of studies examining the stages before treatment initiation despite evidence suggesting that over 50% of patients with hypertension and diabetes who could benefit from treatment never start medication [ 3 , 72 ]. These pretreatment losses accounted for a much greater reduction in effective care than nonadherence to medication [ 101 ]. Modeling studies showed that treatment losses earlier on can result in a greater overall reduction in the public health benefit of hypertension management [ 142 , 143 ]. Potential gaps exist in identifying problems and developing strategies to improve awareness, screening, and diagnosis of the 2 diseases. Based on microsimulation modeling, it is estimated that scaling up diagnosis, treatment, and control of diabetes to achieve a hypothetical 80% target for each component of the care cascade would be highly cost-effective [ 143 , 144 ]. Regarding interventions to improve retention across cascade stages, the review emphasizes the importance of awareness campaigns and health education programs to improve patient retention in care and medication adherence. Moreover, interventions targeting the health system (ie, multidiscipline collaborative care, training for primary health care providers, and increasing access to medications) showed promise in improving diagnosis and treatment outcomes. Other innovations in hypertension and diabetes service delivery have been developed and could further enhance quality, but they require further study and proof of effectiveness at scale. Examples include electronic case record–based clinical decision support systems and telephone peer coaching [ 27 , 32 ]. There was a relative dearth of studies incorporating informatics, internet techniques, and mass media to capture public opinions and enhance patient engagement in the management of these conditions. These technologies and communication strategies have only recently gained prominence, and their full potential in the context of hypertension and diabetes care has not yet been comprehensively explored. Our findings parallel another review about the implementation of telemedicine interventions for hypertension and diabetes, indicating that successful implementation of these interventions necessitates comprehensive efforts at all stages of planning, execution, engagement, and reflection and evaluation [ 145 ]. The adaptation of interventions to diverse contexts, particularly in LMICs with fragile health systems, warrants future studies. Implementation studies are essential to develop context-specific strategies for incorporating evidence-based interventions effectively into practice [ 146 ].

The review also revealed several facilitators and barriers affecting different stages of the care cascade across different income contexts. These insights are of paramount importance, serving as a compass for forthcoming investigations. Future studies can harness these nuanced factors to craft precise context-specific strategies that seamlessly integrate evidence-based interventions into clinical practice. Tailored interventions that address specific patient characteristics, cultural beliefs, and health system constraints are pivotal to enhancing care delivery. The implementation of evidence-based strategies, coupled with the cultivation of patient-centered care, paves the way for health care systems to embark on a journey toward equitable and ameliorated outcomes in hypertension and diabetes management, thereby catering to the unique needs of diverse patient populations.

This review highlights that the provision of integrated care for individuals with both hypertension and diabetes within primary care settings has the potential to be a judicious and efficient approach. The rationale behind this integration lies in the substantial overlap between the risk factors and management pathways of these 2 prevalent chronic conditions. This shared etiological foundation emphasizes the importance of addressing common risk factors, such as dietary patterns, physical activity levels, smoking habits, and weight management, concurrently. By focusing on integrated interventions that aim to modify these shared risk factors, primary care providers can foster holistic and synergistic management. Moreover, primary care providers play a pivotal role in early diagnosis, timely initiation of treatment, and regular follow-up. This proactive approach is essential for mitigating the burden of hypertension and diabetes, as well as their associated complications.

Our study has several strengths. We identified studies from a wide range of geographic and care delivery settings. In addition, this review expands upon the evidence regarding interventions throughout the hypertension and diabetes care cascade, offering insights into diverse strategies to address each stage. By encompassing studies conducted in both HICs and LMICs, this review captures the global perspective on interventions for hypertension and diabetes care. This strengthens the generalizability of the findings and provides insights into the varying challenges and approaches across different health care settings. While this scoping review offers valuable insights into the extensive body of literature concerning the hypertension and diabetes care cascade, it is important to recognize the inherent limitations of this approach compared to systematic reviews and meta-analyses. This breadth of mapping key concepts across diverse domains and disciplines might come at the cost of depth. The interventions described in our review predominantly featured descriptive accounts in the included reports, with the absence of a quantitative assessment of intervention effects, which is important for informing designs in other settings but does not allow for inferences about their effectiveness. As is typical with scoping reviews, we did not assess the quality of the included articles. This inherent limitation underscores the need for further research, particularly systematic reviews and meta-analyses, to delve deeper into the efficacy of interventions across various stages of the hypertension and diabetes care cascade. Moreover, the focus of this review was on studies that explicitly applied the cascade care lens to one or more stages of hypertension and diabetes care, which may have inadvertently excluded studies that explored these critical stages without using the term “cascade” or its associated lexicon. While this search strategy enabled a more targeted examination of research aligned with the cascade model, it also introduced an inadvertent restriction, potentially omitting relevant investigations that did not employ the cascade framework explicitly. This limitation underscores the need for future studies to explore these care stages more comprehensively, even when the cascade terminology is not explicitly invoked, providing a more holistic view of hypertension and diabetes care. Despite this limitation, our scoping review offers valuable insights into a broad landscape of influencing factors and interventions across the care cascade.

In conclusion, this scoping review offers valuable insights into the evidence of the hypertension and diabetes care cascade, highlighting the importance of comprehensive interventions that address all stages of disease management. By identifying facilitators and barriers, the study emphasizes the need for tailored health care strategies to improve patient outcomes. Moving forward, integrating collaborative care models, tailored education programs, and health care system enhancements can potentially enhance disease control and improve the quality of life for individuals living with hypertension and diabetes. These findings have significant implications for clinical practice and health policy, serving as a foundation for future research and efforts to optimize the care cascade for chronic disease management.

Acknowledgments

The study was supported by the nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences (grant number: 2021-RC330-004). RS ([email protected]) and XY are cocorresponding authors for this study.

Data Availability

The data sets generated during or analyzed during this study are available from the corresponding author on reasonable request.

Authors' Contributions

XY and RS conceived and designed the study. XY developed the search strategy. JW and FT ran the search. JW, FT, ZW, YY, and XY conducted the study selection processes (title and abstract screening followed by full-text screening). JW, FT, ZW, and YY extracted the data. XY verified the data extraction. JW, FT, and XY analyzed and interpreted the data. JW wrote the first draft of the manuscript with XY. All authors contributed to the writing of the manuscript. All authors critically revised the manuscript and approved the final version.

Conflicts of Interest

None declared.

Search strategy.

Details of the included studies.

PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) checklist.

  • NCD Countdown 2030 collaborators. NCD Countdown 2030: worldwide trends in non-communicable disease mortality and progress towards Sustainable Development Goal target 3.4. Lancet. Sep 22, 2018;392(10152):1072-1088. [ http://hdl.handle.net/10044/1/63328 ] [ CrossRef ] [ Medline ]
  • Gupta R, Xavier D. Hypertension: The most important non communicable disease risk factor in India. Indian Heart J. 2018;70(4):565-572. [ https://linkinghub.elsevier.com/retrieve/pii/S0019-4832(17)30593-X ] [ CrossRef ] [ Medline ]
  • NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet. Sep 11, 2021;398(10304):957-980. [ http://hdl.handle.net/2318/1805296 ] [ CrossRef ] [ Medline ]
  • Wang L, Peng W, Zhao Z, Zhang M, Shi Z, Song Z, et al. Prevalence and Treatment of Diabetes in China, 2013-2018. JAMA. Dec 28, 2021;326(24):2498-2506. [ https://europepmc.org/abstract/MED/34962526 ] [ CrossRef ] [ Medline ]
  • Ogurtsova K, Guariguata L, Barengo NC, Ruiz PL, Sacre JW, Karuranga S, et al. IDF diabetes Atlas: Global estimates of undiagnosed diabetes in adults for 2021. Diabetes Res Clin Pract. Jan 2022;183:109118. [ CrossRef ] [ Medline ]
  • Subbaraman R, Nathavitharana RR, Mayer KH, Satyanarayana S, Chadha VK, Arinaminpathy N, et al. Constructing care cascades for active tuberculosis: A strategy for program monitoring and identifying gaps in quality of care. PLoS Med. Feb 27, 2019;16(2):e1002754. [ https://dx.plos.org/10.1371/journal.pmed.1002754 ] [ CrossRef ] [ Medline ]
  • Muiruri C, Manavalan P, Jazowski SA, Knettel BA, Vilme H, Zullig LL. Opportunities to Leverage Telehealth Approaches Along the Hypertension Control Cascade in Sub-Saharan Africa. Curr Hypertens Rep. Aug 26, 2019;21(10):75. [ https://europepmc.org/abstract/MED/31451940 ] [ CrossRef ] [ Medline ]
  • Gardner EM, McLees MP, Steiner JF, Del Rio C, Burman WJ. The spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection. Clin Infect Dis. Mar 15, 2011;52(6):793-800. [ https://europepmc.org/abstract/MED/21367734 ] [ CrossRef ] [ Medline ]
  • Polaris Observatory HCV Collaborators. Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: a modelling study. Lancet Gastroenterol Hepatol. May 2022;7(5):396-415. [ CrossRef ] [ Medline ]
  • Zhao Y, Anindya K, Atun R, Marthias T, Han C, McPake B, et al. Provincial heterogeneity in the management of care cascade for hypertension, diabetes, and dyslipidaemia in China: Analysis of nationally representative population-based survey. Front Cardiovasc Med. 2022;9:923249. [ https://europepmc.org/abstract/MED/36093142 ] [ CrossRef ] [ Medline ]
  • Arksey H, O'Malley L. Scoping studies: towards a methodological framework. International Journal of Social Research Methodology. Feb 2005;8(1):19-32. [ CrossRef ]
  • Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med. Oct 02, 2018;169(7):467-473. [ https://www.acpjournals.org/doi/abs/10.7326/M18-0850?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed ] [ CrossRef ] [ Medline ]
  • Peters M, Godfrey C, Mcinerney P, Soares C, Khalil H, Parker D. In: Aromataris E, editor. Methodology for JBI Scoping Reviews: The Joanna Briggs Institute Reviewers' Manual. South Australia. Joanna Briggs Institute; 2015;3-24.
  • World Bank Country and Lending Groups. The World Bank. URL: https:/​/datahelpdesk.​worldbank.org/​knowledgebase/​articles/​906519-world-bank-country-and-lending-groups [accessed 2024-01-11]
  • Chham S, Buffel V, Van Olmen J, Chhim S, Ir P, Wouters E. The cascade of hypertension care in Cambodia: evidence from a cross-sectional population-based survey. BMC Health Serv Res. Jun 29, 2022;22(1):838. [ https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-022-08232-7 ] [ CrossRef ] [ Medline ]
  • Geldsetzer P, De Neve J, Mohan V, Prabhakaran D, Roy A, Tandon N, et al. Health System Performance for Multimorbid Cardiometabolic Disease in India: A Population-Based Cross-Sectional Study. Glob Heart. 2022;17(1):7. [ https://europepmc.org/abstract/MED/35174048 ] [ CrossRef ] [ Medline ]
  • Byun DH, Chang RS, Park M, Son H, Kim C. Prioritizing Community-Based Intervention Programs for Improving Treatment Compliance of Patients with Chronic Diseases: Applying an Analytic Hierarchy Process. Int J Environ Res Public Health. Jan 08, 2021;18(2):455. [ https://www.mdpi.com/resolver?pii=ijerph18020455 ] [ CrossRef ] [ Medline ]
  • Kargar Jahromi M, Ramezanli S, Taheri L. Effectiveness of diabetes self-management education on quality of life in diabetic elderly females. Glob J Health Sci. Jul 29, 2014;7(1):10-15. [ https://europepmc.org/abstract/MED/25560339 ] [ CrossRef ] [ Medline ]
  • Wang H, Wang W, Fan L. The impact of continuous nursing intervention on T2DM patients’ prognoses and quality of life. Int J Clin Exp Med. 2020;13(12):9495-9505. [ https://e-century.us/files/ijcem/13/12/ijcem0108825.pdf ]
  • Wozniak G, Khan T, Gillespie C, Sifuentes L, Hasan O, Ritchey M, et al. Hypertension Control Cascade: A Framework to Improve Hypertension Awareness, Treatment, and Control. J Clin Hypertens (Greenwich). Mar 2016;18(3):232-239. [ https://europepmc.org/abstract/MED/26337797 ] [ CrossRef ] [ Medline ]
  • Xu DR, Dev R, Shrestha A, Zhang L, Shrestha A, Shakya P, et al. NUrse-led COntinuum of care for people with Diabetes and prediabetes (NUCOD) in Nepal: study protocol for a cluster randomized controlled trial. Trials. May 29, 2020;21(1):442. [ https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04372-5 ] [ CrossRef ] [ Medline ]
  • Lee J, Smith JP. The effect of health promotion on diagnosis and management of diabetes. J Epidemiol Community Health. Apr 2012;66(4):366-371. [ https://europepmc.org/abstract/MED/21282142 ] [ CrossRef ] [ Medline ]
  • Heller DJ, Balzer LB, Kazi D, Charlebois ED, Kwarisiima D, Mwangwa F, et al. Hypertension testing and treatment in Uganda and Kenya through the SEARCH study: An implementation fidelity and outcome evaluation. PLoS One. 2020;15(1):e0222801. [ https://dx.plos.org/10.1371/journal.pone.0222801 ] [ CrossRef ] [ Medline ]
  • Sudharsanan N, Chen S, Garber M, Bärnighausen T, Geldsetzer P. The Effect Of Home-Based Hypertension Screening On Blood Pressure Change Over Time In South Africa. Health Aff (Millwood). Jan 2020;39(1):124-132. [ CrossRef ] [ Medline ]
  • Patel SA, Sharma H, Mohan S, Weber MB, Jindal D, Jarhyan P, et al. The Integrated Tracking, Referral, and Electronic Decision Support, and Care Coordination (I-TREC) program: scalable strategies for the management of hypertension and diabetes within the government healthcare system of India. BMC Health Serv Res. Nov 09, 2020;20(1):1022. [ https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-020-05851-w ] [ CrossRef ] [ Medline ]
  • Gabert R, Ng M, Sogarwal R, Bryant M, Deepu RV, McNellan CR, et al. Identifying gaps in the continuum of care for hypertension and diabetes in two Indian communities. BMC Health Serv Res. Dec 27, 2017;17(1):846. [ https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-017-2796-9 ] [ CrossRef ] [ Medline ]
  • McGowan P, Lynch S, Hensen F. The Role and Effectiveness of Telephone Peer Coaching for Adult Patients With Type 2 Diabetes. Can J Diabetes. Aug 2019;43(6):399-405. [ CrossRef ] [ Medline ]
  • Wang Y, Li M, Zhao X, Pan X, Lu M, Lu J, et al. Effects of continuous care for patients with type 2 diabetes using mobile health application: A randomised controlled trial. Int J Health Plann Manage. Jul 31, 2019;34(3):1025-1035. [ CrossRef ] [ Medline ]
  • Heisler M, Burgess J, Cass J, Chardos JF, Guirguis AB, Strohecker LA, et al. Evaluating the Effectiveness of Diabetes Shared Medical Appointments (SMAs) as Implemented in Five Veterans Affairs Health Systems: a Multi-site Cluster Randomized Pragmatic Trial. J Gen Intern Med. Jun 2021;36(6):1648-1655. [ CrossRef ] [ Medline ]
  • Youens D, Robinson S, Doust J, Harris MN, Moorin R. Associations between regular GP contact, diabetes monitoring and glucose control: an observational study using general practice data. BMJ Open. Nov 10, 2021;11(11):e051796. [ https://bmjopen.bmj.com/lookup/pmidlookup?view=long&pmid=34758997 ] [ CrossRef ] [ Medline ]
  • Noor Abdulhadi NM, Al-Shafaee MA, Wahlström R, Hjelm K. Doctors' and nurses' views on patient care for type 2 diabetes: an interview study in primary health care in Oman. Prim Health Care Res Dev. Jul 2013;14(3):258-269. [ https://europepmc.org/abstract/MED/23259934 ] [ CrossRef ] [ Medline ]
  • Ramallo-Fariña Y, García-Pérez L, Castilla-Rodríguez I, Perestelo-Pérez L, Wägner A, de Pablos-Velasco P, Salinero-Fort; et al. INDICA team. Effectiveness and cost-effectiveness of knowledge transfer and behavior modification interventions in type 2 diabetes mellitus patients--the INDICA study: a cluster randomized controlled trial. Implement Sci. Apr 09, 2015;10:47. [ https://implementationscience.biomedcentral.com/articles/10.1186/s13012-015-0233-1 ] [ CrossRef ] [ Medline ]
  • Hong J, Kang H. Relationship between continuity of ambulatory care and medication adherence in adult patients with type 2 diabetes in Korea: a longitudinal analysis. Med Care. May 2014;52(5):446-453. [ CrossRef ] [ Medline ]
  • Joseph L, Greenfield S, Lavis A, Lekha TR, Panniyammakal J, Manaseki-Holland S. Exploring Factors Affecting Health Care Providers' Behaviors for Maintaining Continuity of Care in Kerala, India; A Qualitative Analysis Using the Theoretical Domains Framework. Front Public Health. 2022;10:891103. [ https://europepmc.org/abstract/MED/35875019 ] [ CrossRef ] [ Medline ]
  • Shamsi SA, Salehzadeh M, Ghavami H, Asl RG, Vatani KK. Impact of lifestyle interventions on reducing dietary sodium intake and blood pressure in patients with hypertension: A randomized controlled trial. Turk Kardiyol Dern Ars. Mar 2021;49(2):143-150. [ https://doi.org/10.5543/tkda.2021.81669 ] [ CrossRef ] [ Medline ]
  • Hirsch JD, Steers N, Adler DS, Kuo GM, Morello CM, Lang M, et al. Primary care-based, pharmacist-physician collaborative medication-therapy management of hypertension: a randomized, pragmatic trial. Clin Ther. Sep 01, 2014;36(9):1244-1254. [ https://europepmc.org/abstract/MED/25085406 ] [ CrossRef ] [ Medline ]
  • Roy D, Meador M, Sasu N, Whelihan K, Lewis JH. Are Community Health Center Patients Interested in Self-Measured Blood Pressure Monitoring (SMBP) – And Can They Do It? IBPC. Feb 2021;Volume 14:19-29. [ CrossRef ]
  • Bay N, Juga E, Macuacua C, João J, Costa M, Stewart S, et al. Assessment of care provision for hypertension at the emergency Department of an Urban Hospital in Mozambique. BMC Health Serv Res. Dec 18, 2019;19(1):975. [ https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-019-4820-8 ] [ CrossRef ] [ Medline ]
  • Barrera L, Oviedo D, Silva A, Tovar D, Méndez F. Continuity of Care and the Control of High Blood Pressure at Colombian Primary Care Services. Inquiry. 2021;58:469580211047043. [ https://journals.sagepub.com/doi/10.1177/00469580211047043?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed ] [ CrossRef ] [ Medline ]
  • Choi D, Choi S, Kim H, Kim K, Kim N, Ko A, et al. Impact of continuity of care on cardiovascular disease risk among newly-diagnosed hypertension patients. Sci Rep. Nov 17, 2020;10(1):19991. [ https://doi.org/10.1038/s41598-020-77131-w ] [ CrossRef ] [ Medline ]
  • Chalermsri C, Paisansudhi S, Kantachuvesiri P, Pramyothin P, Washirasaksiri C, Srivanichakorn W, et al. The effectiveness of holistic diabetic management between Siriraj Continuity of Care clinic and medical out-patient department. J Med Assoc Thai. Mar 2014;97 Suppl 3:S197-S205. [ Medline ]
  • Chen C, Cheng S. Does pay-for-performance benefit patients with multiple chronic conditions? Evidence from a universal coverage health care system. Health Policy Plan. Feb 2016;31(1):83-90. [ CrossRef ] [ Medline ]
  • Son K, Son H, Park B, Kim H, Kim C. A Community-Based Intervention for Improving Medication Adherence for Elderly Patients with Hypertension in Korea. Int J Environ Res Public Health. Feb 28, 2019;16(5):721. [ https://www.mdpi.com/resolver?pii=ijerph16050721 ] [ CrossRef ] [ Medline ]
  • Lee W, Yoo K, Jeong J, Koo JH. Chronic Disease Management for People With Hypertension. Int J Public Health. 2022;67:1604452. [ https://europepmc.org/abstract/MED/35719730 ] [ CrossRef ] [ Medline ]
  • Chen C, Cheng S. Continuity of care and changes in medication adherence among patients with newly diagnosed diabetes. Am J Manag Care. Feb 2016;22(2):136-142. [ https://www.ajmc.com/pubMed.php?pii=86530 ] [ Medline ]
  • Chen C, Tseng C, Cheng S. Continuity of care, medication adherence, and health care outcomes among patients with newly diagnosed type 2 diabetes: a longitudinal analysis. Med Care. Mar 2013;51(3):231-237. [ CrossRef ] [ Medline ]
  • Desse TA, Namara KM, Yifter H, Manias E. Development of a Complex Intervention for Effective Management of Type 2 Diabetes in a Developing Country. J Clin Med. Feb 22, 2022;11(5):1149. [ https://www.mdpi.com/resolver?pii=jcm11051149 ] [ CrossRef ] [ Medline ]
  • Stuart RM, Khan O, Abeysuriya R, Kryvchun T, Lysak V, Bredikhina A, et al. Diabetes care cascade in Ukraine: an analysis of breakpoints and opportunities for improved diabetes outcomes. BMC Health Serv Res. May 11, 2020;20(1):409. [ https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-020-05261-y ] [ CrossRef ] [ Medline ]
  • Halalau A, Sonmez M, Uddin A, Karabon P, Scherzer Z, Keeney S. Efficacy of a pharmacist-managed diabetes clinic in high-risk diabetes patients, a randomized controlled trial - "Pharm-MD" : Impact of clinical pharmacists in diabetes care. BMC Endocr Disord. Mar 16, 2022;22(1):69. [ https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-022-00983-y ] [ CrossRef ] [ Medline ]
  • Sisson EM, Dixon DL, Kildow DC, Van Tassell BW, Carl DE, Varghese D, et al. Effectiveness of a Pharmacist-Physician Team-Based Collaboration to Improve Long-Term Blood Pressure Control at an Inner-City Safety-Net Clinic. Pharmacotherapy. Mar 2016;36(3):342-347. [ CrossRef ] [ Medline ]
  • Gomes LC, Coelho ACM, Gomides DDS, Foss-Freitas MC, Foss MC, Pace AE. Contribution of family social support to the metabolic control of people with diabetes mellitus: A randomized controlled clinical trial. Appl Nurs Res. Aug 2017;36:68-76. [ CrossRef ] [ Medline ]
  • Foti K, Wang D, Appel LJ, Selvin E. Hypertension Awareness, Treatment, and Control in US Adults: Trends in the Hypertension Control Cascade by Population Subgroup (National Health and Nutrition Examination Survey, 1999-2016). Am J Epidemiol. Dec 31, 2019;188(12):2165-2174. [ https://europepmc.org/abstract/MED/31504121 ] [ CrossRef ] [ Medline ]
  • Amarchand R, Kulothungan V, Krishnan A, Mathur P. Hypertension treatment cascade in India: results from National Noncommunicable Disease Monitoring Survey. J Hum Hypertens. May 2023;37(5):394-404. [ https://europepmc.org/abstract/MED/35513442 ] [ CrossRef ] [ Medline ]
  • Chen H, Su B. Factors Related to the Continuity of Care and Self-Management of Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Study in Taiwan. Healthcare (Basel). Oct 20, 2022;10(10):2088. [ https://www.mdpi.com/resolver?pii=healthcare10102088 ] [ CrossRef ] [ Medline ]
  • Prenissl J, Jaacks LM, Mohan V, Manne-Goehler J, Davies JI, Awasthi A, et al. Variation in health system performance for managing diabetes among states in India: a cross-sectional study of individuals aged 15 to 49 years. BMC Med. May 13, 2019;17(1):92. [ https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1325-6 ] [ CrossRef ] [ Medline ]
  • Passi-Solar Á, Margozzini P, Mindell JS, Ruiz M, Valencia-Hernandez CA, Scholes S. Hypertension care cascade in Chile: a serial cross-sectional study of national health surveys 2003-2010-2017. BMC Public Health. Sep 14, 2020;20(1):1397. [ https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-020-09483-x ] [ CrossRef ] [ Medline ]
  • Dedefo MG, Abate SK, Ejeta BM, Korsa AT. Predictors of poor glycemic control and level of glycemic control among diabetic patients in west Ethiopia. Ann Med Surg (Lond). Jul 2020;55:238-243. [ https://linkinghub.elsevier.com/retrieve/pii/S2049-0801(20)30076-5 ] [ CrossRef ] [ Medline ]
  • Aggarwal R, Chiu N, Wadhera RK, Moran AE, Raber I, Shen C, et al. Racial/Ethnic Disparities in Hypertension Prevalence, Awareness, Treatment, and Control in the United States, 2013 to 2018. Hypertension. Dec 2021;78(6):1719-1726. [ CrossRef ] [ Medline ]
  • Tapela NM, Clifton L, Tshisimogo G, Gaborone M, Madidimalo T, Letsatsi V, et al. Prevalence and Determinants of Hypertension Awareness, Treatment, and Control in Botswana: A Nationally Representative Population-Based Survey. Int J Hypertens. 2020;2020:8082341. [ https://doi.org/10.1155/2020/8082341 ] [ CrossRef ] [ Medline ]
  • Dhungana RR, Pedisic Z, Dhimal M, Bista B, de Courten M. Hypertension screening, awareness, treatment, and control: a study of their prevalence and associated factors in a nationally representative sample from Nepal. Glob Health Action. Dec 31, 2022;15(1):2000092. [ https://europepmc.org/abstract/MED/35132939 ] [ CrossRef ] [ Medline ]
  • Chikafu H, Chimbari M. Hypertension care cascade in the Ingwavuma rural community, uMkhanyakude District, KwaZulu-Natal province of South Africa. PeerJ. 2021;9:e12372. [ https://europepmc.org/abstract/MED/34824908 ] [ CrossRef ] [ Medline ]
  • Berry KM, Parker W, Mchiza ZJ, Sewpaul R, Labadarios D, Rosen S, et al. Quantifying unmet need for hypertension care in South Africa through a care cascade: evidence from the SANHANES, 2011-2012. BMJ Glob Health. 2017;2(3):e000348. [ https://gh.bmj.com/lookup/pmidlookup?view=long&pmid=29082013 ] [ CrossRef ] [ Medline ]
  • Jorgensen JMA, Hedt KH, Omar OM, Davies JI. Hypertension and diabetes in Zanzibar - prevalence and access to care. BMC Public Health. Sep 04, 2020;20(1):1352. [ https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-020-09432-8 ] [ CrossRef ] [ Medline ]
  • Odland ML, Bockarie T, Wurie H, Ansumana R, Lamin J, Nugent R, et al. Prevalence and access to care for cardiovascular risk factors in older people in Sierra Leone: a cross-sectional survey. BMJ Open. Sep 09, 2020;10(9):e038520. [ https://bmjopen.bmj.com/lookup/pmidlookup?view=long&pmid=32907906 ] [ CrossRef ] [ Medline ]
  • Shah SA, Rosenberg M, Ahmad D, Ahmad S, Safian N, Shobugawa Y. Prevalence and determinants of unmet needs for hypertension care among the older population in Selangor: cross-sectional study. Health Res Policy Syst. Nov 29, 2022;20(Suppl 1):127. [ https://health-policy-systems.biomedcentral.com/articles/10.1186/s12961-022-00915-1 ] [ CrossRef ] [ Medline ]
  • Kothavale A, Puri P, Yadav S. The burden of hypertension and unmet need for hypertension care among men aged 15-54 years: a population-based cross-sectional study in India. J Biosoc Sci. Nov 2022;54(6):1078-1099. [ CrossRef ] [ Medline ]
  • Fraser-Hurt N, Naseri LT, Thomsen R, Matalavea A, Ieremia-Faasili V, Reupena MS, et al. Improving services for chronic non-communicable diseases in Samoa: an implementation research study using the care cascade framework. Aust N Z J Public Health. Feb 2022;46(1):36-45. [ https://onlinelibrary.wiley.com/doi/10.1111/1753-6405.13113 ] [ CrossRef ] [ Medline ]
  • Macinko J, Leventhal DGP, Lima-Costa MF. Primary Care and the Hypertension Care Continuum in Brazil. J Ambul Care Manage. 2018;41(1):34-46. [ CrossRef ] [ Medline ]
  • Geraedts TJM, Boateng D, Lindenbergh KC, van Delft D, Mathéron H, Mönnink G, et al. Evaluating the cascade of care for hypertension in Sierra Leone. Trop Med Int Health. Nov 2021;26(11):1470-1480. [ https://europepmc.org/abstract/MED/34350675 ] [ CrossRef ] [ Medline ]
  • Price AJ, Crampin AC, Amberbir A, Kayuni-Chihana N, Musicha C, Tafatatha T, et al. Prevalence of obesity, hypertension, and diabetes, and cascade of care in sub-Saharan Africa: a cross-sectional, population-based study in rural and urban Malawi. Lancet Diabetes Endocrinol. Mar 2018;6(3):208-222. [ https://linkinghub.elsevier.com/retrieve/pii/S2213-8587(17)30432-1 ] [ CrossRef ] [ Medline ]
  • Abu Hamad BA, Jamaluddine Z, Safadi G, Ragi M, Ahmad RES, Vamos EP, et al. The hypertension cascade of care in the midst of conflict: the case of the Gaza Strip. J Hum Hypertens. Oct 2023;37(10):957-968. [ https://europepmc.org/abstract/MED/36509988 ] [ CrossRef ] [ Medline ]
  • Manne-Goehler J, Geldsetzer P, Agoudavi K, Andall-Brereton G, Aryal KK, Bicaba BW, et al. Health system performance for people with diabetes in 28 low- and middle-income countries: A cross-sectional study of nationally representative surveys. PLoS Med. Mar 1, 2019;16(3):e1002751. [ https://dx.plos.org/10.1371/journal.pmed.1002751 ] [ CrossRef ] [ Medline ]
  • Osetinsky B, Mhalu G, Mtenga S, Tediosi F. Care cascades for hypertension and diabetes: Cross-sectional evaluation of rural districts in Tanzania. PLoS Med. Dec 2022;19(12):e1004140. [ https://dx.plos.org/10.1371/journal.pmed.1004140 ] [ CrossRef ] [ Medline ]
  • Zhao E, Wu Q, Crimmins E, Zhang Y. Hypertension Diagnosis, Treatment, and Control among Older Chinese: Trends in the Hypertension Care Cascade. Innov Aging. 2021;5(Suppl 1):607-608. [ CrossRef ]
  • Carrillo-Larco RM, Guzman-Vilca WC, Neupane D. Estimating the gap between demand and supply of medical appointments by physicians for hypertension care: a pooled analysis in 191 countries. BMJ Open. Apr 04, 2022;12(4):e059933. [ CrossRef ] [ Medline ]
  • Lewis CP, Newell JN. Patients' perspectives of care for type 2 diabetes in Bangladesh -a qualitative study. BMC Public Health. Jul 21, 2014;14:737. [ https://bmcpublichealth.biomedcentral.com/articles/10.1186/1471-2458-14-737 ] [ CrossRef ] [ Medline ]
  • Yen S, Kung P, Sheen Y, Chiu L, Xu X, Tsai W. Factors related to continuing care and interruption of P4P program participation in patients with diabetes. Am J Manag Care. Jan 01, 2016;22(1):e18-e30. [ https://www.ajmc.com/pubMed.php?pii=86487 ] [ Medline ]
  • Mayer V, Mijanovich T, Egorova N, Flory J, Mushlin A, Calvo M, et al. Impact of New York State's Health Home program on access to care among patients with diabetes. BMJ Open Diabetes Res Care. Dec 2021;9(Suppl 1):e002204. [ https://drc.bmj.com/lookup/pmidlookup?view=long&pmid=34933873 ] [ CrossRef ] [ Medline ]
  • Doubova SV, Borja-Aburto VH, Guerra-Y-Guerra G, Salgado-de-Snyder VN, González-Block M. Loss of job-related right to healthcare is associated with reduced quality and clinical outcomes of diabetic patients in Mexico. Int J Qual Health Care. May 01, 2018;30(4):283-290. [ CrossRef ] [ Medline ]
  • Qiu C, Chen S, Yao Y, Zhao Y, Xin Y, Zang X. Adaption and validation of Nijmegen continuity questionnaire to recognize the influencing factors of continuity of care for hypertensive patients in China. BMC Health Serv Res. Jan 29, 2019;19(1):79. [ https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-019-3915-6 ] [ CrossRef ] [ Medline ]
  • Jalilian H, Heydari S, Mir N, Fehresti S, Khodayari-Zarnaq R. Forgone care in patients with type 2 diabetes: a cross-sectional study. BMC Public Health. Aug 24, 2021;21(1):1588. [ CrossRef ] [ Medline ]
  • Soriano EC, Lenhard MJ, Gonzalez JS, Tennen H, Otto AK, Perndorfer C, et al. Momentary Partner Involvement in Diabetes Self-Care and Continuously Measured Glucose: A Dynamic Analysis. Psychosom Med. Sep 01, 2022;84(7):808-812. [ https://europepmc.org/abstract/MED/35792706 ] [ CrossRef ] [ Medline ]
  • Mwangome M, Geubbels E, Klatser P, Dieleman M. Perceptions on diabetes care provision among health providers in rural Tanzania: a qualitative study. Health Policy Plan. Apr 01, 2017;32(3):418-429. [ https://europepmc.org/abstract/MED/27935802 ] [ CrossRef ] [ Medline ]
  • Desse TA, Mc Namara K, Yifter H, Manias E. Current practices and future preferences of type 2 diabetes care in Ethiopia: A qualitative study on the perspectives of patients, health professionals, and policymakers. Diabetes Metab Syndr. Aug 2022;16(8):102585. [ CrossRef ] [ Medline ]
  • Jayanna K, Swaroop N, Kar A, Ramanaik S, Pati MK, Pujar A, et al. Designing a comprehensive Non-Communicable Diseases (NCD) programme for hypertension and diabetes at primary health care level: evidence and experience from urban Karnataka, South India. BMC Public Health. Apr 16, 2019;19(1):409. [ https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-019-6735-z ] [ CrossRef ] [ Medline ]
  • David NJ, Bresick G, Moodaley N, Von Pressentin KB. Measuring the impact of community-based interventions on type 2 diabetes control during the COVID-19 pandemic in Cape Town - A mixed methods study. S Afr Fam Pract (2004). Aug 18, 2022;64(1):e1-e9. [ https://europepmc.org/abstract/MED/36073102 ] [ CrossRef ] [ Medline ]
  • Dambha-Miller H, Silarova B, Irving G, Kinmonth AL, Griffin SJ. Patients' views on interactions with practitioners for type 2 diabetes: a longitudinal qualitative study in primary care over 10 years. Br J Gen Pract. Jan 2018;68(666):e36-e43. [ https://bjgp.org/lookup/pmidlookup?view=long&pmid=29203681 ] [ CrossRef ] [ Medline ]
  • Kazemian P, Shebl FM, McCann N, Walensky RP, Wexler DJ. Evaluation of the Cascade of Diabetes Care in the United States, 2005-2016. JAMA Intern Med. Oct 01, 2019;179(10):1376-1385. [ https://europepmc.org/abstract/MED/31403657 ] [ CrossRef ] [ Medline ]
  • Ortiz MS, Baeza-Rivera MJ, Salinas-Oñate N, Flynn P, Betancourt H. [Healthcare mistreatment attributed to discrimination among mapuche patients and discontinuation of diabetes care]. Rev Med Chil. Oct 2016;144(10):1270-1276. [ http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0034-98872016001000006&lng=en&nrm=iso&tlng=en ] [ CrossRef ] [ Medline ]
  • Kim H, Moon K, Park T, Park S, Yoon S, Oh I. Factors affecting treatment compliance in new hypertensive patients in Korea. Clin Exp Hypertens. 2016;38(8):701-709. [ CrossRef ] [ Medline ]
  • Metz M, Pierre JL, Yan LD, Rouzier V, St-Preux S, Exantus S, et al. Hypertension continuum of care: Blood pressure screening, diagnosis, treatment, and control in a population-based cohort in Haiti. J Clin Hypertens (Greenwich). Mar 2022;24(3):246-254. [ https://europepmc.org/abstract/MED/35199944 ] [ CrossRef ] [ Medline ]
  • Isangula KG, Seale H, Jayasuriya R, Nyamhanga TM, Stephenson N. What factors shape doctors' trustworthiness? Patients' perspectives in the context of hypertension care in rural Tanzania. Rural Remote Health. Aug 2020;20(3):5826. [ https://www.rrh.org.au/articles/subviewnew.asp?ArticleID=5826 ] [ CrossRef ] [ Medline ]
  • Chukwuma A, Gong E, Latypova M, Fraser-Hurt N. Challenges and opportunities in the continuity of care for hypertension: a mixed-methods study embedded in a primary health care intervention in Tajikistan. BMC Health Serv Res. Dec 03, 2019;19(1):925. [ https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-019-4779-5 ] [ CrossRef ] [ Medline ]
  • Khetan A, Zullo M, Hejjaji V, Barbhaya D, Agarwal S, Gupta R, et al. Prevalence and pattern of cardiovascular risk factors in a population in India. Heart Asia. 2017;9(2):e010931. [ https://europepmc.org/abstract/MED/29469903 ] [ CrossRef ] [ Medline ]
  • Adinkrah E, Bazargan M, Wisseh C, Assari S. Adherence to Hypertension Medications and Lifestyle Recommendations among Underserved African American Middle-Aged and Older Adults. Int J Environ Res Public Health. Sep 08, 2020;17(18):6538. [ https://www.mdpi.com/resolver?pii=ijerph17186538 ] [ CrossRef ] [ Medline ]
  • Onwudiwe NC, Mullins CD, Winston RA, Shaya FT, Pradel FG, Laird A, et al. Barriers to self-management of diabetes: a qualitative study among low-income minority diabetics. Ethn Dis. 2011;21(1):27-32. [ Medline ]
  • Dey S, Mukherjee A, Pati MK, Kar A, Ramanaik S, Pujar A, et al. Socio-demographic, behavioural and clinical factors influencing control of diabetes and hypertension in urban Mysore, South India: a mixed-method study conducted in 2018. Arch Public Health. Nov 15, 2022;80(1):234. [ https://archpublichealth.biomedcentral.com/articles/10.1186/s13690-022-00996-y ] [ CrossRef ] [ Medline ]
  • Lustman A, Comaneshter D, Vinker S. Interpersonal continuity of care and type two diabetes. Prim Care Diabetes. Jun 2016;10(3):165-170. [ CrossRef ] [ Medline ]
  • Fung CSC, Wan EYF, Jiao F, Lam CLK. Five-year change of clinical and complications profile of diabetic patients under primary care: a population-based longitudinal study on 127,977 diabetic patients. Diabetol Metab Syndr. 2015;7:79. [ https://dmsjournal.biomedcentral.com/articles/10.1186/s13098-015-0072-x ] [ CrossRef ] [ Medline ]
  • Maroof M, Faizi N, Thekkur P, Raj S, Goel S. Is the rule of halves in hypertension valid uniformly across India? A cross-sectional analysis of national family health survey-4 data. Indian J Public Health. 2022;66(3):269-275. [ https://doi.org/10.4103/ijph.ijph_2143_21 ] [ CrossRef ] [ Medline ]
  • Ali MK, Bullard KM, Gregg EW, Del Rio C. A cascade of care for diabetes in the United States: visualizing the gaps. Ann Intern Med. Nov 18, 2014;161(10):681-689. [ CrossRef ] [ Medline ]
  • Geldsetzer P, Manne-Goehler J, Marcus ME, Ebert C, Zhumadilov Z, Wesseh CS, et al. The state of hypertension care in 44 low-income and middle-income countries: a cross-sectional study of nationally representative individual-level data from 1·1 million adults. Lancet. Aug 24, 2019;394(10199):652-662. [ CrossRef ] [ Medline ]
  • Obagha CE, Danladi B, Kamateeka M, Chori BS, Ogbonnaya U, Maduka D, et al. Unmet needs of hypertension care in Nigeria: results of the community action against non-communicable diseases (COMAAND) project preintervention survey. Blood Press Monit. Feb 01, 2022;27(1):27-32. [ CrossRef ] [ Medline ]
  • Gee ME, Janssen I, Pickett W, McAlister FA, Bancej CM, Joffres M, et al. Prevalence, awareness, treatment, and control of hypertension among Canadian adults with diabetes, 2007 to 2009. Can J Cardiol. May 2012;28(3):367-374. [ CrossRef ] [ Medline ]
  • Jug J, Peček I, Bukvić S, Petrovčić M, Bosnić F, Rukavina A, et al. Continuity of care in patients with type 2 diabetes in Croatian primary care setting during COVID-19 pandemic: A retrospective observational study. Prim Care Diabetes. Dec 2022;16(6):768-774. [ https://europepmc.org/abstract/MED/36220766 ] [ CrossRef ] [ Medline ]
  • Dalal MR, Robinson SB, Sullivan SD. Real-world evaluation of the effects of counseling and education in diabetes management. Diabetes Spectr. Nov 2014;27(4):235-243. [ https://europepmc.org/abstract/MED/25647045 ] [ CrossRef ] [ Medline ]
  • Smith JJ, Johnston JM, Hiratsuka VY, Dillard DA, Tierney S, Driscoll DL. Medical home implementation and trends in diabetes quality measures for AN/AI primary care patients. Prim Care Diabetes. Apr 2015;9(2):120-126. [ CrossRef ] [ Medline ]
  • Zhang Y, Tang W, Zhang Y, Liu L, Zhang L. Effects of integrated chronic care models on hypertension outcomes and spending: a multi-town clustered randomized trial in China. BMC Public Health. Mar 11, 2017;17(1):244. [ https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-017-4141-y ] [ CrossRef ] [ Medline ]
  • Hsu CH, Chou YJ, Pu C. The effect of continuity of care on emergency room use for diabetic patients varies by disease severity. J Epidemiol. Aug 05, 2016;26(8):413-419. [ https://dx.doi.org/10.2188/jea.JE20150045 ] [ CrossRef ] [ Medline ]
  • Athinarayanan SJ, Adams RN, Hallberg SJ, McKenzie AL, Bhanpuri NH, Campbell WW, et al. Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: a 2-year non-randomized clinical trial. Front Endocrinol (Lausanne). 2019;10:348. [ https://europepmc.org/abstract/MED/31231311 ] [ CrossRef ] [ Medline ]
  • Brain M, Reynolds C, Nesbeda H, Walsh M, Fem R, Magruder A, et al. Intervisit management of patients with diabetes: synchronized phone calls. JNP. Sep 2019;15(8):e157-e160. [ CrossRef ]
  • Reutens AT, Hutchinson R, Van Binh T, Cockram C, Deerochanawong C, Ho LT, et al. The GIANT study, a cluster-randomised controlled trial of efficacy of education of doctors about type 2 diabetes mellitus management guidelines in primary care practice. Diabetes Res Clin Pract. Oct 2012;98(1):38-45. [ CrossRef ] [ Medline ]
  • Pan CC, Kung PT, Chiu LT, Liao YP, Tsai WC. Patients with diabetes in pay-for-performance programs have better physician continuity of care and survival. Am J Manag Care. Feb 01, 2017;23(2):e57-e66. [ https://www.ajmc.com/pubMed.php?pii=86967 ] [ Medline ]
  • Andrich D, Foronda C. Improving glycemic control and quality of life with diabetes self-management education: a pilot project. J Contin Educ Nurs. Mar 01, 2020;51(3):119-123. [ CrossRef ] [ Medline ]
  • Korcegez EI, Sancar M, Demirkan K. Effect of a pharmacist-led program on improving outcomes in patients with type 2 diabetes mellitus from northern Cyprus: a randomized controlled trial. J Manag Care Spec Pharm. May 2017;23(5):573-582. [ https://europepmc.org/abstract/MED/28448779 ] [ CrossRef ] [ Medline ]
  • Sousa Santos F, Tavares Bello C, Roque C, Capitão R, Castro Fonseca R, Limbert C, et al. The effect of changing regular care provider in type 2 diabetes mellitus: a retrospective study. Acta Med Port. Sep 02, 2019;32(9):580-587. [ http://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/11304 ] [ CrossRef ] [ Medline ]
  • Cole RE, Boyer KM, Spanbauer SM, Sprague D, Bingham M. Effectiveness of prediabetes nutrition shared medical appointments: prevention of diabetes. Diabetes Educ. 2013;39(3):344-353. [ CrossRef ] [ Medline ]
  • Goudge J, Chirwa T, Eldridge S, Gómez-Olivé FXF, Kabudula C, Limbani F, et al. Can lay health workers support the management of hypertension? Findings of a cluster randomised trial in South Africa. BMJ Glob Health. 2018;3(1):e000577. [ https://gh.bmj.com/lookup/pmidlookup?view=long&pmid=29527345 ] [ CrossRef ] [ Medline ]
  • Lee SY, Chun SY, Park H. The impact of COVID-19 protocols on the continuity of care for patients with hypertension. Int J Environ Res Public Health. Feb 02, 2022;19(3) [ https://www.mdpi.com/resolver?pii=ijerph19031735 ] [ CrossRef ] [ Medline ]
  • Thomas T, Dyer W, Adams A, Grant R, Schmittdiel J. Address changes are associated with unmet glycemic targets: opportunities to improve processes and outcomes of care among people with type 2 diabetes. Perm J. Jun 29, 2022;26(2):1-10. [ https://www.thepermanentejournal.org/doi/10.7812/TPP/21.144?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed ] [ CrossRef ] [ Medline ]
  • Meador M, Coronado F, Roy D, Bay RC, Lewis JH, Chen J, et al. Impact of COVID-19-related care disruptions on blood pressure management and control in community health centers. BMC Public Health. Dec 08, 2022;22(1):2295. [ https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-022-14763-9 ] [ CrossRef ] [ Medline ]
  • Yan JW, Liu S, Van Aarsen K, Columbus MP, Spaic T. Do adult patients with type 1 or 2 diabetes who present to the emergency department with hyperglycemia have improved outcomes if they have access to specialized diabetes care? Can J Diabetes. Feb 2021;45(1):59-63. [ CrossRef ] [ Medline ]
  • Jermendy G, Wittmann I, Nagy L, Kiss Z, Rokszin G, Abonyi-Tóth Z, et al. Persistence of initial oral antidiabetic treatment in patients with type 2 diabetes mellitus. Med Sci Monit. Feb 2012;18(2):CR72-CR77. [ https://europepmc.org/abstract/MED/22293880 ] [ CrossRef ] [ Medline ]
  • Kunwar A, Durgad K, Kaur P, Sharma M, Swasticharan L, Mallela M, et al. Interventions to ensure the continuum of care for hypertension during the COVID-19 pandemic in five Indian states-India Hypertension Control Initiative: Global Heart. Glob Heart. 2021;16(1):82. [ https://europepmc.org/abstract/MED/34909373 ] [ CrossRef ] [ Medline ]
  • Malcolm JC, Maranger J, Taljaard M, Shah B, Tailor C, Liddy C, et al. Into the abyss: diabetes process of care indicators and outcomes of defaulters from a Canadian tertiary care multidisciplinary diabetes clinic. BMC Health Serv Res. Aug 10, 2013;13:303. [ https://bmchealthservres.biomedcentral.com/articles/10.1186/1472-6963-13-303 ] [ CrossRef ] [ Medline ]
  • Hanafi NS, Abdullah A, Lee PY, Liew SM, Chia YC, Khoo EM. Personal continuity of care in a university-based primary care practice: impact on blood pressure control. PLoS One. 2015;10(7):e0134030. [ https://dx.plos.org/10.1371/journal.pone.0134030 ] [ CrossRef ] [ Medline ]
  • Hong JS, Kang HC. Continuity of ambulatory care and health outcomes in adult patients with type 2 diabetes in Korea. Health Policy. Feb 2013;109(2):158-165. [ CrossRef ] [ Medline ]
  • Senteio CR, Akincigil A. Illuminating racial inequity in diabetes control: differences based on gender and geography. J Racial Ethn Health Disparities. Jun 2021;8(3):704-711. [ CrossRef ] [ Medline ]
  • Madede T, Damasceno A, Lunet N, Augusto O, Silva-Matos C, Beran D, et al. Changes in prevalence and the cascade of care for type 2 diabetes over ten years (2005-2015): results of two nationally representative surveys in Mozambique. BMC Public Health. Nov 25, 2022;22(1):2174. [ https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-022-14595-7 ] [ CrossRef ] [ Medline ]
  • Holman N, Khunti K, Wild SH, Sattar N, Knighton P, Young B, et al. Care processes in people in remission from type 2 diabetes: a cohort study using the National Diabetes Audit. Diabet Med. Mar 2023;40(3):e15016. [ https://europepmc.org/abstract/MED/36440921 ] [ CrossRef ] [ Medline ]
  • Wollum A, Gabert R, McNellan CR, Daly JM, Reddy P, Bhatt P, et al. Identifying gaps in the continuum of care for cardiovascular disease and diabetes in two communities in South Africa: baseline findings from the HealthRise project. PLoS One. 2018;13(3):e0192603. [ https://dx.plos.org/10.1371/journal.pone.0192603 ] [ CrossRef ] [ Medline ]
  • Londoño Agudelo E, Pérez Ospina V, Battaglioli T, Taborda Pérez C, Gómez-Arias R, Van der Stuyft P. Gaps in hypertension care and control: a population-based study in low-income urban Medellin, Colombia. Trop Med Int Health. Aug 2021;26(8):895-907. [ https://europepmc.org/abstract/MED/33938098 ] [ CrossRef ] [ Medline ]
  • Olry de Labry Lima A, Bermúdez Tamayo C, Pastor Moreno G, Bolívar Muñoz J, Ruiz Pérez I, Johri M, Prados Quel; et al. Effectiveness of an intervention to improve diabetes self-management on clinical outcomes in patients with low educational level. Gac Sanit. 2017;31(1):40-47. [ http://www.elsevier.es/en/linksolver/ft/pii/S0213-9111(16)30123-6 ] [ CrossRef ] [ Medline ]
  • Leniz J, Gulliford MC. Continuity of care and delivery of diabetes and hypertensive care among regular users of primary care services in Chile: a cross-sectional study. BMJ Open. Oct 28, 2019;9(10):e027830. [ https://bmjopen.bmj.com/lookup/pmidlookup?view=long&pmid=31662353 ] [ CrossRef ] [ Medline ]
  • Hallberg SJ, McKenzie AL, Williams PT, Bhanpuri NH, Peters AL, Campbell WW, et al. Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study. Diabetes Ther. Apr 2018;9(2):583-612. [ https://europepmc.org/abstract/MED/29417495 ] [ CrossRef ] [ Medline ]
  • Collier IA, Baker DM. Implementation of a pharmacist-supervised outpatient diabetes treatment clinic. Am J Health Syst Pharm. Jan 01, 2014;71(1):27-36. [ CrossRef ] [ Medline ]
  • Ramli AS, Selvarajah S, Daud MH, Haniff J, Abdul-Razak S, Tg-Abu-Bakar-Sidik TMI, et al. EMPOWER-PAR Investigators. Effectiveness of the EMPOWER-PAR Intervention in Improving Clinical Outcomes of Type 2 Diabetes Mellitus in Primary Care: A Pragmatic Cluster Randomised Controlled Trial. BMC Fam Pract. Nov 14, 2016;17(1):157. [ https://bmcfampract.biomedcentral.com/articles/10.1186/s12875-016-0557-1 ] [ CrossRef ] [ Medline ]
  • LaMonica LC, McGarvey ST, Rivara AC, Sweetman CA, Naseri T, Reupena MS, et al. Cascades of diabetes and hypertension care in Samoa: Identifying gaps in the diagnosis, treatment, and control continuum - a cross-sectional study. Lancet Reg Health West Pac. Jan 2022;18:100313. [ https://linkinghub.elsevier.com/retrieve/pii/S2666-6065(21)00222-4 ] [ CrossRef ] [ Medline ]
  • Kothavale A, Puri P, Sangani PG. Quantifying population level hypertension care cascades in India: a cross-sectional analysis of risk factors and disease linkages. BMC Geriatr. Feb 04, 2022;22(1):98. [ https://bmcgeriatr.biomedcentral.com/articles/10.1186/s12877-022-02760-x ] [ CrossRef ] [ Medline ]
  • Mathew BK, De Roza JG, Liu C, Goh LJ, Ooi CW, Chen E, et al. Which Aspect of Patient-Provider Relationship Affects Acceptance and Adherence of Insulin Therapy in Type 2 Diabetes Mellitus? A Qualitative Study in Primary Care. Diabetes Metab Syndr Obes. 2022;15:235-246. [ https://europepmc.org/abstract/MED/35153494 ] [ CrossRef ] [ Medline ]
  • Lee EL, Wong PS, Tan MY, Sheridan J. What role could community pharmacists in Malaysia play in diabetes self-management education and support? The views of individuals with type 2 diabetes. Int J Pharm Pract. Apr 2018;26(2):138-147. [ CrossRef ] [ Medline ]
  • Datta BK, Ansa BE, Husain MJ. An analytical model of population level uncontrolled hypertension management: a care cascade approach. J Hum Hypertens. Jul 05, 2021;36(8):726-731. [ https://europepmc.org/abstract/MED/34226635 ] [ CrossRef ] [ Medline ]
  • Basu S, Flood D, Geldsetzer P, Theilmann M, Marcus ME, Ebert C, et al. Estimated effect of increased diagnosis, treatment, and control of diabetes and its associated cardiovascular risk factors among low-income and middle-income countries: a microsimulation model. Lancet Glob Health. Nov 2021;9(11):e1539-e1552. [ https://linkinghub.elsevier.com/retrieve/pii/S2214-109X(21)00340-5 ] [ CrossRef ] [ Medline ]
  • Pickersgill SJ, Msemburi WT, Cobb L, Ide N, Moran AE, Su Y, et al. Modeling global 80-80-80 blood pressure targets and cardiovascular outcomes. Nat Med. Aug 2022;28(8):1693-1699. [ https://europepmc.org/abstract/MED/35851877 ] [ CrossRef ] [ Medline ]
  • Khalid A, Dong Q, Chuluunbaatar E, Haldane V, Durrani H, Wei X. Implementation Science Perspectives on Implementing Telemedicine Interventions for Hypertension or Diabetes Management: Scoping Review. J Med Internet Res. Mar 14, 2023;25:e42134. [ https://www.jmir.org/2023//e42134/ ] [ CrossRef ] [ Medline ]
  • Nilsen P, Bernhardsson S. Context matters in implementation science: a scoping review of determinant frameworks that describe contextual determinants for implementation outcomes. BMC Health Serv Res. Mar 25, 2019;19(1):189. [ https://bmchealthservres.biomedcentral.com/articles/10.1186/s12913-019-4015-3 ] [ CrossRef ] [ Medline ]

Abbreviations

Edited by A Mavragani; submitted 15.08.23; peer-reviewed by S Wei, P Mathur; comments to author 11.10.23; revised version received 22.10.23; accepted 27.12.23; published 16.02.24

©Jie Wang, Fangqin Tan, Zhenzhong Wang, Yiwen Yu, Jingsong Yang, Yueqing Wang, Ruitai Shao, Xuejun Yin. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 16.02.2024.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Public Health and Surveillance, is properly cited. The complete bibliographic information, a link to the original publication on https://publichealth.jmir.org, as well as this copyright and license information must be included.

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  • Volume 2, Issue 1
  • β-Blockers in hypertension, diabetes, heart failure and acute myocardial infarction: a review of the literature
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  • James J DiNicolantonio 1 ,
  • Hassan Fares 2 ,
  • Asfandyar K Niazi 3 ,
  • Saurav Chatterjee 4 ,
  • Fabrizio D'Ascenzo 5 ,
  • Enrico Cerrato 5 ,
  • Giuseppe Biondi-Zoccai 6 ,
  • Carl J Lavie 2 , 7 ,
  • David S Bell 8 and
  • James H O'Keefe 9
  • 1 Mid America Heart Institute at Saint Luke's Hospital , Kansas City, Missouri , USA
  • 2 John Ochsner Heart and Vascular Institute, Ochsner Clinical School- The University of Queensland School of Medicine , New Orleans, Louisiana , USA
  • 3 Shifa College of Medicine , Islamabad , Pakistan
  • 4 St Luke's Roosevelt Hospital Center , New York, New York , USA
  • 5 University of Turin, Citta Della Salute e Della Scienza , Torino , Italy
  • 6 Sapienza University of Rome , Latina , Italy
  • 7 Department of Preventive Medicine , Pennington Biomedical Research Center , Baton Rouge, Louisiana , USA
  • 8 Southside Endocrinology, University of Alabama at Birmingham
  • 9 Mid America Heart Institute at Saint Luke's Hospital, University of Missouri-Kansas City , Kansas City, Missouri , USA
  • Correspondence to Dr James J DiNicolantonio; jjdinicol{at}gmail.com

β-Blockers (BBs) are an essential class of cardiovascular medications for reducing morbidity and mortality in patients with heart failure (HF). However, a large body of data indicates that BBs should not be used as first-line therapy for hypertension (HTN). Additionally, new data have questioned the role of BBs in the treatment of stable coronary heart disease (CHD). However, these trials mainly tested the non-vasodilating β 1 selective BBs (atenolol and metoprolol) which are still the most commonly prescribed BBs in the USA. Newer generation BBs, such as the vasodilating BBs carvedilol and nebivolol, have been shown not only to be better tolerated than non-vasodilating BBs, but also these agents do not increase the risk of diabetes mellitus (DM), atherogenic dyslipidaemia or weight gain. Moreover, carvedilol has the most evidence for reducing morbidity and mortality in patients with HF and those who have experienced an acute myocardial infarction (AMI). This review discusses the cornerstone clinical trials that have tested BBs in the settings of HTN, HF and AMI. Large randomised trials in the settings of HTN, DM and stable CHD are still needed to establish the role of BBs in these diseases, as well as to determine whether vasodilating BBs are exempt from the disadvantages of non-vasodilating BBs.

  • beta-blockers
  • HEART FAILURE
  • myocardial infarction

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/openhrt-2014-000230

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Hypertension and diabetes

Hypertension (HTN) is a largely asymptomatic disease affecting around 50 million Americans and one billion people worldwide. 1–3 Patients with HTN are at an increased risk for heart failure (HF), stroke, renal disease and acute myocardial infarction (AMI). 1 , 3 Although HTN is the most common primary care diagnosis in the USA, it remains undertreated. 3

Pharmacological treatment of HTN includes the class of medications known as β-blockers (BBs). The various agents in this class differ substantially in their pharmacological properties. Atenolol, metoprolol, bisoprolol and nebivolol are β 1 selective BBs, preferentially inhibiting cardiac β 1 receptors as opposed to β 2 receptors. Carvedilol, in contrast, inhibits β 1 , β 2 (postsynaptic and presynaptic) and α 1 receptors, upregulates cardiac muscarinic M 2 receptors and possesses antioxidant effects. 4–7 Additionally, nebivolol (which is highly selective for the β 1 receptor) also has vasodilating properties due to its ability to increase the endogenous production and release of endothelial nitric oxide (NO). 3 , 8

The Medical Research Council (MRC) elderly HTN treatment trial was a placebo-controlled, single-blind trial that randomised 4396 patients between the age of 65–74 years to receive either hydrochlorothiazide (HCTZ; plus amiloride), atenolol or placebo. 9 Despite the fact that atenolol reduced blood pressure (BP) to levels below that of placebo (approximately −10/7 mm Hg over 60 months), patients receiving atenolol, compared with patients assigned to placebo, did not have a significant reduction in any cardiovascular (CV) end point during 5.8 years of the study (stroke (relative risk (RR) 0.82, 95% CI 0.60 to 1.14, p=0.25); coronary heart disease (CHD; RR=0.97, 95% CI 0.73 to 1.30, p=0.85); CV events (RR=0.96, 95% CI 0.77 to 1.19, p=0.69); CV death (RR=1.06, 95% CI 0.81 to 1.39, p=0.66) and total death (RR=1.08, 95% CI 0.88 to 1.34, p=0.46)). On the other hand, patients receiving HCTZ plus amiloride had a significantly reduced risk of stroke (31%, 95% CI 3% to 51%, p=0.04); CHD events (44%, 95% CI 21% to 60%, p=0.0009) and all CV events (35%, 95% CI 17% to 49%, p=0.0005). Even after adjusting for lower than atenolol-induced BP changes, HCTZ plus amiloride still led to a lower risk of CV events (p=0.01) than atenolol. Despite this fact, both the HCTZ plus amiloride and the atenolol groups compared with placebo had significantly increased withdrawals per 1000 patient years due to impaired glucose tolerance 6.9 (HCTZ) versus 2.7 (placebo) per 1000 patient years and 5.8 (atenolol) versus 2.7 (placebo) per 1000 patient years.

In summary, atenolol provided no CV or all-cause mortality reduction in elderly hypertensive patients over a period of 5.8 years but increased glucose intolerance. 8 A limitation in the interpretation of these results is the fact that after 5.8 years only 52% of patients remained on HCTZ plus amiloride and only 37% of patients remained on atenolol.

The Heart Attack Primary Prevention in Hypertension (HAPPHY) study trial randomised 6569 men aged 40–64 years with mild-to-moderate HTN to a thiazide diuretic (bendrofluazide or HCTZ) or a BB (atenolol or metoprolol) to determine if BBs differed from thiazides in the prevention of CHD events and death. 10 Although both groups had a similar BP lowering effect (140/89 mm Hg in the BB group and 140/88 mm Hg in the thiazide group, p value not significant), when compared with each other, the BB group did not show any difference in fatal/non-fatal CHD per 1000 patient years (10.62 vs 9.48/years, respectively; OR=0.88, 95% CI 0.68 to 1.14), fatal/non-fatal stroke (2.58 vs 3.35/years, respectively; OR=1.29, 95% CI 0.82 to 2.04) or all deaths (7.73/years vs 8.25/years, respectively; OR=1.06, 95% CI 0.80 to 1.41). This was unexpected since HCTZ monotherapy (without amiloride, etc) has never been shown to reduce CV events compared with placebo or controls. 11–13 Therefore, the first generation BBs (atenolol and metoprolol) in this study offer no additional benefit when compared with a thiazide diuretic (HCTZ), which suggests that atenolol or metoprolol may not be superior to placebo for improving CV prognosis in HTN.

Left ventricular hypertrophy (LVH), which typically develops as a consequence of poorly controlled HTN as well as obesity and ageing, carries a higher CV morbidity and mortality rate; it remains uncertain whether or not BBs reduce the risk of CV events in this patient population. In the Losartan Intervention For Endpoint Reduction (LIFE) trial, atenolol was compared with losartan in patients with HTN with evidence of LVH on ECG. 14 Losartan was statistically superior to atenolol for reducing the primary composite end point of CV death and stroke (11% vs 13%, adjusted HR=0.87, 95% CI 0.77 to 0.98, p=0.021). Similarly, the incidence of stroke (5% vs 7%, HR=0.75, 95% CI 0.63 to 0.89, p=0.001) as well as new-onset diabetes mellitus (DM; 6% vs 8%, HR=0.75, 95% CI 0.63 to 0.88, p=0.001) was significantly lower in the losartan group. However, CV mortality (4% vs 5%, HR=0.89, 95% CI 0.73 to 1.07, p=0.206), MI (4% vs 4%, HR=1.07, 95% CI 0.88 to 1.31, p=0.491) and total mortality (8% vs 9%, HR=0.90, 95% CI 0.78 to 1.03, p=0.128) were not statistically different between the two groups. The incidence of adverse effects was lower in the losartan group as compared with the atenolol group. These adverse events included bradycardia (1% vs 9%, p<0.0001), cold extremities (4% vs 6%, p<0.0001), hypotension (3% vs 2%, p=0.001), sexual dysfunction (4% vs 5%, p=0.009), albuminuria (5% vs 6%, p=0.0002), hyperglycaemia (5% vs 7%, p=0.007), asthenia/fatigue (15% vs 17%, p=0.001), back pain (12% vs 10%, p=0.004), dyspnoea (10% vs 14%, p<0.0001), lower extremity oedema (12% vs 14%, p=0.002) and pneumonia (5% vs 6%, p=0.018). 14

The rebound peripheral vasoconstriction that occurs from decreased cardiac output (CO) and unopposed α stimulation due to β 1 selective BB therapy results in decreased skeletal muscle perfusion causing adverse effects on lipid and glucose metabolism by increasing insulin resistance. Significant increases in glucose concentrations have been seen with atenolol, metoprolol and propranolol. 15–18 As discussed previously, the LIFE study showed a 25% (HR=0.75, 95% CI 0.63 to 0.88, p=0.001) lower risk of new-onset DM in the losartan-treated group compared with the atenolol group. 19 In the Atherosclerosis Risk in Communities (ARIC) cohort study of 3804 patients with HTN, the BB group had a 28% higher risk of type 2 DM (T2DM) compared with the control group (RR=1.28, 95% CI 1.04 to 1.57). 14 The Captopril Prevention Project (CAPP) trial investigated in 10 985 patients with HTN the effect of captopril (50–100 mg/day) versus a conventional anti-HTN treatment regimen that included a diuretic, a BB or both. 20 The patients in the conventional treatment group most frequently received atenolol (50–100 mg/day) or metoprolol (50–100 mg/day) and/or HCTZ (25 mg/day) or bendrofluazide (2.5 mg/day); CV mortality (0.77, p=0.092) and the incidence of T2DM (RR=0.79; p=0.007) were found to be lower in the captopril than in the conventional therapy group. Conversely, fatal and non-fatal strokes showed a higher incidence with captopril treatment (1.25, p=0.044), whereas fatal and non-fatal MI had similar incidences (0.96, p=0.68).

In the International Verapamil-Trandolapril Study (INVEST) trial, approximately 23 000 patients with HTN and CHD were randomised to verapamil or atenolol. Verapamil-treated patients had a significantly lower incidence of new-onset DM versus atenolol (15% lower risk; RR=0.85, 95% CI 0.77 to 0.95). 21 In the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) trial, atenolol given for 5.5 years increased CV mortality (p=0.001), all-cause mortality (p=0.025), and the development of DM (p<0.0001) compared with amlodipine. 22 In a post hoc analysis of the ASCOT-BPLA study, use of atenolol was a significant predictor for the development of DM. 23 In a 5-year study of 228 patients comparing treatment with doxazosin to atenolol, atenolol caused a significant reduction in high-density lipoprotein cholesterol from baseline (p<0.05), as well as a significant increase in triglycerides from baseline (p<0.0001); both of these changes suggest that atenolol triggered an increase in insulin resistance. Several other studies have confirmed the negative effects of atenolol on lipids in patients with HTN. 24 Thus, it is clear that β 1 selective BBs (atenolol and metoprolol) can worsen the metabolic syndrome (increased insulin resistance, worsened atherogenic dyslipidaemia and increased weight gain).

The Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) trial was a post hoc analysis of the metoprolol arm of the HAPPHY study. 25 It focused on male patients between 40 and 64 years of age who had a history of HTN with an untreated diastolic BP of over 100 mm Hg and investigated the effects of metoprolol on the incidence of CHD events (sudden cardiac death (SCD) and MI) compared with thiazide diuretics. Patients receiving metoprolol were significantly less likely to experience a CHD event as compared with those on diuretics (111 vs 144 cases, p=0.001, corresponding to 14.3 vs 18.8 cases/1000 patient years; RR=0.76 at the end of the trial; 95% CI 0.58 to 0.98). Moreover, the incidence of SCD, fatal and non-fatal MI was reduced with metoprolol as compared with the diuretic treatment (p=0.024). Similarly, the risk of silent MI (p=0.016) and first definite non-fatal MI (p=0.0034, 10.6 vs 14.3 cases/1000 patient years at the end of the trial) were also lower with metoprolol. It is important to note that all baseline characteristics, including BP, were similar in the 255 participants who had a CV event versus those who did not. This suggests that the benefit demonstrated by metoprolol occurred due to something other than an anti-HTN effect. Despite these beneficial results, MAPHY should be interpreted with caution because of its post hoc subgroup design.

Metoprolol has been shown to have less favourable effects on glycaemic control when compared with carvedilol. The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial showed that compared with metoprolol, carvedilol significantly reduced new-onset DM (10.3% vs 12.6%, p=0.048), and significantly improved insulin sensitivity (p<0.004 vs p=0.48). 4 Additionally, carvedilol decreased triglycerides significantly more than metoprolol (−2.9%; p=0.001 for the between-group difference) and caused significantly less weight gain (0.17 vs 1.2 kg, respectively; p<0001). 4 In addition, microalbuminuria, a surrogate marker for endothelial function, occurred less often in the carvedilol group (6.4% vs 10.3%; p=0.04). 4 Pharmacological comparisons between carvedilol versus atenolol and metoprolol are listed in table 1 .

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Atenolol and metoprolol versus carvedilol

Meta-analyses

Almost two decades ago, conflicting meta-analyses came out, just a year apart from each other. While the first suggested BB therapy was appropriate as a first-line antihypertensive agent, another meta-analysis published a year later indicated that BBs are indeed inappropriate first-line antihypertensives in uncomplicated HTN in elderly patients. 26 , 27 A recent meta-analysis of 13 randomised controlled trials (RCTs) encompassing 105 951 patients with primary HTN indicated that the RR of stroke was higher for BBs than other anti-HTN medications (RR=16%; 95% CI 4% to 30%); 28 in these meta-analyses, atenolol was the most frequently utilised BB for first-line treatment of HTN. The meta-analysis concluded that BBs (mainly atenolol) increased the risk of stroke and were less effective than other antihypertensives as first-line therapy.

Another meta-analysis evaluated the effects of atenolol on morbidity and mortality in patients with HTN 29 and demonstrated that although there was a significant difference in the BP lowering effect of atenolol and placebo, this anti-HTN effect of atenolol failed to translate into a significant reduction in the all-cause mortality (RR=1.01, 95% CI 0.89 to 1.15). Similarly, CV mortality (RR=0.99, 95% CI 0.83 to 1.18) and MI (RR=0.99, 95% CI 0.83 to 1.19) were not significantly different between the placebo and the atenolol groups. However, the risk of stroke was decreased, but not significantly, in the atenolol group as compared with placebo (RR=0.85, 95% CI 0.72 to 1.01). When compared with other anti-HTN agents, there was no significant difference in the anti-HTN effect; there was, however, a significantly higher mortality in the atenolol group (RR=1.13, 95% CI 1.02 to 1.25). Moreover, there was a higher risk of CV mortality (RR=1.16, 95% CI 1.00 to 1.34) and stroke (RR=1.30, 95% CI 1.12 to 1.50) with atenolol as compared with the other antihypertensives. Thus, this meta-analysis illustrated that although atenolol produces a marginal benefit as compared with placebo with regard to stroke prevention, it does not hold any benefit over other antihypertensives. The authors concluded that the results of this meta-analysis question whether atenolol should be used as a first-line anti-HTN agent.

A Cochrane review was conducted on the effectiveness and safety of BBs on the rates of morbidity and mortality in patients with HTN. 30 This meta-analysis failed to show any significant benefit of BBs on the total mortality rates when compared with placebo (RR=0.99, 95% CI 0.88 to 1.11), diuretics (RR=1.04, 95% CI 0.91 to 1.19) or renin-angiotensin aldosterone system (RAAS) inhibitors (RR=1.10, 95% CI 0.98 to 1.24). Conversely, total mortality was higher when BBs were compared with calcium-channel blockers (CCBs; RR 1.07, 95% CI 1.00 to 1.14). There was a statistically significant decrease in the risk of total CV disease (RR=0.88, 95% CI 0.79 to 0.97) and stroke (RR=0.80, 95% CI 0.66–0.96) when BBs were compared with placebo. However, there was no difference in the risk of CHD between BBs and placebo (RR=0.93, 95% CI 0.81 to 1.07) or total CV disease between BBs and diuretics or RAAS inhibitors. There was a higher risk of total CV disease (RR=1.18, 95% CI 1.08 to 1.29) and stroke (RR=1.24, 95% CI 1.11 to 1.40) when BBs were compared with CCBs. The risk of stroke was also higher with BB as compared with RAAS inhibitors (RR=1.30, 95% CI 1.11 to 1.53). Additionally, patients on BBs had a higher rate of discontinuation when compared with RAAS inhibitors (RR=1.41, 95% CI 1.29 to 1.54), but such a difference was not seen with the other drugs. This analysis shows that the benefit of BB therapy is only moderately superior to placebo and is significantly inferior to other anti-HTN drugs. However, these results with the older BB agents cannot be generalised to the newer vasodilating BBs (carvedilol and nebivolol).

The risk of development of new-onset DM with BBs was assessed in a systematic review. 31 This review included 12 studies with a total of 94 492 participants and found that there was a 22% increase in the risk of development of new-onset DM with BB therapy as compared with non-diuretic anti-HTN therapy (RR=1.22, 95% CI 1.12 to 1.33). There was also an increased risk of DM with BB therapy as compared with placebo (fixed-effects model: 33% increase, RR=1.33, 95% CI 1.00 to 1.76, p=0.05; random-effects model: 44% increase, RR=1.44, 95% CI 0.69 to 3.00, p=0.33; heterogeneity χ 2 6.18, p=0.013). The risk of DM was, however, less with BB therapy than with thiazide diuretics (fixed effect model: 26% decrease, RR=0.74, 95% CI 0.61 to 0.90, p=0.002; random effect model: 21% decrease, RR=0.79, 95% CI 0.45 to 1.41, p=0.43; heterogeneity χ 2 =23.18, p<0.0001). Among BBs, the risk of DM was greatest with atenolol treatment and the risk of new-onset DM increased with the duration of the treatment. BB therapy increased the risk of death by 4% (pooled RR=1.04, 95% CI 1.00 to 1.09, p=0.056; heterogeneity χ 2 10.63, p=0.560) and the risk of stroke by 15% (pooled RR=1.15, 95% CI 1.01 to 1.30, p=0.029; heterogeneity χ 2 27.8, p=0.001) compared with other anti-HTN agents. There was no effect on MI (pooled RR=1.02, 95% CI 0.92 to 1.12, p=0.769; heterogeneity χ 2 19.30, p=0.023). The risk of DM, death and stroke is, therefore, increased by BB therapy as compared with other non-diuretic anti-HTN drugs and this effect was more pronounced with atenolol therapy.

In another meta-analysis, the role of BBs for the prevention of developing HF in patients with HTN was evaluated. 32 This review included 12 RCTs with 112 177 patients with HTN and showed that the BP was reduced by 12.6/6.1 mm Hg by BB therapy as compared with placebo (systolic BP weighted mean reduction 12.6±7.8 mm Hg; diastolic BP weighted mean reduction 6.1±4.4 mm Hg). As compared with other anti-HTN agents, the BP lowering efficacy was similar across all groups (vs diuretics 0.0/−1.0 mm Hg; vs RAAS inhibitors−0.3/−0.6 mm Hg; vs CCBs −0.1/+0.7 mm Hg) and the decrease in the HF risk was also similar (RR=1.00, 95% CI 0.92 to 1.08). When compared with placebo, BBs showed a 23% decrease in the risk of HF (p=0.055). However, comparison between BBs and other anti-HTN agents showed no statistically significant difference (BB vs others, 2.1% vs 2.1%, p=0.91). In trials comparing atenolol with other anti-HTN agents, atenolol had a similar effect in preventing HF (1.8% vs 1.7%; p=0.72) and the risk of stroke was increased by 19% in the BB group. In addition, there was no additional anti-HTN benefit of BB therapy when compared with other anti-HTN drugs. Moreover, there was a higher incidence of stroke in this elderly population. Therefore, this evidence confirms that first generation BBs should not be prescribed as first-line anti-HTN agents, especially in the elderly.

Heart failure

An estimated 5 million people in the USA have HF and more than 550 000 people are diagnosed with this condition each year. 33 , 34 During the past two decades, based on impressive RCT data, BBs have become one of the most important pharmacological treatments for improving the CV prognosis for patients with systolic HF. It has been shown that the most frequently prescribed BBs in patients with HF in the USA and in Europe are metoprolol and atenolol. 35 , 36 Among 11 326 adults who survived a hospitalisation for HF, pharmacy records revealed that the most commonly prescribed BBs in descending order were metoprolol tartrate (43.2%), atenolol (38.5%), carvedilol (11.6%) and other BBs (6.7%). 36 A recent national prescription audit of BBs dispensed in the USA in 2011 indicated that the most commonly prescribed BBs in descending order are metoprolol tartrate/succinate (71.9 million), atenolol (36.3 million), carvedilol (24 million), nebivolol (15 million) and bisoprolol (9 million; figure 1 ). Disturbingly, these BB choices in the patients with HF are not evidence-based.

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β-Blocker prescriptions dispensed in the USA in 2011 (in millions).

Clinical trials testing atenolol on outcomes in patients with HF are lacking. Atenolol (mean dose 50 mg daily) was compared with metoprolol tartrate (mean dose 65.5 mg daily) in a RCT in 150 patients with mild-to-moderate HF (aged 70 or less) with New York Heart Association (NYHA) functional class II and III, and a left ventricular ejection fraction (LVEF) ≤40%. 35 , 36 During a follow-up of 12 months, atenolol significantly reduced the combined end point (all-cause death plus CV hospitalisation) versus control (p=0.0001); however, significantly more patients had a combined end point on control (n=19) and on atenolol (n=8) versus metoprolol (n=4; p=0.0428 for the difference between atenolol, p=0.0002 for the difference between control). Moreover, the hospitalisation rate was significantly reduced with metoprolol (4%) versus atenolol (12%) and placebo (26.3%). Additionally, the combined end point (all-cause mortality and CV hospitalisation) was significantly reduced with metoprolol (RR reduction (RRR) 77%) versus atenolol (RRR=53%). This trial indicated that both atenolol and metoprolol are beneficial in patients with HF but that metoprolol is more effective than atenolol.

In another study, 100 patients with class II or III HF (LVEF ≤25%) already receiving high-dose enalapril (40 mg daily) were randomised to atenolol (maintenance dose 89 mg/day) or placebo for 395 days. 39 The primary combined end point (worsening HF or death) was significantly reduced with atenolol versus placebo (p<0.01). Despite this fact, there was no significant reduction in death or worsening HF with atenolol versus placebo when these end points were individually assessed (death: 5 vs 8, worsening HF: 8 vs 19, respectively). However, hospitalisations for CV events (6 vs 21, p=0.07), hospitalisations for worsening HF (5 vs 12, p=0.05) and hospitalisations for arrhythmias (1 vs 9, p<0.01) were all reduced with atenolol.

Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) was a double-blind, randomised, placebo-controlled study testing metoprolol CR/XL (target dose was 200 mg once daily) in 3991 patients with chronic HF (NYHA functional class II–IV and LVEF of 40% or less). 40 Metoprolol significantly reduced all-cause mortality by 34% (RR=0.66, 95% CI 0.53 to 0.81, p=0.00009). However, there was an increase in mortality with metoprolol versus placebo in the US geographical region (HR=1.05, 95% CI 0.71 to 1.56), which included almost one-third of the mortality events in MERIT-HF. An increase in mortality with metoprolol versus placebo is also supported by the Metoprolol in Dilated Cardiomyopathy (MDC) trial, which showed an 18% increased risk of death, although not statistically significant, with metoprolol versus placebo in patients with dilated cardiomyopathy (RR=1.18, 95% CI 0.66 to 2.09, p=0.57). 41 Thus, while geographical disparity must be interpreted with caution, there does not seem to be evidence in the USA (US patients and how clinicians treat them in the USA may differ from that outside the USA) supporting the use of metoprolol in patients with HF.

The Cardiac Insufficiency Bisoprolol Study (CIBIS)-I trial was conducted in 641 patients with a history of HF and a LVEF of <40%. 42 These patients were randomised to receive either bisoprolol or placebo in addition to diuretic and vasodilator therapy. There was no significant difference between the groups’ mortality (RR=0.80, 95% CI 0.56 to 1.15, p=0.22), SCD or death due to ventricular tachycardia (VT) or ventricular fibrillation (VF). Conversely, the rate of hospitalisation for CV decompensation was lower in the group receiving bisoprolol (p<0.01). Non-lethal events, such as acute pulmonary oedema, HF without pulmonary oedema and cardiogenic shock, that is, pump failure, were less commonly seen in the bisoprolol group (p<0.001). Documented cases of VT and VF were also fewer (p=0.03) in the bisoprolol group and treatment withdrawals were similar across both groups. This study supports the beneficial effects of bisoprolol in patients with a history of HF.

The CIBIS-II trial was conducted to assess the effect of BBs on the survival of patients with HF. 43 This study randomised 2647 patients with CHF NYHA class III or IV and LVEF of less than 35% to receive either bisoprolol or placebo in addition to diuretics and ACE inhibitors. This study was stopped early because bisoprolol showed a significant reduction in the incidence of all-cause mortality. As compared with the placebo group, the group receiving bisoprolol had significantly lower mortality rates (11.8% vs 17.3%, HR=0.66, 95% CI 0.54 to 0.81, p<0.0001) and the incidence of SCD was also lower in the bisoprolol group (3.6% vs 6.3%, HR=0.56, 95% CI 0.39 to 0.80, p=0.0011). Similarly, CV deaths (p=0.0049), hospitalisations for any cause (p=0.0006) and the combined end point of CV death and hospitalisation for CV event (p=0.0004) were also seen more infrequently in the group treated with bisoprolol. Hospitalisations due to VT and fibrillation (p=0.006), and hypotension (p=0.03) were also less common in the bisoprolol group, whereas hospitalisations due to bradycardia (p<0.004) and stroke (p=0.04) were more common with bisoprolol.

Several major trials have established the CV benefits of carvedilol over traditional non-vasodilating BBs in patients with HF. A meta-analysis of 19 placebo-controlled RCTs tested the efficacy of carvedilol versus metoprolol in terms of LVEF in patients with chronic HF. Carvedilol significantly increased LVEF when compared with metoprolol (placebo-corrected increases of +0.065 vs +0.038, p=0.0002) as well as in the four active-controlled trials which directly compared carvedilol versus metoprolol (+0.084 vs +0.057, p=0.009), and these benefits were derived in both patients with and without CHD. 44

A randomised trial of 51 patients with HF with a mean LVEF of 37% and chronic obstructive pulmonary disease were treated with carvedilol, bisoprolol and metoprolol, and subsequently returned to their original BB treatment. N -terminal prohormone brain natriuretic peptide (NT-proBNP) levels, which are elevated in HF and have been shown to be a better predictor of major CV events than C reactive protein, were measured. 45 Carvedilol reduced NT-proBNP levels significantly better than did either metoprolol or bisoprolol (mean NT-proBNP level were: 1001, 1371, 1349 ng/L, respectively (p<0.01). 46

An investigation of 136 patients with HF on cardiac resynchronisation therapy showed that on carvedilol there was a 7% mortality whereas the mortality was 18% and 36% on metoprolol succinate and placebo, respectively. 47 Moreover, in the MADIT-CRT (multicentre automatic defibrillator implantation trial with cardiac resynchronisation therapy), patients with HF with NYHA functional class I and II with wide QRS complexes derived a significant 30% reduction in hospitalisation for HF or death with carvedilol when compared with metoprolol (HR=0.70, 95% CI 0.57 to 0.87, p=0.001), as well as a 39% reduction in the subgroup with implantable cardioverter-defibrillator (CRT-D; HR=0.61, 95% CI 0.46 to 0.82, p=0.001) and a 49% reduction in CRT-D patients with left bundle branch block (HR=0.51, 95% CI 0.35 to 0.76, p<0.001). 48 Additionally, there was a marginally significant reduction in ventricular arrhythmias with carvedilol versus metoprolol (22% vs 26%, HR=0.80, 95% CI 0.63 to 1.00, p=0.050).

In patients with HF with DM, the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial was a double-blinded, placebo-controlled trial, which enlisted 2289 patients within the group to carvedilol or placebo. 49 , 50 In this trial, it was shown that the annual mortality rate in the carvedilol group was reduced by 35% (12.8% vs 19.7%, p=0.00013) and risk of death or hospitalisation reduced by 24% (p=0.00004) as compared with the placebo group. Owing to the overwhelming benefit of carvedilol as compared with placebo, the study was terminated early due to the mortality benefit in the carvedilol group. In patients with recent or recurrent CV decompensation or depressed cardiac function, the risk of death or hospitalisation due to a CV cause was reduced by 33% (95% CI 14% to 48%, p=0.002) and the risk of death or hospitalisation due to HF was decreased by 33% (95% CI 13% to 49%, p=0.002) in the group receiving carvedilol. In the group receiving carvedilol, patients also showed a lower incidence of hospitalisations due to HF (17.1% vs 23.7%, p=0.0001), for a CV reason (21.3% vs 27.7%, p=0.0003) or for any reason (32.2% vs 38.1%, p=0.003) as compared with the placebo group. Additionally, carvedilol in comparison with placebo showed a reduced incidence of all adverse effects (39.0% vs 45.5%, p=0.002), HF (p<0.0001), SCD (p=0.016), VT (p=0.019) and cardiogenic shock (p=0.003).

The US Carvedilol HF study was a RCT enrolling 1094 patients with chronic HF to receive either carvedilol or placebo. 51 The mortality rate in the carvedilol group was reduced by 65% (3.2% vs 7.8%, 95% CI 39% to 80%, p<0.001), the risk of hospitalisation for CV causes was reduced by 27% (14.1% vs 19.6%, p=0.036), and the combined risk of hospitalisation and death was reduced by 38% (24.6% vs 15.8%, p<0.001). Owing to the clear survival advantage with carvedilol treatment, the trial had to be terminated early. There was also a greater decrease in the mean heart rate with the carvedilol group as compared with placebo (12.6±12.8 vs 1.4±12.2 bpm, p<0.001). This study confirms that carvedilol provides profound survival benefit over placebo in patients with chronic HF.

In the Australia-New Zealand HF trial, the researchers randomised 415 patients with chronic stable HF to receive either carvedilol or placebo. 52 The results of this trial showed a 5.3% increase in the LVEF (p<0.0001) and decrease in the end-diastolic and end-systolic heart dimensions by 1.7 mm (p=0.06) and 3.2 mm (p=0.001) in the carvedilol group compared with the placebo group. The incidence of death or hospitalisation was also lower in the carvedilol group as compared with the placebo group (104 vs 131, RR=0.74, 95% CI 0.57 to 0.95). This trial showed beneficial effects of carvedilol on LVEF and cardiac dimensions in patients with HF.

A recent network meta-analysis comparing the BBs carvedilol, atenolol, metoprolol, bucindolol, bisoprolol and nebivolol indicated that carvedilol showed the greatest reduction in mortality (6.6% reduction) with a number needed to treat of 15 to prevent one death in patients with systolic HF. 53 Moreover, carvedilol had the best tolerability (lowest pooled discontinuation rates) versus the other five BBs.

Finally, a systematic review and meta-analysis of randomised direct comparison trials of carvedilol versus β 1 selective BBs was performed. 54 Compared with β 1 selective BBs used in HF (8 trials; n=4563), carvedilol significantly reduced all-cause mortality (RR=0.85, 95% CI 0.78 to 0.93, p=0.0006; table 2 ). This meta-analysis provides some rationale for the preferred use of carvedilol in patients with systolic HF versus β 1 selective BBs. Despite this fact, larger RCTs are required to confirm these results as most of the benefit of carvedilol came from one trial (Carvedilol Or Metoprolol European Trial, COMET), which has been critiqued for comparing carvedilol to metoprolol tartrate (instead of succinate), and the use of a lower dose of metoprolol than what was used in MERIT-HF. However, heart rate was quite similar between carvedilol and metoprolol in COMET and thus somewhat diminished the credibility of this argument.

Carvedilol reduces all-cause mortality versus β 1 -selective BBs in patients with systolic heart failure and AMI 54

Nebivolol is a recently approved β 1 selective BB with the unique effect of enhancing NO effects; decreased NO synthesis can exacerbate myocardial ischaemia through NO-dependent endothelial vasodilation. 8 Furthermore, nebivolol inhibits the process of endothelial proliferation, which leads to the formation of atherosclerosis. The positive haemodynamic effects of increased NO synthesis include decreased peripheral vascular resistance and increased stroke volume, which can benefit the patient with HF. 55 The Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure (SENIORS) trial was a randomised study of elderly patients >70 years of age with HF. Nebivolol was effective in reducing the combined end point of mortality and morbidity irrespective of LVEF; 8 , 56 , 57 however, this agent has relatively little data on CV event reduction in large cohorts with CHD. Two smaller trials have also concurred with the findings in the SENIORS trial in HF management. These studies looked at LVEF and exercise tolerability as their end points; nebivolol did show a significantly improved LVEF at 2 and 12 months. 8 Among the commonly prescribed BBs, only carvedilol and nebivolol have vasodilating effects, thereby not causing reductions in CO and unlike the other BBs, neither of these drugs increases insulin resistance or risk for new-onset T2DM. 58 , 59

Acute myocardial infarction

Approximately 715 000 people in the USA have an AMI per year. 60 , 61 Moreover, CHD kills more than 385 000 people in the USA annually. 59 , 60 As the cost of CHD in the USA is approximately $109 billion per year, 59 , 61 medications that can reduce this burden are of utmost importance.

It has been shown that metoprolol and atenolol are frequently prescribed BBs in patients with MI. 62 In the COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial), a randomised trial involving 45 852 patients with AMI, patients were randomised to receive intravenous and then oral metoprolol or placebo. 63 The treatment group received up to 15 mg of intravenous metoprolol and 200 mg orally daily, thereafter. There was no statistically significant reduction in the primary composite end point of death, recurrent AMI or cardiac arrest (OR=0.96, 95% CI 0.90 to 1.01, p=0.10) or death alone (OR=0.99, 95% CI 0.92 to 1.05, p=0.69). Cardiogenic shock was seen in 5.0% of the patients randomised to metoprolol and 3.9% in the placebo group (OR=1.30, 1.19 to 1.41; p<0.00001). Reinfarction (2.0% vs 2.5%, OR=0.82, 95% CI 0.72 to 0.92, p=0.001) and VF (2.5% vs 3.0%, OR=0.83, 95% CI 0.75 to 0.93, p=0.001) were less frequently seen in the metoprolol-treated group. This study concluded that the early use of the BB metoprolol in patients who had experienced an AMI, though it reduced the risk of reinfarction and VF, it increased the risk of cardiogenic shock. 63

The Carvedilol Post Infarction Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial enrolled 1959 patients in this multicentre, randomised, placebo-controlled trial. Patients with a LVEF <40% and who had an AMI were randomised to carvedilol 6.25 mg twice daily or placebo. 64 The primary end point was all-cause mortality or CV readmissions. All-cause mortality was lower in the carvedilol group compared with placebo (116 (12%) vs 151 (15%), 0.77 (0.60 to 0.98), p=0.03). Additionally, carvedilol caused a 76% reduction in arrhythmias (VT and VF/flutter, p<0.0001), a 52% reduction in supraventricular arrhythmias (p=0.0015) and a 26% reduction in SCD (p=0.098) compared with placebo.

The Carvedilol Acute Myocardial Infarction Study (CAMIS) trial enlisted 232 patients with post-MI to receive carvedilol or atenolol for a 12-month period. Patients received therapy within 24 h of onset of chest pain. There was no difference in the LVEF between the two groups and no significant reduction in the occurrence of a first serious CV event with carvedilol versus atenolol (RR=0.88, 95% CI 0.59 to 1.30, p=0.524). 63 However, compared with atenolol, carvedilol was better tolerated (20% vs 33%; p=0.025) and there were numerically fewer deaths (2 vs 5, RR=0.39, 95% CI 0.08 to 1.95, p=0.25). This trial highlights the fact that carvedilol might be better tolerated than atenolol, but a larger trial is required to know if carvedilol is superior to atenolol in patients with post-AMI with normal LVEF.

A systematic review and meta-analysis of randomised direct comparison trials of carvedilol versus β 1 selective BBs was performed on patients with AMI. 54 Compared with β 1 selective BBs (three trials, n=644), carvedilol significantly reduced all-cause mortality by 45% (fixed-effects model: RR=0.55, 95% CI 0.32 to 0.94, p=0.03) but not when the random-effects model was used (RR=0.56, 95% CI 0.26 to 1.12, p=0.10; table 2 ). Thus, carvedilol may improve outcomes compared with β 1 selective BBs in patients with AMI; however, further RCTs are required. A more complete list covering the cornerstone trials in HTN, HF and AMI are provided in table 3 .

Cornerstone hypertension, HF and AMI trials with atenolol, metoprolol and carvedilol

Numerous trials in patients with HTN indicate that atenolol should not be used as a first-line anti-HTN agent. Further trials are required to determine the optimal BB for use in patients with HF and AMI. Until then, the evidence strongly suggests that carvedilol may have an advantage over the first generation BBs in patients with HF and AMI, as carvedilol has the greatest amount of evidence for reducing CV morbidity and mortality in these settings and is effective in HTN with less adverse effects on lipids and promotion of DM.

  • Chobanian AV ,
  • Baksris GL ,
  • Black HR , et al
  • Wojciechowski D ,
  • Papademetriou V
  • DiNicolantonio JJ ,
  • Bristow MR ,
  • Ginsburg R ,
  • Umans V , et al
  • Motomura S ,
  • Deighton NM ,
  • Zerkowski HR , et al
  • Arumanayagam M ,
  • Tong S , et al
  • ↵ Medical Research Council Working Party . Medical Research Council trial of treatment of hypertension in older adults: principal results . BMJ 1992 ; 204 : 405 – 12 . OpenUrl
  • Wilhelmsen L ,
  • Berglund G ,
  • Elmfeldt D , et al
  • Helgeland A
  • ↵ Multiple Risk Factor Intervention Trail Research Group . Mortality after 10 1/2 years for hypertensive participants in the multiple risk factor intervention trail . Circulation 1990 ; 82 : 1616 – 28 . doi:10.1161/01.CIR.82.5.1616 OpenUrl Abstract / FREE Full Text
  • DiNicolantonio JJ
  • Devereux RB ,
  • Kjeldsen SE , et al
  • Rett K , et al
  • Andersson O ,
  • ↵ [No authors listed] . Propranolol or hydrochlorothiazide alone for the initial treatment of hypertension. Effect on plasma glucose and glucose tolerance. Vererans Administration Cooperative Study Group on Antihypertensive Agents . Hypertension 1985 ; 7 : 1008 – 16 . doi:10.1161/01.HYP.7.6.1008 OpenUrl CrossRef
  • Sarafidis PA ,
  • Hansson L ,
  • Lindholm LH ,
  • Niskanen L , et al
  • Pepine CJ ,
  • Handberg EM ,
  • Cooper-DeHoff RM , et al
  • Poulter NR , et al
  • Dobson J , et al
  • Wikstrand J ,
  • Warnold I ,
  • Tuomilehto J , et al
  • Siscovick DS , et al
  • Messerli FH ,
  • Grossman E ,
  • Goldbourt U
  • Carlberg B ,
  • Samuelsson O
  • Samuelsson O ,
  • Lindholm LH
  • Wiysonge CS ,
  • Bradley HA ,
  • Volmink J , et al
  • Bangalore S ,
  • Grossman E , et al
  • Parkar S , et al
  • ↵ American Heart Association . Heart Disease and Stroke Statistics: 2005 Update . Dallas, TX : American Heart Association , 2005 .
  • Bennett S ,
  • Casey DE , et al
  • Zentgraf C , et al
  • Gurwitz JH , et al
  • Dekleva M , et al
  • http://bengtablad.wordpress.com/2012/01/19/metoprolol-better-than-atenolol-in-therapy-of-cardiac-failure-role-of-peripheral-npy/
  • Strametz-Juranek J , et al
  • ↵ [No authors listed] . Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) . Lancet 1999 ; 353 : 2001 – 7 . doi:10.1016/S0140-6736(99)04440-2 OpenUrl CrossRef PubMed Web of Science
  • Waagstein F ,
  • Swedberg K , et al
  • ↵ CIBIS investigators and committees . A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees . Circulation 1994 ; 90 : 1765 – 73 . doi:10.1161/01.CIR.90.4.1765 OpenUrl Abstract / FREE Full Text
  • ↵ CIBIS-II Investigators and Committees . The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial . Lancet 1999 ; 353 : 9 – 13 . doi:10.1016/S0140-6736(98)11181-9 OpenUrl CrossRef PubMed Web of Science
  • Antonopoulos GV ,
  • Berlin JA , et al
  • Wannamethee SG ,
  • Lowe GD , et al
  • Jabbour A ,
  • Macdonald PS ,
  • Keogh AM , et al
  • Aronow WS , et al
  • Ruwald MH ,
  • Ruwald AC ,
  • Jons C , et al
  • Fowler MB ,
  • Roecker EB , et al
  • Eichhorn EJ ,
  • Cohn JN , et al
  • ↵ Australia-New Zealand Heart Failure Research Collaborative Group . Randomised placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischemic heart disease . Lancet 1997 ; 349 : 375 – 80 . doi:10.1016/S0140-6736(97)80008-6 OpenUrl CrossRef PubMed Web of Science
  • Chatterjee S ,
  • Biondi-Zoccai G ,
  • Abbate A , et al
  • Fares H , et al
  • Mollnau H ,
  • Daiber A , et al
  • Taylor AA ,
  • Flather MD ,
  • Shibata MC ,
  • Coats AJ , et al
  • Bakris GL ,
  • Fonseca V ,
  • Katholi RE , et al
  • DeMatteo A , et al
  • Lloyd-Jones DM , et al
  • ↵ http://www.cdc.gov/heartdisease/facts.htm
  • Lev E , et al
  • Chen YP , et al
  • Jonsson G ,
  • Abdelnoor M ,
  • Muller C , et al
  • ISIS-1 Collaborative Group . Randomised trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group . Lancet 1986 ; 2 : 57 – 66 . OpenUrl CrossRef PubMed Web of Science
  • Hjalmarson A ,
  • Herlitz J ,
  • Holmberg S , et al
  • MIAMI Trial Research Group . Metoprolol in Acute Myocardial Infarction (MIAMI). A randomized placebo-controlled international trial . Eur Heart J 1985 ; 6 : 199 – 226 . OpenUrl Abstract / FREE Full Text
  • Lopressor Intervention Trial Research Group . Multicentre study of metoprolol in survivors of acute myocardial infarction . Eur Heart J 1987 ; 8 : 1056 – 64 . OpenUrl Abstract / FREE Full Text
  • Raval U , et al
  • Poole-Wilson PA ,
  • Swedberg K ,
  • Cleland JG , et al

Contributors JJD conceived the manuscript, performed the literature review and wrote parts of the paper. HF, AKN and DSB wrote parts of the manuscript and contributed select citations. SC, FD, EC, GB-Z, DSB and JHO reviewed and edited the manuscript.

Competing interests CJL has served as a consultant and speaker for GlaxoSmithKline (but not regarding β-blockers) and JHO has been a speaker for GlaxoSmithKline and Forest Pharmaceuticals. DSB has been a consultant for GlaxoSmithKline but not in the past 8 years.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement No additional data are available.

Read the full text or download the PDF:

Literature Review of Type 2 Diabetes Management and Health Literacy

Affiliation.

  • 1 Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA.
  • PMID: 34866874
  • PMCID: PMC8603116
  • DOI: 10.2337/ds21-0014

Objective: The purpose of this literature review was to identify educational approaches addressing low health literacy for people with type 2 diabetes. Low health literacy can lead to poor management of diabetes, low engagement with health care providers, increased hospitalization rates, and higher health care costs. These challenges can be even more profound among minority populations and non-English speakers in the United States.

Methods: A literature search and standard data extraction were performed using PubMed, Medline, and EMBASE databases. A total of 1,914 articles were identified, of which 1,858 were excluded based on the inclusion criteria, and 46 were excluded because of a lack of relevance to both diabetes management and health literacy. The remaining 10 articles were reviewed in detail.

Results: Patients, including ethnic minorities and non-English speakers, who are engaged in diabetes education and health literacy improvement initiatives and ongoing follow-up showed significant improvement in A1C, medication adherence, medication knowledge, and treatment satisfaction. Clinicians considering implementing new interventions to address diabetes care for patients with low health literacy can use culturally tailored approaches, consider ways to create materials for different learning styles and in different languages, engage community health workers and pharmacists to help with patient education, use patient-centered medication labels, and engage instructors who share cultural and linguistic similarities with patients to provide educational sessions.

Conclusion: This literature review identified a variety of interventions that had a positive impact on provider-patient communication, medication adherence, and glycemic control by promoting diabetes self-management through educational efforts to address low health literacy.

© 2021 by the American Diabetes Association.

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Treatment of Hypertension : A Review

  • 1 Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville
  • 2 Division of General Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, New York
  • 3 Departments of Epidemiology and Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana
  • Original Investigation Antihypertensive Medication Reduction vs Usual Care in Short-term Blood Pressure Control James P. Sheppard, PhD; Jenni Burt, PhD; Mark Lown, MRCGP; Eleanor Temple, BSc; Rebecca Lowe, BSc; Rosalyn Fraser, MSc; Julie Allen, BSc; Gary A Ford, MB, BChir; Carl Heneghan, DPhil; F. D. Richard Hobbs, MBChB; Sue Jowett, PhD; Shahela Kodabuckus, MSc; Paul Little, MD; Jonathan Mant, MD; Jill Mollison, PhD; Rupert A. Payne, MRCGP; Marney Williams, BEd; Ly-Mee Yu, DPhil; Richard J. McManus, PhD; for the OPTIMISE Investigators JAMA
  • Original Investigation Trends in Blood Pressure Control Among US Adults With Hypertension, 1999-2000 to 2017-2018 Paul Muntner, PhD; Shakia T. Hardy, PhD; Lawrence J. Fine, MD; Byron C. Jaeger, PhD; Gregory Wozniak, PhD; Emily B. Levitan, ScD; Lisandro D. Colantonio, MD, PhD JAMA
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  • US Preventive Services Task Force USPSTF Recommendation: Screening for Hypertension in Adults US Preventive Services Task Force; Alex H. Krist, MD, MPH; Karina W. Davidson, PhD, MASc; Carol M. Mangione, MD, MSPH; Michael Cabana, MD, MA, MPH; Aaron B. Caughey, MD, PhD; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; Chyke A. Doubeni, MD, MPH; Martha Kubik, PhD, RN; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Lori Pbert, PhD; Michael Silverstein, MD, MPH; James Stevermer, MD, MSPH; Chien-Wen Tseng, MD, MPH, MSEE; John B. Wong, MD JAMA
  • US Preventive Services Task Force USPSTF Review: Screening for Hypertension in Adults Janelle M. Guirguis-Blake, MD; Corinne V. Evans, MPP; Elizabeth M. Webber, MS; Erin L. Coppola, MPH; Leslie A. Perdue, MPH; Meghan Soulsby Weyrich, MPH JAMA
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  • JAMA Insights Management of Chronic Hypertension During Pregnancy Suchitra Chandrasekaran, MD, MSCE; Martina L. Badell, MD; Denise J. Jamieson, MD, MPH JAMA
  • Original Investigation Dual Combination Therapies in Treatment of Hypertension in a Multinational Cohort Yuan Lu, ScD; Mui Van Zandt, BS; Yun Liu, PhD; Jing Li, MS; Xialin Wang, MS; Yong Chen, PhD; Zhengfeng Chen, MBBS, MMed; Jaehyeong Cho, PhD; Sreemanee Raaj Dorajoo, PhD; Mengling Feng, PhD; Min-Huei Hsu, MD, PhD; Jason C. Hsu, PhD; Usman Iqbal, PharmD, MBA, PhD; Jitendra Jonnagaddala, PhD; Yu-Chuan Li, MD, PhD; Siaw-Teng Liaw, MBBS, PhD; Hong-Seok Lim, MD, PhD; Kee Yuan Ngiam, MBBS, MMed; Phung-Anh Nguyen, PhD; Rae Woong Park, MD, PhD; Nicole Pratt, PhD; Christian Reich, MD, PhD; Sang Youl Rhee, MD; Selva Muthu Kumaran Sathappan, MSc; Seo Jeong Shin, PhD; Hui Xing Tan, MTech; Seng Chan You, MD, PhD; Xin Zhang, MS; Harlan M. Krumholz, MD, SM; Marc A. Suchard, MD, PhD; Hua Xu, PhD JAMA Network Open
  • Original Investigation Lifestyle Coaching vs Enhanced Pharmacotherapy Among Black Adults With Hypertension Mai N. Nguyen-Huynh, MD, MAS; Joseph D. Young, MD; Bruce Ovbiagele, MD; Janet G. Alexander, MSPH; Stacey Alexeeff, PhD; Catherine Lee, PhD; Noelle Blick, MPH; Bette J. Caan, DrPH; Alan S. Go, MD; Stephen Sidney, MD, MPH JAMA Network Open

Importance   Hypertension, defined as persistent systolic blood pressure (SBP) at least 130 mm Hg or diastolic BP (DBP) at least 80 mm Hg, affects approximately 116 million adults in the US and more than 1 billion adults worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (coronary heart disease, heart failure, and stroke) and death.

Observations   First-line therapy for hypertension is lifestyle modification, including weight loss, healthy dietary pattern that includes low sodium and high potassium intake, physical activity, and moderation or elimination of alcohol consumption. The BP-lowering effects of individual lifestyle components are partially additive and enhance the efficacy of pharmacologic therapy. The decision to initiate antihypertensive medication should be based on the level of BP and the presence of high atherosclerotic CVD risk. First-line drug therapy for hypertension consists of a thiazide or thiazidelike diuretic such as hydrochlorothiazide or chlorthalidone, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker such as enalapril or candesartan, and a calcium channel blocker such as amlodipine and should be titrated according to office and home SBP/DBP levels to achieve in most people an SBP/DBP target (<130/80 mm Hg for adults <65 years and SBP <130 mm Hg in adults ≥65 years). Randomized clinical trials have established the efficacy of BP lowering to reduce the risk of CVD morbidity and mortality. An SBP reduction of 10 mm Hg decreases risk of CVD events by approximately 20% to 30%. Despite the benefits of BP control, only 44% of US adults with hypertension have their SBP/DBP controlled to less than 140/90 mm Hg.

Conclusions and Relevance   Hypertension affects approximately 116 million adults in the US and more than 1 billion adults worldwide and is a leading cause of CVD morbidity and mortality. First-line therapy for hypertension is lifestyle modification, consisting of weight loss, dietary sodium reduction and potassium supplementation, healthy dietary pattern, physical activity, and limited alcohol consumption. When drug therapy is required, first-line therapies are thiazide or thiazidelike diuretics, angiotensin-converting enzyme inhibitor or angiotensin receptor blockers, and calcium channel blockers.

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Carey RM , Moran AE , Whelton PK. Treatment of Hypertension : A Review . JAMA. 2022;328(18):1849–1861. doi:10.1001/jama.2022.19590

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  • Published: 01 May 2022

Interventions in hypertension: systematic review and meta-analysis of natural and quasi-experiments

  • Tong Xia   ORCID: orcid.org/0000-0001-7136-8361 1 ,
  • Fan Zhao   ORCID: orcid.org/0000-0002-1261-5841 1 &
  • Roch A. Nianogo   ORCID: orcid.org/0000-0001-5932-6169 1 , 2  

Clinical Hypertension volume  28 , Article number:  13 ( 2022 ) Cite this article

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Hypertension is an urgent public health problem. Consistent summary from natural and quasi-experiments employed to evaluate interventions that aim at preventing or controlling hypertension is lacking in the current literature. This study aims to summarize the evidence from natural and quasi-experiments that evaluated interventions used to prevent or control hypertension.

We searched PubMed, Embase and Web of Science for natural and quasi-experiments evaluating interventions used to prevent hypertension, improve blood pressure control or reduce blood pressure levels from January 2008 to November 2018. Descriptions of studies and interventions were systematically summarized, and a meta-analysis was conducted.

Thirty studies were identified, and all used quasi-experimental designs including a difference-in-difference, a pre-post with a control group or a propensity score matching design. Education and counseling on lifestyle modifications such as promoting physical activity (PA), promoting a healthy diet and smoking cessation consultations could help prevent hypertension in healthy people. The use of computerized clinical practice guidelines by general practitioners, education and management of hypertension, the screening for cardiovascular disease (CVD) goals and referral could help improve hypertension control in patients with hypertension. The educating and counseling on PA and diet, the monitoring of patients’ metabolic factors and chronic diseases, the combination of education on lifestyles with management of hypertension, the screening for economic risk factors, medical needs, and CVD risk factors and referral all could help reduce blood pressure. In the meta-analysis, the largest reduction in blood pressure was seen for interventions which combined education, counseling and management strategies: weighted mean difference in systolic blood pressure was − 5.34 mmHg (95% confidence interval [CI], − 7.35 to − 3.33) and in diastolic blood pressure was − 3.23 mmHg (95% CI, − 5.51 to − 0.96).

Conclusions

Interventions that used education and counseling strategies; those that used management strategies; those that used combined education, counseling and management strategies and those that used screening and referral strategies were beneficial in preventing, controlling hypertension and reducing blood pressure levels. The combination of education, counseling and management strategies appeared to be the most beneficial intervention to reduce blood pressure levels.

Cardiovascular diseases (CVD) represent the leading cause of death, accounting for one in three deaths in the United States (US) and worldwide [ 1 , 2 , 3 ]. One of their most potent risk factors, hypertension (also known as high blood pressure), is a common risk factor for CVD [ 3 , 4 ]. Approximately 40% of adults aged 25 and over had elevated blood pressure in 2008 [ 3 ]. What is more, hypertension is responsible for at least 45% of deaths due to heart diseases and 51% of deaths due to stroke worldwide [ 3 , 4 ]. In the US alone, the direct medical and indirect expenses from CVDs were estimated at approximately $329 billion in 2013 to 2014 [ 5 ]. Effective large-scale interventions to prevent or treat hypertension are therefore urgently needed to reverse this trend. Yet, as new and promising interventions are surfacing every day, the need for rigorous evaluation of these interventions to inform evidence-based policies and clinical practice is ever growing.

To this effect, several randomized clinical trials (RCT) have been conducted to evaluate interventions used to prevent hypertension or improve its control [ 6 , 7 , 8 ]. However, although RCTs represent the gold standard for evaluating the efficacy (i.e., impact under ideal conditions) of most health interventions because of their high internal validity [ 9 , 10 ], they are not always feasible, appropriate or ethical for the evaluation of certain types of interventions. Furthermore, results from RCTs are not always generalizable to populations or settings of interest due to the highly selected sample and because the intervention is generally conducted under more stringent conditions ( low external validity ) [ 11 ]. To evaluate the effectiveness of an intervention (i.e., impact under real conditions) and to increase the uptake and implementation of evidence-based health interventions in the communities of interests, other types of experimental designs have been proposed. One such example is natural and quasi-experiments. The terms “natural experiments” and “quasi-experiments” are sometimes used interchangeably. In this study, and as described by others [ 12 ], we will distinguish these two concepts. Natural and quasi-experiments are similar in that, in both cases, there is no randomization of treatments or exposures (i.e., no random assignment). They differ, however, in that, natural experiments are those that involve naturally occurring or unplanned events (e.g., a national policy, new law), while quasi-experiments involve intentional or planned interventions implemented (typically for the purpose of research/evaluation) to change a specific outcome of interest (e.g., a community intervention program). Furthermore, in natural experiments, the investigator does not have control over the treatment assignment whereas in quasi-experiments, the investigator has control over the treatment assignment [ 12 ]. These experiments include difference-in-difference (DID) designs, synthetic controls and regression discontinuity designs to name a few [ 13 , 14 , 15 ].

As utilization of natural and quasi-experiments is increasing in public health and in the biomedical field [ 13 , 14 , 15 ], more natural and quasi-experiments are being conducted to evaluate interventions targeted to prevent or control hypertension [ 16 , 17 , 18 , 19 ]. This could be due to recent development or the reframing of classical approaches for determining causality in natural and quasi- experiments [ 13 , 14 , 15 , 20 ]. However, unlike RCTs of interventions aiming to prevent hypertension or improve its control [ 6 , 7 , 8 ], consistent summary and synthesis of evidence from natural and quasi- experiments is lacking in the current literature. The primary aim of the current systematic review is to summarize the evidence from natural and quasi-experiments that have evaluated interventions used to prevent, control hypertension or reduce blood pressure levels. A secondary aim of this study is to conduct a meta-analysis to summarize intervention effectiveness.

Data sources and strategy

We searched PubMed, Embase and Web of Science from January 2008 to November 2018. This time frame was selected to encompass studies that would have likely benefited from recent development and improvement in natural and quasi- experiments [ 13 , 20 ]. Briefly, the search strategy consisted in intersecting keywords related to the study methods (e.g., natural experiments, quasi-experiments, DID, synthetic control, interrupted time series, etc.) with the environment or settings (e.g., community, nation, organization, etc.) and the outcome (e.g., hypertension, elevated blood pressure, etc.). The full search strategy is described in Table S 1 . This systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement [ 21 ] (Fig. 1 ).

figure 1

Study search and selection flow

Study selection

Two trained members (TX, FZ) screened abstracts and full-text articles. Disagreements were decided by a third member (RN). We included studies that used natural and quasi-experiments to evaluate interventions aimed at preventing hypertension, controlling hypertension or reducing blood pressure levels. The outcome measures were prevalence of hypertension and changes in mean blood pressure. Studies were excluded if they were not in English, were not a natural experiment or a quasi-experimental design, did not include a control group (as it has higher risk to internal validity due to the absence of comparison to adjust for time trends and confounding) [ 22 ], did not include blood pressure or hypertension as their outcome or included participants that were 13 years old or younger. In addition, we excluded studies that were not original research articles (e.g., study protocol, books, commentary, dissertations, conference proceedings, comments, systematic reviews, modeling and simulation studies), or had no full text available.

Data extraction and quality assessment

The following information was extracted: study design, sample size, study duration, data source, geographic location, participants’ socio-demographic characteristics, intervention types, intervention levels (e.g., individuals, community, school, clinic and national levels as suggested by the socio-ecological model [ 23 ]), behavior targeted and outcome measures (prevalence of hypertension or mean blood pressure change) (Table 1 , Table S 2 ).

The interventions were classified by strategies into four types:

Education and counseling: This subcategory includes strategies that aim at educating and providing knowledge and counseling to participants on lifestyle modifications (e.g., increasing physical activity (PA), eating better, avoiding or stopping smoking, etc.).

Management: This subcategory includes strategies that aim at monitoring patients’ metabolic factors and chronic diseases (e.g., blood pressure, cholesterol level, etc.) as well as patients’ adherence to medication. These strategies are generally done or facilitated by physicians, general practitioners (e.g., by assessing computerized clinical guidelines in the electronic health record management system), nurses, other staffs, or patients themselves.

Education, counseling and management: This subcategory combines education and counseling strategies with management strategies as described above.

Screening and referral for management: This subcategory includes strategies that aim at screening for (i.e., checking for the presence of) economic risk factors, medical needs, and CVD risk factors, followed by the referral of participants who screened positive to professionals who specialize in the management of those needs.

We also classified the interventions by settings into (1) community level; (2) health center level (i.e., primary care center or general practices), (3) organization level and (4) nationwide. In addition, we have classified the intervention by duration of the study into short-term (i.e., participants were followed for less than 12 months) and long-term (i.e., participants were followed for longer than or equal to 12 months).

We implemented the Cochrane Risk of Bias Tool for risk of bias and used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to assess the quality of the evidence for mean blood pressure change outcome [ 50 ], since the meta-analysis focused on this outcome. The risk of bias for studies included in this review could be found in Table S 3 and the quality of studies has also been summarized in Table S 4 .

Meta-analysis

To summarize the effectiveness of interventions on mean blood pressure changes, we also conducted a meta-analysis. Due to the high heterogeneity in the studies and interventions, we undertook a random-effects model and only summarized the effectiveness of intervention strategies by subgroup defined by intervention types, settings and duration. We estimated the weighted mean difference (WMD) of blood pressure and 95% confidence intervals (CIs). The studies included in the meta-analysis were only those whose outcomes were mean differences (MDs) in blood pressure ( n = 27) [ 16 , 19 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ] as these studies provided the data needed for performing the meta-analysis. Three studies [ 38 , 39 , 43 ] were excluded as they did not provide enough information to compute the standard errors (SEs). To estimate the average effect of the intervention when not directly provided, we subtracted the before-and-after change in the intervention group from that in the control group or subtracted the intervention-to-control difference at follow-up to that at baseline (pre-post design with a control group). Methods to calculate intervention impact and SEs were outlined in the appendix (Figs. S 1 , S 2 , Table S 5 ).

We presented the meta-analysis results using forest plots (Table 2 , Fig. 2 , Figs. S 3 , S 4 ). We assessed the heterogeneity by using the I 2 (Table 2 , Fig. 2 , Figs. S 3 , S 4 ). We did not perform meta-regression as it is not recommended when the number of studies is small (< 10 studies per covariate) [ 51 ]. We assessed publication bias by using funnel plots of SEs (Figs. S 5 , S 6 , S 7 ). To test the robustness of our results, we performed sensitivity analyses by removing one study at a time from the pool of studies to assess its impact on the findings (Tables S 6  , S 7 , S 8 , Figs. S 8 , S 9 , S 10 ). Data were analyzed with Stata 15.1 (StataCorp LLC, College Station, TX, USA).

figure 2

Forest plot stratified by intervention types for blood pressure. A Forest plot stratified by intervention types for systolic blood pressure (SBP). B Forest plot stratified by intervention types for diastolic blood pressure (DBP)

Overall, 788 titles of potentially relevant studies were identified and screened. In total, 545 were excluded and 243 full papers were retrieved, then 30 studies were included in the final sample ( Fig. 1 ) .

Study characteristics

Of the 30 studies included in this review [ 16 , 17 , 18 , 19 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ], three studies reported changes in hypertension prevalence, among which one study reported preventing hypertension in the general population [ 24 ] and two studies reported blood pressure control in patients with hypertension [ 17 , 18 ]; 25 studies reported mean blood pressure changes [ 16 , 19 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]; two studies reported both outcome measures (changes in hypertension prevalence and mean blood pressure changes) [ 25 , 26 ]. Thirteen studies used education and counseling intervention strategies [ 24 , 25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]; four studies used management intervention strategies [ 18 , 19 , 38 , 39 ]; seven studies combined education, counseling and management intervention strategies [ 26 , 40 , 41 , 42 , 43 , 44 , 45 ]; and six studies used screening and referral for management intervention strategies [ 16 , 17 , 46 , 47 , 48 , 49 ]. Fourteen studies followed participants for less than 12 months (i.e., short-term interventions) [ 17 , 26 , 27 , 29 , 30 , 32 , 33 , 34 , 36 , 40 , 41 , 42 , 43 , 45 ]. Twelve studies were conducted in the US [ 16 , 17 , 19 , 24 , 27 , 28 , 32 , 33 , 39 , 41 , 43 , 46 ] and most studies included both genders [ 16 , 17 , 18 , 19 , 24 , 25 , 26 , 28 , 29 , 30 , 31 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ] and all racial/ethnic groups [ 16 , 17 , 18 , 19 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. We found no natural experiments according to the definition used in this study (Table 1 , Table S 2 ).

Quality ratings

According to the Cochrane Risk of Bias Tool, most studies included in this review were found to have a high risk of bias ( Table S 3 ). This was so because the Cochrane Risk of Bias Tool was mostly designed for RCTs. Studies included in this review only used quasi-experiment designs and as such did not use randomization, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment. Using the GRADE approach, the quality of evidence was deemed of low quality for the mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) change outcome (Table S 4 ).

Studies that reported prevalence of hypertension in the general population or changes in the prevalence of controlled blood pressure in hypertension patients after intervention

Outcome of interest: prevention of hypertension in healthy people, education and counseling intervention strategies.

Two studies evaluated the education and counseling intervention strategies, and both found that those strategies could help prevent hypertension in healthy people [ 24 , 25 ]. One study in the US found that nutritional education and giving access to fruits and vegetables through community gardens helped reduce hypertension prevalence (61.0% vs. 45.0%; P < 0.01), whereas the prevalence of hypertension in the control group did not change (46.7% vs. 49.8%; P = 0.39) [ 24 ]. The other study in Africa showed that an education strategy which promoted PA and healthy diet and combined with free smoking cessation consultations could help reduce the prevalence of hypertension (22.8% vs. 16.2%; P = 0.01), compared to that in control group (14.0% vs. 15.1%; P = 0.52) [ 25 ].

Outcome of interest: improvement of hypertension control in patients with hypertension

Management intervention strategies.

A study in the US showed that patients whose general practitioners accessed the computerized clinical practice guideline at least twice a day improved their hypertension control compared to the patients whose general practitioners never accessed the computerized clinical practice guideline ( P < 0.001) [ 18 ].

Education, counseling and management intervention strategies

A study in the US found that patients who received education about hypertension and did home blood pressure monitoring had a better control of their hypertension compared to the control group ( P = 0.03) [ 26 ].

Screening and referral for management intervention strategies

A study in the US showed that for White patients, interventions which involved a coordinator who identified and reached out to patients not meeting CVD goals and linked them to management programs could improve the odds of blood pressure control (odds ratio, 1.13; 95% CI, 1.05 to 1.22) compared to no intervention [ 17 ].

Studies that reported mean blood pressure changes after intervention

Outcome of interest: reduction in mean blood pressure.

Seven [ 25 , 27 , 28 , 29 , 30 , 34 , 35 ] of twelve [ 25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ] (58.3%) studies showed that the education and counseling intervention strategies could help reduce mean blood pressure compared to the control group. Education and counseling interventions targeting lifestyle modifications (e.g., diet and PA) have been found effective in reducing blood pressure in the workplace. A study in US female nursing assistants found that combining education and continuing motivation (e.g., counseling on questions of interventions and receiving feedback) on diet and PA led to more reduction in DBP compared to the control group who only received the education (MD, − 6.70 mmHg; 95% CI, − 13.35 to − 0.05) [ 27 ]. Two other studies also found that multi-component lifestyle interventions in the workplace including sharing health information by messages, putting up posters, using pedometers, and giving education on PA could help healthy employees or employees with hypertension lower blood pressure [ 28 , 29 ]. Besides the workplace, interventions implemented in a community setting also appeared to work in reducing blood pressure. A study that included participants age 55 years or more in Asia found that people who attended 60-min Tai Chi three times per week for 12 weeks had a larger reduction in SBP (MD, − 14.30 mmHg; 95% CI, − 19.20 to − 9.40) and in DBP (MD, − 7.02 mmHg; 95% CI, − 10.62 to − 3.42) compared to people maintaining usual daily activities [ 30 ]. Another study among patients with hypertension in Asia found that education about the nutritional behavior and guidelines from dietary approaches to stop hypertension (DASH) approach could help reduce blood pressure more in the intervention group compared to the control group who only received the instruction booklets used in intervention group (SBP: MD, − 13.50 mmHg; 95% CI, − 16.15 to − 10.85; DBP: MD, − 6.60 mmHg; 95% CI, − 8.17 to − 5.03) [ 34 ]. One study in Africa also showed that education on promoting PA and healthy diet, combined with free smoking cessation consultations could help reduce SBP in the intervention group [ 25 ].

Two [ 19 , 39 ] of three [ 19 , 38 , 39 ] (66.7%) studies showed that the management intervention strategies could help reduce mean blood pressure compared to the control group. A study in the US showed that supporting diabetes patients’ self-management of hypertension by team-based chronic models (e.g., proactive patient outreach, depression screening, and health coaching) could decrease more DBP over a 6-month period compared to the usual care (MD, − 1.13 mmHg; 95% CI, − 2.23 to − 0.04) [ 19 ]. A study among hypertension patients in Asia showed that improving the social health insurance system by increasing outpatient expenditure reimbursement ratio could help reduce more SBP (MD, − 2.9 mmHg; P = 0.01) compared to outpatient expense not covered [ 38 ]. The other study among diabetes patients in the US also showed that team-based treatment with trained staff on medical management and self-management helped lower SBP (MD, − 0.88 mmHg; P = 0.01), but it did not compare the MD between treatment and control group [ 39 ].

Six [ 26 , 40 , 42 , 43 , 44 , 45 ] of seven [ 26 , 40 , 41 , 42 , 43 , 44 , 45 ] (85.7%) studies showed that the combination of education, counseling and management intervention strategies led to more blood pressure reduction compared to the control group. One study among hypertension patients in Europe found that management of stress by biofeedback-assisted relaxation and lifestyle counseling on diet and PA reduced more SBP (MD, − 2.62 mmHg; 95% CI, − 3.96 to − 1.29) and DBP (MD, − 1.00 mmHg; 95% CI, − 1.90 to − 0.93) compared to the control group [ 40 ]. One study among hypertension patients in the US also found that education about hypertension and home blood pressure monitoring could help reduce more SBP (MD, − 4.70 mmHg; 95% CI, − 7.14 to − 2.26) and DBP (MD, − 2.20 mmHg; 95% CI, − 3.80 to − 0.60) compared to controls [ 26 ]. A study among 65-year-and-older hypertension patients in Asia found that the intervention group who received education on hypertension management, community-based eHealth monitoring, and monthly telephone counseling had more reduction in SBP (MD, − 10.80 mmHg; 95% CI, − 14.99 to − 6.61) compared to the control group who only received a poster about hypertension management [ 42 ]. A study among hypertension patients in the US also showed that interventions on lifestyle modifications, and nutritional, pharmacological therapies as well as medication adherence lowered SBP and DBP compared to the control group [ 43 ]. A study among hypertension patients in Asia found that integration of preventive-curative services delivery and cooperation among village-town-county physicians for education on lifestyle modifications, taking blood pressure drugs regularly and monitoring the blood pressure could help reduce blood pressure more in the intervention group [ 44 ]. The other study in Asia also found that integrated program with health education on home blood pressure monitoring and hypertension measurement skills could help reduce blood pressure more in the intervention group [ 45 ].

Four [ 16 , 46 , 47 , 48 ] of five [ 16 , 46 , 47 , 48 , 49 ] (80.0%) studies showed that the screening and referral for management intervention strategies could help reduce more blood pressure compared to the control group. Screening for medical or economic needs followed by offering treatment and resources has been found helpful. One study in the US found that screening for unmet needs in primary care and offering those who screened positive some resources could reduce SBP (MD, − 2.6 mmHg; 95% CI, − 3.5 to − 1.7]) and DBP (MD, − 1.4 mmHg; 95% CI, − 1.9 to − 0.9) in patients [ 16 ]. The other study among patients with serious mental illness in the US also found that using registry for general medical needs and outcomes, screening and referral for general medical illness prevention and treatment could help reduce more DBP compared to controls (MD, − 3.00 mmHg; 95% CI, − 4.96 to − 1.04) [ 46 ]. Assessing and screening CVD risk followed by a management program has also been found beneficial to reduce blood pressure. A study in Europe showed that participating in CVD risk assessment and management program, including screening and tailored strategies for lifestyle advice on CVD risk factors could reduce more SBP (MD, − 2.51 mmHg; 95% CI, − 2.77 to − 2.25) and DBP (MD, − 1.46 mmHg; 95% CI, − 1.62 to − 1.29) compared to controls [ 47 ]. A study among hypertension patients in Asia also found that a standardized CVD-risk assessment, a hypertension complication screening and adherence to medications could help reduce more blood pressure compared to the usual care [ 48 ].

Meta-analysis of the effectiveness of interventions on mean blood pressure change

Intervention type sub-group analysis.

The largest blood pressure reduction (SBP: WMD, − 5.34 mmHg; 95% CI, − 7.35 to − 3.33; DBP: WMD, − 3.23 mmHg; 95% CI, − 5.51 to − 0.96) was seen for interventions that combined education, counseling and management intervention strategies (Table 2 , Fig. 2 ).

Intervention setting sub-group analysis

Participants who experienced interventions implemented in community settings (WMD, − 3.77 mmHg; 95% CI, − 6.17 to − 1.37) and in health center settings (WMD, − 3.77 mmHg; 95% CI, − 5.78 to − 1.76) had large SBP reduction. Participants experienced interventions implemented in organization settings had large DBP reduction (WMD, − 3.92 mmHg; 95% CI, − 5.80 to − 2.04) (Table 2 , Fig. S 3 ).

Intervention duration sub-group analysis

Participants who were followed for less than 12 months (i.e., short-term interventions) had a large reduction in blood pressure (SBP: WMD, − 6.25 mmHg; 95% CI, − 9.28 to − 3.21; DBP: WMD, − 3.54 mmHg; 95% CI, − 5.21 to − 1.87) and participants who were followed for longer than or equal to 12 months (i.e., long-term interventions) had a moderate reduction in blood pressure (SBP: WMD, − 1.89 mmHg; 95% CI, − 2.80 to − 0.97; DBP: WMD, − 1.33 mmHg; 95% CI, − 2.11 to − 0.55) (Table 2 , Fig. S 4 ).

We summarized the evidence from quasi-experiments that have evaluated interventions used to (1) prevent hypertension in the general population, (2) improve hypertension control in patients with hypertension or (3) reduce blood pressure levels in both the general population and patients.

In this systematic review, we found that the intervention strategies such as (1) education and counseling, (2) management, (3) education, counseling and management and (4) screening and referral for management were beneficial in preventing, controlling hypertension or reducing blood pressure levels. In particular, we found that education and counseling on lifestyle modifications (i.e., promoting PA, healthy diet, smoking cessation consultations) could help prevent hypertension in healthy people. The use of computerized clinical practice guidelines by general practitioners, education and management of hypertension, screening for CVD goals and referral to management could help improve hypertension control in patients with hypertension. The education and counseling on lifestyle modifications, the monitoring of patients’ metabolic factors and chronic diseases (e.g., blood pressure, cholesterol level, etc.) as well as patients’ adherence to medication, the combined education and management of hypertension, the screening for economic risk factors, medical needs, and CVD risk factors, followed by the referral to management all could help reduce blood pressure levels. Our study is one of the few systematic reviews that have summarized the evidence from quasi-experiments on hypertension prevention and control. A previous systematic review [ 52 ] which summarized evidence from cluster-randomized trials and quasi-experimental studies had been conducted and found that education, counseling and management strategies were also beneficial in controlling hypertension and reducing blood pressure. It showed that educating healthcare providers and patients, facilitating relay of clinical data to providers, promoting patients’ accesses to resources were associated with improved hypertension control and decreased blood pressure [ 52 ]. Another systematic review which summarized evidence from RCTs found that several interventions including blood pressure self-monitoring, educational strategies, improving the delivery of care, and appointment reminder systems could help control hypertension and reduce blood pressure [ 6 ]. Another study also found that community-based health workers interventions including health education and counseling, navigating the health care system, managing care, as well as giving social services and support had a significant effect on improving hypertension control and decreasing blood pressure [ 53 ]. A review from observational studies and RCT evidence from the US Preventive Services Task Force found that office measurement of blood pressure could effectively screen adults for hypertension [ 7 ].

Our review did not find natural experiments studies according to the definition used in this study. Quasi-experimental designs included DID, propensity score matching and pre-post designs with a control group (PPCG). While PPCG designs generally involve two groups (intervention and control) and two different time points (before and after the intervention), DID designs generally involve two or more intervention and control groups and multiple time points [ 13 ]. In this review, we did not include pre-post without a control group design because of its higher risk to internal validity due to the absence of comparison to adjust for time trends and confounding [ 22 ]. The findings in this review, highlight that, quasi-experiments are increasingly used to evaluate the effectiveness of health interventions for hypertension management when RCTs are not feasible or appropriate. For instance, several studies included in our systematic review often indicated that RCTs would have been difficult to be implemented given that the intervention was conducted in a particular setting such as a pragmatic clinical setting [ 16 , 43 , 45 , 48 ], a community setting [ 24 , 35 , 36 , 42 ], or a real-world organizational setting [ 33 ] because of ethical concerns and human resources issues. Another reason why quasi-experiments were chosen had to do with the need for translation and generalizability of the evidence in a specific community setting [ 32 ]. In fact, RCTs are not always generalizable to the communities or settings of interests [ 11 ]. The growing interest in and hence the increase in the use of natural and quasi-experiments in public health may be due to the recognition and realization of its usefulness in evaluating health interventions [ 14 , 54 ].

Given that there was high heterogeneity in the studies included in this systematic review, we have performed a random effects model and have only presented the subgroup analysis by intervention types, settings and duration of the study. Overall, our study suggested that interventions that combined education, counseling and management strategies appeared to show a relatively large beneficial effect for reducing blood pressure. However, our finding should be interpreted with caution due to the high-risk of bias and lower quality of evidence given the quasi-experimental nature of the designs (as opposed to evidence from randomized experiments). Nevertheless, the findings here can give us some insights on the benefit of interventions such as education, counseling and management, especially given that our findings are in line with previous studies [ 6 , 8 , 52 , 55 ]. Given that RCTs are not always feasible or appropriate, scientists should develop more rigorous methods to increase the internal validity of non-randomized studies. Compared to previous studies, one systematic review with meta-analysis including cluster-randomized trials and quasi-experiment studies showed that multi-component interventions which incorporated education of health care providers and patients, facilitating relay of clinical data to providers, and promoting patients’ accesses to resources could reduce more blood pressure compared to controls [ 52 ]. A recent systematic review with meta-analysis of RCTs also reported that interventions which included blood pressure self-monitoring, appointment reminder systems, educational strategies, and improving the delivery of care showed beneficial effects on lowering blood pressure [ 6 ]. Another systematic review and meta-analysis of RCTs also showed that self-measured blood pressure monitoring lowered SBP by 3.9 mmHg and DBP by 2.4 mmHg at 6 months compared to the usual care group [ 8 ]. One systematic review and meta-analysis of RCTs found that diet improvement, aerobic exercise, alcohol and sodium restriction, and fish oil supplements reduced blood pressure as well [ 55 ].

Limitations

This review has some limitations. First, the definition of natural and quasi-experiments is not consistent across fields. Second, the main limitation in most if not all the quasi-experimental study designs noted in this review was the potential for unobserved and uncontrolled confounding, which is a threat to internal validity and could lead to biased findings. Third, our findings may not be generalizable to all countries and settings as we only included studies published in the English language in this review. Fourth, as is the case in most other reviews, we could have missed relevant studies despite our best attempt to conduct a thorough search of the literature. Fifth, we found that most studies included in this study had a high risk of bias. It might be because we used the Cochrane Risk of Bias Tool to assess bias which was designed for examining RCTs. Studies in this review only used quasi-experiment designs and did not have randomization, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment. Sixth, studies generally reported the measure of intervention impact differently across studies, making it difficult to combine the findings. In addition, studies were highly heterogeneous in terms of the types of individuals included in the study (e.g., healthy individuals and patients). We conducted the subgroup meta-analysis to reduce the heterogeneity, but the high heterogeneity still existed. Therefore, the results from meta-analysis need to be interpreted with caution. The individual impact reported for each individual study and the results from systematic review should be given more consideration.

In this systematic review, interventions that used education and counseling strategies; those that used management strategies; those that combined education, counseling and management strategies and those that used screening and referral for management strategies were beneficial in preventing, controlling hypertension and reducing blood pressure levels. The combination of education, counseling and management strategies appeared to be the most beneficial intervention to reduce blood pressure levels. The findings in this review, highlight that, a number of interventions that aim at preventing, controlling hypertension or reducing blood pressure levels are being evaluated through the use of quasi-experimental studies. Given that RCTs are not always feasible or appropriate, scientists should develop more rigorous methods to increase the internal validity of such quasi-experimental studies.

Availability of data and materials

The data supporting the conclusions of this article is included within the article and the additional file.

Abbreviations

Confidence interval

Cardiovascular disease

Dietary approaches to stop hypertension

Diastolic blood pressure

Difference-in-difference

Grading of Recommendations, Assessment, Development, and Evaluation

Mean difference

Physical activity

Pre-post designs with a control group

Randomized clinical trial

Systolic blood pressure

Standard error

United States

Weighted mean difference

National Center for Health Statistics & Heron, M. Deaths: Leading Causes for 2018. Atlanta: CDC; 2021.

Lewington S, Lacey B, Clarke R, Guo Y, Kong XL, Yang L, et al. The burden of hypertension and associated risk for cardiovascular mortality in China. JAMA Intern Med. 2016;176:524–32.

Article   PubMed   Google Scholar  

World Health Organization (WHO). A global brief on hypertension: silent killer, global public health crisis: World Health Day 2013. Geneva: WHO; 2013.

Sun D, Liu J, Xiao L, Liu Y, Wang Z, Li C, et al. Recent development of risk-prediction models for incident hypertension: an updated systematic review. PLoS One. 2017;12:e0187240.

Article   PubMed   PubMed Central   Google Scholar  

Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation. 2018;137:e67–492.

Glynn LG, Murphy AW, Smith SM, Schroeder K, Fahey T. Interventions used to improve control of blood pressure in patients with hypertension. Cochrane Database Syst Rev. 2010;3:CD005182.

Google Scholar  

Sheridan S, Pignone M, Donahue K. Screening for high blood pressure: a review of the evidence for the U.S. preventive services task force. Am J Prev Med. 2003;25:151–8.

Uhlig K, Patel K, Ip S, Kitsios GD, Balk EM. Self-measured blood pressure monitoring in the management of hypertension: a systematic review and meta-analysis. Ann Intern Med. 2013;159:185–94.

de Simone G, Izzo R, Verdecchia P. Are observational studies more informative than randomized controlled trials in hypertension? Pro side of the argument. Hypertension. 2013;62:463–9.

Li DZ, Zhou Y, Yang YN, Ma YT, Li XM, Yu J, et al. Acupuncture for essential hypertension: a meta-analysis of randomized sham-controlled clinical trials. Evid Based Complement Alternat Med. 2014;2014:279478.

Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA. 2004;291:2720–6.

Article   CAS   PubMed   Google Scholar  

Remler DK, Van Ryzin GG. Research methods in practice: strategies for description and causation. 2nd ed. SAGE: Los Angeles; 2014.

Handley MA, Lyles CR, McCulloch C, Cattamanchi A. Selecting and improving quasi-experimental designs in effectiveness and implementation research. Annu Rev Public Health. 2018;39:5–25.

Basu S, Meghani A, Siddiqi A. Evaluating the health impact of large-scale public policy changes: classical and novel approaches. Annu Rev Public Health. 2017;38:351–70.

Craig P, Katikireddi SV, Leyland A, Popham F. Natural experiments: an overview of methods, approaches, and contributions to public health intervention research. Annu Rev Public Health. 2017;38:39–56.

Berkowitz SA, Hulberg AC, Standish S, Reznor G, Atlas SJ. Addressing unmet basic resource needs as part of chronic cardiometabolic disease management. JAMA Intern Med. 2017;177:244–52.

James A, Berkowitz SA, Ashburner JM, Chang Y, Horn DM, O’Keefe SM, et al. Impact of a population health management intervention on disparities in cardiovascular disease control. J Gen Intern Med. 2018;33:463–70.

Comin E, Catalan-Ramos A, Iglesias-Rodal M, Grau M, Del Val JL, Consola A, et al. Impact of implementing electronic clinical practice guidelines for the diagnosis, control and treatment of cardiovascular risk factors: a pre-post controlled study. Aten Primaria. 2017;49:389–98.

Panattoni L, Hurlimann L, Wilson C, Durbin M, Tai-Seale M. Workflow standardization of a novel team care model to improve chronic care: a quasi-experimental study. BMC Health Serv Res. 2017;17:286.

Bor J. Capitalizing on natural experiments to improve our understanding of population health. Am J Public Health. 2016;106:1388–9.

Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

Ho AM, Phelan R, Mizubuti GB, Murdoch JAC, Wickett S, Ho AK, et al. Bias in before-after studies: narrative overview for anesthesiologists. Anesth Analg. 2018;126:1755–62.

Bronfenbrenner U. The ecology of human development: experiments by nature and design. Cambridge: Harvard University Press; 1979.

Barnidge EK, Baker EA, Schootman M, Motton F, Sawicki M, Rose F. The effect of education plus access on perceived fruit and vegetable consumption in a rural African American community intervention. Health Educ Res. 2015;30:773–85.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Sahli J, Maatoug J, Harrabi I, Ben Fredj S, Dendana E, Ghannem H. Effectiveness of a community-based intervention program to reduce hypertension prevalence among adults: results of a quasiexperimental study with control group in the region of Sousse. Tunisia Glob Heart. 2016;11:131–7.

Fikri-Benbrahim N, Faus MJ, Martínez-Martínez F, Alsina DG, Sabater-Hernandez D. Effect of a pharmacist intervention in Spanish community pharmacies on blood pressure control in hypertensive patients. Am J Health Syst Pharm. 2012;69:1311–8.

Flannery K, Resnick B, Galik E, Lipscomb J, McPhaul K, Shaughnessy M. The worksite heart health improvement project (WHHIP): feasibility and efficacy. Public Health Nurs. 2012;29:455–66.

Gemson DH, Commisso R, Fuente J, Newman J, Benson S. Promoting weight loss and blood pressure control at work: impact of an education and intervention program. J Occup Environ Med. 2008;50:272–81.

Lin YP, Lin CC, Chen MM, Lee KC. Short-term efficacy of a “sit less, walk more” workplace intervention on improving cardiometabolic health and work productivity in office workers. J Occup Environ Med. 2017;59:327–34.

Chang MY, Yeh SC, Chu MC, Wu TM, Huang TH. Associations between Tai chi Chung program, anxiety, and cardiovascular risk factors. Am J Health Promot. 2013;28:16–22.

Verberne LD, Hendriks MR, Rutten GM, Spronk I, Savelberg HH, Veenhof C, et al. Evaluation of a combined lifestyle intervention for overweight and obese patients in primary health care: a quasi-experimental design. Fam Pract. 2016;33:671–7.

Xu F, Letendre J, Bekke J, Beebe N, Mahler L, Lofgren IE, et al. Impact of a program of Tai chi plus behaviorally based dietary weight loss on physical functioning and coronary heart disease risk factors: a community-based study in obese older women. J Nutr Gerontol Geriatr. 2015;34:50–65.

Zhu W, Gutierrez M, Toledo MJ, Mullane S, Stella AP, Diemar R, et al. Long-term effects of sit-stand workstations on workplace sitting: a natural experiment. J Sci Med Sport. 2018;21:811–6.

Kamran A, Sharifirad G, Heydari H, Sharifian E. The effect of theory based nutritional education on fat intake, weight and blood lipids. Electron Physician. 2016;8:3333–42.

Ibrahim N, Ming Moy F, Awalludin IA, Mohd Ali Z, Ismail IS. Effects of a community-based healthy lifestyle intervention program (co-HELP) among adults with prediabetes in a developing country: a quasi-experimental study. PLoS One. 2016;11:e0167123.

Kassim MSA, Manaf MRA, Nor NSM, Ambak R. Effects of lifestyle intervention towards obesity and blood pressure among housewives in Klang Valley: a quasi-experimental study. Malays J Med Sci. 2017;24:83–91.

PubMed   PubMed Central   Google Scholar  

Fazliana M, Liyana AZ, Omar A, Ambak R, Mohamad Nor NS, Shamsudin UK, et al. Effects of weight loss intervention on body composition and blood pressure among overweight and obese women: findings from the MyBFF@home study. BMC Womens Health. 2018;18(Suppl 1):93.

Miao Y, Gu J, Zhang L, He R, Sandeep S, Wu J. Improving the performance of social health insurance system through increasing outpatient expenditure reimbursement ratio: a quasi-experimental evaluation study from rural China. Int J Equity Health. 2018;17:89.

Scanlon DP, Hollenbeak CS, Beich J, Dyer AM, Gabbay RA, Milstein A. Financial and clinical impact of team-based treatment for medicaid enrollees with diabetes in a federally qualified health center. Diabetes Care. 2008;31:2160–5.

Darviri C, Artemiadis AK, Protogerou A, Soldatos P, Kranioutou C, Vasdekis S, et al. A HEALth promotion and STRESS management program (HEAL-STRESS study) for prehypertensive and hypertensive patients: a quasi-experimental study in Greece. J Hum Hypertens. 2016;30:397–403.

Fernandez S, Scales KL, Pineiro JM, Schoenthaler AM, Ogedegbe G. A senior center-based pilot trial of the effect of lifestyle intervention on blood pressure in minority elderly people with hypertension. J Am Geriatr Soc. 2008;56:1860–6.

Jung H, Lee JE. The impact of community-based eHealth self-management intervention among elderly living alone with hypertension. J Telemed Telecare. 2017;23:167–73.

Hussain T, Franz W, Brown E, Kan A, Okoye M, Dietz K, et al. The role of care management as a population health intervention to address disparities and control hypertension: a quasi-experimental observational study. Ethn Dis. 2016;26:285–94.

Miao Y, Zhang L, Sparring V, Sandeep S, Tang W, Sun X, et al. Improving health related quality of life among rural hypertensive patients through the integrative strategy of health services delivery: a quasi-experimental trial from Chongqing. China Int J Equity Health. 2016;15:132.

Visanuyothin S, Plianbangchang S, Somrongthong R. An integrated program with home blood-pressure monitoring and village health volunteers for treating poorly controlled hypertension at the primary care level in an urban community of Thailand. Integr Blood Press Control. 2018;11:25–35.

Scharf DM, Schmidt Hackbarth N, Eberhart NK, Horvitz-Lennon M, Beckman R, Han B, et al. General medical outcomes from the primary and behavioral health care integration grant program. Psychiatr Serv. 2016;67:1226–32.

Chang KC, Lee JT, Vamos EP, Soljak M, Johnston D, Khunti K, et al. Impact of the National Health Service Health Check on cardiovascular disease risk: a difference-in-differences matching analysis. CMAJ. 2016;188:E228–38.

Yu EY, Wan EY, Wong CK, Chan AK, Chan KH, Ho SY, et al. Effects of risk assessment and management programme for hypertension on clinical outcomes and cardiovascular disease risks after 12 months: a population-based matched cohort study. J Hypertens. 2017;35:627–36.

van de Vijver S, Oti SO, Gomez GB, Agyemang C, Egondi T, Moll van Charante E, et al. Impact evaluation of a community-based intervention for prevention of cardiovascular diseases in the slums of Nairobi. the SCALE-UP study Glob Health Action. 2016;9:30922.

Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions. 2nd ed. Wiley-Blackwell: Hoboken; 2020.

Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to meta-analysis. Chichester: John Wiley & Sons; 2009.

Book   Google Scholar  

Walsh JM, McDonald KM, Shojania KG, Sundaram V, Nayak S, Lewis R, et al. Quality improvement strategies for hypertension management: a systematic review. Med Care. 2006;44:646–57.

Kim K, Choi JS, Choi E, Nieman CL, Joo JH, Lin FR, et al. Effects of community-based health worker interventions to improve chronic disease management and care among vulnerable populations: a systematic review. Am J Public Health. 2016;106:e3–28.

Rehkopf DH, Basu S. A new tool for case studies in epidemiology-the synthetic control method. Epidemiology. 2018;29:503–5.

Dickinson HO, Mason JM, Nicolson DJ, Campbell F, Beyer FR, Cook JV, et al. Lifestyle interventions to reduce raised blood pressure: a systematic review of randomized controlled trials. J Hypertens. 2006;24:215–33.

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Additional file 1: table s1..

Search words. Table S2. Summary of the characteristics of the studies included in this review ( n = 30). Table S3. Risk of Bias Tool Assessments Across Studies (n = 30). Table S4. GRADE Evidence Profiles Across Studies in Meta-analysis ( n = 24). Table S5. Estimates and parameters in studies that reported on the mean difference in blood pressure ( n = 27). Table S6. Sensitivity analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in meta-analysis stratified by intervention type. Table S7. Sensitivity analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in meta-analysis stratified by intervention setting. Table S8. Sensitivity analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in meta-analysis stratified by intervention duration. Fig. S1. Methods to calculate mean differences (MD). Fig. S2. Methods to calculate standard errors (SE). Fig. S3. Forest plot stratified by intervention settings for blood pressure. (A) Forest plot stratified by intervention settings for systolic blood pressure (SBP). (B) Forest plot stratified by intervention settings for diastolic blood pressure (DBP). Fig. S4. Forest plot stratified by intervention duration for blood pressure. ( A) Forest plot stratified by intervention duration for systolic blood pressure (SBP). ( B) Forest plot stratified by intervention duration for diastolic blood pressure (DBP). Fig. S5. Funnel plot of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention types. Fig. S6. Funnel plot of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention settings. Fig. S7. Funnel plot of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention duration. Fig. S8. Sensitivity analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention types. Fig. S9. Sensitivity analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention settings. Fig. S10. Sensitivity analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention duration

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Xia, T., Zhao, F. & Nianogo, R.A. Interventions in hypertension: systematic review and meta-analysis of natural and quasi-experiments. Clin Hypertens 28 , 13 (2022). https://doi.org/10.1186/s40885-022-00198-2

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Update on Hypertension Research in 2021

  • Masaki Mogi 1 ,
  • Tatsuya Maruhashi 2 ,
  • Yukihito Higashi 2 , 3 ,
  • Takahiro Masuda 4 ,
  • Daisuke Nagata 4 ,
  • Michiaki Nagai 5 ,
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  • Ayumi Toba 8 ,
  • Keisuke Narita 9 ,
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  • Atsushi Tanaka 10 ,
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  • Masanari Kuwabara 13 ,
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In 2021, 217 excellent manuscripts were published in Hypertension Research. Editorial teams greatly appreciate the authors’ contribution to hypertension research progress. Here, our editorial members have summarized twelve topics from published work and discussed current topics in depth. We hope you enjoy our special feature, “Update on Hypertension Research in 2021”.

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Usefulness of vascular function tests for cardiovascular risk assessment and a better understanding of the pathophysiology of atherosclerosis in hypertension (see Supplementary Information  1 )

Vascular function tests and vascular imaging tests are useful for assessing the severity of atherosclerosis. Since vascular dysfunction and vascular morphological alterations are closely associated with the maintenance and progression of atherosclerosis, vascular tests may provide additional information for cardiovascular risk assessment (Fig.  1 ) [ 1 , 2 , 3 , 4 , 5 ]. Measurement of the ankle-brachial index (ABI) has been performed not only for screening for peripheral artery disease but also for cardiovascular risk assessment in clinical practice [ 6 ]. However, the ABI method does not always provide reliable data because the ABI value is falsely elevated despite the presence of occlusive arterial lesions in the lower extremities of patients with noncompressible lower limb arteries, which can lead to incorrect cardiovascular risk assessment [ 7 , 8 , 9 ]. Tsai et al. [ 10 ] reported that a combination of an ABI value <0.9 and an interleg ABI difference ≥0.17 was more useful for predicting all-cause mortality and cardiovascular mortality than was an ABI value <0.9 alone. Therefore, attention should be given not only to the ABI value but also to the interleg ABI difference for more precise cardiovascular risk assessment. Sang et al. [ 11 ] conducted a systematic review and meta-analysis to investigate the usefulness of brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, for risk assessment and showed that higher baPWV was significantly associated with a higher risk of cardiovascular events, cardiovascular mortality, and all-cause mortality in patients with a history of coronary artery disease or stroke.

figure 1

Vascular function tests and vascular imaging tests for the assessment of cardiovascular risk. CV cardiovascular

Vascular tests are also useful to achieve a better understanding of the underlying pathophysiology of cardiac disorders. Harada et al. [ 12 ] reported that short stature defined as height <155.0 cm was associated with low flow-mediated vasodilation (FMD), an index of endothelial function, in Japanese men, supporting the association between short stature and high risk of cardiovascular events [ 13 ]. Cassano et al. [Supplementary Information  1 - 1 ] reported that low levels of endothelial progenitor cells (EPCs) at baseline were associated with impaired endothelial function assessed by the reactive hyperemia index (RHI) and impaired arterial stiffness assessed by carotid-femoral PWV (cfPWV) at baseline and that EPC levels at baseline were also associated with longitudinal changes in RHI and cfPWV three years after the initiation of antihypertensive drug treatment in patients with hypertension. Murai et al. [Supplementary Information  1 - 2 ]. reported that a higher area under the curve value of insulin during a 75-g oral glucose tolerance test, but not insulin sensitivity indices, was significantly associated with higher baPWV in young Japanese subjects aged <40 years. Miyaoka et al. [ 14 ] reported that baPWV and central systolic blood pressure were significantly associated with renal microvascular damage assessed by using renal biopsy specimens in patients with nondiabetic kidney disease. Vila et al. [Supplementary Information  1 - 3 ] reported that carotid intima-media thickness (IMT) was significantly greater in male patients with autoimmune disease than in age-matched male controls without autoimmune disease, supporting a role for immune-mediated inflammation in the pathogenesis of atherosclerosis. Li et al. [Supplementary Information  1 - 4 ] showed in a cross-sectional study that increased carotid IMT was significantly associated with cognitive impairment assessed by the Mini-Mental State Examination in Chinese patients with hypertension, especially patients who were ≥60 years of age and patients with low high-density lipoprotein cholesterol levels (<40 mg/dL).

Vascular function is profoundly affected by habitual behavior. Fryer et al. [Supplementary Information  1 - 5 ] reported that central arterial stiffness and peripheral arterial stiffness assessed by cfPWV and PWV β were more deteriorated by uninterrupted prolonged sitting (180 min) combined with prior high-fat meal consumption (61 g fat, 1066 kcal) than by uninterrupted prolonged sitting combined with prior low-fat meal consumption (10 g fat, 601 kcal) in healthy nonsmoking male subjects, suggesting that high-fat meal consumption should be avoided before uninterrupted prolonged sitting to prevent the progression of arterial stiffening. Yamaji et al. [ 15 ] reported that endothelial function assessed by FMD and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation of the brachial artery were more impaired in patients without daily stair climbing activity than in patients who habitually climbed stairs to the ≥3 rd floor among patients with hypertension. Funakoshi et al. [ 16 ] reported that eating within 2 h before bedtime ≥3 days/week was associated with the development of hypertension defined as blood pressure ≥140/90 mmHg or initiation of antihypertensive drug treatment during an average follow-up period of 4.5 years in the general Japanese population, suggesting that avoiding late dinners may be helpful for preventing the development of hypertension. These findings indicate the importance of lifestyle modifications for maintaining vascular function and preventing the development of hypertension and the progression of atherosclerosis.

(TM and YH)

Keywords : vascular function, endothelial function, arterial stiffness, carotid intimathickness, ankle-brachial index.

Advances in hypertension management for better renal outcomes (See Supplementary Information 2 )

In chronic kidney disease (CKD) patients, hypertension is a risk factor for end-stage renal disease (ESRD), cardiovascular events and mortality. Thus, the prevention and appropriate management of hypertension in CKD patients are important strategies for preventing ESRD and cardiovascular disease (Fig.  2 ).

figure 2

Advantages of hypertension in CKD. CKD chronic kidney disease, GFR glomerular filtration rate, MR mineralocorticoid receptor, SGLT2 sodium–glucose cotransporter 2

Risk factors for hypertension

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that is mainly secreted by the liver. Circulating FGF21 levels are reported to be increased in CKD patients, while higher circulating FGF21 levels were reported to be associated with all-cause mortality in ESRD patients [ 17 , 18 ]. Additionally, Matsui et al. reported that higher circulating FGF21 levels partially mediate the association of elevated BP and/or aortic stiffness with renal dysfunction in middle-aged and older adults [ 19 ]. A study by Funakoshi et al. showed that eating before bed was correlated with the future risk of developing hypertension in the Iki Epidemiological Study of Atherosclerosis and Chronic Kidney Disease [Supplementary Information  2 - 1 ].

Prognostic markers

Several promising prognostic markers for renal and cardiovascular outcomes have been suggested. Matsukuma et al. reported that a higher urinary sodium-to-potassium ratio was independently associated with poor renal outcomes in patients with CKD [Supplementary Information  2 - 2 ]. Chinese hypertensive patients with higher albumin-to-creatinine ratios had a significantly increased risk of first ischemic stroke [Supplementary Information  2 - 3 ]. The number of nephrons in hypertensive patients was significantly lower than that in controls [ 20 ]. Tsuboi et al. suggested the usefulness of methods to estimate the total nephron count and single nephron GFR in living patients, which helped to tailor patient care depending on age or disease stage as well as to predict the response to therapy and the disease outcome [ 21 ].

Mineralocorticoid receptor (MR) blockers (e.g., esaxerenone) are used in the treatment of essential hypertension and hyperaldosteronism. Recently, a new MR antagonist, finerenone, has been introduced as a treatment for CKD patients with type 2 diabetes. However, hyperkalemia has been recognized as a potential side effect during treatment with MR blockers. A recent review article by Rakugi et al. suggested that being aware of at-risk patient groups, choosing appropriate dosages, and monitoring serum potassium during therapy are required to ensure the safe clinical use of these agents [Supplementary Information  2 - 4 ].

The clinical use of sodium–glucose cotransporter-2 inhibitors (SGLT2is) has recently been expanded to nondiabetic patients with CKD and heart failure as well as diabetic patients [ 22 , 23 ]. Several novel findings regarding the renal protective properties of SGTL2is were reported in 2021. In a real-world registry study of Japanese type 2 diabetes patients with CKD, SGLT2is were associated with significantly better kidney outcomes in comparison to other glucose-lowering drugs, irrespective of the presence or absence of proteinuria [ 24 ]. Kitamura et al. reported that the addition of metformin to SGLT2is blunts the decrease in eGFR but that the coadministration of RAS inhibitors ameliorates this response [Supplementary Information  2 - 5 ]. Thomson and Vallon reported that (1) SGLT2i treatment reduces glomerular capillary pressure that is mediated through tubuloglomerular feedback (TGF) and (2) the TGF response to SGLT2is involves preglomerular vasoconstriction and postglomerular vasorelaxation [ 25 ].

SGLT2is have an antihypertensive effect, which is greater in subjects with higher salt sensitivity and BMI [ 26 , 27 , 28 ]. Furthermore, the degree of BP change in patients undergoing SGLT2i therapy depends on the baseline BP; a larger reduction is observed in patients with higher baseline BP, and a smaller reduction or slight increase is observed in patients with lower baseline BP [ 29 ]. These BP regulation mechanisms may partially depend on body fluid homeostasis by SGLT2is. SGLT2is ameliorate fluid retention through osmotic diuresis and natriuresis but are associated with a low rate of hypovolemia [ 30 , 31 , 32 , 33 ], which is evident by the compensatory upregulation of renin and vasopressin levels [ 33 , 34 , 35 ]. These fluid homeostatic mechanisms exerted by SGLT2is may contribute to the stabilization of BP. Moreover, recent clinical studies have shown that SGLT2is reduce BP without changes in urinary sodium and fluid excretion or plasma volume [ 35 , 36 , 37 ], suggesting the role of other factors, such as the inhibition of the sympathetic nervous system, restoration of endothelial function, and reduction of arterial stiffness [ 38 , 39 ].

(TM and DN)

Keywords : fibroblast growth factor 21, nephron number, mineralocorticoid receptor blocker, SGLT2 inhibitor, fluid homeostasis.

Hypertension and heart disease-focusing on the relationship with HFpEF (See Supplementary Information 3 )

With the increasing longevity of ‘Westernized’ populations, heart failure (HF) in the elderly has become a problem of growing scale and complexity worldwide [ 40 ].

Stages of HF are classified from A to D [ 41 ]. HF patients are also divided into patients with preserved ejection fraction (EF) (HFpEF), those with mildly reduced EF and those with reduced EF (HFrEF). Persistent hypertension and increased arterial stiffness in stage A HF result in left ventricular (LV) hypertrophy (LVH), at which point it is classified as stage B HF. Although the etiology of HFpEF is diverse, patients with HFpEF have been reported to have a high prevalence of hypertension, which is closely associated with increased arterial stiffness, LVH and diastolic LV dysfunction [ 41 ].

In adult Sprague–Dawley rats, a novel flavoprotein, renalase, was increased in hypertrophic cardiac tissue, and recombinant renalase improved cardiac function and suppressed myocardial fibrosis in the HF model [ 42 ]. In stroke-prone spontaneously hypertensive rats, carboxypeptidase X 2 (Cpxm2) was identified as a locus that affects LV mass. Analysis of endomyocardial biopsies from LVH patients showed significant upregulation of CPXM2 expression [ 43 ]. In this way, basic research applied to humans has shown in detail the pathophysiology of LVH.

Left atrial (LA) enlargement (LAe) is also associated with HFpEF [ 44 ]. In response to proinflammatory mediators, microvascular endothelial cells become inappropriately activated, resulting in microvascular endothelial dysfunction, perpetuating the inflammatory process and LA fibrosis [ 45 ]. Manifestations of these mechanisms have been related to LAe, which can be detected prior to the incidence of atrial fibrillation. Sympathetic overdrive from the central autonomic network, including the insular cortex, causes LA-pulmonary vein (PV) border fibrosis. LA-PV border fibrosis was suggested to originate from local inflammation triggered by preganglionic fibers ending in ganglionated plexi [ 45 , 46 ].

In the SPRINT study, intensive BP management was not associated with LA abnormalities defined based on ECG [ 47 ]. Although LA volume (LAV) according to body surface area was recommended to assess LA size [ 48 ], LAV indexed for height 2 was shown to be more sensitive for detecting subclinical hypertensive organ damage in females [ 49 ]. In the ARIC study, the minimum but not the maximum LAV index was significantly associated with the risk of incident HFpEF or death [ 50 ].

In the 2021 European Society of Cardiology guidelines for the treatment of HFrEF, angiotensin receptor/neprilysin inhibitor (ARNI) and sodium–glucose cotransporter 2 inhibitor (SGLT2i) are newly recommended for first-line treatment. In contrast, no guideline-directed treatment has been shown to convincingly reduce mortality and morbidity in HFpEF patients [ 44 ].

BP control is important to prevent adverse events in HFpEF patients with high BP. In a randomized study of hypertension patients, a significant reduction in systolic blood pressure (BP) (SBP) and diastolic BP was observed during daytime and nighttime in the ARNI group compared to the placebo group [ 51 ]. ARNI was also associated with reduced BP in patients with refractory hypertension with HFpEF [ 52 ]. In the PARAGON-HF trial, a decrease in pulse pressure, a marker of large arterial stiffness, during ARNI run-in was associated with a significant improvement in the prognosis of HFpEF [ 53 ]. On the other hand, the SACRA study showed that a significant reduction in BP occurred after adding SGLT2i to existing antihypertensive and antidiabetic agents in nonsevere obese diabetic elderly with uncontrolled nocturnal hypertension [ 54 ]. Recently, in the EMPEROR-Preserved Trial, SGLT2i improved the prognosis of patients with HFpEF [ 55 ]. From the above, it is suggested that reducing nighttime BP and improving diurnal BP patterns improves the prognosis of HFpEF [ 56 , 57 ].

Accumulated evidence from basic and clinical studies suggests that hypertension is a crucial risk factor for HFpEF (Fig.  3 ). These data may contribute to future studies aimed at elucidating the more detailed pathophysiology of HFpEF in hypertension research and the development of therapeutic agents and/or strategies that improve the prognosis of HFpEF in hypertension.

figure 3

A scheme of the relationship between hypertension and HFpEF. The dysregulation of the central autonomic network is associated with enhanced sympathetic nervous system activity in hypertension linked to HFpEF via left atrial remodeling, left ventricular hypertrophy and increased arterial stiffness. HFpEF heart failure with preserved ejection fraction, LA left atrium, PV pulmonary vein

Keywords : heart failure with preserved ejection fraction, arterial stiffness, leftventricular hypertrophy, diastolic left ventricular dysfunction, left atrial remodeling.

Up-to-date preeclampsia knowledge; what we should know for mother and child (See Supplementary Information 4 )

Diagnostic criterion.

In 2017, the American College of Cardiology/American Heart Association hypertension treatment guidelines identified hypertension as blood pressure (BP) ≥ 130/80 mmHg. The reference BP for hypertension during pregnancy as specified in international guidelines [e.g., the International Society for the Study of Hypertension in Pregnancy guidelines (ISSHP) [ 58 ] and the American College of Obstetricians and Gynecologists guidelines (ACOG) [ 59 , 60 ]] is ≥140/90 mmHg. A large number of studies have examined the incidence of PE and fetal outcomes according to BP levels. The meta-analysis of these studies has shown that BP ≥ 120/80 mmHg, particularly ≥130/80 mmHg, in early pregnancy is also associated with increased maternal and perinatal risks and proposed new BP categories of <120/80 mmHg (normal), 120–129/<80 mmHg (high normal), and 130–139/80–89 mmHg (elevated) for pregnant women [ 61 ].

Prognostic tools

The predictive value of BP and other clinical characteristics for PE is relatively low [ 62 , 63 ]. Soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio testing resulted in reduced unnecessary hospitalization [ 64 , 65 ]. Circulating cell-free DNA (cfDNA) and human suppression of tumorigenesis 2 (ST2) were increased in individual with gestational hypertension (GH) and PE and served as diagnostic biomarkers [Supplementary Information  4 - 1 ]. Nocturnal hypertension was a significant predictor of early-onset PE in high-risk pregnancies [ 66 ]. BP variability was higher in pregnant women with hypertensive disorders and was significantly associated with left ventricular mechanics [Supplementary Information  4 - 2 ]. Including these factors in multivariate models may improve the detection rates of PE and may identify women who could benefit from preventive interventions (Fig.  4 ).

figure 4

Schematic presentation of the topics of preeclampsia 2021. HTN hypertension, PE preeclampsia, BP blood pressure, cfDNA cell-free DNA, ST2 human suppression of tumorigenesis 2, sFlt-1 soluble fms-like tyrosine kinase-1, PIGF placental growth factor, PRES posterior reversible encephalopathy syndrome, AKI acute kidney injury, ACE angiotensinogen converting enzyme, Ang angiotensin

The ISSHP recommends that BP ≥ 140/90 mmHg should be treated, with a goal BP of 110–140/85 mmHg, while the ACOG recommends antihypertensive medications when BP ≥ 160/110 mmHg, with goal BP below this threshold (Fig.  4 ). Systolic BP (sBP) < 130 mmHg within 14 weeks of gestation reduced the risk of developing early-onset superimposed PE in women with chronic hypertension [ 67 ]. The Chronic Hypertension and Pregnancy (CHAP) project also showed that BP control to <140/90 was associated with a reduction in composite adverse outcomes, with no significant increase in small for gestational age infants [ 68 ].

Long-term outcomes

PE is linked to major chronic diseases such as hypertension, type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease (Fig.  4 ). The American Heart Association lists hypertension during pregnancy as a major cardiovascular risk factor and recommends that affected women undergo cardiovascular risk screening within 3 months after giving birth [ 69 ]. Since many cardiovascular risk factors are modifiable and related to lifestyle, all women with prior PE should be followed up by physicians even after the resolution of PE.

COVID-19 and Pregnancy

Pregnancy could potentially affect the susceptibility to and severity of COVID-19. Severe cases of COVID-19 present with PE-like symptoms. PE mimicry by COVID-19 was confirmed following the alleviation of preeclamptic symptoms without delivery of the placenta [ 70 ]. In COVID-19, angiotensin-converting enzyme 2 (ACE 2) function decreases, and subsequently, angiotensin II (Ang) activity increases [ 71 ]. Similar to PE, COVID-19 results in an increase in the sFlt-1/PlGF ratio due to pathologic Ang II/Ang (1-7) imbalance [ 72 ] (Fig.  4 ). Most experts believe that SARS-CoV-2 is likely to become endemic, and continued collection of data on the effects of COVID-19 during pregnancy is needed.

Further investigation is needed to decrease PE-related maternal and fetal deaths and to reduce maternal risks for chronic diseases in later life. The participation of physicians is necessary to offer appropriate medical care to women with prior PE, and continued publications of issues regarding PE in Hypertension Research are expected.

(KB and AI)

Keywords : preeclampsia, gestational hypertension, chronic hypertension, soluble fms-like tyrosine kinase 1, placental growth factor.

Appropriate blood pressure assessment methods for the prevention of hypertension complications (See Supplementary Information 5 )

Blood pressure (BP) values can vary and fluctuate widely depending on the method and the environment of blood measurement. Via appropriate measurement and interpretation of BP values, hypertension can be correctly diagnosed, treated and guided [ 73 ]. To give an example, appropriate body posture is important for accurate BP measurement. Wan et al. [Supplementary Information  5 - 1 ] demonstrated that BP levels measured with the back in an unsupported position were 2.3/1.0 mmHg higher than those measured with the back in a supported position. Glenning et al. [Supplementary Information  5 - 2 ] demonstrated the feasibility of measuring diastolic blood pressure by the onset of the fourth Korotkoff phase (K4), when K5 is undetectable under exercise conditions in children and adolescents. In recent years, a variety of BP measurement devices and techniques have appeared, and accumulating evidence has shown the feasibility, reproducibility, and usefulness of these devices [ 74 , 75 ]. Kario et al. [ 76 ] demonstrated the relationship between BP by a newly released wrist-cuff oscillometric wearable BP device and left ventricular hypertrophy. They concluded the feasibility and usefulness of wearable BP devices to detect masked daytime hypertension. Automated office blood pressure (AOBP) measurement includes recording of several BP readings using a fully automated oscillometric sphygmomanometer with the patient resting alone in a quiet place, thereby potentially minimizing the white-coat effect. The most comprehensive meta-analysis [ 77 ] reported that AOBP is equivalent to home BP (HBP), but the diagnostic value and viability of AOBP are still controversial. Lee et al. [ 78 ] assessed the diagnostic accuracies of two AOBP machines and manual office blood pressure measurements (MOBP) in Chinese individuals and clarified the lower diagnostic significance of AOBP than that of MOBP. Recent studies strongly recommended the wide use of self-measured HBP [ 79 ] because HBP has better reproducibility than office BP (OBP), improves adherence to treatment, enables us to detect high-risk populations and has prognostic value for cardiovascular disease (CVD) events [ 80 , 81 , 82 ]. Both elevated morning and nocturnal BP values and disrupted circadian BP rhythm assessed by each BP measurement method or devices are associated with worsened cardiovascular outcomes (Fig.  5 ). Zhan et al. [ 83 ] demonstrated that HBP monitoring improved treatment adherence and BP control in stage 2 and 3 hypertension. Hoshide et al. [ 84 ] demonstrated the association of nighttime BP assessed by HBP and CVD events, independent of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, in the Japanese clinical population. Narita et al. [Supplementary Information  5 - 3 ] demonstrated that the elevated difference between morning and evening systolic BP was associated with a higher incidence of CVD events in the J-HOP study. Narita et al. [Supplementary Information  5 - 4 ] also demonstrated that treatment-resistant hypertension diagnosed by HBP monitoring was associated with increased CVD risk independent of cardiovascular damage in the same Japanese cohort. Oliveira et al. [Supplementary Information  5 - 5 ] demonstrated that the SAGE score calculated by systolic BP, age, fasting blood glucose and estimated glomerular filtration rate was associated with pulse wave velocity measured by oscillometric devices and concluded that a SAGE score ≥8 could be used to identify a high risk of CVD events. ABPM is currently regarded as the reference method for hypertension diagnosis in children and pregnancy. Salazar et al. [Supplementary Information  5 - 6 ] demonstrated nocturnal hypertension assessed by ABPM as a significant predictor of early-onset preeclampsia/eclampsia in high-risk pregnant women in a cohort study in Argentina. ABPM also helped us to notice abnormal circadian patterns in BP, which are associated with increased circulating volume, largely determined by salt sensitivity and salt intake. Understanding these pathogenic mechanisms under conditions of nocturnal hypertension and heart failure suggests several new antihypertensive pharmacotherapies, including sodium–glucose cotransporter 2 inhibitors, angiotensin receptor neprilysin inhibitors and mineralocorticoid receptor antagonists [ 56 , 85 , 86 ]. Kario et al. [Supplementary Information  5 - 7 ] demonstrated the effect of esaxerenone, a highly selective mineralocorticoid receptor blocker, for improving nocturnal hypertension and NT-proBNP levels. Esaxerenon could be an effective treatment option, especially for nocturnal hypertensive patients with a riser pattern.

figure 5

Methods of measuring variable blood pressure and evaluating factors associated with the prognosis of cardiovascular disease

Keywords : hypertension management, BP measurement devices, BP variability, home BP, cardiovascular disease

Considering frailty and exercise in the management of hypertension and hypertensive organ damage (See Supplementary Information 6 )

Frailty is defined as physiological decline and a state of vulnerability to stress and results in adverse health outcomes [ 87 ]. Frailty consists of multiple domains, such as physical, social, and psychological factors. Cognitive decline is one of the factors related to frailty, and blood pressure (BP) control significantly reduced dementia or cognitive decline in a meta-analysis [ 88 ]. However, in the elderly population above 80 years, the positive effect of antihypertensive therapy for preventing dementia was not proven [ 89 , 90 , 91 ].

A systematic review and meta-analysis of the prevalence of mild cognitive impairment (MCI) among hypertensive patients was conducted by Quin et al. The prevalence of MCI was 30% in a sample of 47,179 hypertensive patients. Heterogeneity was seen due to ethnicity, study design (cross-sectional or cohort study), and cognition assessment tools [ 92 ]. Li. et al. investigated the association between carotid intima thickness (CIMT) and cognitive function in hypertensive patients [Supplementary Information  6 - 1 ]. CIMT was significantly and negatively associated with MMSE scores in people aged ≥60 years but not in those aged <60 years.

BP guidelines in various countries suggest that BP management should be carried out in the context of frailty or end of life, and careful observation, including personalized BP control among elderly individuals, is essential (Fig.  6 ). A total of 535 patients with hypertension (age 78 [ 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ] years, 51% men, 37% with frailty) were prospectively followed for 41 months, and mortality associated with frailty and BP was evaluated by Inoue et al. [ 93 ]. Frailty was assessed by the Kihon checklist. Among 49 patients who died, mortality rates were lowest in those with systolic BP < 140 mmHg and nonfrailty and highest in those with systolic BP < 140 mmHg and frailty. The results indicate that frail patients have a higher risk of all-cause mortality than nonfrail patients, and BP should be managed considering frailty status, which is in line with previous reports [ 94 ]. Our latest study showed that in patients with preserved MMSE scores, higher BP was associated with cognitive impairment, and those with MMSE scores below 24 points had the opposite results [ 95 ]. Elderly individuals with hearing impairment have higher rates of hospitalization, mortality, falls, frailty, dementia, and depression. Miyata et al. performed a study using data from medical records from health checkups: higher SBP levels were associated with an increased risk of objective hearing impairment at 1 kHz [Supplementary Information  6 - 2 ].

figure 6

Hypertension management in frail patients. ADL activities of daily living, IADL instrumental activities of daily living

In the era of technical advancement, people are spending less time being active, which leads to cardiovascular risks, including hypertension. However, guidelines emphasize the importance of nonpharmacological strategies such as lifestyle modification and exercise to prevent diseases [ 96 ].

Sardeli et al. compared types of exercise that are beneficial to health. The study compared the effects of aerobic training (AT), resistance training (RT), and combined training (CT) in hypertensive older adults aged >50 years. There were extensive health benefits associated with exercise training, and CT was the most effective intervention at improving a wide spectrum of health conditions, including cardiorespiratory fitness, muscle strength BMI, fat mass, glucose, TC and TGs [ 97 ]. J Almeida et al. showed that isometric handgrip exercise training reduced systolic BP in treated hypertensive patients [Supplementary Information  6 - 3 ]. Stair climbing and vascular function were assessed by Yamaji et al. There was a significant difference in nitroglycerine-induced vasodilatation between the group with no habits of climbing stairs and the other groups with two or more climbing habits [Supplementary Information  6 - 4 ].

The safety of resistance training was studied by Hansford et al who concluded that isometric resistance training (IRT) was safe and led to a potentially clinically meaningful reduction in BP [Supplementary Information  6 - 5 ].

Keywords : physical and social frailty, elderly, cognitive function, resistance training, cardiorespiratory function

Blood pressure variability—therapeutic target for the prevention of cardiovascular disease (See Supplementary Information 7 )

In the past three decades, there have been many reports on the associations of various parameters of blood pressure (BP) variability with increased risk of cardiovascular disease (CVD) events; these parameters include short-term BP variability (BPV), i.e., beat-by-beat BPV and ambulatory BPV, abnormality of nocturnal BP dipping pattern, and mid- to long-term BPV, i.e., day-by-day BPV, visit-to-visit BPV, and seasonal variations in BP [ 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 ]. In addition, BPV has been associated with the progression of endovascular organ damage related to heart failure, chronic kidney disease, and cognitive function [ 107 , 108 , 109 , 110 , 111 ] [Supplementary Information  7 - 1 ]. Several factors that are associated with abnormal BPV [ 112 ], as well as environmental factors such as cold or warm temperatures and seasonal changes in climate, increase fluctuations in BP. Individual intrinsic factors, such as sympathetic nervous tone, arterial stiffness, physical activity, and mental stress, also contribute to elevated BPV. According to evaluations of BPV abnormalities, out-of-office BP measurements, such as ambulatory and home BP monitoring, are needed. To evaluate nighttime BP levels, home BP monitoring devices equipped with a function for nighttime BP readings and new wrist-type nocturnal BP monitoring devices are available [ 76 ]. Although there are issues regarding measurement accuracy, cuffless BP monitoring devices, for example, those using pulse transit time, may be used to estimate nighttime BP levels [Supplementary Information  7 - 2 ]. Such cuffless BP devices can also evaluate beat-by-beat BPV. Moreover, by using the multisensor-equipped ambulatory BP monitoring device developed by our research group, it is possible to evaluate BPV associated with changes in temperature, physical activity, and/or atmospheric pressure [ 113 ].

Based on the mechanism(s) underlying a given patient’s BPV abnormality, several methods may be considered for the management of that abnormality (Fig.  7 ). For example, improving excessive sympathetic nervous system activation may be useful in the management of BPV abnormalities [ 114 ], and renal denervation has been reported to decrease ambulatory BPV [ 115 ]. Abnormal nocturnal BP dips may be treated by decreasing nighttime BP. In patients with sleep apnea, improving sleep quality and implementing continuous positive airway pressure are recognized to be useful for nighttime BP control [ 116 ]. Moreover, early adjustment of antihypertensive drugs has been reported to be useful in suppressing seasonal variations in BP, leading to a decreased risk of CVD events [ 99 ]. Furthermore, housing conditions and room temperature are closely related to BP levels, and adaptive control of room temperature would be useful to suppress winter increases in BP [ 117 , 118 ]. In clinical practice, we must not forget that BPV parameters are interrelated. For instance, frequent evaluation of BP levels and adjustment of antihypertensive drugs can suppress visit-to-visit BPV, which in turn leads to the suppression of seasonal variations in BP.

figure 7

Current and future perspectives in the management of blood pressure variability. Short- and long-term BP variability is associated with CVD event risk independent of each BP level. Out-of-office BP measurements, such as ABPM and home BP monitoring, and other new BP devices are useful for evaluating the various types of BP variability. To suppress BP variability, several management methods, including new antihypertensive medications, chronotherapy, housing condition, and sympathetic nervous denervation, are considered. ABPM ambulatory blood pressure monitoring, ABPV ambulatory blood pressure variability, ARNI angiotensin receptor neprilysin inhibitor, BP blood pressure, BPV blood pressure variability, CVD cardiovascular disease, ICT information and communication technology, SGLT2i sodium–glucose cotransporter 2 inhibitor

Over the next decade, more data on how to manage and control BPV need to be accumulated. Additionally, future studies should be conducted to verify whether the different types of BVP management are useful in preventing CVD events.

(KN, SH and KK)

Keywords : blood pressure variability, out-of-office blood pressure monitoring, cardiovascular disease prevention, wearable blood pressure monitoring device, environmental factors.

Optimal therapy and clinical management of obesity/diabetes (See Supplementary Information 8 )

Obesity/diabetes is a major comorbidity in patients with hypertension, and these conditions often share common pathological conditions, such as insulin resistance and the risk of cardiovascular diseases (CVD). One of the biggest highlights of recent years in the area of obesity/diabetes has been the remarkable benefits of newer glucose-lowering agents seen in large-scale clinical trials on cardiorenal outcomes (Fig.  8 ), followed by the relevant clinical guideline updates and the expansion of the clinical application of those agents [ 119 ]. In particular, sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists are now preferentially recommended in patients with type 2 diabetes (T2D) and specific cardiorenal risk, independent of diabetes status or background use of metformin [ 120 ]. It is noteworthy, of course, that those agents reduced the risk of cardiorenal events, and their multifaceted effects beyond hypoglycemic effects are also attracting clinical attention. In a review series ‘New Horizons in the Treatment of Hypertension’ in Hypertension Research, Tanaka and Node [ 121 ] discussed the modest effects of those agents on blood pressure (BP)-reduction and the clinical perspectives. They also proposed a new-normal style care for diabetes and its complications using such evidence-based agents with multidisciplinary effects, partly aiming at reduced polypharmacy and avoidance of its possible harm. This action will improve the quality of hypertension care in patients with obesity/diabetes; however, a substantial population with treated hypertension still has inadequate blood pressure control, which is recognized as resistant hypertension (RH). Due to the difficulty in distinguishing true RH from pseudo-RH due to nonadherence, little is known about the clinical characteristics of true RH. Chiu et al. from Boston [Supplementary Information  8 - 1 ] reported a notable prevalence (26.6%) of true RH in patients with T2D registered in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure trial and identified several independent predictors, such as higher baseline BP, higher number of baseline antihypertensives, macroalbuminuria, chronic kidney disease, and history of stroke. Moreover, patients with true RH exhibited poorer prognosis than those without, suggesting an emerging need for effective screening and intensified treatment for patients with true RH.

figure 8

Schematic presentation of the topic ‘Obesity/Diabetes’ in 2021

The BP treatment goal in patients with diabetes and hypertension is less than 130/80 mmHg [ 122 ], and intensified BP control was associated with reduced stroke risk [ 123 , 124 , 125 ]. Intensive lipid-lowering therapy is also recommended for patients with T2D at risk of CVD [ 126 ]; however, an original EMPATHY study investigating the effect of intensive lipid-lowering therapy (target of low-density lipoprotein cholesterol [LDL-C] < 70 mg/dL) on cardiovascular outcomes failed to show the clinical benefits of intensive statin therapy in patients with T2D, diabetic retinopathy, elevated LDL-C levels, and no known CVD [ 127 ]. In a subanalysis of the EMPATHY study, Shinohara et al. [ 128 ] revealed for the first time that intensive statin therapy was associated with a reduced risk of cardiovascular events compared with standard therapy (target of ≥100 to <120 mg/dL) in a subgroup with baseline BP ≥ 130/80 mmHg but not in another subgroup with baseline BP < 130/80 mmHg. Their findings suggest that baseline BP is also a possible determinant of the target LDL-C in that patient population, although the precise reasons for the difference in the clinical benefits of intensive statin therapy between subgroups according to baseline BP levels are still uncertain.

Obesity is a crucial global health concern across generations. Obesity and insulin resistance cause several cardiometabolic disorders, including hypertension, and increase the risk of subsequent CVD. Hence, further actions against obesity and cardiometabolic disorders are urgently needed for individuals of all generations [ 129 , 130 ]. In this context, Fernandes et al. from Brazil [Supplementary Information  8 - 2 ] revealed for the first time that Ang-(1-7) and des-Arg9BK metabolites were novel biological markers of adolescent obesity and relevant cardiovascular risk profiles, such as elevated BP, lipids, and inflammation. Thu et al. from Singapore [Supplementary Information  8 - 3 ] found a positive association between accumulated visceral adipose tissue and systolic BP in midlife-aged women, independent of burdens of inflammatory markers. Intriguingly, Haze et al. [ 131 ] clearly demonstrated that an increased ratio of visceral-to subcutaneous fat volume was an independent risk factor for renal dysfunction in Japanese patients with primary aldosteronism. These findings should highlight the clinical importance and the need for further research to explore surrogate markers of obesity in the care of hypertension and its related conditions (Fig.  8 ).

Finally, we briefly introduce some exciting progress in vascular function in the area of “Obesity/Diabetes” (Fig.  8 ). Murai et al. [ 132 ] elegantly showed that postload hyperinsulinemia was independently associated with increased arterial stiffness as assessed by brachial-ankle pulse wave velocity (PWV) in young medical students at Jichi Medical University. Given the close pathological relationship between hyperinsulinemia and most CVDs, including heart failure [ 133 , 134 ], their findings suggest that hyperinsulinemia-induced vascular failure is one of the key drivers of that pathological link. Interestingly, Fryer et al. from the UK [Supplementary Information  8 - 4 ] also found that arterial stiffness as assessed by carotid-femoral PWV was exacerbated by the consumption of a high-fat meal relative to a low-fat meal prior to 180 min of uninterrupted sitting. Importantly, arterial stiffness testing could accurately reflect even such a combination of unfavorable behaviors, and thus vascular function assessment has the potential to reflect a wide spectrum of cardiovascular risk and provide a clinical opportunity for better risk stratification and optimal modification [ 135 ]. We look forward to accumulating and consolidating evidence of vascular function tests and further applying them to actual cardiovascular care [ 136 ].

(AT and KN)

Keywords : glucose-lowering agent, resistant hypertension, statin, surrogate marker, vascular function

A new era of progress in primary aldosteronism treatment: mineralocorticoid receptor antagonists, a new aldosterone assay, and a clinical practice guideline (See Supplementary Information 9 )

A hot topic in 2021 was advances in the treatment of mineralocorticoid receptor (MR)-associated hypertension [ 137 ], particularly primary aldosteronism (PA). The nonsteroidal MR antagonist (MRA) esaxerenone is now widely used in Japan. Kario et al. [ 138 ] reported that esaxerenone reduced nocturnal blood pressure in patients with essential hypertension, according to ambulatory blood pressure assessment and N-terminal pro-brain natriuretic peptide assays. Yoshida et al. [ 139 ] reported that MRAs such as esaxerenone improved quality of life in PA patients. Ito et al. [ 140 ] reported that add-on treatment using esaxerenone with maximal tolerable doses of a renin-angiotensin system (RAS) inhibitor reduced the urinary albumin-creatinine ratio in patients with type 2 diabetes mellitus (ESAX-DN), suggesting a renoprotective effect against diabetic nephropathy. Several clinical studies of another nonsteroidal MRA, finerenone (FIDELIO-DKD [ 141 ], FIGARO-DKD [ 142 ], and FIDELITY [ 143 ]), have shown its renoprotective effect against diabetic nephropathy as well as cardiovascular events, particularly hospitalization for heart failure in patients with type 2 diabetes and chronic kidney disease. Although there are no reports of clinical studies on finerenone for PA, finerenone may be used in the future for type 2 diabetes patients with PA, as obesity, glucose intolerance, and sleep apnea are common complications in patients with PA [ 144 ]. Similarly, sodium–glucose cotransporter 2 inhibitors (SGLT2i) have been demonstrated to improve the prognosis of cardiovascular disease and chronic kidney disease in individuals with type 2 diabetes (EMPA-REG OUTCOME [ 145 ], DECLARE–TIMI 58 [ 146 ], DAPA-HF[ 147 ], and DAPA-CKD [ 22 ]). As steroidal MRAs such as spironolactone and eplerenone are effective in the treatment of mild to severe stages of heart failure (RALES, EPHESUS [ 148 ], and EPHESUS-HF [ 149 ]), combined treatment with MRA and SGLT2i, in addition to an RAS inhibitor, may be a novel effective treatment for cardiac and renal protection in type 2 diabetic patients (Fig.  9 ). Second, radiofrequency ablation of macroscopic adrenal tumors [ 150 , 151 , 152 ] has been reported as an alternative treatment for PA to lower blood pressure and plasma aldosterone levels. This treatment has been covered by health insurance providers in Japan since April 2022, but long-term outcomes need to be validated.

figure 9

Potential drug therapy regimen. Combined administration of an MRA and an SGLT2i may afford cardiac and renal protection. MRA mineralocorticoid receptor antagonist, SGLT2i sodium–glucose cotransporter 2 inhibitor

Another hot topic was the launch of serum aldosterone measurement using a chemiluminescent enzyme immunoassay (CLEIA), which utilizes a two-step sandwich method. Previously, low aldosterone levels may have been measured incorrectly [ 153 ]. The new CLEIA figures are closely correlated with liquid chromatography/tandem mass spectrometry values; the new assay is more accurate than the previous radioimmunoassay, which overestimated serum aldosterone levels [ 154 , 155 , 156 ]. Thus, the Japan Endocrine Society issued a Primary Aldosteronism Clinical Guideline in 2021 [ 157 ]. The CLEIA method is also used to measure urinary aldosterone levels; Ozeki et al. [ 158 ] proposed a PA diagnostic cutoff of ≥3 μg/day for the oral salt loading test. The CLEIA method is currently available only in Japan.

Exosomes may serve as biomarkers of MR activity. Ochiai-Homma et al. [ 159 ] focused on pendrin, a Cl – /HCO3 – exchanger that is only expressed by renal intercalated cells. In a rat model, the pendrin level in the urinary exosome was reduced by therapeutic interventions favored for PA patients; the urinary level was correlated with the renal level. This model may help to elucidate the pathophysiology of PA-induced organ injury [ 160 ].

Finally, Haze et al. [Supplementary Information  9 - 1 ], Segawa et al. [Supplementary Information  9 - 2 ], Nishimoto et al. [Supplementary Information  9 - 3 ], Chen et al. [Supplementary Information  9 - 4 ], and Liu et al. [Supplementary Information  9 - 5 ] have conducted intriguing clinical studies regarding PA.

(YY and HS)

Keywords : mineralocorticoid receptor-associated hypertension, mineralocorticoid receptor antagonist, hypertension, primary aldosteronism, chemiluminescent enzyme immunoassay

Advances in renal denervation for treating hypertension: current evidence and future perspectives (See Supplementary Information 10 )

It is well established that renal denervation (RDN) decreases blood pressure (BP) in various models of hypertension in animals and in humans [ 161 , 162 , 163 , 164 , 165 ]. Here, we reviewed studies related to RDN published in Hypertension Research in 2021 (Fig.  10 ). The antihypertensive effect of RDN is mediated by interrupting both the efferent outputs from the brain to the kidney and the afferent inputs from the kidney to the brain, suppressing systemic sympathetic outflow [ 165 , 166 ]. In basic research, there are two methods of RDN: total RDN (TRDN) performed by surgical cutting of renal nerves to ablate both efferent and afferent nerves and selective afferent RDN (ARDN) performed via capsaicin application to renal nerves to specifically ablate afferent nerves expressing capsaicin receptors [ 167 , 168 ]. Katsurada et al. [ 169 ] reviewed previous reports that address the different effects of TRDN and ARDN in different animal models of hypertension, suggesting potentially complicated and diversified origins of hypertension. The potential therapeutic effects of TRDN and ARDN have also been reported in animal models of heart failure [ 170 ].

figure 10

Topics on renal denervation. BP blood pressure, RDN renal denervation

In clinical practice, radiofrequency, ultrasound, and alcohol-based RDN devices have been developed as second-generation catheter devices and evaluated in randomized control trials. Ogoyama et al. [ 171 ] reported a meta-analysis of nine randomized sham-controlled trials of RDN that showed that RDN significantly reduced a range of office, home and 24 h BP parameters in patients with resistant, uncontrolled, and drug-naïve hypertension. There were no significant differences in the magnitude of BP reduction between radiofrequency-based and ultrasound-based devices.

The Global SYMPLICITY Registry (GSR) is a prospective all-comer registry to evaluate the safety and efficacy of RDN in a real-world population [ 172 ]. The overall GSR has enrolled over 2700 patients, and more than 2300 of these have now been followed for 3 years [ 173 ]. GSR Korea is a Korean registry substudy of GSR ( N  = 102) [ 174 ]. Kim et al. [Supplementary Information  10 - 1 ] reported the 3-year follow-up outcomes from the GSR Korea showing that RDN led to sustained reductions in office systolic BP at 12, 24 and 36 months (−26.7 ± 18.5, −30.1 ± 21.6, and −32.5 ± 18.8 mmHg, respectively) without safety concerns. Recently, the efficacy and safety of second-generation radiofrequency RDN up to 36 months have been reported [ 175 ].

The REQUIRE trial by Kario et al. [Supplementary Information  10 - 2 ] is the first trial of ultrasound RDN in Asian patients from Japan and South Korea with hypertension receiving antihypertensive therapy. The study findings were neutral for the primary endpoint, with similar reductions in 24 h systolic BP at 3 months in the RDN (−6.6 mmHg) and sham control groups (−6.5 mmHg). Although BP reduction after RDN was similar to other sham-controlled studies [ 161 , 162 , 164 , 176 ], the sham group in this study showed much greater reduction. Unlike RADIANCE-HTN TRIO that used an ultrasound catheter system to measure its primary endpoint, REQUIRE did not standardize medications or measure medication adherence, which may lead to increased variability in BP outcome; moreover, REQUIRE was not a double-blind study, which may result in a substantial bias. Another important factor is that 32.4% of patients showed hyperaldosteronism in the REQUIRE trial. Patients with primary aldosteronism have decreased sympathetic nerve activity and are likely to respond poorly to RDN [ 177 ]. The lessons from REQUIRE will enable us to design a follow-up trial to make a definitive evaluation of the effectiveness of RDN in Asian patients with hypertension.

Another topic is the patient preference for RDN. Kario et al. [Supplementary Information  10 - 3 ] conducted a nationwide web-based survey in Japan and reported that preference for RDN was expressed by 755 of 2392 Japanese patients (31.6%) and was higher in males, in younger patients, in those with higher BP, in patients who were less adherent to antihypertensive drug therapy, in those who had antihypertensive drug-related side effects, and in those with comorbid heart failure. This should be taken into account when making shared decisions about antihypertensive therapy.

Keywords : renal nerves, hypertension, renal denervation, patient preference, heart failure

Hot topics in uric acid research: the difficulties of managing hyperuricemia (See Supplementary Information 11 )

The mechanisms linking hyperuricemia, arteriosclerosis, hypertension, chronic kidney disease, and cardiovascular disease are becoming clearer (Fig.  11 ) [ 178 , 179 , 180 , 181 ]. However, it remains unclear whether treatment of hyperuricemia improves these diseases. Some recent topics of uric acid research are introduced below.

figure 11

Mechanisms linking hyperuricemia and arteriosclerosis, hypertension, chronic kidney disease, and cardiovascular disease. ATP adenosine triphosphate, CKD chronic kidney disease

First, urate-lowering treatment with allopurinol, a xanthine oxidase (XO) inhibitor, did not slow the decline in eGFR compared with placebo in either the PERL (Preventing Early Renal Loss in Diabetes) trial [ 182 ] or CKD-FIX (Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase) [ 183 ]. These results were similar to the results of FEATHER (Febuxostat Versus Placebo Randomized Controlled Trial Regarding Reduced Renal Function in Patients with Hyperuricemia Complicated by Chronic Kidney Disease Stage 3) from Japan [ 184 ]. Moreover, the PRIZE (Program of Vascular Evaluation Under Uric Acid Control by the Xanthine Oxidase Inhibitor Febuxostat: Multicenter, Randomized, Controlled) study showed that febuxostat did not delay the progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia [ 185 ]. These results suggest the difficulties of managing hyperuricemia for preventing chronic kidney disease (CKD) and/or arteriosclerosis.

Second, FAST (the Febuxostat versus Allopurinol Streamlined Trial) showed that febuxostat was noninferior to allopurinol therapy with respect to the primary cardiovascular endpoint, all-cause or cardiovascular deaths [ 186 ]. The results of FAST were different from the results of the CARES (The Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities) trial [ 187 ], and the authors summarized that regulatory advice to avoid the use of febuxostat in patients with cardiovascular disease should be reconsidered and modified [ 186 ].

In Hypertension Research 2021, several important articles on uric acid research were published. Mori et al. reported that a high serum uric acid level is associated with an increase in systolic blood pressure in women but not in men in subjects who underwent annual health checkups [ 188 ]. Their group also reported that a low uric acid level is a significant risk factor for CKD over 10 years in only women, and an elevated UA level increases the risk of CKD in both sexes [Supplementary Information  11 - 1 ]. Moreover, Li et al. reported that elevated serum uric acid levels in subjects without stroke, coronary heart disease, and medication for hyperuricemia or gout aged 40–79 years were independent predictors of total stroke, especially ischemic stroke, in women but not in men in a 10-year cohort study [Supplementary Information  11 - 2 ]. These results suggested the possibility that both hyperuricemia and hypouricemia in women could be associated with a higher risk for hypertension, CKD, and stroke than those in men.

Azegami et al. reported a prediction model of high blood pressure in young adults aged 12–13 years followed up for an average of 8.6 years. The results showed that uric acid was an important predictor of high blood pressure [ 189 ].

Kawasoe et al. reported that high (4.1–5.0, 5.1–6.0, and >/=6.1 mg/dL) and low (</=2.0 mg/dL) serum uric acid levels were significantly associated with an increased prevalence of high blood pressure compared to 2.1–4.0 mg/dL serum uric acid in subjects who underwent health checkups [ 190 ]. The results were compatible with a previous report stratified by sex [ 191 ]. Serum uric acid levels and the risks for diseases are largely different between men and women, and it is desirable to conduct every analysis by sex when conducting uric acid research.

Furuhashi et al. reported that plasma xanthine oxidoreductase (XOR) activity was associated with hypertension in 271 nondiabetic subjects in the Tanno–Sobetsu Study [ 192 ]. Kusunose et al. reported that additional febuxostat treatment in patients with asymptomatic hyperuricemia for 24 months might have potential prevention effects on impaired diastolic dysfunction in the subanalysis of the PRIZE study [ 193 ]. These reports suggested the potential direct antioxidant effects of the treatment as reflected in serum uric acid levels as well as its xanthine-oxidase-lowering properties in tissue [Supplementary Information  11 - 3 ]. Whether the preferential use of xanthine oxidoreductase XO inhibitors becomes a new therapeutic strategy for the prevention of cardiovascular disease in patients with asymptomatic hyperuricemia awaits further high-quality trials [Supplementary Information  11 - 4 ].

Finally, Nishizawa et al. reported a mini review article focusing on the relationship between hyperuricemia and CKD or cardiovascular diseases, and they summarized that high-quality and detailed clinical and basic science studies of hyperuricemia and purine metabolism are needed [Supplementary Information  11 - 5 ].

(MK and TK)

Keywords : uric acid, cardiovascular disease, chronic kidney disease, arteriosclerosis, xanthine oxidase

Basic research: elucidation of the “mosaic” pathogenesis of hypertension (See Supplementary Information 12 )

The pathogenesis of hypertension is multifactorial and highly complex, as described by the “mosaic theory” of hypertension. Basic research plays critical roles in elucidating the “mosaic” pathogenesis of hypertension and developing its treatment (Fig.  12 ).

figure 12

Topics in basic research. Each ref. number indicates the reference paper cited in the text. AT1R angiotensin type 1 receptor, EV extracellular vesicles, KO knockout, RAS renin-angiotensin system, Snx1 soring nexin 1, SIRT6 sirtuin 6, TWIST1 twist-related protein 1

In the field of the brain and autonomic nervous system, Chen et al. demonstrated that mild cold exposure elicits autonomic dysregulation, such as increased sympathetic activity, decreased baroreflex sensitivity, and poor sleep quality, causing blood pressure (BP) elevation in normotensive rats [ 194 ]. This finding may have critical implications for cardiovascular event occurrence at low ambient temperatures. In addition, Domingos-Souza et al. showed that the ability of baroreflex activation to modulate hemodynamics and induce lasting vascular adaptation is critically dependent on the electrical parameters and duration of carotid sinus stimulation in spontaneously hypertensive rats (SHRs) [ 195 ], proposing a rationale for improving baroreflex activation therapy in humans. Although only normotensive and hypertensive rats were used in these two studies, without comparing the two strains, previous studies have shown that neuronal function and activity in the cardiovascular sympathoregulatory nuclei, including the nucleus tractus solitarius and rostral ventrolateral medulla, which are involved in baroreflex regulation, are different between normotensive and hypertensive rats [ 196 , 197 ]. Further studies comparing normotensive and various hypertensive animal models would be interesting.

In the kidney, Kasacka et al. showed that the activity of the Wnt/β-catenin pathway is increased in SHRs and two-kidney, one-clip (2K1C) hypertensive rats, while it is inhibited in deoxycorticosterone acetate (DOCA)-salt rats according to kidney immunohistochemistry [ 198 ]. The intrarenal renin-angiotensin system (RAS) is also involved in BP regulation. In renal damage with an impaired glomerular filtration barrier, liver-derived angiotensinogen filtered through damaged glomeruli regulates intrarenal RAS activity [ 199 ]. Matsuyama et al. further showed that the glomerular filtration of liver-derived angiotensinogen depending on glomerular capillary pressure causes circadian rhythm of the intrarenal RAS with in vivo imaging using multiphoton microscopy [ 200 ]. Fukuda and his colleagues have shown that complement 3 (C3) is a primary factor that activates intrarenal RAS [Supplementary Information  12 - 1 , 2 ]. Otsuki and Fukuda et al. additionally demonstrated that TWIST1, a transcription factor that regulates mesodermal embryogenesis, transcriptionally upregulates C3 in glomerular mesangial cells from SHRs [ 201 ].

The RAS in the vascular system, as well as in other organ systems, plays a major role in BP regulation. Soring nexins (SNXs) are cellular sorting proteins that can regulate the expression and function of G protein-coupled receptors (GPCRs) [Supplementary Information  12 - 3 , 4 , 5 ]. Liu C et al. demonstrated that SNX1 knockout mice exhibit hypertension through vasoconstriction mediated by increased expression of AT1R, a GPCR mediating most of the effects of angiotensin II (Ang II), within the arteries [ 202 ]. Moreover, in vitro studies suggest that SNX1 sorts arterial AT1R for proteasomal degradation. These findings indicate that SNX1 impairment increases arterial AT1R expression, leading to vasoconstriction and hypertension. Liu X et al. found that sirtuin 6 (SIRT6) expression is downregulated in the aortae of aged rats and showed that SIRT6 knockdown enhances Ang II-induced vascular adventitial aging by activating the NF-κB pathway in vitro [ 203 ]. This study suggests that SIRT6 may be a biomarker of vascular aging and that activating SIRT6 can be a therapeutic strategy for delaying vascular aging.

Several reports indicate the potential treatment for hypertension and the associated organ damage. Narita et al. showed that rivaroxaban exerts a protective effect against cardiac hypertrophy by inhibiting protease-activated receptor-2 signaling in renin-overexpressing hypertensive mice [Supplementary Information  12 - 6 ]. In addition, the efficacy of nebivolol (a third-generation β-blocker), maximakinin (a bradykinin agonist peptide extracted from the skin venom of toad), and Pinggan-Qianyang decoction (a traditional Chinese medicine) were also shown in hypertensive animal models [Supplementary Information  12 - 7 , 8 , 9 ]. In animal models of gestational hypertension, melatonin and crocin have each exhibited an antihypertensive effect [Supplementary Information  12 - 10 , 11 ].

Studies investigating extracellular vesicles (EVs) have increased. Ochiai-Homma et al. showed that pendrin in urinary EVs can be a useful biomarker for the diagnosis and treatment of primary aldosteronism, which was supported by studies using a rat model of aldosterone excess [ 159 ]. Another report indicated that pulmonary arterial hypertension induces the release of circulating EVs with oxidative content and alters redox and mitochondrial homeostasis in the brains of rats [Supplementary Information  12 - 12 ]. Studies on the role of gut microbiota in BP regulation have also been accumulating. Wu et al. demonstrated that captopril has the potential to rebalance the dysbiotic gut microbiota of DOCA-salt hypertensive rats, suggesting that the alteration of the gut flora by captopril may contribute to the hypotensive effect of this drug [ 204 ]. Moreover, important basic studies, including review papers, have been reported in Hypertension Research. See Supplementary Information.

Keywords : autonomic nervous system, kidney, vascular system, renin-angiotensin system, extracellular vesicles, gut microbiota.

Higashi Y, Noma K, Yoshizumi M, Kihara Y. Endothelial function and oxidative stress in cardiovascular diseases. Circ J. 2009;73:411–8.

Article   CAS   PubMed   Google Scholar  

Maruhashi T, Kihara Y, Higashi Y. Assessment of endothelium-independent vasodilation: from methodology to clinical perspectives. J Hypertens. 2018;36:1460–7.

Ohkuma T, Ninomiya T, Tomiyama H, Kario K, Hoshide S, Kita Y, et al. Brachial-ankle pulse wave velocity and the risk prediction of cardiovascular disease: an individual participant data meta-analysis. Hypertension 2017;69:1045–52.

Polak JF, Pencina MJ, Pencina KM, O’Donnell CJ, Wolf PA, D’Agostino RB Sr. Carotid-wall intima-media thickness and cardiovascular events. N Engl J Med. 2011;365:213–21.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Tanaka A, Tomiyama H, Maruhashi T, Matsuzawa Y, Miyoshi T, Kabutoya T, et al. Physiological diagnostic criteria for vascular failure. Hypertension. 2018;72:1060–71.

Ankle Brachial Index C, Fowkes FG, Murray GD, Butcher I, Heald CL, Lee RJ, et al. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA. 2008;300:197–208.

Article   Google Scholar  

Potier L, Halbron M, Bouilloud F, Dadon M, Le Doeuff J, Ha Van G, et al. Ankle-to-brachial ratio index underestimates the prevalence of peripheral occlusive disease in diabetic patients at high risk for arterial disease. Diabetes Care. 2009;32:e44.

Article   PubMed   Google Scholar  

Maruhashi T, Kajikawa M, Kishimoto S, Hashimoto H, Takaeko Y, Yamaji T, et al. Upstroke time is a useful vascular marker for detecting patients with coronary artery disease among subjects with normal Ankle-Brachial Index. J Am Heart Assoc. 2020;9:e017139.

Article   PubMed   PubMed Central   Google Scholar  

Maruhashi T, Matsui S, Yusoff FM, Kishimoto S, Kajikawa M, Higashi Y. Falsely normalized ankle-brachial index despite the presence of lower-extremity peripheral artery disease: two case reports. J Med Case Rep. 2021;15:622.

Tsai WC, Lee WH, Chen YC, Liu YH, Chang CT, Hsu PC, et al. Combination of low ankle-brachial index and high ankle-brachial index difference for mortality prediction. Hypertens Res. 2021;44:850–7.

Sang T, Lv N, Dang A, Cheng N, Zhang W. Brachial-ankle pulse wave velocity and prognosis in patients with atherosclerotic cardiovascular disease: a systematic review and meta-analysis. Hypertens Res. 2021;44:1175–85.

Harada T, Kajikawa M, Maruhashi T, Kishimoto S, Yamaji T, Han Y, et al. Short stature is associated with low flow-mediated vasodilation in Japanese men. Hypertens Res. 2022;45:308–14.

Paajanen TA, Oksala NK, Kuukasjarvi P, Karhunen PJ. Short stature is associated with coronary heart disease: a systematic review of the literature and a meta-analysis. Eur Heart J. 2010;31:1802–9.

Miyaoka Y, Okada T, Tomiyama H, Morikawa A, Rinno S, Kato M, et al. Structural changes in renal arterioles are closely associated with central hemodynamic parameters in patients with renal disease. Hypertens Res. 2021;44:1113–21.

Yamaji T, Harada T, Hashimoto Y, Nakano Y, Kajikawa M, Yoshimura K, et al. Stair climbing activity and vascular function in patients with hypertension. Hypertens Res. 2021;44:1274–82.

Funakoshi S, Satoh A, Maeda T, Kawazoe M, Ishida S, Yoshimura C, et al. Eating before bed and new-onset hypertension in a Japanese population: the Iki city epidemiological study of atherosclerosis and chronic kidney disease. Hypertens Res. 2021;44:1662–7.

Anuwatmatee S, Tang S, Wu BJ, Rye KA, Ong KL. Fibroblast growth factor 21 in chronic kidney disease. Clin Chim Acta. 2019;489:196–202.

Kohara M, Masuda T, Shiizaki K, Akimoto T, Watanabe Y, Honma S, et al. Association between circulating fibroblast growth factor 21 and mortality in end-stage renal disease. PLoS One. 2017;12:e0178971.

Article   PubMed   PubMed Central   CAS   Google Scholar  

Matsui M, Kosaki K, Kuro OM, Saito C, Yamagata K, Maeda S. Circulating fibroblast growth factor 21 links hemodynamics with kidney function in middle-aged and older adults: a mediation analysis. Hypertens Res. 2022;45:125–34.

Lenihan CR, Busque S, Derby G, Blouch K, Myers BD, Tan JC. The association of predonation hypertension with glomerular function and number in older living kidney donors. J Am Soc Nephrol. 2015;26:1261–7.

Tsuboi N, Sasaki T, Okabayashi Y, Haruhara K, Kanzaki G, Yokoo T. Assessment of nephron number and single-nephron glomerular filtration rate in a clinical setting. Hypertens Res. 2021;44:605–17.

Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–46.

Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–24.

Nagasu H, Yano Y, Kanegae H, Heerspink HJL, Nangaku M, Hirakawa Y, et al. Kidney outcomes associated with SGLT2 inhibitors versus other glucose-lowering drugs in real-world clinical practice: the Japan chronic kidney disease database. Diabetes Care. 2021;44:2542–51.

Thomson SC, Vallon V. Effects of SGLT2 inhibitor and dietary NaCl on glomerular hemodynamics assessed by micropuncture in diabetic rats. Am J Physiol Ren Physiol. 2021;320:F761–F71.

Article   CAS   Google Scholar  

Kario K, Ferdinand KC, O’Keefe JH. Control of 24-hour blood pressure with SGLT2 inhibitors to prevent cardiovascular disease. Prog Cardiovasc Dis. 2020;63:249–62.

Masuda T, Nagata D. Recent advances in the management of secondary hypertension: chronic kidney disease. Hypertens Res. 2020;43:869–75.

Kravtsova O, Bohovyk R, Levchenko V, Palygin O, Klemens CA, Rieg T, et al. SGLT2 inhibition effect on salt-induced hypertension, RAAS, and sodium transport in Dahl SS rats. Am J Physiol Renal Physiol. 2022. https://doi.org/10.1152/ajprenal.00053.2022 .

Bohm M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, et al. Empagliflozin improves cardiovascular and renal outcomes in heart failure irrespective of systolic blood pressure. J Am Coll Cardiol. 2021;78:1337–48.

Article   PubMed   CAS   Google Scholar  

Ohara K, Masuda T, Murakami T, Imai T, Yoshizawa H, Nakagawa S, et al. Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on fluid distribution: A comparison study with furosemide and tolvaptan. Nephrology. 2019;24:904–11.

CAS   PubMed   Google Scholar  

Masuda T, Watanabe Y, Fukuda K, Watanabe M, Onishi A, Ohara K, et al. Unmasking a sustained negative effect of SGLT2 inhibition on body fluid volume in the rat. Am J Physiol Ren Physiol. 2018;315:F653–F64.

Ohara K, Masuda T, Morinari M, Okada M, Miki A, Nakagawa S, et al. The extracellular volume status predicts body fluid response to SGLT2 inhibitor dapagliflozin in diabetic kidney disease. Diabetol Metab Syndr. 2020;12:37.

Masuda T, Muto S, Fukuda K, Watanabe M, Ohara K, Koepsell H, et al. Osmotic diuresis by SGLT2 inhibition stimulates vasopressin-induced water reabsorption to maintain body fluid volume. Physiol Rep. 2020;8:e14360.

Eickhoff MK, Dekkers CCJ, Kramers BJ, Laverman GD, Frimodt-Moller M, Jorgensen NR, et al. Effects of dapagliflozin on volume status when added to renin-angiotensin system inhibitors. J Clin Med. 2019;8:779.

Sen T, Scholtes R, Greasley PJ, Cherney D, Dekkers CCJ, Vervloet M, et al. Effects of dapagliflozin on volume status and systemic hemodynamics in patients with CKD without diabetes: results from DAPASALT and DIAMOND. Diabetes Obes Metab. 2022. https://doi.org/10.1111/dom.14729 .

Scholtes RA, Muskiet MHA, van Baar MJB, Hesp AC, Greasley PJ, Karlsson C, et al. Natriuretic effect of two weeks of dapagliflozin treatment in patients with type 2 diabetes and preserved kidney function during standardized sodium intake: results of the DAPASALT trial. Diabetes Care. 2021;44:440–7.

Zanchi A, Pruijm M, Muller ME, Ghajarzadeh-Wurzner A, Maillard M, Dufour N, et al. Twenty-four hour blood pressure response to empagliflozin and its determinants in normotensive non-diabetic subjects. Front Cardiovasc Med. 2022;9:854230.

Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17:1180–93.

Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28.

Nagai M, Forster CY, Dote K, Shimokawa H. Sex hormones in heart failure revisited? Eur J Heart Fail. 2019;21:308–10.

Takami T, Hoshide S, Kario K. Differential impact of antihypertensive drugs on cardiovascular remodeling: a review of findings and perspectives for HFpEF prevention. Hypertens Res. 2022;45:53–60.

Wu Y, Quan C, Yang Y, Liang Z, Jiang W, Li X. Renalase improves pressure overload-induced heart failure in rats by regulating extracellular signal-regulated protein kinase 1/2 signaling. Hypertens Res. 2021;44:481–8.

Grabowski K, Herlan L, Witten A, Qadri F, Eisenreich A, Lindner D, et al. Cpxm2 as a novel candidate for cardiac hypertrophy and failure in hypertension. Hypertens Res. 2022;45:292–307.

McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–726.

Balint B, Jaremek V, Thorburn V, Whitehead SN, Sposato LA. Left atrial microvascular endothelial dysfunction, myocardial inflammation and fibrosis after selective insular cortex ischemic stroke. Int J Cardiol. 2019;292:148–55.

Nagai M, Dote K, Kato M. Left atrial fibrosis after ischemic stroke: How the insular cortex-ganglionated plexi axis interacts? Int J Cardiol. 2019;294:16.

Kamel H, Rahman AF, O’Neal WT, Lewis CE, Soliman EZ. Effect of intensive blood pressure lowering on left atrial remodeling in the SPRINT. Hypertens Res. 2021;44:1326–31.

Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015;16:233–70.

Airale L, Paini A, Ianniello E, Mancusi C, Moreo A, Vaudo G, et al. Left atrial volume indexed for height(2) is a new sensitive marker for subclinical cardiac organ damage in female hypertensive patients. Hypertens Res. 2021;44:692–9.

Inciardi RM, Claggett B, Minamisawa M, Shin SH, Selvaraj S, Goncalves A, et al. Association of left atrial structure and function with heart failure in older adults. J Am Coll Cardiol. 2022;79:1549–61.

Kario K, Sun N, Chiang FT, Supasyndh O, Baek SH, Inubushi-Molessa A, et al. Efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, double-blind, placebo-controlled study. Hypertension. 2014;63:698–705.

Jackson AM, Jhund PS, Anand IS, Dungen HD, Lam CSP, Lefkowitz MP, et al. Sacubitril-valsartan as a treatment for apparent resistant hypertension in patients with heart failure and preserved ejection fraction. Eur Heart J. 2021;42:3741–52.

Suzuki K, Claggett B, Minamisawa M, Nochioka K, Mitchell GF, Anand IS, et al. Pulse pressure, prognosis, and influence of sacubitril/valsartan in heart failure with preserved ejection fraction. Hypertension. 2021;77:546–56.

Kario K, Okada K, Kato M, Nishizawa M, Yoshida T, Asano T, et al. 24-hour blood pressure-lowering effect of an SGLT-2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension: results from the randomized, placebo-controlled SACRA study. Circulation. 2018. https://doi.org/10.1161/CIRCULATIONAHA.118.037076 .

Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Bohm M, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385:1451–61.

Kario K, Williams B. Nocturnal hypertension and heart failure: mechanisms, evidence, and new treatments. Hypertension. 2021;78:564–77.

Kario K, Williams B. Angiotensin receptor-neprilysin inhibitors for hypertension-hemodynamic effects and relevance to hypertensive heart disease. Hypertens Res. 2022. https://doi.org/10.1038/s41440-022-00923-2 .

Brown MA, Magee LA, Kenny LC, Karumanchi SA, McCarthy FP, Saito S, et al. Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice. Hypertension. 2018;72:24–43.

Gestational Hypertension and Preeclampsia. ACOG practice bulletin, number 222. Obstet Gynecol. 2020;135:e237–e60.

American College of O, Gynecologists’ Committee on Practice B-O. ACOG Practice Bulletin No. 203: chronic hypertension in pregnancy. Obstet Gynecol. 2019;133:e26–e50.

Suzuki H, Takagi K, Matsubara K, Mito A, Kawasaki K, Nanjo S, et al. Maternal and perinatal outcomes according to blood pressure levels for prehypertension: A review and meta-analysis. Hypertens Res Pregnancy. 2022. https://doi.org/10.14390/jsshp.HRP2021-018 .

North RA, McCowan LM, Dekker GA, Poston L, Chan EH, Stewart AW, et al. Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort. BMJ. 2011;342:d1875.

Zhang J, Klebanoff MA, Roberts JM. Prediction of adverse outcomes by common definitions of hypertension in pregnancy. Obstet Gynecol. 2001;97:261–7.

Ohkuchi A, Masuyama H, Yamamoto T, Kikuchi T, Taguchi N, Wolf C, et al. Economic evaluation of the sFlt-1/PlGF ratio for the short-term prediction of preeclampsia in a Japanese cohort of the PROGNOSIS Asia study. Hypertens Res. 2021;44:822–9.

Ohkuchi A, Saito S, Yamamoto T, Minakami H, Masuyama H, Kumasawa K, et al. Short-term prediction of preeclampsia using the sFlt-1/PlGF ratio: a subanalysis of pregnant Japanese women from the PROGNOSIS Asia study. Hypertens Res. 2021;44:813–21.

Salazar MR, Espeche WG, Leiva Sisnieguez CE, Minetto J, Balbin E, Soria A, et al. Nocturnal hypertension and risk of developing early-onset preeclampsia in high-risk pregnancies. Hypertens Res. 2021;44:1633–40.

Ueda A, Hasegawa M, Matsumura N, Sato H, Kosaka K, Abiko K, et al. Lower systolic blood pressure levels in early pregnancy are associated with a decreased risk of early-onset superimposed preeclampsia in women with chronic hypertension: a multicenter retrospective study. Hypertens Res. 2022;45:135–45.

Tita AT, Szychowski JM, Boggess K, Dugoff L, Sibai B, Lawrence K, et al. Treatment for mild chronic hypertension during pregnancy. N Engl J Med. 2022;386:1781–92.

Cho L, Davis M, Elgendy I, Epps K, Lindley KJ, Mehta PK, et al. Summary of updated recommendations for primary prevention of cardiovascular disease in women: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75:2602–18.

Mendoza M, Garcia-Ruiz I, Maiz N, Rodo C, Garcia-Manau P, Serrano B, et al. Pre-eclampsia-like syndrome induced by severe COVID-19: a prospective observational study. BJOG. 2020;127:1374–80.

Wu J, Deng W, Li S, Yang X. Advances in research on ACE2 as a receptor for 2019-nCoV. Cell Mol Life Sci. 2021;78:531–44.

Giardini V, Carrer A, Casati M, Contro E, Vergani P, Gambacorti-Passerini C. Increased sFLT-1/PlGF ratio in COVID-19: a novel link to angiotensin II-mediated endothelial dysfunction. Am J Hematol. 2020;95:E188–E91.

Kallioinen N, Hill A, Horswill MS, Ward HE, Watson MO. Sources of inaccuracy in the measurement of adult patients’ resting blood pressure in clinical settings: a systematic review. J Hypertens. 2017;35:421–41.

Kario K. Management of hypertension in the digital era. Hypertension, 2020;76:640–50.

Parati G, Stergiou GS, Bilo G, Kollias A, Pengo M, Ochoa JE, et al. Home blood pressure monitoring: methodology, clinical relevance and practical application: a 2021 position paper by the Working Group on Blood Pressure Monitoring and Cardiovascular Variability of the European Society of Hypertension. J Hypertens. 2021;39:1742–67.

Kario K, Tomitani N, Morimoto T, Kanegae H, Lacy P, Williams B. Relationship between blood pressure repeatedly measured by a wrist-cuff oscillometric wearable blood pressure monitoring device and left ventricular mass index in working hypertensive patients. Hypertens Res. 2022;45:87–96.

Roerecke M, Kaczorowski J, Myers MG. Comparing automated office blood pressure readings with other methods of blood pressure measurement for identifying patients with possible hypertension. JAMA Intern Med. 2019;179:351.

Lee EKP, Zhu M, Chan DCC, Yip BHK, McManus R, Wong SYS. Comparative accuracies of automated and manual office blood pressure measurements in a Chinese population. Hypertens Res. 2022;45:324–32.

Shimbo D, Artinian NT, Basile JN, Krakoff LR, Margolis KL, Rakotz MK, et al. Self-measured blood pressure monitoring at home: a joint policy statement from the American Heart Association and American Medical Association. Circulation 2020;142:e42–e63.

Cohen JB, Lotito MJ, Trivedi UK, Denker MG, Cohen DL, Townsend RR. Cardiovascular events and mortality in white coat hypertension: a systematic review and meta-analysis. Ann Intern Med. 2019;170:853–62.

Bobrie G, Clerson P, Menard J, Postel-Vinay N, Chatellier G, Plouin PF. Masked hypertension: a systematic review. J Hypertens. 2008;26:1715–25.

Uhlig K, Patel K, Ip S, Kitsios GD, Balk EM. Self-measured blood pressure monitoring in the management of hypertension: a systematic review and meta-analysis. Ann Intern Med. 2013;159:185–94.

Zhang D, Huang QF, Li Y, Wang JG. A randomized controlled trial on home blood pressure monitoring and quality of care in stage 2 and 3 hypertension. Hypertens Res. 2021;44:533–40.

Hoshide S, Kanegae H, Kario K. Nighttime home blood pressure as a mediator of N-terminal pro-brain natriuretic peptide in cardiovascular events. Hypertens Res. 2021;44:1138–46.

Kario K, Okada K, Kato M, Nishizawa M, Yoshida T, Asano T, et al. Twenty-four-hour blood pressure–lowering effect of a sodium-glucose cotransporter 2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension. Circulation. 2019;139:2089–97.

Kario K. The sacubitril/valsartan, a first-in-class, angiotensin receptor neprilysin inhibitor (ARNI): potential uses in hypertension, heart failure, and beyond. Current Cardiol Rep. 2018;20:5.

Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet. 2013;381:752–62.

Gupta A, Perdomo S, Billinger S, Beddhu S, Burns J, Gronseth G. Treatment of hypertension reduces cognitive decline in older adults: a systematic review and meta-analysis. BMJ Open. 2020;10:e038971.

Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887–98.

Group SMIftSR, Williamson JD, Pajewski NM, Auchus AP, Bryan RN, Chelune G, et al. Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA. 2019;321:553–61.

Streit S, Poortvliet RKE, Gussekloo J. Lower blood pressure during antihypertensive treatment is associated with higher all-cause mortality and accelerated cognitive decline in the oldest-old. Data from the Leiden 85-plus Study. Age Ageing. 2018;47:545–50.

Qin J, He Z, Wu L, Wang W, Lin Q, Lin Y, et al. Prevalence of mild cognitive impairment in patients with hypertension: a systematic review and meta-analysis. Hypertens Res. 2021;44:1251–60.

Inoue T, Matsuoka M, Shinjo T, Tamashiro M, Oba K, Kakazu M, et al. Blood pressure, frailty status, and all-cause mortality in elderly hypertensives; The Nambu Cohort Study. Hypertens Res. 2022;45:146–54.

Benetos A, Petrovic M, Strandberg T. Hypertension management in older and frail older patients. Circ Res. 2019;124:1045–60.

Ishikawa J, Seino S, Kitamura A, Toba A, Toyoshima K, Tamura Y, et al. The relationship between blood pressure and cognitive function. Int J Cardiol Cardiovasc Risk Prev. 2021;10:200104.

Dempsey PC, Larsen RN, Dunstan DW, Owen N, Kingwell BA. Sitting less and moving more: implications for hypertension. Hypertension. 2018;72:1037–46.

Sardeli AV, Griffth GJ, Dos Santos M, Ito MSR, Chacon-Mikahil MPT. The effects of exercise training on hypertensive older adults: an umbrella meta-analysis. Hypertens Res. 2021;44:1434–43.

Frattola A, Parati G, Cuspidi C, Albini F, Mancia G. Prognostic value of 24-hour blood pressure variability. J Hypertens. 1993;11:1133–7.

Hanazawa T, Asayama K, Watabe D, Hosaka M, Satoh M, Yasui D, et al. Seasonal variation in self-measured home blood pressure among patients on antihypertensive medications: HOMED-BP study. Hypertens Res. 2017;40:284–90.

Hoshide S, Yano Y, Mizuno H, Kanegae H, Kario K. Day-by-day variability of home blood pressure and incident cardiovascular disease in clinical practice: The J-HOP Study (Japan Morning Surge-Home Blood Pressure). Hypertension. 2018;71:177–84.

Johansson JK, Niiranen TJ, Puukka PJ, Jula AM. Prognostic value of the variability in home-measured blood pressure and heart rate: the Finn-Home Study. Hypertension. 2012;59:212–8.

Kario K, Hoshide S, Mizuno H, Kabutoya T, Nishizawa M, Yoshida T, et al. Nighttime blood pressure phenotype and cardiovascular prognosis: practitioner-based nationwide JAMP study. Circulation. 2020;142:1810–20.

Kario K, Pickering TG, Umeda Y, Hoshide S, Hoshide Y, Morinari M, et al. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study. Circulation. 2003;107:1401–6.

Muntner P, Whittle J, Lynch AI, Colantonio LD, Simpson LM, Einhorn PT, et al. Visit-to-visit variability of blood pressure and coronary heart disease, stroke, heart failure, and mortality: a cohort study. Ann Intern Med. 2015;163:329–38.

Narita K, Hoshide S, Kario K. Difference between morning and evening home blood pressure and cardiovascular events: the J-HOP Study (Japan Morning Surge-Home Blood Pressure). Hypertens Res. 2021;44:1597–605.

Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlof B, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010;375:895–905.

de Heus RAA, Tzourio C, Lee EJL, Opozda M, Vincent AD, Anstey KJ, et al. Association between blood pressure variability with dementia and cognitive impairment: a systematic review and meta-analysis. Hypertension. 2021;78:1478–89.

Ishiyama Y, Hoshide S, Kanegae H, Kario K. Increased arterial stiffness amplifies the association between home blood pressure variability and cardiac overload: the J-HOP study. Hypertension. 2020;75:1600–6.

Kokubo A, Kuwabara M, Ota Y, Tomitani N, Yamashita S, Shiga T, et al. Nocturnal blood pressure surge in seconds is a new determinant of left ventricular mass index. J Clin Hypertens. 2022;24:271–82.

Peters R, Xu Y, Eramudugolla R, Sachdev PS, Cherbuin N, Tully PJ, et al. Diastolic blood pressure variability in later life may be a key risk marker for cognitive decline. Hypertension. 2022;79:1037–44.

Wang Y, Zhao P, Chu C, Du MF, Zhang XY, Zou T, et al. Associations of long-term visit-to-visit blood pressure variability with subclinical kidney damage and albuminuria in adulthood: a 30-year prospective cohort study. Hypertension. 2022. https://doi.org/10.1161/HYPERTENSIONAHA.121.18658):101161HYPERTENSIONAHA12118658 .

Kario K, Chirinos JA, Townsend RR, Weber MA, Scuteri A, Avolio A, et al. Systemic hemodynamic atherothrombotic syndrome (SHATS) - Coupling vascular disease and blood pressure variability: Proposed concept from pulse of Asia. Prog Cardiovasc Dis. 2020;63:22–32.

Kario K, Tomitani N, Kanegae H, Yasui N, Nishizawa M, Fujiwara T, et al. Development of a new ICT-based multisensor blood pressure monitoring system for use in hemodynamic biomarker-initiated anticipation medicine for cardiovascular disease: the National IMPACT Program Project. Prog Cardiovasc Dis. 2017;60:435–49.

Huang JF, Zhang DY, Sheng CS, An DW, Li M, Cheng YB, et al. Isolated nocturnal hypertension in relation to host and environmental factors and clock genes. J Clin Hypertens. 2022. In press.

Ewen S, Dorr O, Ukena C, Linz D, Cremers B, Laufs U, et al. Blood pressure variability after catheter-based renal sympathetic denervation in patients with resistant hypertension. J Hypertens. 2015;33:2512–8.

Hoshide S, Yoshida T, Mizuno H, Aoki H, Tomitani N, Kario K. Association of night-to-night adherence of continuous positive airway pressure with day-to-day morning home blood pressure and its seasonal variation in obstructive sleep apnea. J Am Heart Assoc. 2022;11:e024865.

Narita K, Hoshide S, Kario K. Seasonal variation in blood pressure: current evidence and recommendations for hypertension management. Hypertens Res. 2021;44:1363–72.

Umishio W, Ikaga T, Kario K, Fujino Y, Hoshi T, Ando S, et al. Cross-sectional analysis of the relationship between home blood pressure and indoor temperature in winter: a nationwide smart wellness housing survey in Japan. Hypertension. 2019;74:756–66.

Marx N, Davies MJ, Grant PJ, Mathieu C, Petrie JR, Cosentino F, et al. Guideline recommendations and the positioning of newer drugs in type 2 diabetes care. Lancet Diabetes Endocrinol. 2021;9:46–52.

Draznin B, Aroda VR, Bakris G, Benson G, Brown FM, Freeman R.American Diabetes Association Professional Practice Committee et al. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45:S125–S43.

Tanaka A, Node K. Hypertension in diabetes care: emerging roles of recent hypoglycemic agents. Hypertens Res. 2021;44:897–905.

Umemura S, Arima H, Arima S, Asayama K, Dohi Y, Hirooka Y, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019). Hypertens Res. 2019;42:1235–481.

Bangalore S, Kumar S, Lobach I, Messerli FH. Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and bayesian random-effects meta-analyses of randomized trials. Circulation. 2011;123:2799–810.

Reboldi G, Gentile G, Angeli F, Ambrosio G, Mancia G, Verdecchia P. Effects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes: a meta-analysis in 73,913 patients. J Hypertens. 2011;29:1253–69.

Ueki K, Sasako T, Okazaki Y, Kato M, Okahata S, Katsuyama H, et al. Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): an open-label, randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5:951–64.

Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41:255–323.

Itoh H, Komuro I, Takeuchi M, Akasaka T, Daida H, Egashira Y, et al. Intensive treat-to-target statin therapy in high-risk japanese patients with hypercholesterolemia and diabetic retinopathy: report of a randomized study. Diabetes Care. 2018;41:1275–84.

Shinohara K, Ikeda S, Enzan N, Matsushima S, Tohyama T, Funakoshi K, et al. Efficacy of intensive lipid-lowering therapy with statins stratified by blood pressure levels in patients with type 2 diabetes mellitus and retinopathy: Insight from the EMPATHY study. Hypertens Res. 2021;44:1606–16.

Node K, Kishi T, Tanaka A, Itoh H, Rakugi H, Ohya Y, et al. The Japanese Society of Hypertension-Digest of plan for the future. Hypertens Res. 2018;41:989–90.

Tanaka M. Improving obesity and blood pressure. Hypertens Res. 2020;43:79–89.

Haze T, Hatakeyama M, Komiya S, Kawano R, Ohki Y, Suzuki S, et al. Association of the ratio of visceral-to-subcutaneous fat volume with renal function among patients with primary aldosteronism. Hypertens Res. 2021;44:1341–51.

Murai N, Saito N, Nii S, Nishikawa Y, Suzuki A, Kodama E, et al. Postloading insulinemia is independently associated with arterial stiffness in young Japanese persons. Hypertens Res. 2021;44:1515–23.

Burchfiel CM, Sharp DS, Curb JD, Rodriguez BL, Abbott RD, Arakaki R, et al. Hyperinsulinemia and cardiovascular disease in elderly men: the Honolulu Heart Program. Arterioscler Thromb Vasc Biol. 1998;18:450–7.

Packer M. Differential Pathophysiological Mechanisms in Heart Failure With a Reduced or Preserved Ejection Fraction in Diabetes. JACC Heart Fail. 2021;9:535–49.

Tanaka A, Toyoda S, Node K. Vascular functional tests and preemptive medicine. Hypertens Res. 2021;44:117–9.

Tanaka A, Node K. Better vascular function tests in cardiovascular care: learning from evidence and providing improved diagnostics to the patient. Hypertens Res. 2022;45:538–40.

Shibata H, Itoh H. Mineralocorticoid receptor-associated hypertension and its organ damage: clinical relevance for resistant hypertension. Am J Hypertens. 2012;25:514–23.

Kario K, Ito S, Itoh H, Rakugi H, Okuda Y, Yamakawa S. Effect of esaxerenone on nocturnal blood pressure and natriuretic peptide in different dipping phenotypes. Hypertens Res. 2022;45:97–105.

Yoshida Y, Yoshida R, Shibuta K, Ozeki Y, Okamoto M, Gotoh K, et al. Quality of life of primary aldosteronism patients by mineralocorticoid receptor antagonists. J Endocr Soc. 2021;5:bvab020.

Ito S, Kashihara N, Shikata K, Nangaku M, Wada T, Okuda Y, et al. Esaxerenone (CS-3150) in patients with type 2 diabetes and microalbuminuria (ESAX-DN): phase 3 randomized controlled clinical trial. Clin J Am Soc Nephrol. 2020;15:1715–27.

Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383:2219–29.

Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris GL, Rossing P, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021;385:2252–63.

Agarwal R, Filippatos G, Pitt B, Anker SD, Rossing P, Joseph A, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43:474–84.

Okazaki-Hada M, Moriya A, Nagao M, Oikawa S, Fukuda I, Sugihara H. Different pathogenesis of glucose intolerance in two subtypes of primary aldosteronism: Aldosterone-producing adenoma and idiopathic hyperaldosteronism. J Diabetes Investig. 2020;11:1511–9.

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.

Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–57.

McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008.

Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.

Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21.

Bouhanick B, Delchier MC, Lagarde S, Boulestreau R, Conil C, Gosse P, et al. Radiofrequency ablation for adenoma in patients with primary aldosteronism and hypertension: ADERADHTA, a pilot study. J Hypertens. 2021;39:759–65.

Cano-Valderrama O, Gonzalez-Nieto J, Abad-Cardiel M, Ochagavia S, Runkle I, Mendez JV, et al. Laparoscopic adrenalectomy vs. radiofrequency ablation for the treatment of primary aldosteronism. A single center retrospective cohort analysis adjusted with propensity score. Surg Endosc. 2022;36:1970–8.

Guo RQ, Li YM, Li XG. Comparison of the radiofrequency ablation versus laparoscopic adrenalectomy for aldosterone-producing adenoma: a meta-analysis of perioperative outcomes and safety. Updates Surg. 2021;73:1477–85.

Brown JM, Auchus RJ, Honzel B, Luther JM, Yozamp N, Vaidya A. Recalibrating interpretations of aldosterone assays across the physiologic range: immunoassay and liquid chromatography-tandem mass spectrometry measurements under multiple controlled conditions. J Endocr Soc. 2022;6:bvac049.

Nishikawa T, Satoh F, Takashi Y, Yanase T, Itoh H, Kurihara I, et al. Comparison and commutability study between standardized liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and chemiluminescent enzyme immunoassay for aldosterone measurement in blood. Endocr J. 2022;69:45–54.

Ozeki Y, Tanimura Y, Nagai S, Nomura T, Kinoshita M, Shibuta K, et al. Development of a new chemiluminescent enzyme immunoassay using a two-step sandwich method for measuring aldosterone concentrations. Diagnostics. 2021;11:433.

Teruyama K, Naruse M, Tsuiki M, Kobayashi H. Novel chemiluminescent immunoassay to measure plasma aldosterone and plasma active renin concentrations for the diagnosis of primary aldosteronism. J Hum Hypertens. 2022;36:77–85.

Naruse M, Katabami T, Shibata H, Sone M, Takahashi K, Tanabe A, et al. Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021. Endocr J. 2022;69:327–59.

Ozeki Y, Kinoshita M, Miyamoto S, Yoshida Y, Okamoto M, Gotoh K, et al. Re-assessment of the oral salt loading test using a new chemiluminescent enzyme immunoassay based on a two-step sandwich method to measure 24-hour urine aldosterone excretion. Front Endocrinol. 2022;13:859347.

Ochiai-Homma F, Kuribayashi-Okuma E, Tsurutani Y, Ishizawa K, Fujii W, Odajima K, et al. Characterization of pendrin in urinary extracellular vesicles in a rat model of aldosterone excess and in human primary aldosteronism. Hypertens Res. 2021;44:1557–67.

Shibata H. Exosomes and exosomal cargo in urinary extracellular vesicles: novel potential biomarkers for mineralocorticoid-receptor-associated hypertension. Hypertens Res. 2021;44:1668–70.

Azizi M, Sanghvi K, Saxena M, Gosse P, Reilly JP, Levy T, et al. Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial. Lancet. 2021;397:2476–86.

Azizi M, Schmieder RE, Mahfoud F, Weber MA, Daemen J, Davies J, et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial. Lancet. 2018;391:2335–45.

Bohm M, Kario K, Kandzari DE, Mahfoud F, Weber MA, Schmieder RE, et al. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial. Lancet. 2020;395:1444–51.

Kandzari DE, Bohm M, Mahfoud F, Townsend RR, Weber MA, Pocock S, et al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet. 2018;391:2346–55.

Osborn JW, Foss JD. Renal nerves and long-term control of arterial pressure. Compr Physiol. 2017;7:263–320.

Kario K. Essential manual on perfect 24-hour blood pressure management from morning to nocturnal hypertension: up-to-date for anticipation medicine. Wiley Publishing Japan: Tokyo, Japan, 2018, p. 1–328

Foss JD, Wainford RD, Engeland WC, Fink GD, Osborn JW. A novel method of selective ablation of afferent renal nerves by periaxonal application of capsaicin. Am J Physiol Regul Integr Comp Physiol. 2015;308:R112–22.

Zheng H, Katsurada K, Liu X, Knuepfer MM, Patel KP. Specific afferent renal denervation prevents reduction in neuronal nitric oxide synthase within the paraventricular nucleus in rats with chronic heart failure. Hypertension. 2018;72:667–75.

Katsurada K, Ogoyama Y, Imai Y, Patel KP, Kario K. Renal denervation based on experimental rationale. Hypertens Res. 2021;44:1385–94.

Katsurada K, Shinohara K, Aoki J, Nanto S, Kario K. Renal denervation: basic and clinical evidence. Hypertens Res. 2022;45:198–209.

Ogoyama Y, Tada K, Abe M, Nanto S, Shibata H, Mukoyama M, et al. Effects of renal denervation on blood pressures in patients with hypertension: a systematic review and meta-analysis of randomized sham-controlled trials. Hypertens Res. 2022;45:210–20.

Bohm M, Mahfoud F, Ukena C, Hoppe UC, Narkiewicz K, Negoita M, et al. First report of the Global SYMPLICITY Registry on the effect of renal artery denervation in patients with uncontrolled hypertension. Hypertension. 2015;65:766–74.

Mahfoud F, Bohm M, Schmieder R, Narkiewicz K, Ewen S, Ruilope L, et al. Effects of renal denervation on kidney function and long-term outcomes: 3-year follow-up from the Global SYMPLICITY Registry. Eur Heart J. 2019;40:3474–82.

Kim BK, Bohm M, Mahfoud F, Mancia G, Park S, Hong MK, et al. Renal denervation for treatment of uncontrolled hypertension in an Asian population: results from the Global SYMPLICITY Registry in South Korea (GSR Korea). J Hum Hypertens. 2016;30:315–21.

Mahfoud F, Kandzari DE, Kario K, Townsend RR, Weber MA, Schmieder RE, et al. Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial. Lancet. 2022;399:1401–10.

Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393–401.

Miyajima E, Yamada Y, Yoshida Y, Matsukawa T, Shionoiri H, Tochikubo O, et al. Muscle sympathetic nerve activity in renovascular hypertension and primary aldosteronism. Hypertension. 1991;17:1057–62.

Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359:1811–21.

Kuwabara M. Hyperuricemia, cardiovascular disease, and hypertension. Pulse. 2016;3:242–52.

Johnson RJ, Bakris GL, Borghi C, Chonchol MB, Feldman D, Lanaspa MA, et al. Hyperuricemia, acute and chronic kidney disease, hypertension, and cardiovascular disease: report of a scientific workshop organized by the national kidney foundation. Am J Kidney Dis. 2018;71:851–65.

Lanaspa MA, Andres-Hernando A, Kuwabara M. Uric acid and hypertension. Hypertens Res. 2020;43:832–4.

Doria A, Galecki AT, Spino C, Pop-Busui R, Cherney DZ, Lingvay I, et al. Serum urate lowering with allopurinol and kidney function in type 1 diabetes. N Engl J Med. 2020;382:2493–503.

Badve SV, Pascoe EM, Tiku A, Boudville N, Brown FG, Cass A, et al. Effects of allopurinol on the progression of chronic kidney disease. N Engl J Med. 2020;382:2504–13.

Kimura K, Hosoya T, Uchida S, Inaba M, Makino H, Maruyama S, et al. Febuxostat therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: a randomized trial. Am J Kidney Dis. 2018;72:798–810.

Tanaka A, Taguchi I, Teragawa H, Ishizaka N, Kanzaki Y, Tomiyama H, et al. Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: a randomized, controlled trial. PLoS Med. 2020;17:e1003095.

Mackenzie IS, Ford I, Nuki G, Hallas J, Hawkey CJ, Webster J, et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020;396:1745–57.

White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018;378:1200–10.

Mori K, Furuhashi M, Tanaka M, Higashiura Y, Koyama M, Hanawa N, et al. Serum uric acid level is associated with an increase in systolic blood pressure over time in female subjects: Linear mixed-effects model analyses. Hypertens Res. 2022;45:344–53.

Azegami T, Uchida K, Arima F, Sato Y, Awazu M, Inokuchi M, et al. Association of childhood anthropometric measurements and laboratory parameters with high blood pressure in young adults. Hypertens Res. 2021;44:711–9.

Kawasoe S, Kubozono T, Ojima S, Kawabata T, Miyahara H, Tokushige K, et al. J-shaped curve for the association between serum uric acid levels and the prevalence of blood pressure abnormalities. Hypertens Res. 2021;44:1186–93.

Kuwabara M, Hisatome I, Niwa K, Bjornstad P, Roncal-Jimenez CA, Andres-Hernando A, et al. The optimal range of serum uric acid for cardiometabolic diseases: a 5-year japanese cohort study. J Clin Med. 2020;9:942.

Furuhashi M, Higashiura Y, Koyama M, Tanaka M, Murase T, Nakamura T, et al. Independent association of plasma xanthine oxidoreductase activity with hypertension in nondiabetic subjects not using medication. Hypertens Res. 2021;44:1213–20.

Kusunose K, Yoshida H, Tanaka A, Teragawa H, Akasaki Y, Fukumoto Y, et al. Effect of febuxostat on left ventricular diastolic function in patients with asymptomatic hyperuricemia: a sub analysis of the PRIZE Study. Hypertens Res. 2022;45:106–15.

Chen CW, Wu CH, Liou YS, Kuo KL, Chung CH, Lin YT, et al. Roles of cardiovascular autonomic regulation and sleep patterns in high blood pressure induced by mild cold exposure in rats. Hypertens Res. 2021;44:662–73.

Domingos-Souza G, Santos-Almeida FM, Meschiari CA, Ferreira NS, Pereira CA, Pestana-Oliveira N, et al. The ability of baroreflex activation to improve blood pressure and resistance vessel function in spontaneously hypertensive rats is dependent on stimulation parameters. Hypertens Res. 2021;44:932–40.

Hirooka Y. Sympathetic activation in hypertension: importance of the central nervous system. Am J Hypertens. 2020;33:914–26.

Iyonaga T, Shinohara K, Mastuura T, Hirooka Y, Tsutsui H. Brain perivascular macrophages contribute to the development of hypertension in stroke-prone spontaneously hypertensive rats via sympathetic activation. Hypertens Res. 2020;43:99–110.

Kasacka I, Piotrowska Z, Domian N, Acewicz M, Lewandowska A. Canonical Wnt signaling in the kidney in different hypertension models. Hypertens Res. 2021;44:1054–66.

Matsusaka T, Niimura F, Shimizu A, Pastan I, Saito A, Kobori H, et al. Liver angiotensinogen is the primary source of renal angiotensin II. J Am Soc Nephrol. 2012;23:1181–9.

Matsuyama T, Ohashi N, Aoki T, Ishigaki S, Isobe S, Sato T, et al. Circadian rhythm of the intrarenal renin-angiotensin system is caused by glomerular filtration of liver-derived angiotensinogen depending on glomerular capillary pressure in adriamycin nephropathy rats. Hypertens Res. 2021;44:618–27.

Otsuki T, Fukuda N, Chen L, Ueno T, Otsuki M, Abe M. TWIST1 transcriptionally upregulates complement 3 in glomerular mesangial cells from spontaneously hypertensive rats. Hypertens Res. 2022;45:66–74.

Liu C, Li X, Fu J, Chen K, Liao Q, Wang J, et al. Increased AT1 receptor expression mediates vasoconstriction leading to hypertension in Snx1(-/-) mice. Hypertens Res. 2021;44:906–17.

Liu X, Jiang D, Huang W, Teng P, Zhang H, Wei C, et al. Sirtuin 6 attenuates angiotensin II-induced vascular adventitial aging in rat aortae by suppressing the NF-kappaB pathway. Hypertens Res. 2021;44:770–80.

Wu H, Lam TYC, Shum TF, Tsai TY, Chiou J. Hypotensive effect of captopril on deoxycorticosterone acetate-salt-induced hypertensive rat is associated with gut microbiota alteration. Hypertens Res. 2022;45:270–82.

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Masaki Mogi

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Mogi, M., Maruhashi, T., Higashi, Y. et al. Update on Hypertension Research in 2021. Hypertens Res 45 , 1276–1297 (2022). https://doi.org/10.1038/s41440-022-00967-4

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To study the value of ultrasound in the diagnosis of juxtaglomerular cell tumor (JGCT).

From January 2005 to July 2020, fifteen patients diagnosed as JGCT by surgical pathology in Peking Union Medical College Hospital were collected. All patients underwent preoperative ultrasound examination. The clinical, laboratory, ultrasound, computed tomography (CT), surgical, and pathological features of the patients were analyzed retrospectively.

The 15 patients were 5 males and 10 females with a median age of 29 years (10 ∼ 72 years). 14 of them had hypertension and one had normal blood pressure. The tumors were all solitary, with a median diameter of 1.5 cm (0.9–5.9 cm). Among the fifteen patients, eleven were correctly detected by preoperative ultrasound, and four were missed. There was a significant difference in tumor size (2.64 ± 1.48 cm vs. 1.23 ± 0.21 cm) and whether the tumor protruded outward (9/11 vs. 0/4) between the ultrasound-detected group and the ultrasound-missed group ( p  = 0.010, p  = 0.011). Of the 11 tumors detected by ultrasound, four were extremely hypoechoic, two were hypoechoic, three were isoechoic, and two were hyperechoic. Color Doppler showed no blood flow in five tumors with the size range from 0.9 to 2.0 cm, and mild blood flow in six tumors with the size range from 2.8 to 5.9 cm.

Conclusions

JGCT is rare, and has characteristic clinical manifestations. Diagnosis should be suspected in case of secondary hypertension, particularly in young women, if no renal vascular cause was found. Ultrasound, combined with clinical manifestations, was helpful for the diagnosis.

Peer Review reports

Introduction

JGCT is a rare and benign renal tumor that originate from the juxtaglomerular cells of the capillary adventitia in the juxtaglomerular complex. The tumor is also called reninoma because it can secrete renin [ 1 , 2 ]. Since the first report of JGCT in 1967 [ 3 ], fewer than 200 cases have been reported in the literature [ 4 ]. It is more common in young females aged 20–39 years, with a male: female ratio of 1:2 [ 5 ]. Occasionally cases in children and elderly patients were reported [ 2 , 6 , 7 ]. Typical clinical manifestations are hypertension, high renin activity, secondary aldosteronism, and hypokalemia [ 8 ], but some patients may have atypical clinical manifestations. Surgery is an effective treatment for JGCT [ 9 , 10 , 11 ].

Improvements in imaging techniques have led to a shorter interval between the occurrence of hypertension and the diagnosis of JGCT [ 12 ]. However, the diagnosis of JGCT remains challenging because it is rare, generally small, located in the renal cortex or subcortical regions, and may be missed or misdiagnosed [ 5 ]. Ultrasound could be helpful, however, the ultrasound manifestations of JGCT have not been fully studied. This study retrospectively summarized the clinical, laboratory, ultrasound and computed tomography (CT) characteristics of 15 JGCT patients and reviewed the literature to study the value of ultrasound in the diagnosis of JGCT.

This study was approved by the institutional review board of our hospital. From January 2005 to July 2020, fifteen patients diagnosed as JGCT by surgical pathology in Peking Union Medical College Hospital were collected. The clinical, laboratory, ultrasound, CT, surgical, and pathological features of the patients were analyzed retrospectively.

Ultrasound examination

The ultrasound examination was performed by the PHLIPS HDI 5000, PHILIPS IU 22 machine (Philips Healthcare, Amsterdam, Netherland) and GE LOGIQ 9 (GE Healthcare, Wauwatosa, WI), equipped with 3.5–5 MHz probe, kidney presets. The grayscale and Color Doppler images of each patient were acquired and saved by radiologists with more than 5 years of experience in ultrasound examination. Image analysis was carried out by two radiologists with more than 5 years of experience with no knowledge of any clinical information. In case of disagreement between the two radiologists, the consensus was reached by discussion.

Image analysis included the location of the tumor (right/left kidney, cortex/cortex and medulla, protruded outward or not), size (the longest diameter), echo pattern (hypoechoic/isoechoic/ hyperechoic), shape (regular/irregular), margin (clear/indistinct), capsule (existent/ inexistent), blood flow signal (no/mild/abundant). Compared with the adjacent renal cortex, the echo pattern is divided into hypoechoic, isoechoic, and hyperechoic. The shape is classified as regular (round or lobulated), and irregular [ 13 ]. Clear margin meant that the tumor had a clear demarcation with the surrounding tissues. Otherwise, the margin was defined as indistinct. The capsule referred to the fibrous connective tissue membrane around the tumor, which appeared as a hyperechoic line on ultrasound. The blood flow was classified as no, mild (1–2 blood flows), and abundant (≥ 3 blood flows) according to Adler’s grading [ 14 ].

Surgery and histopathological examinations

Surgeries were performed after the completion of necessary examinations. The location and size of the tumors were recorded during surgeries. Histopathological results were considered as the golden standard.

Literature review

The literature search was conducted in Pub Medline and Embase with the keyword string “juxtaglomerular cell tumor ultrasound”. The study inclusion criteria included the diagnosis of JGCT with ultrasound descriptions (at least size and echo). The exclusion criteria were review articles, irrelevant or duplicate papers, and papers without full text available.

Statistical analysis

SPSS 20.0 software was used for statistical analysis. Shapiro-wilk test was used to determine the normality of the data. Independent-samples T test or Fisher’s exact test was used to compare the differences between the two groups. P-values < 0.05 were considered statistically significant.

Baseline characteristics

The clinical, ultrasound, and CT manifestations of 15 patients with JGCT were shown in Table  1 . Among the 15 patients, there were 5 males and 10 females with a median age of 29 years (min-max, 10–72 years). Eleven (73.3%, 11/15) patients had grade III hypertension, three (20.0%, 3/15) patients had grade II hypertension, and one (6.7%, 1/15) patient had normal blood pressure. Six patients had blurred vision, six had dizziness or headache, and one had cerebral hemorrhage. The median interval from the diagnosis of hypertension to JGCT was 27 months (min-max, 1 month-12 years). Serum potassium was low in 10 patients (median 2.75 mmol/L, min-max, 2.3–3.2 mmol/L), and normal in 5 patients. The renin activity test was conducted in nine patients, and the results all showed high activity (median 6.17 ng/ml/h, min-max, 3.07–17.6 ng/ml/h). Plasma renin was tested in three patients, two of whom showed high levels (859 µIU/ml, 583 pg/ml) and one normal. The aldosterone test was performed in eleven patients, yielding ten elevated results (median: 348.95 pg/ml, min-max, 164.7–967 pg/ml) and one normal. Three patients were hospitalized for renal tumor surgery with no blood tests for reninoma, two of them had hypertension, and one had normal blood pressure. The serum potassium was normal in these three patients.

All 15 JGCTs were solitary tumors, including seven in the right kidney and eight in the left kidney. The median longest diameter of the tumors was 1.5 cm (min-max, 0.9–5.9 cm).

Ultrasound manifestations

Among the 15 JGCTs, 11 were correctly detected by preoperative ultrasound, and 4 were missed.

Of the 11 tumors detected by ultrasound, the median longest diameter of the tumors was 2.8 cm (min-max, 0.9–5.9 cm). Nine protruded outward, one protruded toward the collecting system, and one was completely in the renal cortex with no protrusion. Four were extremely hypoechoic (Fig.  1 ), two were hypoechoic, three were isoechoic (Fig.  2 ), and two were hyperechoic. The morphology was regular in ten cases and irregular in one case. The margin was clear in eight cases and indistinct in three cases. Ultrasound showed a capsule in two cases and no capsule in nine cases. Color Doppler showed no blood flow in five tumors with the size range from 0.9 to 2.0 cm, and mild blood flow in six tumors with the size range from 2.8 to 5.9 cm. The preoperative diagnosis was one reninoma, one renal cell carcinoma, and nine undetermined tumors.

figure 1

A JGCT lesion in the right kidney. Ultrasound showed extremely hypoechoic lesion (arrow), 1.2 × 1.0 × 0.8 cm,with regular morphology and clear boundary

figure 2

A JGCT lesion in the left kidney. (a) Grayscale ultrasound showed isoechoic lesion (arrow), 4.0 × 3.4 × 3.1 cm, with regular morphology and clear boundary. (b) Color Doppler ultrasound showed mild blood flow. (c) Morphologic features on hematoxylin-eosin stain. The diagnosis of JGCT was confirmed by the postoperative pathology

Of the 4 tumors missed by ultrasound, the longest diameter was 1.0 cm, 1.2 cm, 1.5 cm, and 1.2 cm respectively. All of them located in the renal cortex with no protrusion outward.

There was a significant difference in tumor size (2.64 ± 1.48 cm vs. 1.23 ± 0.21 cm, Independent-samples T test, p  = 0.010) between the ultrasound-detected group and ultrasound-missed group. There was also a significant difference in whether the tumor protruded outward (9/11 vs. 0/4, Fisher’s exact test, p  = 0.011) between the two groups (Table  2 ).

CT manifestations

Of the 11 tumors detected by ultrasound, non-contrast enhanced CT showed five low density, three isodensity, one slightly high density and two mixed density. Dynamic contrast-enhanced CT showed nine mild enhancement, and two moderate enhancement in parenchymal phase. The preoperative CT diagnosis was three reninoma, one renal cell carcinoma, and seven undetermined tumors.

Of the 4 lesions missed by ultrasound, two tumors located in the cortex, with the size of 1.0 and 1.2 cm respectively, showed similar density with the cortex on non-contrast enhanced CT and mild enhancement during parenchymal phase on contrast enhanced CT. One tumor located in the cortex with the size of 1.2 cm, showed slightly high density on non-contrast enhanced CT and mild enhancement during parenchymal phase on contrast enhanced CT. One tumor located in the cortex and medulla, with the size of 1.5 cm, showed slightly high density on non-contrast enhanced CT and moderate enhancement during parenchymal phase on contrast enhanced CT. The preoperative CT diagnosis was three reninoma, and one renal cell carcinoma.

Surgery and follow-up

All 15 patients underwent partial nephrectomy. Two of them underwent intraoperative ultrasound localization, which successfully guided the laparoscopic partial nephrectomy. The blood pressure returned to normal in 13 patients after operation. No tumor relapse was found in any of the 15 patients during the follow-up of 6 months to 15 years.

Eighty-five papers (65 papers in PubMed and 20 papers in Embase) were retrieved. A total of 25 patients in 13 papers met the inclusion criteria including 17 females and 8 males with a median age of 24 years (11–57 years) [ 4 , 11 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. All tumors were solitary, with a median size of 3.3 cm (0.6–6.5 cm). Two JGCTs were extremely hypoechoic, 12 were hypoechoic, 1 were isoechoic, 10 were hyperechoic.

JGCT is a rare renal tumor. Haab et al. reported eight cases of JGCT among 30,000 hypertensive patients in a 15-year period [ 26 ]. The tumor is usually solitary, small in size (< 3 cm, rarely > 4 cm) [ 1 , 5 ]. Surgery is an effective treatment. To our knowledge, this is the largest report describing the clinical, laboratory, ultrasound and CT manifestations of JGCT, providing detailed descriptions of the ultrasound characteristics of 15 cases.

In our series, JGCT showed extremely hypoechoic, hypoechoic, isoechoic or hyperechoic, with no or mild blood flow, as described previously [ 4 , 5 , 6 , 7 , 8 , 10 , 11 , 19 , 20 , 22 , 23 , 25 , 26 , 27 , 28 , 29 ]. Hypoechoic, especially extremely hypoechoic, may be explained by the closely packed cellular, highly organized, and compact architectural organization, as seen in other endocrine tumors. Extremely hypoechoic might be the characteristics, however, the data remained insufficient and further study is needed. The tumor showed no or mild blood flow might be related to the vasoconstriction caused by renin and the decreased blood flow caused by the proliferation of intima and middle layer of tumor arterioles [ 29 ]. Pathologically, JGCT generally has fibrous capsule [ 11 , 22 , 28 ], however we observed capsule in only two patients, which might be due to the thin capsule hardly detected by ultrasound.

The ultrasound diagnosis of JGCT is still challenging. In our study, four tumors, with small size (1.0 ∼ 1.5 cm) and located completely in the cortex with no protrusion, were missed by ultrasound. Two of them showed similar density with the cortex and were missed on the non-contrast enhanced CT. Because ultrasound and non-enhanced CT can fail, contrast enhanced CT should be performed when a JGCT is suspected. The contrast enhanced CT was positive in all of the 15 JGCTs in our study, as well as in the cases reported [ 5 , 26 , 30 , 31 , 32 ]. Taken together, contrast enhanced CT should be considered in all cases of JGCT. Contrast enhanced ultrasound might be helpful [ 4 , 25 ]. Li et al. reported two cases of JGCT, invisible by previous conventional ultrasound, found by contrast enhanced ultrasound. They were complete endophytic, and showed hypoenhancement, slow wash in and slow wash out. One was 1.0 × 1.0 × 0.7 cm, the other was 3.0 × 2.0 × 1.0 cm [ 25 ]. The small sample size precluded a firm recommendation of contrast enhanced ultrasound for JGCT diagnosis. JGCT may have specific features in enhanced ultrasound, which needs to be confirmed by future studies. However, the application of enhanced ultrasound needs to be based on the two-dimensional ultrasound localization of the lesion. Therefore, enhanced ultrasound may not be helpful in reducing ultrasound misdiagnosis of JGCT cell tumors, which requires other solutions.

The limitation of our study was the small number of cases and techniques such as contrast enhanced ultrasound was not applied. Most of the studies were case reports, so we did not conduct a meta-analysis. A multicenter study and more in-depth prospective studies should be conducted in the future to provide a more comprehensive information of this rare tumor.

JGCT is rare, and has characteristic clinical manifestations. Diagnosis should be suspected in case of secondary hypertension, particularly in young women, if no renal vascular cause is found. Ultrasound, combined with clinical manifestations, was helpful for the diagnosis.

Data availability

The data and material can be provided if asked on a basis of good reasons.

Abbreviations

juxtaglomerular cell tumor

computed tomography

Duan X, Bruneval P, Hammadeh R, Fresco R, Eble JN, Clark JI, Vigneswaran WT, Flanigan RC. Picken MM.Metastatic juxtaglomerular cell tumor in a 52-year-old man. Am J Surg Pathol. 2004;28:1098–102.

Article   PubMed   Google Scholar  

Shera AH, Baba AA, Bakshi IH, Lone IA. Recurrent malignant juxtaglomerular cell tumor: a rare cause of malignant hypertension in a child. J Indian Assoc Pediatr Surg. 2011;16:152–4.

Article   PubMed   PubMed Central   Google Scholar  

Robertson PW, Klidjian A, Harding LK, Walters G, Lee MR. Robb-Smith AHT.Hypertension due to a renin-secreting renal tumour. Am J Med. 1967;43:963–76.

Article   CAS   PubMed   Google Scholar  

Zhang R, Xu M, Xie XY. The role of Real-Time contrast-enhanced Ultrasound in Guiding Radiofrequency ablation of Reninoma: Case Report and Literature Review. Front Oncol. 2021;11:585257.

Wong L, Hsu THS, Perlroth MG, Hofmann LV, Haynes CM, Katznelson L. Reninoma: case report and literature review. J Hypertens 2008, 26.

Onder S, Baydar DE. A case of juxtaglomerular cell tumor with novel histologic features. Int J Surg Pathol. 2011;19:65–70.

Shao L, Manalang M, Cooley L. Juxtaglomerular cell tumor in an 8-year-old girl. Pediatr Blood Cancer. 2008;50:406–9.

Elouazzani H, Jahid A, Bernoussi Z. Mahassini N.Juxtaglomerular cell tumor: a distinct mesenchymal tumor of kidney. J Clin Imaging Sci. 2014;4:33.

Jiang S, Yang Y, Wu R, Yang Q, Zhang C, Tang Y, Mo C. Characterization and management of Juxtaglomerular Cell Tumor: analysis of 9 cases and literature review. Balkan Med J. 2020;37:287–90.

CAS   PubMed   PubMed Central   Google Scholar  

Mezoued M, Habouchi MA, Azzoug S, Mokkedem K, Meskine D, JUXTAGLOMERULAR CELL CAUSE OF SECONDARY HYPERTENSION IN AN ADOLESCENT. Acta Endocrinol (Buchar). 2020;16:359–61.

Trnka P, Orellana L, Walsh M, Pool L, Borzi P. Reninoma: an uncommon cause of renin-mediated hypertension. Front Pediatr. 2014;2:89.

Ruyer A, Millet I, Ribstein J, Taourel P. [Renin-producing tumor: a rare case of curable hypertension. A case report]. J Radiol. 2011;92:58–61.

ACR BI-RADS breast imaging and reporting data system. Breast imaging atlas. 5th ed. edn. Reston, VA: American College of Radiology; 2013.

Google Scholar  

Adler DD, Carson PL, Rubin JM, Quinn-Reid D. Doppler ultrasound color flow imaging in the study of breast cancer: preliminary findings. Ultrasound Med Biol. 1990;16:553–9.

Kashiwabara H, Inaba M, Itabashi A, Ishii J, Katayama SA. Case of renin-producing Juxtaglomerular Tumor: effect of ACE inhibitor or angiotensin II receptor antagonist. Blood Press. 1997;6:147–53.

Yang H, Wang Z, Ji J. Juxtaglomerular cell tumor: a case report. Oncol Lett. 2016;11:1418–20.

Chambô JL, Falci Júnior R, Lucon AM. Juxtaglomerular cell tumor as a rare cause of hypertension in adults. Int Braz J Urol. 2004;30:119–20.

Squires JP, Ulbright TM, DeSchryver-Kecskemeti K. Engleman W.Juxtaglomerular cell tumor of the kidney. Cancer. 1984;53:516–23.

Lachvac L, Svajdler M, Valansky L, Nagy V, Benicky M, Frohlichova L. Nyitrayova O.Juxtaglomerular cell tumor, causing fetal demise. Int Urol Nephrol. 2011;43:365–70.

Tessi C, Szklarz MT, Vásquez M, López Imizcoz F, Ruiz J, Weller S, Villoldo G, Sager C, Burek CM. Corbetta JP.Laparoscopic Nephro-Sparing surgery of a Reninoma Tumor in a Pediatric patient. Urology. 2020;143:261.

Xue M, Chen Y, Zhang J, Guan Y, Yang L, Wu B. Reninoma coexisting with adrenal adenoma during pregnancy: a case report. Oncol Lett. 2017;13:3186–90.

Dunnick NR, Hartman DS, Ford KK, Davis CJ Jr., Amis ES. Jr.The radiology of juxtaglomerular tumors. Radiology. 1983;147:321–6.

Chen Z, Tang Z-Y, Liu H-T, Chen X. Treatment of Juxtaglomerular Cell Tumor of the kidney by retroperitoneal laparoscopic partial nephrectomy. Urol J. 2014;10:1160–1.

PubMed   Google Scholar  

Weiss JP, Pollack HM, McCormick JF, Malloy TM, Hanno PM, Carpiniello VL. Renal hemangiopericytoma: surgical, radiological and pathological implications. J Urol. 1984;132:337–9.

Qiuyang Li M, Ying Zhang MD, Yong Song MD, Aitao Guo MD, Nan Li BS, Yukun Luo MD. Jie Tang, MD.Clinical Application of Ultrasound in the diagnosis and treatment of Reninoma. Adv Ultrasound Diagnosis Therapy. 2020;4:211–6.

Article   Google Scholar  

Haab F, Duclos JM, Guyenne T, Plouin PF, Corvol PR. Secreting tumors: diagnosis, Conservative Surgical Approach and Long-Term results. J Urol. 1995;153:1781–4.

Brandal P, Busund LT, Heim S. Chromosome abnormalities in juxtaglomerular cell tumors. Cancer. 2005;104:504–10.

Hagiya A, Zhou M, Hung A, Aron MJ. Cell Tumor with atypical pathological features: report of a case and review of literature. Int J Surg Pathol. 2020;28:87–91.

Prasad SR, Surabhi VR, Menias CO, Raut AA, Chintapalli KN. Benign renal neoplasms in adults: cross-sectional imaging findings. AJR Am J Roentgenol. 2008;190:158–64.

Corvol P, Pinet F, Plouin PF, Bruneval P, Menard J. Renin-secreting tumors. Endocrinol Metab Clin North Am. 1994;23:255–70.

Tanabe A, Naruse M, Ogawa T, Ito F, Takagi S, Takano K, Ohashi H, Tsuchiya K, Sone M, Nihei H, et al. Dynamic computer tomography is useful in the Differential diagnosis of Juxtaglomerular Cell Tumor and Renal Cell Carcinoma. Hypertens Res. 2001;24:331–6.

Faucon A-L, Bourillon C, Grataloup C, Baron S, Bernadet-Monrozies P, Vidal-Petiot E, Azizi M, Amar L. Usefulness of Magnetic Resonance Imaging in the diagnosis of Juxtaglomerular Cell tumors: a report of 10 cases and review of the literature. Am J Kidney Dis. 2019;73:566–71.

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Li Wang and Meiying Li contributed equally to this work.

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Department of Ultrasound, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan 1, Dongcheng District, 100730, Beijing, China

Li Wang, Meiying Li, Siqi Jin, Yunshu Ouyang, Ke Lv, Jianchu Li, Yuxin Jiang, He Liu & Qingli Zhu

Department of Ultrasound, Tangshan Central Hospital, West of Youyi Road, Lubei District, 063000, Tangshan City, Hebei, China

Li Wang & Fenglan Wang

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Correspondence: [email protected] and [email protected]. Joint corresponding authors: HL and QZ. LW and ML have contributed equally. All authors have contributed significantly to this paper. LW and ML collected and analyzed the data, then wrote the manuscript; SJ, YO, FW, and KL provided professional opinions about JGCT and ultrasound manifestations; JL and YJ revised the manuscript; HL and QZ designed and supervised the study. All authors read and approved the final manuscript.

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Correspondence to He Liu or Qingli Zhu .

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The study was conducted in accordance with the Declaration of Helsinki. The Institutional Review Board of Peking Union Medical College Hospital has reviewed the protocol of this manuscript and determined that this study is a retrospective study and the need for informed consent is waived.

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Wang, L., Li, M., Jin, S. et al. How to identify juxtaglomerular cell tumor by ultrasound: a case series and review of the literature. BMC Med Imaging 24 , 46 (2024). https://doi.org/10.1186/s12880-024-01220-9

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New Approaches in Hypertension Management: a Review of Current and Developing Technologies and Their Potential Impact on Hypertension Care

1 Radcliffe Department of Medicine (Cardiovascular Division), University of Oxford, Oxford, UK

Rachael Fox

2 Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Primary Care, Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2 6GG UK

Katherine L. Tucker

Richard j. mcmanus.

Hypertension is a key risk factor for cardiovascular disease. Currently, around a third of people with hypertension are undiagnosed, and of those diagnosed, around half are not taking antihypertensive medications. The World Health Organisation (WHO) estimates that high blood pressure directly or indirectly causes deaths of at least nine million people globally every year.

Purpose of Review

In this review, we examine how emerging technologies might support improved detection and management of hypertension not only in the wider population but also within special population groups such as the elderly, pregnant women, and those with atrial fibrillation.

Recent Findings

There is an emerging trend to empower patients to support hypertension screening and diagnosis, and several studies have shown the benefit of tele-monitoring, particularly when coupled with co-intervention, in improving the management of hypertension.

Novel technology including smartphones and Bluetooth®-enabled tele-monitoring are evolving as key players in hypertension management and offer particular promise within pregnancy and developing countries. The most pressing need is for these new technologies to be properly assessed and clinically validated prior to widespread implementation in the general population.

Introduction

Hypertension has been identified by WHO [ 1 ] as one of the most significant risk factors for morbidity and mortality worldwide and is responsible for the deaths of approximately nine million people annually [ 1 ]. In the UK, the National Institute for Health and Care Excellence (NICE) [ 2 ] defines high blood pressure (BP), also known as hypertension, as a clinic blood pressure of 140/90 mmHg or higher confirmed by a subsequent ambulatory blood pressure monitoring daytime average (or home blood pressure monitoring average) of 135/85 mmHg or higher.

High blood pressure does not just develop in older adults. Over 2.1 million people under 45 years old had high blood pressure in England in 2015 [ 3 ]. This is important because treating hypertension results in significant reductions in risk of subsequent cardiovascular disease [ 4 , 5 ]. Despite strong evidence for such treatment, studies suggest that many people remain sub-optimally controlled [ 6 ]. New approaches, including new technologies, are therefore needed to improve screening, detection and control of raised blood pressure in the community.

High blood pressure is largely asymptomatic, especially in the early stages, leading to its description as a ‘silent killer’ [ 1 ]. The asymptomatic nature of hypertension in conjunction with its disease burden necessitates routine blood pressure screening. In the UK, NICE guidelines recommend blood pressure measurement at least yearly among normotensive adults [ 3 ] and currently hypertension is largely identified in this way by physicians routinely or opportunistically assessing blood pressure in a primary care clinic setting [ 7 ]. However, it has been estimated that between a third and a half of hypertensive patients remain undiagnosed, indicating the need for better screening [ 8 ]. Developments in non-physician-based blood pressure measurements utilising new technologies may provide an opportunity for increased detection of hypertension.

Self-screening allows patients to measure their own blood pressure outside of physician consultations, either in their own home or with public validated solid cuff automatic sphygmomanometers that require no training, just simple instructions for use [ 7 ]. In Japan, the market penetration of home blood pressure monitoring is such that it is estimated that more than enough monitors have been sold for one per household. In the UK, at least 1:10 normotensive adults have measured their own blood pressure at some time in the past [ 9 ]. A recent systematic review [ 7 ] identified three studies of self-screening, which utilised public blood pressure cuffs in a variety of settings including pharmacies and grocery stores (Hamilton 2003 [ 10 ], Houle 2013 [ 11 ], Nykamp 2016 [ 12 ]). The majority of these were conducted in North America, where out-of-office blood pressure self-screening stations in pharmacies and work places are estimated to be used more than one million times a day [ 13 ]. Providing additional blood pressure self-monitoring equipment in physician waiting rooms has been proposed in the UK to increase blood pressure screening [ 14 ], and such monitors are available in around a third of practice in the UK [ 15 ]. Whilst several studies to date show promising results for feasibility, patient autonomy, convenience, and increased detection of hypertension (Hamilton 2003 [ 10 ], Houle 2013 [ 11 ] and Tompson 2017 [ 14 ]), a number of barriers are yet to be overcome before widespread community self-screening can be recommended. These include limited privacy, poor awareness of the availability of the facilities, and a lack of education regarding the asymptomatic nature of hypertension and the benefits of screening [ 14 ].

Breaking away from traditional cuff-based measurement of blood pressure, the widespread accessibility of smartphones and mobile health applications also offer new potential for the ubiquitous monitoring of parameters such as blood pressure. Recently, for example, the Cardiogram® application on the Apple® watch has been evaluated for its utility at using deep learning algorithms to predict hypertension from inputs of heart rate and step count. Data were collected from 6115 app users for an average of 9 weeks and predicted hypertension moderately well [ 16 ]. This particular ‘app’ can now utilise multiple other wearable devices such as Fitbit®, Garmin® and Android devices; however, further research into its diagnostic utility is required. Furthermore, in the UK at least, current market penetration of smartphones into elderly populations is not sufficient for these techniques to be widely available in this key age group, but they have definite potential to aid detection of hypertension in younger adults [Ofcom communications market 2018]. In addition, cognitive deficits and visual or hearing impairments, which are more prominent in the older population, can decrease the accessibility of smartphone applications. It seems likely that further advances in technology will increase the spread of such techniques, but the need for long-term treatment of hypertension means that a formal diagnosis of hypertension is likely to remain paramount.

Hypertension Diagnosis

Once a person has been screened and found to have high blood pressure, ambulatory blood pressure monitoring (ABPM) is regarded as the most accurate way to diagnose hypertension and is recommended by guidelines to routinely to confirm elevated blood pressure readings [ 2 , 17 , 18 ]. Ambulatory monitors typically involve portable, automated cuffs worn continuously that measure blood pressure every 15–30 min during the day and 15–60 min overnight [ 19 ]. Despite their utility in diagnosis, ambulatory monitors may not be available to many clinicians and patients due to cost and time limitations [ 19 ] and can be uncomfortable and disruptive to daily life and sleep [ 9 , 20 ]. Advances in technology have allowed for the development of new ‘cuff-less’ BP monitoring devices however, which continuously monitor BP without disruption to daily activities. Cuff-less BP monitoring devices utilise smartphone or wearable sensor technologies that can estimate BP from ECG signals, photoplethysmogram (PPG) signals (using infrared light on the finger to estimation of skin blood flow), or a combination of both [ 21 ]. For example, one system developed consists of a wearable wrist band to collect PPG signals, a wearable heart rate belt to collect ECG signals, and a smartphone. The signals from the wearable device communicate via Bluetooth with the smartphone to synchronise their measurements and continuously stream the wearer’s blood pressure. Other devices that have been developed utilise sensors in T-shirts [ 22 ], placed behind the ear [ 23 ] and in a computer mouse [ 24 ] to calculate and record blood pressure measurements.

As with screening, the use of ‘smartphone apps’ is increasingly popular to aid in diagnosis. One US survey of ‘app users’ showed that 31% of mobile phone owners used their phone to look for health information, with the largest proportion (52%) among smartphone users [ 25 ]. Although this is a hugely expanding field, with > 180 apps now existing to measure blood pressure, in only 3.8% (7/184) of the blood pressure apps was any involvement of medical experts mentioned in its development and very few apps have been robustly evaluated [ 25 ]. Moreover, at present, no mobile apps have formally obtained approval for use as measuring/diagnostic devices by the US Food and Drug Administration or European Commission. The American Heart Association (AHA) has stated that there are too many errors with smartphone blood pressure apps [ 26 ] with mobile app–based blood pressure measurements being inaccurate four out of five times when one popular mobile application was tested [ 25 , 26 ].

A vital issue with both the apps and novel non-invasive devices is the lack of a universally agreed standard for the validation of this technology, and current protocols simply do not include them. There are plans to rectify this [ 27 •] with some apps exploring clinical validation [ 28 , 29 ] so the future does look brighter. At present, however, there is limited incorporation of this technology into widespread clinical practice as a result of this key issue [ 26 ].

Hypertension Management

Around 14% of the adult population in England and Wales currently appear on primary care hypertension registers [ 8 ] which equates to over seven million people. This provides a significant market for technology to assist in control. Currently, 60% of those on hypertensive registers are controlled [ 30 ], and only 50% of those starting on a new antihypertensive remaining taking it after 6 months [ 3 ]. In this cohort of people, the technology to facilitate management has been available for some years but has only recently acquired a solid evidence base. Options considered in this section range from self-monitoring and tele-monitoring to virtual clinics and artificial intelligence (AI)–assisted management.

  • Self-monitoring of blood pressure can improve blood pressure control and is an increasingly common part of hypertension management. It is well tolerated by patients and has been shown to be a better predictor of end organ damage than clinic measurement [ 2 , 20 , 32 , 33 ]. Trials of self-monitoring show improved blood pressure control, mainly in the context of additional co-interventions such as pharmacist intervention or nurse-led education [ 34 ]. A caveat to self-monitoring is that it relies on good communication between patients and physicians, and perhaps 50% of patients do not tell clinicians they are self-monitoring or share the readings with their physician, in a meaningful manner [ 35 ]. A solution to this may be the remote monitoring of blood pressure readings measured at a patient’s home, i.e. tele-monitoring, something explored more below.

Another option to enhance ongoing self-monitoring compliance could be BP monitoring apps. These can communicate between smartphone and BP monitor allowing the patient to control (e.g. start/stop/configure) the BP measurement procedure from the app and to download automatically the current or previous BP readings. BP estimation is computed in the device microchip using the oscillometric signal, which is sampled and filtered from device pressure sensors, during the cuff inflation or deflation. Examples of BP self-monitoring analytics subsequently available include tracking the average BP over time, alerting on concerning BP trends, e.g. high/low readings, or normal/abnormal circadian BP patterns (dipper/non-dipper trend). When an app is used to communicate with a clinician, this becomes a type of tele-monitoring (see below).

Self-monitoring can also be combined with self-titration of medication, a process known as self-management. Trials undertaken before the current generation of mobile devices have shown that self-management can lead to improved blood pressure control through medication optimisation in both hypertensive and higher risk populations [ 36 •, 37 •].

  • 2. Tele-monitoring is a particular application of telemedicine—the transfer of data remotely—which in this case consists of automatic data transmission of BP readings. It can also be combined with the transfer of other parameters such as heart rate, oxygen saturations, and pacemaker/defibrillator data from the patient’s home or workplace to a professional healthcare environment such as a primary care clinic/surgery or the hospital [ 38 ]. Several tele-monitoring systems are available which differ in their modality of data collection, transmission, and reporting and by the presence/absence of additional features such as reminders for BP measurement to be performed or medication reminders. Randomised controlled trials [ 39 •] performed in recent decades have tested the effectiveness of home blood pressure tele-monitoring for the improvement of hypertension control and associated healthcare outcomes. In a large meta-analysis [ 39 •], all studies included demonstrated a high degree of acceptance of the technologies by doctors and patients, good adherence to tele-monitoring programs and confirmed that the technology has the potential to enhance hypertension management, improve patient outcomes, and reduce healthcare costs, particularly when considering long-term follow-up.

Another meta-analysis demonstrated that BP tele-monitoring in conjunction with co-intervention, such as medication titration by a case manager or education/lifestyle counselling, led to significantly larger and persistent (up to 12 months) BP reductions when compared with self-BP monitoring alone without transmission of BP data and counselling [ 34 ].

Until recently, the key evidence missing from trials of self-monitoring and tele-monitoring was whether the use of such data by clinicians actually led to lower blood pressure. In 2018, the TASMINH4 trial [ 40 •] showed that GPs using self-monitored blood pressure to titrate antihypertensives, with or without tele-monitoring, achieved better blood pressure control for their patients than those using clinic readings. As with previous trials, the mechanism of action appeared to be medication optimisation. The tele-monitoring group achieved lower blood pressure quicker than the self-monitoring group, but readings were not significantly different at the primary end point of 1 year. Forthcoming work shows that patient and clinician experience was largely positive from tele-monitoring with some important caveats in particular patients. Cost-effectiveness analysis suggests that self-monitoring in this context is cost-effective by NICE criteria, i.e. costing well under £20,000 per QALY [Grant S et al. BJGP 2019, In Press; and Monaghan M et al. Hypertension 2019, In Press ].

Interactive digital interventions now offer the ability to provide users with additional support over and above simple tele-monitoring which can also result in lower blood pressure than usual care [ 41 ]. This can include, for example, multi-media demonstrations of lifestyle advice utilising video and web links. The ‘Home BP’ trial will report later in 2019 on the effectiveness of a web-based digital intervention with a lifestyle module testing the efficacy over and above usual care [ 42 ]. Where a digital intervention utilises mobile phone technology to underpin tele-monitoring, this is increasingly termed ‘M-health’.

  • 3. ‘Virtual clinics/visits’ provide a system-level option for the use of such technology and comprise structured asynchronous online interactions between a patient and a clinician to extend medical care beyond the initial office visit. A study by Levine et al. in 2018 showed that for primary care patients managed for hypertension with a virtual visit vs. a real-life in-person visit, there was no significant adjusted difference in systolic blood pressure control, number of specialist visits, emergency department presentations, or inpatient admissions [ 43 ].
  • 4. Other novel advances in hypertension management

Artificial intelligence underpins interfaces such as Alexa® and Siri® which can wirelessly update medication lists and set reminders (e.g. alarm reminders to take medications to improve adherence to treatment), and although there is a current dearth of evidence of the efficacy of these, it seems likely that their use will increase over time. Incorporation of tele-monitored data on blood pressure into digital healthcare programmes can now also allow combination with other physiological variables including blood glucose, heart rate and exercise allowing adaptation of management recommendations based on pre-determined variables including user demographics, indicated morbidities and comorbidities, self-identified barriers and actions recorded over the course of a programme or set by a physician. Examples of this include the ‘WellDoc Hypertension and diabetes management platform’ and ‘Omada Health’s digital program’.

Implementation of Technology in Special Groups

Hypertension is an ideal area for the use of new technology but does require consideration of a number of special groups, the most important of which are discussed below:

Atrial Fibrillation

Hypertension is a risk factor for atrial fibrillation (AF), and half of those with AF have hypertension [ 44 ], making blood pressure measurement an important aspect of care in these patients. However, the accuracy of current methods of blood pressure monitoring is limited in those with AF as demonstrated in a recent meta-analysis [ 45 ]. This is particularly an issue in the elderly where AF can affect over 10% of the population. Validation studies of automated blood pressure devices typically exclude those with AF, resulting in a lack of evidence regarding the accuracy of these devices to measure BP when AF is present, which is turn makes reliable out-of-office BP measurement, including home and ambulatory BP monitoring more difficult in this population. As a result, NICE [ 2 ] and European guidelines [ 17 ] currently both recommend manual measurement of blood pressure when AF is present, making self-monitoring very difficult [ 46 ]. A more recent systematic review analysed studies containing 14 different automated BP devices to determine if their accuracy in the presence of AF has improved as technology and detection algorithms have advanced [ 45 ]. In this study, of the devices compared, four were newer automated BP devices that incorporated the latest algorithms to detect AF, but the marketing for these devices appeared misleading as despite claiming ‘AF detection’ and ‘BP measurement’ within the same device, there was no evidence to suggest that they were more accurate at measuring BP in the presence of any atrial arrhythmia. This particular review [ 45 ] concluded that BP devices known to be accurate for patients in sinus rhythm cannot be assumed to maintain accuracy when used to measure BP in those with AF. Consequently, measurement, and thus management of BP, in patients with AF remains an area in which further development of new technology is required to enable more precise monitoring and management.

Hypertension in pregnancy results in substantial maternal morbidity and mortality worldwide [ 47 , 48 ]. Furthermore, hypertension during pregnancy has been linked to the development of chronic hypertension and an increase in lifetime cardiovascular risk of at least double [ 49 ]. Self-monitoring of BP in pregnancy has been shown to be feasible and to have the potential to detect hypertensive disorders sooner than standard care [ 50 ]. Two large trials are currently recruiting (BUMP1 and BUMP2, https://clinicaltrials.gov/ {"type":"clinical-trial","attrs":{"text":"NCT03334149","term_id":"NCT03334149"}} NCT03334149 ) and aim to assess whether self-monitoring improves the detection and/or control of hypertension in pregnancy. Moreover, a recent feasibility trial of self-management of BP following hypertensive pregnancy [ 35 ] demonstrated that self-management using a purpose-designed app offers great promise in optimising post-partum BP management. This app allowed women to record self-monitored BP, to receive reminders to monitor their BP, and provided real-time automated medication titration feedback based on NICE guidance at that time [ 49 ] regarding self-titration and safety. Feasibility testing suggested that this technique was acceptable, as women self-monitored daily with 85% adherence and a median accuracy of 94% and there was a significant improvement in blood pressure control. This was most marked at 6 weeks, and interestingly, the difference in diastolic readings persisted to 6 months despite all but one woman finishing therapy [ 35 ]. These findings have prompted further follow-up of the women originally in this study and a larger, pilot study on self-management in the post-partum hypertensive cohort, both commencing later in 2019.

The first report on paediatric hypertension by the National Heart, Lung, and Blood Institute (NHLBI), published in 1977 [ 51 ] declared that “Detection and management of hypertension in children and the precursors of hypertension in adults are the next major frontier”. The report also recommended annual BP measurement in all children ≥ 3 years. Unfortunately, nearly 40 years later, the diagnosis of hypertension is missed in the majority of cases, and familiarity with paediatric hypertension among clinicians is extremely poor. This is therefore an area where the technology described above could make a real difference. However, the issues of validation of the technology are even more acute in the paediatric population because children’s vasculature and arm size are not the same as those of adults. The new universal standard provides recommendations aiming to improve this [ 27 •].

Developing Countries

New technology offers huge promise in low- and middle-income countries and is being embraced by projects such as CRADLE. This team have developed and validated several devices [ 52 , 53 ] which were developed specifically to meet the World Health Organisation criteria for use in a low-resource setting. The newest device is low cost at approximately $20 per device, has low-power requirements, and can be charged using a standard mobile phone charger [ 54 ]. It is also robust and capable of accurately detecting abnormalities in vital signs, including during pregnancy [ 55 ]. Severe bleeding, severe infection, and blood pressure disorders [ 55 ] are the most common cause of deaths in pregnancy, and such devices have the potential to be life-saving. Resources are the biggest issue in the developing world however where many hospitals do not currently have appropriate monitoring equipment, let alone the newest technology.

Future Research Needed

Whilst much has been achieved in terms of research to date, several areas are clearly lacking in the kind of evidence needed in primary and secondary care alike. The most pressing need is perhaps for new technologies to be assessed and clinically validated [ 27 •] prior to widespread implementation in the general population.

As healthcare is moving towards greater patient involvement and responsibility, including self-monitoring and self-screening of hypertension, we need to understand how best clinicians and patients alike can integrate these advances into daily practice.

Much previous research around blood pressure monitoring and management has excluded those with additional or complex needs such as the very old, multi-morbid, or pregnant women. It is important to complete research in these populations, as there may be differences in accuracy in some groups [ 56 , 57 ] and the implications of, for instance, white coat hypertension, may be very different in pregnancy compared with the general population.

Conclusions

Hypertension has been identified by WHO as one of the most significant risk factors for morbidity and mortality worldwide [ 1 ], and despite strong evidence for treatment, studies suggest that many people remain sub-optimally controlled [ 6 ]. New approaches, including new technologies, are therefore needed to improve screening, detection and control of raised blood pressure in the community. Breaking away from traditional cuff-based measurement of blood pressure, the widespread accessibility of smartphones and mobile health applications offers new prospects for ubiquitous monitoring of parameters such as blood pressure, but evidence of both accuracy and efficacy is currently lacking.

Current market penetration of smartphones into the elderly is not sufficient for widespread implementation of technology such as smartphone apps in this age group, but M-health has definite potential to aid screening and diagnosis in younger adults, pregnant women, children and adolescents as well as older populations as the technology becomes more commonplace. A key issue with both apps and novel non-invasive devices are the lack of a universally agreed standard for the validation of this technology, and current protocols simply do not include them. There is thus limited incorporation of this technology into clinical practice at present [ 26 ], and this must be addressed as a matter of urgency by European, UK, and American regulators.

Until recently, the key evidence missing from trials of self-monitoring and tele-monitoring was whether the use of such data by clinicians actually led to lower blood pressure. Now trial data combined in meta-analyses provides strong evidence for BP tele-monitoring in conjunction with co-interventions, such as medication titration or education/lifestyle counselling. Further work is needed to ensure the most appropriate and beneficial aspects of technology are effectively utilised within the health system as this could improve care whilst reducing the need for face to face clinical appointments.

Compliance with Ethical Standards

Dr. Tucker reports grants from National Institute for Health Research (NIHR) (Applied Research Programme grant), the NIHR Collaboration for Leadership in Applied Health Research and Care Oxford at Oxford Health NHS Foundation Trust, Research Capacity funding and the National School for Primary Care Research, outside the submitted work. Dr. McManus reports grants from NIHR, during the conduct of the study, and grants from Omron, outside the submitted work. Drs. Kitt and Fox declare no conflict of interest relevant to this manuscript.

The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

This article does not contain any studies with human or animal subjects performed by any of the authors.

This article is part of the Topical Collection on Implementation to Increase Blood Pressure Control: What Works?

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Elizabeth Lorenzo , Alicia Lynn O’Neal , Lisbeth Cantu Garcia , Kenny Mendoza , Rebecca E. Lee; Electronic Health Interventions for Type 2 Diabetes and Obesity in Hispanic or Latino Adults: A Systematic Review of English and Spanish Studies. Diabetes Spectr 15 February 2024; 37 (1): 65–85. https://doi.org/10.2337/ds22-0083

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The objective of this study was to synthesize English and Spanish literature to determine whether electronic health interventions (EHIs) such as telehealth, telemedicine, digital health, and mobile health (mHealth) improve A1C, blood glucose, BMI, and/or weight among Hispanic/Latino adults with type 2 diabetes or overweight/obesity in the Americas.

Searches were conducted in June 2021 using the Scientific Electronic Library Online, Cumulative Index of Nursing and Allied Health Literature, PubMed, and PsycInfo literature databases. Studies were identified that investigated the effect of an EHI on A1C, blood glucose, BMI, or weight in populations that were ≥12% Hispanic/Latino adults with type 2 diabetes or overweight/obesity, were conducted in the Americas, and were published in English or Spanish. Study quality was determined using the Quality Index Score. Data were extracted and synthesized, and themes were identified.

Twenty-five studies met inclusion criteria, including 23 in English (from the United States) and two in Spanish (from Chile). A total of 22 investigated type 2 diabetes, and three investigated overweight/obesity. The studies encompassed 6,230 participants, including 3,413 Hispanic/Latino adults. Sixty-three percent of studies demonstrated significant improvements in A1C or blood glucose and 67% in weight. Thirteen studies offered an EHI in both English and Spanish, and six offered the intervention in either English or Spanish alone. All EHIs involving mHealth exclusively and most (90%) involving more than one electronic modality demonstrated a higher number of significant findings compared with those having only one EHI modality, especially telehealth (44.4%). EHIs lasting ≤12 months had more significant findings (72.7%) than those lasting >12 months (50%). Six studies had industry-related funding, with 83.3% of those demonstrating significant improvements in outcomes.

EHIs improved A1C and weight in adults ( n = 4,355), including 45.5% Hispanic/Latino adults. mHealth and EHIs using more than one electronic modality and those lasting ≤12 months were especially effective. However, overall study quality was modest. Future research should be conducted in Spanish-speaking countries in Latin America and should compare the effectiveness of different EHI modalities.

Type 2 diabetes is a major obesity-related public health concern worldwide ( 1 ) with a marked burden in the Americas. The United States and Mexico have the third and sixth highest prevalence rates of type 2 diabetes in adults globally (13.0 and 15.7%, respectively) ( 2 – 4 ). Incidence of type 2 diabetes in the United States varies among different racial/ethnic groups. After American Indians/Alaska Natives (14.7%), the second highest prevalence of diagnosed type 2 diabetes in the country is concentrated in the Hispanic/Latino population (12.5%), followed by non-Hispanic Blacks (11.7%), non-Hispanic Asians (9.2%), and non-Hispanic Whites (7.5%). Between 2017 and 2018, the incidence of type 2 diabetes in Hispanic/Latino adults was 9.0 cases/1,000 people, a higher rate than in other races/ethnicities ( 3 ). These epidemiological patterns suggest that Hispanic/Latino populations may have a higher risk of other major health outcomes such as cardiovascular diseases and premature death than other populations. Thus, a comprehensive strategy to counteract type 2 diabetes and obesity in these individuals is urgently needed.

Part of the solution to this challenge may be found in the rapid advancements in information and communication technology (ICT) that are a Force of Change shaping individuals’ interactions ( 5 ). Approximately 67% of adults in 40 countries are Internet users, and 76% are involved in online open-access platforms requiring electronic devices ( 6 ). Although disparities among population subgroups remain, some reports indicate that Hispanic people are more likely than non-Hispanic Whites to use mobile devices and the Internet to send and receive emails, access video or pictures, download apps, and send text messages ( 7 , 8 ). Therefore, given its widespread use and diverse scope, ICT can be an allied instrument against the type 2 diabetes and obesity epidemics in the Americas that disproportionately affect Hispanics/Latinos.

Electronic health (eHealth) is a cost-effective and safe use of ICT in support of epidemiological surveillance, education and research, and health care services ( 9 , 10 ). Since 2012, the World Health Organization has promoted the development and evaluation of eHealth strategies to improve health, acknowledging their potential capability to minimize barriers such as language and distance ( 9 , 10 ). Leveraging such features in countries of the Americas such as Mexico is crucial given that 48.5% of the population has no effective access to health services ( 11 ).

eHealth encompasses a series of ICT components. Two examples are mobile health (mHealth), which is the use of mobile phones or digital tablets to collect, process, and report data focused on medical and public health practices, and telehealth, the practice of medicine at a distance ( 9 , 10 ). There are different mechanisms through which eHealth can positively affect obesity-related conditions. For example, online platforms, complex digital systems, artificial intelligence, or apps and features nested in electronic devices have been used to enhance motivation among users of online health and weight loss programs ( 12 – 14 ), improve diet and physical activity patterns ( 15 – 17 ), facilitate effective screening for type 2 diabetes complications ( 18 ), and deliver type 2 diabetes education that reinforces regular medical visits, self-management, and metabolic control ( 19 ).

Recent research provides supportive evidence for the use of eHealth interventions (EHIs) as instrumental actions to prevent and ameliorate type 2 diabetes and obesity. A meta-analysis concluded that EHIs in 21 randomized clinical trials from North America, Europe, and Asia significantly reduced A1C values in 3,787 participants with poorly controlled type 2 diabetes compared with usual care (mean differences up to –0.40% [95% CI –0.54 to –0.26]) ( 20 , 21 ). A pooled analysis of 21 systematic reviews and meta-analyses, eight randomized controlled trials (RCTs), one clinical trial, and one qualitative study from the United States and other countries showed that telemedicine interventions triggered a significant decline in A1C levels of up to a −0.64% weighted mean difference (95% CI −1.01 to −0.26%], P <0.001) in participants with type 2 diabetes ( 22 ). Regarding obesity, a systematic review with meta-analysis of 84 studies from multiple continents involving 139 intervention groups (76%) with at least one technological component showed that EHIs achieved greater weight loss than standard care (mean difference −2.70 kg [95% CI −3.33 to −2.08 kg], P <0.001) ( 23 ). Another systematic review compiling data from six U.S. trials involving racial/ethnic minorities (3–13% Hispanic) suggested that EHIs can yield small amounts of short-term weight loss ( 24 ).

Assessments of evidence quality that account for risk of bias and internal and external validity have been carried out in previous systematic reviews ( 20 – 24 ). However, the presence of potential competing interests has not been extensively incorporated into the narrative of EHI evaluation. Previous literature demonstrates that industry-funded reviews and reviews conducted by authors with conflicts of interest had more favorable findings and/or conclusions related to artificial sweeteners and weight outcomes than reviews without conflicts of interest ( 25 ). Thus, it is important to document whether partially or fully funded studies by industry and/or authors with potential competing interests might generate systematic bias in studies on EHIs.

Despite the literature demonstrating benefits of EHIs, the systematic reviews and meta-analyses cited previously devoted little effort to evaluating the effects of EHIs on type 2 diabetes and obesity specifically among Hispanic/Latino individuals, nor did they include literature published in Spanish ( 20 , 21 , 23 ). Furthermore, one of the reviews that focused on type 2 diabetes only included one EHI ( 22 ), and the review investigating the EHI on weight management in racial/ethnic minorities did not include any studies with mHealth interventions ( 24 ), demonstrating a significant gap in the literature. Therefore, the purpose of this systematic review was to synthesize the available evidence published in English and Spanish on the effects of EHIs on type 2 diabetes and overweight/obesity outcomes among Hispanic/Latino adults from the Americas. Additionally, we explored potential conflicts of interests within this literature.

Overview of Search

This systematic review aimed to determine the state of the science of published interventions for type 2 diabetes and obesity in Hispanic/Latino adults that were executed in English or Spanish via any electronic platform in the region of the Americas and involved EHIs, including telehealth, telemedicine, digital health, and mHealth interventions ( 9 , 10 ). Definitions are provided in Table 1 . The research question was constructed using the PICO (patient/population, intervention, comparison, and outcomes) method ( 26 ). The population under investigation included Hispanic/Latino adults with type 2 diabetes or obesity/overweight. The intervention had to include an EHI with or without comparison group or groups. The outcomes could include changes in A1C, blood glucose, BMI, or weight. The protocol was registered on PROSPERO (#158799).

Definitions of EHIs

Data Sources and Search Strategy

The literature searches were conducted in January and February of 2020 and updated in June 2021 using the Scientific Electronic Library Online (SciELO), Cumulative Index of Nursing and Allied Health Literature (CINAHL), PubMed, and PsychInfo databases. Medical Subject Headings (MeSH) terms were used when applicable. For example, CINAHL included MeSH terms for telehealth, whereas PubMed and PsychInfo did not. Searches were conducted in cycles interchanging Latin*/Hispanic or Latino/Hispanic, type 2 diabetes/type 2 diabetes mellitus, obesity, and telehealth, telemedicine, eHealth, digital health, and mhealth without publication date restrictions. Given that most of the literature available on SciELO is published in Spanish and comes from Latin American countries, the terms Latin*/Latino and Hispanic were omitted for the searches.

Searches were conducted by one author for English articles (A.L.O.) and another for Spanish articles (K.M.). Articles were screened based on inclusion and exclusion criteria by two reviewers separately for articles in English (E.L. and A.L.O.) and Spanish (L.C.G. and K.M.). First, publication titles and abstracts were screened for inclusion independently by the reviewers. When publication titles and abstracts were not sufficiently explicit to determine inclusion, full-text articles were reviewed. Reference lists for all included articles and relevant systematic reviews found during the search were reviewed to identify additional articles for inclusion. The included articles were compared by the authors, and discrepancies were discussed. A third reviewer (R.E.L.) was consulted when consensus could not be reached to resolve discrepancies.

Inclusion Criteria

Studies were included if they met the following criteria: 1 ) original research published in a peer-reviewed journal in English and/or Spanish, 2 ) experimental and/or quasi-experimental study design, 3 ) study sample ≥12% Hispanic/Latino, 4 ) adults ≥18 years of age, 5 ) subjects diagnosed with type 2 diabetes by a health care provider or having an A1C ≥6.5%, and/or diagnosed as having overweight/obesity or having a BMI ≥25.0 kg/m 2 , 6 ) included an EHI intervention (telehealth, telemedicine, digital health, or mHealth), 7 ) reported outcomes related to type 2 diabetes and/or obesity (i.e., A1C, blood glucose, BMI, or weight), and 8 ) conducted in countries that comprise the Americas (North America, Central America, South America) or the Caribbean islands. The criterion that studies have a sample that includes at least 12% Hispanic/Latino adults was chosen because there were limited studies that included 100% Hispanic/Latino adults. Systematic reviews, conference abstracts, dissertations, gray literature, and studies with comorbidities or pregnancy as inclusion criteria were excluded.

Data Extraction

Data extracted from each publication included authors, year of publication, design, sample size and demographics (age, sex, Hispanic/Latino ethnicity, proportion of Spanish speakers), country of implementation, intervention type (telehealth, telemedicine, digital health, or mHealth) and length, intervention components, language of intervention, type 2 diabetes or obesity outcomes (A1C, fasting blood glucose [FBG], serum blood glucose, BMI, or weight), covariates, findings, study quality score, and funding source. Industry-related funding included any funding, supplies, and/or compensation provided by any for-profit organization. Two authors extracted data from each study, and data were compared. Discrepancies were discussed and, if consensus could not be reached, a third reviewer (R.E.L.) was consulted.

Evaluation of Study Quality

The Quality Index Score (QIS) was used to evaluate the quality of included studies ( 27 ). The QIS measure was selected for its versatility to evaluate both randomized and nonrandomized experimental studies and includes 27 questions. For this study, one question related to data dredging was eliminated because this concept is rarely reported. Studies were scored with either 0 (does not meet criteria) or 1 (meets criteria) for all questions except one. This question could receive a score of 0 (does not meet criteria, 1 (partially meets criteria), or 2 (fully meets criteria). Of the 26 questions included, there were 27 possible points, and categories for assessment included a reporting score (of 11), external validity (of 3), internal validity bias (of 6), internal validity selection bias (of 6), and power (of 1).

Narrative Analysis/Synthesis

Because of the high level of heterogeneity among the designs, interventions, and outcomes, a meta-analysis was not conducted. Data were organized, summarized, and narratively synthesized separately for adults with type 2 diabetes and overweight/obesity by EHI type, intervention length and language, and funding support, comparing the number of significant findings with the number of findings that were not significant across studies. Themes were identified and presented.

Searches identified 244 English and 39 Spanish study titles screened after duplicates were removed. One-hundred and fifty-two English and 23 Spanish studies were excluded after reviewing titles and abstracts because they did not meet inclusion criteria. Ninety-two English and 16 Spanish studies were reviewed in full text, with 79 English and 15 Spanish studies excluded because they did not meet inclusion criteria. A total of 10 English and one Spanish study were identified through manually searching reference lists and contributed to a total of 23 studies published in English ( 28 – 50 ) and two published in Spanish ( 51 , 52 ) that were included in this review ( Figure 1 ). Twenty-two studies met inclusion criteria for type 2 diabetes ( 28 – 32 , 34 – 40 , 42 – 51 ), and three met criteria for overweight obesity ( 33 , 41 , 52 ).

Diagram of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart for study selection. aEnglish language. bSpanish language.

Diagram of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart for study selection. a English language. b Spanish language.

Sample Characteristics

Detailed information for each study is presented in Table 2 . A total of 6,230 participants were included across studies, with study samples sizes ranging from 16 ( 38 ) to 1,665 ( 45 ). One study did not report age ( 28 ), but the remainder of the studies included mean, median, or modal age ranges between 18 ( 48 ) and 72 ( 30 ) years. One study did not report female participant enrollment; however, this study focused on veterans and may not have included females ( 30 ). The remaining studies included female sample sizes ranging from 5 to 1,046 with a total of 3,709 female participants (60%). The sample sizes of Hispanic/Latino participants across the 25 studies ranged from 5 (23% of the study sample) ( 40 ) to 586 (35% of the study sample) ( 45 ). The proportion of Hispanic/Latino participants in the combined studies was ∼55% for a total of 3,413. Twenty-three studies were conducted in the United States ( 28 – 50 ) and two in Chile ( 51 , 52 ). Study designs included 15 RCTs ( 28 , 29 , 31 – 34 , 39 , 41 – 43 , 45 – 47 , 50 , 52 ), five feasibility/pilot studies ( 30 , 38 , 40 , 48 , 49 ), one quasi-randomized trial ( 51 ), one randomized reinforcement study ( 37 ), one randomized three-arm trial ( 44 ), and two single pre-/post-test studies ( 35 , 36 ). The studies were published between 2000 and 2021. Of note, the overall sample size and number of female and Hispanic/Latino participants are approximate totals, because the descriptive characteristics provided for each study were inconsistent and based on either participants who completed only baseline or both baseline and follow-up data collections. The first n extracted for each study in Table 2 is the sample size for which sociodemographic characteristics are presented in each study.

Included Articles

Language not specified; assumed to be English because of inclusion of both Hispanic and non-Hispanic adults. CG, control group; IG, intervention group.

Nine studies consisted of only a telehealth intervention ( 28 , 36 , 37 , 42 – 44 , 47 , 50 , 51 ), three included only mHealth ( 29 , 35 , 48 ), and one used only telemedicine ( 30 ). The remaining studies included a combination of EHI, including three with telehealth and mHealth ( 31 , 41 , 52 ), two with telehealth and telemedicine ( 39 , 49 ), two with telehealth and digital health ( 32 , 34 ), and one each with telemedicine and digital health ( 45 ); telehealth, telemedicine, and digital health ( 38 ); telemedicine, mHealth, and digital health ( 33 ); telehealth or telemedicine ( 40 ); and telehealth or mHealth ( 46 ). Table 3 summarizes significant findings by EHI type.

Significant Findings by EHI Type

The length of the interventions ranged from 6 weeks ( 34 , 36 ) to 3.5 years ( 38 ), with a mean length of 9.8 ± 8.7 months. One study had a 3-month EHI with an optional 3-month extension ( 35 ), and another had an EHI that ranged in length from 6 to 9 months ( 52 ). Table 4 shows the number of significant findings by EHI length.

Significant Findings by Intervention Length

The 3-month EHI with an optional 3-month extension is included in both type 2 diabetes 3-month and 6-month outcomes.

A majority of studies (88%) conducted follow-up data collection at conclusion of the EHI ( 28 – 33 , 35 , 37 , 38 , 40 – 43 , 45 , 49 – 52 ) or soon after (i.e., 1 month [39], 1.5 months [34], and 3 months [44] after the EHI). Data collection for one study ranged between immediately post-intervention and 9 months after the EHI ( 48 ), and only one investigated long-term changes in outcomes at 10.5 months ( 36 ). One study only provided preliminary findings after 6 months for a 12-month EHI ( 46 ).

Approximately half of the studies (52%) provided the EHI in both English and Spanish ( 28 , 29 , 31 , 32 , 34 , 38 , 39 , 42 – 45 , 47 , 48 ), and the remaining studies provided the EHI only in English (24%) ( 30 , 33 , 36 , 40 , 41 , 49 ) or only in Spanish (24%) ( 35 , 46 , 50 – 52 ). Table 5 provides the number of significant findings by EHI language.

Significant Findings by Intervention Language

Nine studies compared the EHI with usual care ( 28 , 29 , 31 , 42 , 43 , 45 , 46 , 48 , 51 ), five did not include a comparison group ( 30 , 35 , 36 , 38 , 49 ), and two compared different EHIs ( 33 , 40 ). One study compared the EHI, a nonelectronic intervention (group medical visits), and usual care ( 44 ).

Ten studies included one or more subgroup analyses, which investigated changes in outcomes based on baseline A1C ( 28 , 30 , 35 , 39 , 42 , 45 , 46 ). Depending on the study, these analyses looked at outcomes for those with a baseline A1C <7, 7–9, and >9%; ≥7%; ≥7.4 and ≥7.9% for those ≥65 years of age; ≥8%; ≥9%; <9 and ≥9%; or >10 vs. ≤10%. Some studies included subgroup analyses for Spanish speakers ( 29 , 43 ), Hispanic/Latino adults ( 30 ), age (≤70 vs. >70 years), engagement in EHI (intervention response rate ≥64.5 vs. <64.5%) ( 48 ), site (New York City or upstate New York) ( 45 ), and baseline A1C at the site level (New York City ≥7% and upstate New York ≥7%) ( 45 ). None of the studies investigating overweight/obesity included subgroup analyses.

Type 2 Diabetes

Twenty-two studies investigated the impact of an EHI on type 2 diabetes outcomes ( 28 – 32 , 34 – 40 , 42 – 51 ), all of which included A1C as an outcome. One study also included FBG ( 31 ), and two studies also included serum blood glucose ( 42 , 43 ), of which neither reported whether participants were fasting. The total number of participants included across the 22 studies was 5,691, with 3,327 female (58%) and 3,202 Hispanic/Latino participants (56%).

Telehealth was used in 77.3% of studies ( 28 , 31 , 32 , 34 , 36 – 40 , 42 – 44 , 46 , 47 , 49 – 51 ), followed by telemedicine (27.3%) ( 30 , 38 – 40 , 45 , 49 ), mHealth (22.7%) ( 29 , 31 , 35 , 46 , 48 ), and digital health (18.2%) ( 32 , 34 , 38 , 45 ). EHI types were offered alone, in combination, and/or as an option. Table 3 provides the number of significant findings by EHI type.

EHI length ranged from 6 weeks ( 36 ) to 3.5 years ( 38 ) with a mean length of 9.5 ± 8.6 months. Table 4 provides the number of significant findings by EHI length. Thirteen studies provided the EHI in both English and Spanish ( 28 , 29 , 31 , 32 , 34 , 38 , 39 , 42 – 45 , 47 , 48 ), five only in Spanish ( 35 , 37 , 46 , 50 , 51 ), and four only in English ( 30 , 36 , 40 , 49 ). Table 5 provides the number of significant findings by EHI language.

Fifteen of the 22 studies (68%) ( 29 , 31 , 32 , 34 – 36 , 38 , 39 , 42 , 43 , 45 – 49 ) demonstrated significant improvements in A1C for the sample and/or in subgroup analyses. The total combined sample of adults with significant improvements in A1C was 3,886 with 47.4% ( n = 1,842) Hispanic/Latino adults. Findings demonstrated that A1C significantly improved for the intervention group (IG) in eight studies ( 32 , 34 – 36 , 38 , 39 , 46 , 49 ). Reductions in A1C ranged from −0.4 to −2.4% with a mean reduction of −0.90 ± 0.75%. Three studies ( 45 – 47 ) demonstrated a significant difference in A1C improvements for the IG compared with the control group (CG) for the sample and in one study ( 29 ) that included a subgroup analysis for Spanish speakers (mean difference −0.52 ± 0.41%, range −0.18 to −0.98%). Two studies ( 29 , 35 ) were not included in both mean calculations because they provided median values rather than means.

Three studies demonstrated significantly lower A1C for the IG compared with the CG, including for the total sample ( 31 ), Spanish speakers ( 43 ), and in another study ( 42 ) that analyzed participants with baseline A1C ≥8 and ≥9% separately (mean difference between IG and CG −0.90 ± 0.28%, range −0.5 to −1.1%). In another study, the authors conducted a subgroup analysis based on engagement with the EHI during the intervention and found that participants who engaged more with the EHI (response rate ≥64.5%) had a significant decrease in A1C compared with less engaged participants (response rate <64.5%) (mean difference −2.23%) ( 48 ). However, there were no significant findings related to A1C improvements for the total sample in either study with a subgroup analysis.

One study demonstrated that A1C was maintained for the IG but significantly increased in the CG, with significant differences in A1C between the IG and the CG ( 51 ). In the one study with FBG as an outcome, there were no significant differences or reductions in FBG ( 31 ). Out of the two studies with serum blood glucose as an outcome ( 42 , 43 ), one demonstrated significantly lower serum blood glucose in the IG compared with the CG ( 43 ) even though there were no significant differences in A1C. In the studies by Frosch et al. ( 32 ) and Heisler et al. ( 34 ), there were significant reductions in A1C for both the IG and the CG; however, there were no significant differences between the IG and CG A1C reductions. The only study that examined outcomes more than once post-intervention ( 36 ) demonstrated that A1C improvements persisted 10.5 months after the intervention.

Overweight/Obesity

Three studies investigated the effects of an EHI on overweight/obesity, and all included weight as the outcome of interest ( 33 , 41 , 52 ). The studies included a total of 539 participants, of whom 382 were female (71%) and 211 were Hispanic/Latino (39%). The types of EHI reported in the overweight/obesity studies included telehealth and mHealth ( 41 , 52 ) and telemedicine, mHealth, and digital health ( 33 ). Table 3 provides the number of significant findings by EHI type. The EHI length ranged from 4 to 24 months with a mean length of 12.3 ± 10.4 months. Table 4 provides the number of significant findings by EHI length. Two studies provided the EHI in English only ( 33 , 41 ) and one in Spanish only. Table 5 provides the number of significant findings by EHI language.

Two of the three studies ( 33 , 41 ) demonstrated a significant reduction in weight (66.7%) in the IG compared with the CG. However, one of those studies only demonstrated significant decreases in weight for the IG compared with the CG at 6 and 12 months during a 24-month intervention ( 33 ). In addition, both the IG and CG included an EHI, and the authors did not test for within-group changes. The total combined sample of adults with significant improvements in weight was 469 with 30.1% ( n = 141) Hispanic/Latino adults.

Study Quality Assessment

Quality assessments of each study can be found in Table 6 . Overall, the study quality was moderate, reporting 65.9% of items with a mean score of 17.80 ± 3.5 of 27 possible points. None of the studies reported all items, and the most items included in any study was 24 ( 34 ). Studies demonstrated the lowest quality on external validity criteria, and only 11 of 25 studies reported a power analysis. On the reporting subscale, the average study reported 8.76 of 11 items (79.6%), with reporting of 3.88 (64.7%) for the six internal validity items.

Quality Index Ratings

Overweight/obesity outcomes.

Spanish studies.

Funding Sources

Funding sources of included studies are described in Table 7 . Six of the 25 studies (24.0%) identified industry-related funding ( 29 , 31 , 38 , 39 , 41 , 51 ), and 83.3% of those studies demonstrated significant improvements in outcomes ( 29 , 31 , 38 , 39 , 41 ). Among the studies focusing on type 2 diabetes–related outcomes, five of the 22 studies (22.7%) indicated that they had industry-related funding ( 29 , 31 , 38 , 39 , 51 ). Four of those five (80%) demonstrated significant improvements in outcomes ( 29 , 31 , 38 , 39 ). Of the three studies investigating overweight/obesity-related outcomes ( 33 , 41 , 52 ), only one (33.3%) included any industry-related funding, and that study demonstrated significant improvements (100%) ( 41 ). One study did not identify any sources of funding ( 30 ).

Significant Findings by Funding Source

Any funding, supplies, and/or compensation provided by industry.

Overweight-/obesity-related outcomes.

The purpose of this systematic review was to determine the effects of EHIs on type 2 diabetes and overweight/obesity-related outcomes in samples containing at least 12% Hispanic/Latino adults living in the Americas from literature published in English and Spanish. Overall, this review found that EHIs demonstrated improvements in both A1C ( 29 , 31 , 32 , 34 – 36 , 38 , 39 , 43 , 45 – 47 , 49 ) and weight ( 33 , 41 ) in a large sample of adults ( N = 4,355), nearly half of whom (45.5%, n = 1,983) were Hispanic/Latino. These findings are consistent with previous research from different countries investigating EHIs in samples that included minimal or no Hispanic/Latino adults ( 18 – 22 ).

This review found that mHealth seemed particularly useful. Studies that included only mHealth ( 29 , 35 , 48 ) or more than one type of EHI including mHealth ( 31 , 32 , 34 , 38 , 39 , 45 , 49 ) improved type 2 diabetes outcomes compared with those with only one type of EHI other than mHealth. Furthermore, telehealth demonstrated limited efficacy in improving A1C ( 36 , 42 , 43 , 47 ) unless combined with other types of EHIs ( 31 , 32 , 34 , 38 , 39 , 49 ). All three studies investigating the effect of EHIs on weight included more than one type of EHI ( 33 , 41 , 52 ) with all three including mHealth, which was the type of EHI missing in the previous review conducted with a focus on racial/ethnic minorities ( 19 ).

Overall, the rigor of the available research is relatively modest, impeding best-practice recommendations and improvements in treatment optimization. Most studies in this review compared EHIs to usual care or had no comparison group and lacked comparisons between different EHIs, similar to what has been found in previous reviews including adults with type 2 diabetes or overweight/obesity ( 18 – 22 ). This lack of granularity limits the ability to provide evidence-based recommendations about which specific types of EHI significantly improve outcomes compared with other EHIs and further prevents optimization of EHIs by implementing only the critical components necessary to improve health outcomes. Future research should be conducted to test different EHIs in rigorous trials to determine the most effective types of EHI to improve type 2 diabetes and obesity-related outcomes in Hispanic/Latino adults.

The majority of EHIs were available in Spanish ( 28 , 29 , 31 , 32 , 34 , 35 , 37 – 39 , 42 – 48 , 50 – 52 ) and demonstrated overall improvements in outcomes ( 29 , 31 , 32 , 34 , 35 , 38 , 39 , 42 , 43 , 45 – 48 ). Furthermore, when participants were provided the option to choose the EHI in English or Spanish, there were a greater number of significant findings ( 29 , 31 , 32 , 34 , 38 , 39 , 42 , 43 , 45 , 47 , 48 ). Approximately 28% of Hispanic/Latino adults in the United States are not fluent in English, and 70% speak a language other than English in the home ( 53 ). Offering comfort in terms of intervention language appears crucial to the success of EHIs. It has been documented in face-to-face health care settings that language barriers are associated with less access to medical services, lower adherence to treatments, and poorer health outcomes ( 54 – 56 ).

Most studies included in this review were conducted in the United States ( 28 , 29 , 31 , 32 , 34 , 35 , 37 – 39 , 42 – 48 , 50 ) and published in English. Only two studies that were published in Spanish met inclusion criteria, and both were conducted in Chile ( 51 , 52 ). Although researchers from Mexican government health institutions have encouraged the use of certain eHealth components (i.e., social media platforms) as low-cost tools to address issues in public health nutrition ( 57 ), we did not identify studies carried out in this country. The paucity of studies from Mexico and other Latin American countries prevents generalizability of recommendations regarding EHIs for Hispanic/Latino populations living outside of the United States. As previously noted ( 57 ), and confirmed by this review, the creation of an official commission and national resource allocation are needed to expand research in this field of study and lead the development of policies to ultimately leverage the potential that EHIs have to improve health care access across Latin America and reach those limited by distance, resources, or their respective health care system’s shortcomings ( 57 ), who otherwise may not have the opportunity to receive care.

Funding should also be considered when investigating the quality of the available evidence linking EHIs with health outcomes. Governmental agencies and foundations were the most common sources of funding for the studies in this review. However, all studies with support or resources provided by interested funders from industry ( 29 , 31 , 38 , 39 , 41 ) demonstrated significant improvements in outcomes, except for one ( 51 ). This pattern is consistent with one previous investigation pertaining to a different field of study on how potential conflicts of interest may introduce bias into study findings ( 23 ). Significant improvements in health outcomes from these studies should be interpreted with caution. Replication studies should be conducted with nonindustry funding and investigators who do not have conflicting interests.

Strengths and Limitations

This is the first systematic review conducted to synthesize the evidence published in English and Spanish to determine the efficacy of EHIs to improve type 2 diabetes or overweight/obesity among Hispanic/Latino adults. A systematic and comprehensive approach was used during data extraction following established a priori parameters. This is the first systematic review to consider the presence of potentially conflicting interests in original EHI research.

Limitations included that meta-analysis could not be reliably conducted because of the heterogeneity among studies, including the different combinations of EHIs intervention components, length of the interventions, and outcomes. However, our review yielded summary results whose directionality is generally consistent with that observed in previous studies that meta-analyzed original research from diverse populations ( 18 – 22 ). Technology is constantly evolving, rendering many of the intervention apps, software, or other technological components rapidly obsolete, which limits the ability to translate specific findings into current practice settings. The largest subgroup of Hispanic/Latino adults living in the United States is from Mexico ( 58 ); however, the only published studies identified outside of the United States were conducted in Chile ( n = 2). This threatens external validity, limiting the generalizability of the review beyond the United States.

This systematic review demonstrated that EHIs improve type 2 diabetes and overweight/obesity outcomes in Hispanic/Latino adults. Programs offering more than one type of EHI and those offered in English and Spanish improve health outcomes more than those with only one type of EHI, with the exception for mHealth, and those offered only in English or only in Spanish.

Technology is a Force of Change that can enhance efforts to improve health outcomes for those with type 2 diabetes and overweight/obesity ( 5 ); however, greater efforts are needed from researchers, policymakers, and corporate partners to successfully carry out more EHI-related investigations with timely dissemination of findings, given that technology evolves so rapidly. Future research should be conducted to compare the efficacy of different types of EHI to improve type 2 diabetes and overweight/obesity outcomes, including studies conducted in Mexico and other Spanish-speaking countries in the Americas. Additionally, research should be evaluated for bias related to potential conflicts of interest. Practitioners should recommend EHIs to adult populations, including Hispanic/Latino adults, through programs that include multiple EHI strategies and refrain from recommending programs that only include the EHI of telehealth.

Acknowledgments

The authors acknowledge and thank the J. William Fulbright Foreign Scholarship Board, Council for International Exchange of Scholars, Institute of International Education, U.S., and Comexus Fulbright García-Robles, Mexico, as well as Dr. Simón Barquera and the National Institute for Public Health, Mexico, for hosting R.E.L. as a U.S. Fulbright-García Robles Core Scholar to Mexico in 2019–2020.

This research was supported by a grant awarded to E.L. from the National Heart, Lung, and Blood Institute of the National Institutes of Health (L30 HL159808), the Instituto Nacional de Salud Publica in Mexico, and the Arizona State University Center for Health Promotion and Disease Prevention. This project was also supported by scholarships from the Mexican Council of Science and Technology, Fundación México en Harvard, and Harvard University, provided to K.M.

Duality of Interest

No potential conflicts of interest relevant to this article were reported.

Author Contributions

All authors contributed to article screening and data extraction. E.L., A.L.O., K.M., and R.E.L. synthesized and wrote this manuscript. A.L.O. and K.M. conducted all searches. R.E.L. conceptualized the review. All authors reviewed and edited the manuscript. E.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation

Some of the information in this article was presented in abstract form at the Society of Behavioral Medicine’s 43rd Annual Meeting & Scientific Sessions in Baltimore, MD, on 7 April 2022.

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