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Heart failure and diabetes mellitus

Introduction

Heart failure is the second most common cardiovascular complication in patients with diabetes mellitus. Although the incidence of cardiovascular complications caused by diabetes has decreased over the last two decades, the number of people affected by diabetes has grown, and this trend is expected to continue. Accelerated atherosclerosis is a characteristic of diabetes that can lead to ischemic cardiomyopathy and hypertension, which, in turn, can cause heart failure. In patients with diabetes, heart failure is associated with worse outcomes than in the general population, including higher rates of cardiovascular death.

This collection comprises a selection of recent full-text articles and chapters from the Springer Nature portfolio that discuss this important subject. Over time this collection will be enhanced by the addition of specially commissioned articles and resources that provide further guidance to healthcare practitioners, as well as selected full-text articles sourced from other prominent publishers.

Contents

  1. Overview
  2. Epidemiology
  3. Pathophysiological mechanisms of heart failure in diabetes
  4. Assessment and screening
  5. Glycemic management and heart failure outcomes

Instructions

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Overview

Heart failure: A major cardiovascular complication of diabetes mellitus

This review discusses the epidemiology, pathogenesis and clinical course of heart failure in patients with diabetes and describes therapeutic strategies for the treatment of heart failure in this population.

Summary points
  • Epidemiological studies indicate that a close association exists between diabetes and heart failure.
  • Heart failure with reduced ejection fraction and heart failure with preserved ejection fraction have distinctly different pathogeneses.
  • Many patients with diabetes have undiagnosed heart failure. The prognosis for patients with both diabetes and heart failure is poor and outcomes are worse than in those who only have one of the conditions. Higher levels of plasma glucose are associated with worse outcomes.
  • The treatment of heart failure in patients with diabetes is similar to that in the absence of diabetes. In addition, the impact of glycemic control and anti-hyperglycemic agents on cardiovascular outcomes must be considered.
  • In patients with diabetes and heart failure with reduced ejection fraction, the main goal of therapy is the reversal of the maladaptive effects of pathological activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system.
  • The results of several clinical studies suggest that angiotensin receptor blockade may improve outcomes in patients with diabetes and heart failure with preserved ejection fraction.
  • Although some studies have shown that stricter glycemic control is associated with decreased risk of heart failure in patients with diabetes, others found no correlation.

Bahtiyar G, Gutterman D, Lebovitz H. Curr Diab Rep 2016; 16: 116. doi: 10.1007/s11892-016-0809-4

Clinical update: Cardiovascular disease in diabetes mellitus

This review summarizes the mechanisms of atherosclerotic cardiovascular disease (ACSVD) and heart failure in diabetes mellitus, strategies for management of these conditions in diabetes and special considerations for treatment of diabetes in patients with ASCVD or heart failure.

Summary points
  • Atherosclerotic cardiovascular disease (ACSVD) is the main cause of disability and mortality in patients with diabetes.
  • Multiple pathophysiologic factors contribute to the development of ACSVD in patients with diabetes, including hyperglycemia, insulin resistance and hyperinsulinemia, dyslipidemia, inflammation, oxidative stress, endothelial dysfunction, hypercoagulability and vascular calcification.
  • A complex risk-reduction program simultaneously addressing multiple factors has a greater chance of reducing the risk of ACSVD. Appropriate interventions may include lipid-lowering therapy, blood pressure control and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy, antithrombotic medications, lifestyle modifications, glycemic control and bariatric surgery, or some combination thereof.
  • Of the currently available glucose-lowering therapies, metformin and sodium-glucose cotransporter-2 inhibitors have been shown to improve some cardiovascular outcomes, while glucagon-like peptide 1 receptor agonists were generally neutral and dipeptidyl peptidase 4 inhibitors could increase the risk of heart failure.
  • Because most patients with diabetes are at some risk of developing ASCVD, lifestyle modifications are warranted. In patients with known ASCVD, treatment should be primarily focused on reducing cardiovascular risk.
  • Diabetic cardiomyopathy commonly presents as heart failure with preserved ejection fraction and, less frequently, reduced ejection fraction.
  • Pathophysiological mechanisms underlying the development of heart failure in patients with diabetes are complex and may include metabolic abnormalities, functional alterations, structural changes in the myocardium and autonomic neuropathy.
  • In the management of patients with concurrent diabetes and heart failure, the effects of glucose-lowering therapies on cardiovascular outcomes should be taken into consideration.

Low Wang CC et al. Circulation. 2016; 133:2459-502. DOI:10.1161/CIRCULATIONAHA.116.022194


Epidemiology

High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes

This cross-sectional study assessed the prevalence of previously unknown heart failure and left ventricular dysfunction in elderly patients with type 2 diabetes.

Summary points
  • Patient population consisted of 581 individuals with type 2 diabetes, who did not have a diagnosis of heart failure confirmed by a cardiologist. Mean age was 71.6 years and 53.4% were male.
  • Previously unknown heart failure was diagnosed in 161 patients (27.7%).
  • Of these, 28 patients (4.8%) had reduced ejection fraction, while 133 patients (22.9%) had preserved ejection fraction.
  • The prevalence of heart failure increased with age and was higher in female than in male patients (31.0% vs 24.8%).
  • The prevalence of heart failure was higher in patients with BMI ≥30 kg/m2, dyspnea, fatigue and in those treated for hypertension (compared with patients who did not have these conditions).
  • Left ventricular dysfunction was found in 150 (25.8%) patients, with diastolic dysfunction accounting for the majority (146 patients, 25.1%) of cases.
  • Causes of heart failure were multi-factorial; the most common likely causes of heart failure were hypertension (82.0%), other ischemic heart disease (39.8%), diabetic cardiomyopathy (29.8%), valvular disease (23.6%) and prior myocardial infarction (23.0%).
  • Screening for heart failure should be considered in patients with type 2 diabetes.

Boonman-de Winter LJ et al. Diabetologia 2012; 55: 2154–2162. doi: 10.1007/s00125-012-2579-0


Pathophysiological mechanisms of heart failure in diabetes

Insulin signaling and heart failure

This review covers normal insulin signaling in the myocardium and vasculature, the pathophysiological changes in these processes that occur in heart failure and conditions associated with insulin resistance, as well as and the therapeutic approaches that aiming to address them. 

Summary points
  • Epidemiological data point to a link between elevated blood glucose, insulin resistance and diabetes mellitus, on the one hand, and heart failure, on the other.
  • Binding of insulin to its receptor leads to the activation of several intracellular signaling pathways, including phosphatidylinositol-3-kinase (PI3K)/Akt and mitogen-activated protein MAP kinase pathways.
  • Insulin stimulates a wide variety of processes, such as glycogen and protein synthesis, glucose and fatty acid metabolism, glucose uptake, mitochondrial fusion, gene expression, cell growth, apoptosis, autophagy and vasodilation.
  • Insulin-resistant patients have impaired: glucose uptake in muscle and adipose tissues, suppression of glucose production in the liver and suppression of lipolysis. Conversely, triglyceride synthesis and secretion of very low-density lipoproteins is increased. Low-grade inflammation is commonly observed.
  • Insulin resistance can affect the heart in a number of ways, including through increased fatty acid utilization, accumulation of bioactive lipids, mitochondrial dysfunction, decreased cardiac efficiency, oxidative stress, inflammation, increased apoptosis and altered calcium metabolism.
  • Evidence suggests that left ventricular dysfunction and remodeling can be caused by hyperactivation of PI3K/Act pathway and G-protein receptor kinase-2, repression of myocardial autophagy and FOXO-mediated activation of autophagic and atrophic pathways, myosin isoform switching and lipotoxicity.
  • In some patients with diabetes, worsening of heart failure has been observed after certain glucose-lowering treatments, including thiazolidinediones, dipeptidyl peptidase 4 inhibitors and possibly insulin.
  • Further research is required to devise better strategies to normalize the metabolic milieu characterizing heart failure.

Riehle C, Abel ED. Circ Res 2016; 118: 1151–1169. doi: 10.1161/CIRCRESAHA.116.306206

Insulin resistance: An additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes

This review discusses the pathophysiology of cardiovascular disease in patients with diabetes, in particular the roles played by oxidative stress, inflammation, abnormal glucose uptake and endothelial dysfunction in the development of cardiovascular disease.

Summary points
  • A number of pathological processes commonly observed in patients with diabetes contribute to the development of cardiovascular complications, including oxidative stress, inflammation, hypertension, endothelial dysfunction, obesity, dyslipidemia, hypoglycemia and autonomic neuropathy.
  • Accumulation of excess fat activates an inflammatory cascade that affects several stages of insulin signaling, eventually leading to insulin resistance.
  • Hyperglycemia can lead to oxidative stress by causing activation of the polyol pathway, formation of advanced glycation end products, increasing free fatty acid and leptin levels and stimulating production of reactive oxygen species in mitochondria.
  • Insulin resistance is associated with hypertension, dyslipidemia, hypercoagulability and atherosclerosis.
  • Insulin resistance causes impaired endothelial function by reducing bioavailability of nitric oxide.

Patel TP et al. Heart Fail Rev 2016; 21: 11–23. doi: 10.1007/s10741-015-9515-6

Cardiac structure and function across the glycemic spectrum in elderly men and women free of prevalent heart disease: The Atherosclerosis Risk In the Community study

This large, prospective study provides evidence for the relationship between dysglycemia and alterations in cardiac structure and function characteristic of heart failure.

Summary points
  • Previous studies indicate that patients with diabetes have increased left ventricular wall thickness and mass and impaired diastolic function.
  • The aim of this study was to examine the relationship between dysglycemia and cardiac structure and function measured by transthoracic echocardiography.
  • Patient population consisted of 4419 elderly individuals with no prevalent coronary heart disease or heart failure.
  • Blood glucose levels were normal in 39% of patients, while 31% had pre-diabetes and 30% had diabetes.
  • Higher blood glucose levels were found to be associated with increased left ventricular mass, worse diastolic function and slightly worse left ventricular systolic function (p≤0.01 for all comparisons).
  • Multivariate analysis revealed that for every 1% increase in the level of glycated hemoglobin left ventricular mass was increased by 3.0g, E/E′ by 0.5 and global longitudinal strain by 0.3%.
  • Hyperglycemic states may contribute to subtle subclinical impairments in cardiac structure and function.

Skali H et al. Circ Heart Fail 2015; 8: 448–454. doi: 10.1161/CIRCHEARTFAILURE.114.001990

Cardiometabolic syndrome and increased risk of heart failure

This review covers the pathophysiological mechanisms underlying diastolic dysfunction and heart failure in patients with cardiometabolic syndrome, proposes a solution to attendant diagnostic problems and outlines treatment options. 

Summary points
  • A two-step model of the pathogenesis of heart failure in individuals with metabolic syndrome is proposed. During the first, reversible step, risk factors (obesity, insulin resistance, type 2 diabetes, dyslipoproteinemia and hypertension) cause insufficient energy supply. During the second step, remodeling causes myocardial stiffness and impairment of late diastolic function.
  • Diastolic dysfunction is initially precipitated by metabolic alterations associated with insulin resistance, such as altered substrate use, decreased ATP generation, dysregulation of perfusion and impaired calcium handling in the myocardium. After that the remodeling process is promoted by inflammatory and cytokine abnormalities, lipo- and glucotoxicity, oxidative stress and upregulation of the renin-angiotensin-aldosterone and sympathetic nervous systems.
  • The following definition of diastolic dysfunction was proposed: diastolic dysfunction is the deficit between the E’ and an age-related normal value from healthy individuals E’norm.
  • Non-pharmacological therapies for cardiometabolic syndrome include various dietary approaches, exercise training and bariatric surgery, while pharmacological therapies include orlistat, sibutramine and rimonabant, of which only orlistat is currently available.
  • Non-pharmacological therapies for diastolic dysfunction and heart failure include various dietary approaches, exercise training and bariatric surgery, while pharmacological therapies include metformin, glitazones, glucagon-like peptide-1 analogues, dipeptidyl peptidase 4 inhibitors and sodium-dependent glucose cotransporter 2 inhibitors.

Von Bibra H, Paulus W, St John Sutton M. Curr Heart Fail Rep 2016; 13: 219–229. doi: 10.1007/s11897-016-0298-4

Diastolic dysfunction in the diabetic continuum: Association with insulin resistance, metabolic syndrome, and type 2 diabetes

This study provides evidence for the association between ventricular diastolic dysfunction and insulin resistance, metabolic syndrome and diabetes.

Summary points
  • Obesity is associated with diastolic dysfunction, while insulin resistance has been suggested as one of the underlying pathophysiological mechanisms.
  • This study aimed to evaluate the relationship between left ventricular diastolic dysfunction and insulin resistance, metabolic syndrome and diabetes.
  • The patient population consisted of 1063 individuals ≥45 years old (38% male) selected from a cohort representative of the adult population of Porto, Portugal.
  • Assessments included echocardiography for diastolic function and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) score.
  • Metabolic syndrome was diagnosed in 41.8% of patients, and diabetes in 11.9%.
  • Overall, 23.7% of patients had left ventricular diastolic dysfunction: 14.5% in the mild and 9.2% in the moderate or severe form.
  • Lateral E’ velocity and E/E’ ratio were found to correlate with HOMA-IR score(ρ=−0.20, p<0.0001, and ρ=0.20, p<0.0001, respectively).
  • Across HOMA-IR quartiles, a progressive worsening in E’ velocity (p<0.001 for trend) and E/E’ ratio (p<0.001 for trend) were observed.
  • HOMA-IR score was 0.95 (P25-75: 0.56-1.69) in patients with normal diastolic function, 1.30 (P25-75: 0.70-2.03) in patients with grade I diastolic dysfunction and 1.59 (P25-75: 0.83-2.41) in patients with moderate/severe diastolic dysfunction.
  • Diastolic dysfunction was diagnosed in 16.3% of patients without metabolic syndrome, 32.6% of patients with metabolic syndrome and no diabetes, and 36.6% of patients with metabolic syndrome and diabetes (p for trend <0.001).
  • HOMA-IR score and metabolic syndrome were found to be independently associated with left ventricular diastolic dysfunction.
  • Decrease in diastolic function precedes the onset of diabetes.

Fontes-Carvalho R et al. Cardiovasc Diabetol 2015; 14: 4. doi: 10.1186/s12933-014-0168-x

Can the onset of heart failure be delayed by treating diabetic cardiomyopathy?

This review covers the pathogenesis of diabetic cardiomyopathy, particularly the role of coronary artery disease. The authors propose a novel definition of DC and describe an individualized approach to the management of coronary artery disease in patients with diabetes.

Summary points
  • Diabetic cardiomyopathy is defined as functional and structural abnormalities of myocardium in diabetics, without concomitant coronary artery disease.
  • In patients with diabetes, impaired coronary circulation leads to chronic myocardial ischemia, which, in turn, causes fibrosis characteristic of diabetic cardiomyopathy.
  • The non-ischemic mechanisms of diabetic cardiomyopathy include oxidative stress, increased susceptibility to ischemia/reperfusion injury, altered intracellular Ca2+ turnover, with reduced Ca2+ sensitivity of contractile proteins, the accumulation of advanced glycation end-products and cardiac autonomic neuropathy.
  • Recent advances in the understanding of the etiology of diabetic cardiomyopathy include recognition of the role of resistin, high concentrations of RNA-binding motif protein 9 (RBM9), elevated fructose levels and impairment in the ubiquitin-proteasome system.
  • The authors propose a new definition of diabetic cardiomyopathy: diabetic cardiomyopathy is “…a result of a long-lasting process, affecting the myocardium, that sets up, at a very early stage of metabolic changes (mainly associated with insulin resistance or resistin overexpression), even before diabetes is diagnosed, and soon after its beginning is accelerated by progressive myocardial ischemia.”
  • In diabetic patients with coronary artery disease, the best current approach to prevent diabetic cardiomyopathy from developing to heart failure is surgical revascularization.

Marcinkiewicz A, Ostrowski S, Drzewoski J. Diabetol Metab Syndr 2017; 9: 21. doi: 10.1186/s13098-017-0219-z


Assessment and screening

Cost-effectiveness of screening strategies to detect heart failure in patients with type 2 diabetes

This paper evaluates five screening strategies for heart failure in elderly patients with type 2 diabetes using a Markov decision analytic cohort model of heart failure progression and a cohort of 581 Dutch patients.

Summary points
  • A significant proportion of elderly patients with type 2 diabetes have unrecognized heart failure. Routine screening of elderly patients with diabetes for heart failure will require additional healthcare expenditure. However, it is expected to improve outcomes and may reduce costs in the long-term.
  • The aim of this study was to assess the long-term health effect and costs of five screening strategies to detect heart failure in elderly patients with type 2 diabetes in the Dutch primary care setting.
  • Five screening strategies were assessed:
    • EMR/symptoms; a strategy based on information available from the Electronic Medical Record (EMR) of general practitioners combined with the assessment of presence of dyspnea, fatigue, ankle edema, nocturia and palpitations.
    • EMR/symptoms/physical exam; strategy 1 plus physical examination (PE).
    • EMR/symptoms/physical exam/NTproBNP; strategy 2 plus measurement of natriuretic peptide (NTproBNP).
    • EMR/symptoms/physical exam/NTproBNP/ECG; strategy 3 plus ECG.
    • Echocardiography.
  • Health effects were measured as expected life-years and quality-adjusted life-years (QALYs). A specially developed Markov decision analytic cohort model of heart failure progression was used to assess the costs.
  • The patient population consisted of 581 patients with type 2 diabetes and aged ≥60 years.
  • Patients were required not have a diagnosis of heart failure.
  • For willingness to pay values ranging from €6050/QALY to €31,000/QALY for men and from €6300/QALY to €42,000/QALY for women, the EMR/symptoms strategy had the highest probability of being cost-effective. For lower willingness to pay values, usual care (no screening) strategy was optimal, while for higher willingness to pay values, direct echocardiography was preferable.
  • Cost-effectiveness of all screening strategies improved with the increase in effectiveness of treatment for heart failure.
  • The simplicity of the EMR/symptoms strategy makes it possible to implement within the framework of existing diabetes management programs in primary care.

van Giessen A et al. Cardiovasc Diabetol 2016; 15: 48. doi: 10.1186/s12933-016-0363-z

Assessing cardiovascular risk and testing in type 2 diabetes

This review discusses the state of the art of risk factors, biomarkers, and subclinical disease parameters potentially useful in cardiovascular risk assessment in type 2 diabetes.

Summary points
  • The recommendations for the management of patients with type 2 diabetes provided in the American Heart Association (AHA)/American Diabetes Association (ADA) and the European Society of Cardiology (ESC) guidelines vary based an individual’s risk profile.
  • Risk factors traditionally used in the assessment of patients with diabetes include blood pressure, low-density lipoprotein (LDL) cholesterol, triglycerides and hemoglobin A1c. The evidence of the prognostic value of other risk factors, such as LDL particle concentration, non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B and HDL cholesterol, is less convincing.
  • A number of biomarkers, including highly-sensitive C-reactive protein (hs-CRP), N-terminal pro–B-type natriuretic peptide (NTproBNP), cardiac troponins T and I and urine albumin, have been shown, to varying degrees, to predict cardiovascular risk and can be used in the assessment of patients with diabetes.
  • Electrocardiography, coronary calcium score, non-ionizing radiation ultrasound measurement of the thickness of carotid intima-media and myocardial perfusion scintigraphy have been shown to be useful in the clinical evaluation of cardiovascular risk in patients with diabetes.
  • In addition, screening for diabetic retinopathy and neuropathy can be used to assess cardiovascular risk.
  • An individualized approach to cardiovascular risk management in patients with type 2 diabetes should be used.

Saeed A, Ballantyne CM. Curr Cardiol Rep 2017; 19: 19. doi: 10.1007/s11886-017-0831-4


Glycemic management and heart failure outcomes

Treating diabetes in patients with heart failure: Moving from risk to benefit

This review examines the effects of the newer classes of diabetes therapies on cardiovascular risk.

Summary points
  • There is substantial evidence for the pathophysiological association between heart failure and diabetes mellitus. However, it is uncertain if glycemic control can improve cardiovascular outcomes.
  • Among the older diabetes therapies, thiazolidinediones are known to increase the risk of heart failure, while metformin has been found in a number of studies to reduce the risk of heart failure.
  • Dipeptidyl peptidase-4 inhibitors do not appear to increase the risk of heart failure based on currently available evidence, however, there may be differences in effects within this group.
  • Glucagon-like peptide 1 agonists do not appear to have any cardioprotective properties.
  • Of the sodium-glucose cotransporter 2 inhibitors, empagliflozin has been shown to reduce the risk of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for heart failure. Studies are ongoing studies to evaluate other representatives of this class.

DeFilippis EM, Givertz MM. Curr Heart Fail Rep 2016; 13: 111–118. doi: 10.1007/s11897-016-0291-y

Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes

This review by Fitchett and colleagues summarizes the results of clinical trials that investigated the effects of various glucose-lowering therapies on cardiovascular outcomes.

Summary points
  • Diabetes is a major risk factor for heart failure and a predictor of worse clinical outcomes in patients with heart failure.
  • In patients with diabetes, subclinical left ventricular dysfunction is often observed and can progress to heart failure.
  • There is little evidence at present to suggest that glycemc control itself reduces the risk of heart failure.
  • In patients treated with insulin, the incidence of heart failure is higher and outcomes are worse compared with those treated with oral glucose-lowering therapies. However, this may be due to the sample selection bias, favoring older patients with impaired cardiac function.
  • Metformin is likely to be safe to use in patients at risk of heart failure.
  • Thiazolidinediones are associated with an increased incidence of acute heart failure.
  • The impact of sulphonylureas on cardiovascular outcomes in patients with heart failure and those with established cardiovascular disease is unclear. However, the presence of other adverse effects has made these drugs less popular than other glucose-lowering therapies.
  • The glucagon-like peptide 1 agonists do not appear to improve cardiovascular outcomes.
  • Dipeptidyl peptidase-4 inhibitors sitagliptin and alogliptin have demonstrated non-inferiority versus placebo with respect to the incidence of cardiovascular events and as such, are considered to be safe in the short term. However, they do not appear to improve cardiovascular outcomes. Saxagliptin likely increases the risk of heart failure.
  • The sodium-glucose cotransporter 2 inhibitor empagliflozin reduced the incidence of heart failure and cardiovascular mortality in patients with and without a prior history of heart failure.

Fitchett DH, Udell JA, Inzucchi SE. Eur J Heart Fail 2017; 19: 43–53. doi: 10.1002/ejhf.633

Novel anti-glycemic drugs and reduction of cardiovascular risk in diabetes: Expectations realized, promises unmet

This review presents the information on the cardiovascular safety and efficacy of anti-diabetic therapies, with an emphasis on newer drugs.

Summary points
  • Following suggestions that some glucose-lowering agents might increase cardiovascular mortality, the US FDA introduced a requirement for cardiovascular safety to be shown before marketing approval can be granted. This requirement was that there was <80% increase in the risk of atherosclerotic cardiovascular disease demonstrated in phase II and phase III trials.
  • Among older drugs, the evidence of improvement in cardiovascular outcomes with metformin is inconclusive, while sulfonylureas are associated with concerns about increased cardiovascular risk.
  • Sodium-glucose cotransporter 2 (SGLT2) inhibitors have positive effects on a number of cardiovascular risk factors, including blood pressure, body weight, visceral adiposity, hyperinsulinemia, albuminuria, serum uric acid and oxidative stress. Empagliflozin has been shown to have no negative effect on cardiovascular safety, however, further research is required to prove efficacy.
  • The glucagon-like peptide 1 (GLP-1) agonists liraglutide and semaglutide have been shown to improve cardiovascular outcomes, while lixisenatide had no positive effect. Additional research is required.
  • The results of randomized controlled clinical trials of dipeptidyl peptidase-4 (DPP-4) inhibitors are inconclusive with respect to cardiovascular safety, while observational studies consistently show benefit compared with sulfonylureas.
  • Thiazolidinediones have highly pleiotropic effects, which, in combination with ambiguous clinical trial data, have led to limited application of these drugs.
  • Liraglutide, semaglutide, lixisenatide, and empagliflozin can be considered safe with respect to cardiovascular outcomes, while the safety of DPP4 inhibitors remains uncertain. The clinical data supporting the efficacy of SGLT2 inhibitors and GLP-1 receptor agonists is encouraging but not decisive.

Flory JH, Ukena JK, Floyd JS. Curr Atheroscler Rep 2016; 18: 79. doi: 10.1007/s11883-016-0633-y

Promise of SGLT2 inhibitors in heart failure: Diabetes and beyond

This review describes the effects of sodium-glucose transporter-2 inhibitors with particular emphasis on improvement of cardiovascular function.

Summary points
  • By blocking the sodium-glucose transporter-2 (SGLT2), which leads to decreased reabsorption of glucose in the proximal tubules, SGLT2 inhibitors induce glycosuria of approximately 60–90 g/day.
  • At present, a significant reduction in cardiovascular mortality has been demonstrated for the SGLT2 inhibitor empagliflozin (relative risk reduction 38% after 3 years) and the glucagon-like peptide-1 agonist liraglutide (relative risk reduction 22% after 4 years).
  • Intensive glycemic control can increase the risk of heart failure.
  • In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study, empagliflozin was associated with a 14% reduction in the risk of composite outcome (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke).
  • The non-glycemic effects of SGLT2 inhibitors include reduction of plasma volume, increased hematocrit, protection against glomerular hypertension, improvement of diuretic efficiency, cardiac metabolism and endothelial function and reduction of arterial stiffness.
  • SGLT2 inhibitors have been shown to cause genital infections, usually with Candida species.
  • SGLT2 inhibitors represent an attractive option for the treatment of diabetes in patients with heart failure, as well as other cardiovascular diseases.

Martens P, Mathieu C, Verbrugge FH. Curr Treat Options Cardiovasc Med 2017; 19: 23. doi: 10.1007/s11936-017-0522-x

Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: Systematic review and meta-analysis of randomized and observational studies

This article presents the results of a meta-analysis of 25 eligible studies of glucagon-like peptide 1 agonists, conducted to assess their effects on heart failure in patients with type 2 diabetes.

Summary points
  • MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov databases were searched for randomized controlled trials, cohort studies, and case–control studies of glucagon-like peptide 1 (GLP-1) receptor agonists in adults with type 2 diabetes that explicitly reported heart failure or hospitalization for heart failure.
  • Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to rate the quality of evidence.
  • Overall, 25 studies were selected: 21 RCTs (n=18,270) and 4 observational studies (n=111,029).
  • Low quality evidence from 20 randomized controlled trials (RCTs) suggests a lower incidence of heart failure with GLP-1 agonists versus control.
  • Moderate-quality evidence from one RCT suggests that GLP-1 agonists are not associated with hospitalization for heart failure.
  • Very low quality evidence from three cohort studies comparing GLP-1 agonists to alternative agents suggests that GLP-1 agonists do not increase the incidence of heart failure.
  • Very low quality evidence from one case-control study suggests that GLP-1 agonists are not associated with hospitalization for heart failure.
  • The evidence reviewed in this article indicates that GLP-1 agonists do not increase the risk of heart failure or hospitalization for heart failure in patients with type 2 diabetes; however, this was based on low-quality evidence.

Li L et al. BMC Cardiovasc Disord 2016; 16: 91. doi: 10.1186/s12872-016-0260-0

Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: Systematic review and meta-analysis of randomized and observational studies

This paper presents the results of a systematic review and meta-analysis of randomized and observational studies of dipeptidyl peptidase-4 inhibitors conducted to assess their effect on the risk of heart failure and hospital admission for heart failure in patients with type 2 diabetes.

Summary points
  • Based on randomized controlled and observational studies, the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on heart failure are uncertain.
  • Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched for randomized controlled trials, non-randomized controlled trials, cohort studies and case-control studies that compared DPP-4 inhibitors with placebo, lifestyle modification, or active antidiabetic drugs in adults with type 2 diabetes and explicitly reported the outcome of heart failure or hospital admission for heart failure.
  • Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence.
  • A total of 55 studies were included in the analysis: 43 randomized controlled trials (n=68,775) and 12 observational studies (nine cohort studies, three nested case-control studies; n=1,777,358).
  • Low-quality evidence from 38 trials reporting heart failure outcomes suggested a possible similar risk with DPP-4 inhibitors and control. Moderate-quality evidence from five trials reporting admission for heart failure indicated an increased risk in patients treated with DPP-4 inhibitors compared with control.
  • Very low quality evidence from the observational studies that provided effect estimates was consistent with the findings in trials.
  • Very low quality evidence from pooling of adjusted estimates from observational studies suggested an increased risk of admission for heart failure in patients treated with sitagliptin compared with no use.
  • The results of this meta-analysis suggest that, compared with no use, DPP-4 inhibitors may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for cardiovascular diseases.

Li L et al. BMJ. 2016; 352: i610. doi: 10.1136/bmj.i610

Association of HbA1c with hospitalization and mortality among patients with heart failure and diabetes

This retrospective cohort study of outpatients with heart failure and diabetes examined the association between glycemic control and cardiovascular outcomes, focusing on low-income and ethnic-minority patients.

Summary points
  • The patient population consisted of 4723 adult individuals (mean age 64 years) with heart failure and diabetes, of whom 42.6% were black and 30.5% were Hispanic/Latino.
  • The association between HbA1c levels and all-cause hospitalization, heart failure hospitalization and mortality was measured using Cox proportional hazard models.
  • Of those included in the study, 21.8%, 12.7%, 22.6%, 15.0% and 28.0 % had HbA1c levels of <6.5%, 6.5%–6.9%, 7.0%–7.9%, 8.0%–8.9, and ≥9.0 %, respectively. Overall rates of all-cause hospitalization were similar across HbA1c groups.
  • Only patients with an HbA1c ≥9.0% had a significant increased risk of hospitalization (adjusted HR 1.13; 95 % CI 1.00–1.28) compared with patients with HbA1c level of 8.0%–8.9%.
  • Compared with patients with an HbA1c 8.0%–8.9%, patients with an HbA1c of <6.5%, 6.5%–6.9%, 7.0%–7.9% and ≥9.0% had an adjusted hazard ratio (95 % CI) for all-cause hospitalization of 1.03 (0.90–1.17), 1.05 (0.91–1.22), 1.03 (0.90–1.17), and 1.13 (1.00–1.28), respectively.
  • In a cohort of primarily ethnic-minority and low income patients with heart failure and diabetes, only patients with HbA1c >9 % were found to be at an increased risk of all-cause hospitalization.

Blecker S, Park H, Katz SD. BMC Cardiovasc Disord 2016; 16: 99. doi: 10.1186/s12872-016-0275-6