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Heart Failure in Type 2 Diabetes Mellitus

Impact of Glucose-Lowering Agents, Heart Failure Therapies, and Novel Therapeutic Strategies
Originally publishedhttps://doi.org/10.1161/CIRCRESAHA.118.311371Circulation Research. 2019;124:121–141

    Abstract

    Patients with diabetes mellitus have >2× the risk for developing heart failure (HF; HF with reduced ejection fraction and HF with preserved ejection fraction). Cardiovascular outcomes, hospitalization, and prognosis are worse for patients with diabetes mellitus relative to those without. Beyond the structural and functional changes that characterize diabetic cardiomyopathy, a complex underlying, and interrelated pathophysiology exists. Despite the success of many commonly used antihyperglycemic therapies to lower hyperglycemia in type 2 diabetes mellitus the high prevalence of HF persists. This, therefore, raises the possibility that additional factors beyond glycemia might contribute to the increased HF risk in diabetes mellitus. This review summarizes the state of knowledge about the impact of existing antihyperglycemic therapies on HF and discusses potential mechanisms for beneficial or deleterious effects. Second, we review currently approved pharmacological therapies for HF and review evidence that addresses their efficacy in the context of diabetes mellitus. Dysregulation of many cellular mechanisms in multiple models of diabetic cardiomyopathy and in human hearts have been described. These include oxidative stress, inflammation, endoplasmic reticulum stress, aberrant insulin signaling, accumulation of advanced glycated end-products, altered autophagy, changes in myocardial substrate metabolism and mitochondrial bioenergetics, lipotoxicity, and altered signal transduction such as GRK (g-protein receptor kinase) signaling, renin angiotensin aldosterone signaling and β-2 adrenergic receptor signaling. These pathophysiological pathways might be amenable to pharmacological therapy to reduce the risk of HF in the context of type 2 diabetes mellitus. Successful targeting of these pathways could alter the prognosis and risk of HF beyond what is currently achieved using existing antihyperglycemic and HF therapeutics.

    Heart Failure Risk Is Significantly Increased in Diabetes Mellitus

    Type 2 diabetes mellitus (T2DM) is a global epidemic and is expected to affect over 592 million people worldwide by 2035, a dramatic increase from 382 million people with diabetes mellitus in 2013,1 a prevalence that is likely underestimated.2 In the United States alone, an estimated 30.2 million adults or 12.2% had diabetes mellitus in 2015, of which 7.2 million (23.3%) were not aware or did not report having diabetes mellitus.3 Both type 1 diabetes mellitus and T2DM are heterogenous diseases in which clinical presentation and disease progression may vary considerably. T2DM accounts for 90% to 95% of all diabetes mellitus cases,4 for this reason, this review will focus on pharmacological treatments for T2DM and their impact on heart failure (HF) development. Patients with diabetes mellitus have over twice the risk of developing HF than patients without diabetes mellitus.5,6 The Framingham Heart Study suggests that diabetes mellitus independently increases the risk of HF up to 2-fold in men and 5-fold in women compared with age-matched controls,7,8 highlighting a sex discrepancy that is incompletely understood. The increased incidence of HF in diabetic patients persists even after adjusting for other risk factors such as age, hypertension, hypercholesterolemia, and coronary artery disease. Thus, the term diabetic cardiomyopathy was coined over 40 years ago and was initially used to describe ventricular dysfunction in the absence of coronary artery disease and hypertension in diabetic patients.9 However, its use has been broadened to describe the increased vulnerability of the myocardium to dysfunction that characterizes individuals with diabetes mellitus. While 10% to 15% of the general population have diabetes, a recent study suggested that 44% of patients hospitalized for HF have diabetes mellitus.10 The coexistence of comorbidities pose unique clinical challenges.10 While the association between mortality and HbA1c in diabetes mellitus patients with HF appears to be U-shaped, with the lowest risk of death in patients with HbA1c levels of ≈7.1%,11 other studies suggest that diabetes mellitus is independently associated with greater risk of death and rehospitalization compared with nondiabetics with HF.12 Additionally, observational data suggests a higher HbA1c level was associated with increased incidence of HF.13 Therefore, an important question to address is whether improved glycemic control improves HF outcomes.

    HF Risk and Glycemic Control

    Many landmark clinical trials have addressed the relationship between tight glycemic control and cardiovascular end points. The ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) showed that intensive glucose control, which lowered HbA1c to 6.5% in type 2 diabetics, showed no evidence of a reduction in macrovascular events with no increase in mortality.14 In contrast, the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes), which targeted HbA1c to 6% in the intensive therapy group, had an increased mortality of 22% suggesting a potentially unexpected increased risk of intensive glucose lowering in high-risk patients with T2DM. The finding of higher mortality resulted in this arm of the trial being terminated.15 These findings were further supported by intensive glycemic control in a veteran cohort over a 7.5-year period. They too reported intensive glycemic control in patients with poorly controlled T2DM (baseline HbA1c of 9.4%) had no significant effect on rates of major cardiovascular events or death.16 Similarly, the UKPDS (United Kingdom Prospective Diabetes Study) successfully reduced HbA1c by 11% over a 10-year follow-up but did not substantially reduce diabetes mellitus related mortality or myocardial infarction (MI).17 Together these studies suggested that despite the efficacy of diabetes mellitus therapies in achieving lower HbA1c, these therapies were not necessarily advantageous from a cardiovascular standpoint and some studies even showed an increase in cardiovascular events. These findings underscore the important conundrum that normalization of glycemia might not restore risk of cardiovascular disease (CVD) to the nondiabetic baseline. Although HF was not a primary end point of these studies, post hoc analyses also suggested that intensive glucose lowering did not reduce and in some cases, increased the risk for HF or HF hospitalization.18Table 1 summarizes the relationship between diabetes mellitus therapy and HF. In summary, pharmacological agents that may have beneficial effects on cardiovascular outcomes include metformin, SGLT2i (sodium-glucose cotransporter 2 inhibitor) and certain GLP1RA (glucagon-like peptide 1 receptor agonist). However, others such as sulfonylureas (SUs), thiazolidinediones (TZDs), insulin, some GLP1RAs and some DPP4i (dipeptidyl peptidase 4 inhibitor) might exacerbate or increase the risk for HF.

    Table 1. Summary of Effects of Diabetes Mellitus Treatments on Risk of Heart Failure

    DM TherapyEffects of Diabetes Mellitus Treatments on Risk of HF
    Biguanide (Metformin)Associated with better short-term and long-term prognosis in patients with HF19
    Associated with reduced mortality in HF patients19
    Reduces cardiac hypertrophy by AMPK-mediated repression of mTOR and as a consequence protein synthesis20
    AMPK activation by metformin can stimulate cardiac glucose uptake21
    Sulfonylureas (SU)Originally thought to increase mortality22
    No definitive CV outcome trial to evaluate CV safety of SUs vs placebo or other diabetic agents
    Meta-analysis reports no increased CV risk with SU treatment vs metformin23
    Retrospective cohort study reported an increased CV risk in patients on SU vs metformin or DPP4 inhibitor24
    No definitive CV outcome trials examining SUs in HF have been conducted
    Thiazolidinediones (TZDs)Reports on effects of TZDs on CV safety are conflicting.
    Beneficial effects were anticipated given improvements in glycemic control, inflammatory biomarkers, BP, TG levels and HDL25
    PROactive trial showed no reduction in CV outcomes in patients on pioglitazone26
    A meta-analysis reported an increased risk of MI with rosiglitazone27
    IRIS trial reported lower risk of stroke and MI in patients on pioglitazone vs placebo28
    Occurrence of fluid retention and weight gain is a reproducible side-effect of TZD therapy, which precludes its use in NYHA III and IV HF29,30
    Glucagon-like peptide-I (GLP-I) receptor agonistMeta-analysis reports no increase risk in HF or hospitalization for HF among type 2 diabetics31,32
    A meta-analysis revealed a modest improvement in ejection fraction in HF patients33
    Trial of GLP-1 agonist in advanced HF revealed a trend toward increased hospitalization in diabetes mellitus subgroup34
    Dipeptidyl peptidase 4 (DPP4) InhibitorsSAVOR-TIMI-53 Trial reported a significant increase in hospitalization for HF in patients on saxagliptin vs placebo35
    EXAMINE and TECOS trials do not reveal increased HF risk36,37
    Experimental studies in humans and animals show improvements in cardiac function when GLP-1 was activated by DPP4 inhibitor38,39
    DPP4 knock out mice showed induction of cardioprotective gene signature post-MI40
    Sodium-glucose cotransporters 1 and 2 (SGLT1 and 2) InhibitorsSGLT2 improves CV risk factors (weight reduction, reduction in SBP and improved lipid profile)41
    EMPA-REG OUTCOME trial reported a reduction in CV mortality and hospitalization from HF using empagliflozin42
    CANVAS trial reported similar results for canagliflozin43
    Meta-analysis of CV events in type 2 diabetics on dapagliflozin reported no increased risk for CV events44
    InsulinSome observational trials have suggested a relationship between insulin use and HF risk5,45
    CVOT with long acting insulin analogs do not demonstrate increased CV event rate or HF46,47

    AMPK indicates AMP-activated protein kinase; BP, blood pressure; CV, cardiovascular; CVOT, cardiovascular outcome trial; HDL, high-density lipoprotein; HF, heart failure; MI, myocardial infarction; mTOR, mechanistic target of rapamycin; NYHA, New York Heart Association; and TG, triglycerides.

    The observations that blood glucose lowering might not be sufficient to prevent increased hospitalization and mortality from HF, reinforce the possibility that additional factors beyond glycemia might contribute to the increased HF risk in diabetes mellitus, or that independent mechanisms might exist linking antihyperglycemic therapies and left ventricle (LV) remodeling. Beyond the structural and functional changes that occur with diabetic cardiomyopathy, a complex underlying and interrelated pathophysiology exists and may contribute to HF in the context of diabetes mellitus,48 some of which may be amenable to pharmacological therapy. These pathways will be discussed in greater detail later in this review (Figure 1). A consistently reported finding in the diabetic myocardium is cardiac hypertrophy, characterized by increased LV mass and wall thickness. Population studies have reported an independent association between diabetes mellitus and cardiac hypertrophy and systolic dysfunction.49,50 The ARIC study (Atherosclerosis Risk in Communities) provided evidence for subclinical myocardial damage in subjects with prediabetes and T2DM as measured by subclinical circulating concentrations of TnT (troponin T), using a highly sensitive assay. Subclinical myocardial damage increased in a linear manner across the glycemic spectrum from no diabetes mellitus to prediabetes and diabetes mellitus. This correlated with increased risk for cardiovascular events, HF or death, being highest in those with T2DM.51 A correlation between microvascular complications of diabetes mellitus and HF has long been established.52 More recently direct evidence of microvascular dysfunction and impaired myocardial perfusion reserve has been demonstrated53,54 implicating tissue hypoxia as another mechanism contributing to accelerated ventricular remodeling in diabetes mellitus. Although the correlation between glycemia and myocardial injury could represent cause and effect, it could also reflect the existence of additional risk factors for myocardial injury that track with glycemia. Therefore, any analysis of the relationship between antihyperglycemic therapies and HF risk must also account for the impact of these agents on other potential mechanisms that could lead to cardiac injury. Thus, direct or indirect mechanisms that could link current antihyperglycemic therapies with LV remodeling and myocardial injury that are independent of their blood glucose-lowering effects may exist. The remainder of this review will examine current antihyperglycemic therapies and discuss potential mechanisms that could influence their efficacy in terms of modulating HF risk, and then will review additional pathophysiological targets implicated in diabetic cardiomyopathy that could be amenable to therapeutic manipulation.

    Figure.

    Figure. Current antihyperglycemic therapies and potential therapeutic targets that could modulate diabetes mellitus associated heart failure. Diabetes mellitus is a multi-organ disease state characterized by hyperglycemia and dyslipidemia. Current commonly used therapies may achieve normoglycemia, but they have variable effects on heart failure risk and outcomes. Alternative targets, that could be amenable to pharmacological treatment and that may increase the risk of heart failure in diabetes mellitus are summarized.

    The Effect of Existing Antihyperglycemic Drugs on Cardiovascular Risk in T2DM

    Although this section will emphasize potential direct effects of these therapeutic agents on myocardial function in the context of diabetes mellitus, it is important to note that often times, studies in which these agents are evaluated are confounded by the fact that these agents will alter systemic metabolism. Thus, beneficial effects observed, could represent direct effects or effects that are secondary to metabolic consequences of these agents such as reducing circulating glucose or triglycerides (TG; Table 2).

    Table 2. Diabetes Mellitus Therapies and Their Mode of Action and Physiological Effects

    DM TherapyMode of Action and Physiological Effect
    Biguanide (Metformin)Glucose lowering effect through the reduction in hepatic glucose production by suppressing gluconeogenesis55
    This is achieved by inhibition of complex I of the mitochondrial respiratory chain56
    This reduces ATP production and results in accumulation of AMP56
    Changes in AMP/ATP ratio activates AMPK56,57
    AMPK activation promotes glucose uptake at skeletal muscle and inhibits glucose production by hepatocytes58,59
    Metformin also reduces circulating TGs and VLDL and increases HDL60
    Sulfonylureas (SU)Closes KATP channels on pancreatic β-cell plasma membrane by binding to SU receptors (SUR)61
    Membrane depolarization, promotes calcium influx and release of insulin61
    Extrahepatic actions: SUR2 exists in cardiac and skeletal muscle62
    Thiazolidinediones (TZDs)Mediated through the activation of the ligand activated transcription factor, PPAR-γ primarily expressed in adipose tissue63
    Increases skeletal muscle glucose uptake thereby reducing insulin resistance64
    Reduces hepatic glucose uptake, hepatic glucose production and postprandial gluconeogenesis65
    Promotes adipogenesis65
    Glucagon-like peptide-I (GLP-I) receptor agonistGLP-I is an incretin hormone whose secretion is increased with an oral glucose load66
    GLP-I receptor agonists activate GLP-I receptors which stimulates glucose-dependent insulin secretion in response to oral glucose load66
    Stimulates proinsulin gene in the islets to replenish insulin and may promote β-cell proliferation and survival66
    Suppresses glucagon secretion67
    Delays gastric emptying, increasing satiety and promoting weight loss68
    Dipeptidyl peptidase 4 (DPP4) InhibitorsDPP4 inhibits GLP-169
    DPP4 inhibition increases postprandial active incretin (GLP-I) concentrations69
    Improves glucose-dependent insulin secretion69
    Inhibits secretion of glucagon, suppressing hepatic glucose production and improves insulin sensitivity69
    Sodium-glucose cotransporters 1 and 2 (SGLT1 and 2) InhibitorsSGLT2 causes renal glucose reabsorption across the luminal membrane of the epithelial cells of the proximal convoluted tubule (PCT)70
    SGLT2 inhibitors block SGLT2 in the proximal nephron and therefore glucose reabsorption causing glucosuria71
    InsulinInsulin administration activates insulin receptors
    This results in increased glucose disposal and reduced hepatic glucose production3

    AMPK indicates AMP-activated protein kinase; PPAR-γ, peroxisome proliferator-activated receptor-γ; TG, triglycerides; and VLDL, very-low-density lipoprotein.

    Metformin

    Metformin is the most widely used oral antihyperglycemic agent and is considered first line therapy in T2DM because of its superior safety profile.56 It is both safe and efficacious both as monotherapy and in combination with other antidiabetic agents and insulin. The UKPDS reported that patients with T2DM on metformin had 36% reduced risk of all-cause mortality and 39% lower risk of MI compared with type 2 diabetic patients treated otherwise.17 This risk reduction was greater with metformin therapy than with insulin or SU derivatives despite patients achieving similar glycemic control.17 Other more recent analysis has supported the case for metformin having a survival benefit in diabetic patients with HF compared with alternative glucose-lowering regimens.72,73 Metformin was associated with better short-term and long-term prognosis than any other antidiabetic treatment in patients with acute coronary syndrome74 and HF.19

    The cardioprotective actions of metformin in diabetic patients are not fully understood. Activation of AMPK (AMP-activated protein kinase) is one putative mechanism of action of metformin. AMPK activation inhibits mTOR (mechanistic target of rapamycin) and represses protein synthesis, which could inhibit cardiac hypertrophy.20 Metformin was reported to inhibit hypertrophy in a rat model of pressure overload,75 providing cardioprotection against ischemia-induced HF76 and more recently was shown to protect against transverse aortic constriction-mediated cardiac hypertrophy independently of AMPK.77 Diabetes mellitus is associated with reduced myocardial glucose utilization and increased fatty acid (FA) utilization. Metformin could increase myocardial glucose utilization in part by activating AMPK or by increasing myocardial insulin sensitivity.21 Although AMPK activation could also increase FA oxidation, the extent of any increase in FA utilization might be tempered by improvements in peripheral insulin sensitivity, which would reduce the delivery of FAs to the heart. Cardiac fibrosis has also been shown to be attenuated in HF with metformin treatment in mice subjected to transverse aortic constriction.78 However, the metformin doses in these studies was greater than those used clinically, thus it is uncertain if similar changes occur in a clinical setting. In a human study examining the impact of metformin on myocardial function and metabolism in humans with T2DM, metformin modestly reduced myocardial FA utilization but did not change glucose utilization.79 Taken together, clinical studies suggest that metformin might have negligible effects on myocardial substrate utilization and function. However, population cohort and observational studies have consistently revealed that metformin treatment is associated with a reduction in the prevalence of HF in diabetic subjects.45,80 The mechanisms for this cardioprotection remain to be determined.

    Sulfonylureas

    SUs are insulin secretagogues that lower glucose by a glucose-independent release of insulin from pancreatic β-cells.81 Frequently prescribed SUs include second generation agents such as glyburide/glibenclamide, glipizide, and glimepiride.64 SUs bind to β-cell membrane SU receptors (SURs) leading to closure of ATP-sensitive potassium channels. The subsequent membrane depolarization increases calcium influx and insulin release.61 A second SU receptor SUR2 is highly expressed in cardiac and skeletal muscle.82,83 In vitro studies support a possible insulin mimetic action of SU, whereby SU drugs stimulated glycogenesis and lipogenesis.62 As a direct extension of their mechanism of action, the major adverse effect of SUs is hypoglycemia84,85 Weight gain is another important side effect of SUs. Many studies have demonstrated increased weight gain in patients on SUs versus metformin85 and the UKPDS demonstrated an increase in weight gain with SUs but even more so with insulin17; however, not all studies have reported an increase in weight gain.86

    Although prior studies have suggested a link between first generation SUs and cardiovascular mortality,22 to date there is no definitive cardiovascular outcome trial that has specifically evaluated cardiovascular safety with SU versus placebo or other glucose-lowering agents and for this reason the controversy about the effects of SU on cardiovascular outcome continues. Observational studies, systematic reviews and meta-analyses have attempted to inform the clinically relevant question about cardiovascular safety of SUs. Results are conflicting, whereby some suggest the presence of increased cardiovascular risk and others do not.87 A meta-analysis of 47 randomized control trials was performed to explore the cardiovascular safety of SUs and reported no increased risk of any key outcomes; all-cause death, cardiovascular death, MI or stroke; nor was there any increased cardiovascular risk with SUs versus metformin.23 Other studies have reported an increase in cardiovascular risk in patients on SU versus metformin.24 These data should be interpreted with caution as the reduction in cardiovascular events with metformin may reflect the cardiovascular benefit of metformin. Few studies have directly examined the relationship between SU use and HF. An observational cohort study of >500 000 patients, which revealed an increased risk of all-cause mortality in patients treated with SUs did not reveal a statistical increase in HF.45 Potential reasons for adverse cardiovascular complications with SU therapy could include inhibition of myocardial preconditioning, hypoglycemia, weight gain, and hypertension.87

    Thiazolidinediones

    The glucose-lowering effects of the TZDs are mediated primarily by decreasing insulin resistance in skeletal muscle and liver to increase glucose uptake and reduce hepatic glucose production, respectively.65 They have also been shown to be an acute inhibitor of the mitochondrial pyruvate carrier, thereby having a direct metabolic effect by increasing glucose uptake.88 TZDs directly activate PPAR-γ (peroxisome proliferator-activated receptor-γ). The binding of TZDs to PPAR-γ increases peripheral insulin sensitivity in the liver and skeletal muscle in part by promoting the release of adipokines such as adiponectin,89 while promoting adipogenesis.65 Controversy exists about the specific extent to which TZD treatment increases cardiovascular risk. The recent IRIS trial (Insulin Resistance Intervention After Stroke) reported that in nondiabetic patients with insulin resistance and a recent history of ischemic stroke or transient ischemic attack, treatment with pioglitazone reduced the risk for stroke or MI.28 These findings have been further supported by 2 recent meta-analyses.90,91

    In terms of HF, the most commonly reported side effects of TZDs used either as monotherapy or in combination are weight gain29,92 and fluid retention.30,93 According to a meta-analysis, TZD treatment was associated with a 2-fold increase risk of edema versus placebo, other oral hypoglycemic drugs, or insulin.94 The PROactive trial suggested that pioglitazone was associated with 26.4% increase in edema compared with 15.1% for placebo.95 TZD-induced edema is thought to be linked to increased vascular permeability, vasodilation, and fluid retention by the kidney.96 Activation of PPARs in the nephrons of the kidney by TZDs promotes the expression of epithelial sodium channels in the collecting duct which increases the retention of salt and water leading to fluid retention.97 Zhang et al98 reported that collecting duct specific PPAR-γ knock out were resistant to TZD-induced weight gain and plasma volume expansion further supporting the role of epithelial sodium channels in fluid retention. However, other studies have challenged this mechanism.99 TZDs also failed to augment basal or insulin-stimulated Na+ flux via epithelial sodium channels in cell lines (A6, M-1, and mpkCCDc14).100 Thus, additional mechanisms could contribute to adverse effects of TZDs on LV structure and function. Although increased myocardial insulin signaling could represent 1 mechanism, animal studies in mice-lacking insulin receptors in cardiomyocytes revealed that cardiac hypertrophy still develops in animals treated with a PPAR-γ agonist.101 Other animal studies have also suggested that direct activation of PPAR-γ could lead to ventricular dysfunction.102 Finally, the inhibition of the mitochondrial pyruvate carrier by TZDs, could increase mismatch between glycolysis and glucose oxidation, which could be maladaptive. Thus, the relationship between TZD use and ventricular remodeling is complex and may represent direct and indirect effects on the myocardium.

    DPP4 Inhibitors

    DPP4 inhibition prevents the inactivation of the incretin hormone, GLP-I (glucagon-like peptide I), which promotes glucose-dependent insulin release from β-cells. DPP4i are effective glucose-lowering agents when used as monotherapy or in addition to other agents.103–105 Five DDP4is are currently in clinical use (alogliptin, linagliptin saxagliptin, sitagliptin, and vildagliptin). Although preclinical studies identified many potential mechanisms of action by which DPP4 inhibition or GLP-1 agonism could exhibit direct cardiovascular benefits,38–40,106,107 recent cardiovascular outcome trials have indicated that treatment with DPP4is do not improve cardiovascular morbidity or mortality relative to placebo. The results of these trials have been recently reviewed.108 However, with regard to HF, the SAVOR-TIMI-53 trial (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus [SAVOR]-Thrombolysis in Myocardial Infarction [TIMI] 53) reported a significant increased risk of hospitalization for HF in patients on saxagliptin versus placebo.35 The EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) and TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) trials36,37 did not reveal a statistical increase in HF hospitalization, but meta-analyses including data from these trials have suggested a small effect of DPP4is to increase HF hospitalization.108 The mechanisms responsible for these observations are not understood. One possibility could be effects of other circulating peptides that are substrates for DPP4 that could have independent cardiovascular effects, although this hypothesis remains to be proven. However, a consensus is emerging that DPP4is might not be a preferred agent in patients with T2DM with increased risk for CVD with concomitant HF.

    GLP-I Receptor Agonists

    Direct GLP1R agonists are effective glucose-lowering agents that also promote weight loss. The landmark cardiovascular outcome trial (LEADER [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results]) that examined the impact of the GLP1RA liraglutide on cardiovascular outcomes in patients with diabetes mellitus with increased cardiovascular risk revealed a significant reduction in the composite end point of occurrence of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.109 However, the rates of nonfatal MI, nonfatal stroke, and hospitalization for HF were nonsignificantly lower in the liraglutide group than in the placebo group. A subsequent meta-analysis of randomized and observational trials supported the conclusion that GLP-I receptor agonists might not increase the risk of HF or hospitalization for HF in patients with T2DM.31 By contrast, in a small study of HF patients (stage 3 and 4 New York Heart Association) with and without diabetes mellitus, who were randomized in the FIGHT trial (Functional Impact of GLP-1 for Heart Failure Treatment) to receive Liraglutide or placebo, there was no impact of liraglutide on mortality or HF hospitalizations. However, in a prespecified subgroup analysis of patients who died or who were hospitalized for HF by T2DM diagnosis, there was a strong trend toward adverse outcomes in patients with diabetes mellitus and HF who received liraglutide (hazard ratio, 1.54; 95% CI, 0.97–2.46; log-rank P=0.07).110 Thus, there remains uncertainty about the utility of liraglutide in patients with existing HF although in T2DM patients with high risk for CVD, liraglutide may be a suitable choice to prevent a future cardiovascular event. Although preclinical studies have suggested mechanisms by which GLP1RA may influence LV contractility in the short-term, little is known about the mechanisms that account for the potential worsening of HF when individuals with existing HF are treated with liraglutide.

    Sodium-Glucose Cotransporters 2

    Glucose that is filtered by the glomeruli is reabsorbed in the nephron by an active transport process that is mediated predominantly by SGLT2, which is a member of a larger family of SGLTs. Inhibition of SGLT2 promotes glycosuria and represents a novel therapeutic strategy for treating T2DM.111 Three SGLT2i are currently in clinical use; dapagliflozin, canagliflozin, and empagliflozin.3 All of these agents are effective in lowering blood glucose as monotherapy in combination with other glucose-lowering agents.112–116 Recent cardiovascular outcomes trials revealed an unexpectedly strong cardioprotective signal of SGLT2i in high-risk patients with T2DM. Empagliflozin was the first SGLT2i to show a reduction in cardiovascular mortality and hospitalization from HF in the EMPA-REG outcome trial ([Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients).42 The CANVAS trial (Canagliflozin Cardiovascular Assessment Study) also revealed similar benefits in terms of the composite end point of major adverse cardiovascular events and reduced HF hospitalization in subjects randomized to canagliflozin.43 While no large dapagliflozin cardiovascular outcome trial has been completed yet, a meta-analysis of cardiovascular events from dapagliflozin clinical trials also revealed a significant reduction in HF hospitalizations in patients treated with dapagliflozin.44 Thus, SGLT2i represent the first class of therapeutic glucose-lowering agents that have definitively reduced the risk of HF in T2DM. The mechanisms by which SGLT2i mediate these benefits are not understood. However potential mechanisms that have been proposed include increased natriuresis, reduced blood pressure, renal protection and a modest effect to increase circulating ketones, which might improve myocardial energetics.41 It is important to note that these trials were designed primarily to evaluate cardiovascular safety. Trials designed to evaluate outcomes in subjects with HF (with or without diabetes mellitus) are ongoing, which will enable clinicians to better determine, for example, if addition of SGLT2 inhibition to patients with diabetes mellitus and HF will increase survival and improve the outcomes in these patients. The results of recent cardiovascular outcomes trials have already influenced clinical guidelines that recommend the use of SGLT2i in suboptimally controlled patients with diabetes mellitus, at high risk for CVD or with existing HF.108

    Insulin

    In the management of T2DM, insulin therapy is often added when lifestyle and oral hypoglycemic agents fail to establish glycemic control. As such, it may not be surprising that individuals receiving insulin therapy are older and have greater risk for HF. Observational studies have suggested greater cardiovascular mortality and increased HF prevalence in insulin treated patients with T2DM.45 Several mechanisms linking hyperinsulinemia and HF have been proposed and reviewed.117 Few trials have been designed to prospectively evaluate the relationship between insulin treatment and HF. Such studies are challenging because insulin therapy usually occurs in the context of or in addition to the use of other treatment approaches, which could confound or contribute in uncertain ways to clinical outcomes. A recent cardiovascular outcomes trial, the ORIGIN trial (Outcome Reduction With Initial Glargine Intervention) examined insulin glargine versus standard care in type 2 diabetics with high risk for CVD. After a median follow-up of 6.2 years, the results showed that early use of basal insulin to target fasting plasma glucose levels neither increased nor reduced cardiovascular outcomes compared with the standard care group.46 A recent analysis of HF events in the ORIGIN trial suggested that randomization to insulin glargine did not increase HF hospitalization or HF recurrence.118 Finally, the recently completed DEVOTE trial (A Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Subjects With Type 2 Diabetes at High Risk of Cardiovascular Events) examined the efficacy and safety of degludec, an ultralong acting, once daily basal insulin in patients with T2DM and high cardiovascular risk. This trial compared degludec to glargine and demonstrated no difference between the 2 with respect to incidence of adverse cardiovascular events.47 These trials are reassuring because they suggest that insulin usage in high-risk patients does not invariably lead to adverse cardiovascular outcomes or to increased HF. However, it is important to note improving glycemic control with insulin has not been shown to reduce the elevated risk of HF that exists in diabetes mellitus. Additionally, it has been suggested that exogenous insulin by increasing myocardial glucose uptake in the absence of a compensatory reduction in free FA uptake, could exacerbate insulin-mediated metabolic stress by increasing glucolipotoxicity.119 We also do not understand the interaction between associated comorbidities, insulin use, and HF risk. Thus, additional research is required to further inform therapeutic guidelines that seek to balance metabolic control and cardiovascular outcomes in insulin-requiring individuals.

    HF Therapies and Their Effect on Glycemic Control

    While it is important to determine the impact of antidiabetic drugs on HF, it is also important to address the effects of HF therapies on HF outcome measures and glycemic control in the setting of diabetes mellitus. We will briefly review the relationship between commonly used HF therapies and their potential relationship with glycemic homeostasis in diabetes mellitus.

    Renin Aldosterone Angiotensin System Inhibition

    It is widely accepted that induction of the renin angiotensin aldosterone system (RAAS) represents a mechanism linking diabetes mellitus and cardiovascular complications.120 In addition to systemic activation of the RAAS, induction of this pathway also occurs locally in the heart both in diabetes mellitus and in HF.48 ACE (angiotensin converting enzyme) inhibitors reduce the risk for new onset HF in patients with established CVD or diabetes mellitus,121–123 and correlates with reduced urinary albumin excretion. Activation of RAAS in diabetes mellitus may also contribute to inflammation,124 cardiac fibrosis, and oxidative stress125 which all contribute to cardiac remodeling, and could be reversed or prevented by RAAS blockade.125,126 Thus, ACE inhibition and Ang II (angiotensin II) type 1 receptor blockade remain first line therapy for CVD prevention in patients with diabetes mellitus.127 ACE inhibitors reduce CVD rates and all-cause mortality in patients with diabetes mellitus and increase insulin sensitivity in cells.128,129 ARBs (angiotensin receptor blockers), specifically candesartan improves calcium signaling parameters in atrial tissue with diabetic cardiomyopathy.130 Moreover, renin inhibition improved LV hypertrophy and end-systolic volume in patients with diabetes mellitus.131,132 A recent innovation in the management of HF has been the combination of RAAS inhibition and inhibition of neprilysin that degrades natriuretic peptides. These dual ARNIs (angiotensin receptor-neprilysin inhibitors), such as valsartan in combination with the neprilysin inhibitor, sacubitril, improves cardiac function in experimental models of reperfusion injury133 and reduces hospitalization in patients with HF and diabetes mellitus.134 Natriuretic signaling has recently been shown to promote energy expenditure and augment systemic insulin sensitivity in animal models of obesity and insulin resistance.135 Moreover, in human studies, reduced adipose tissue natriuretic peptide signaling correlated with insulin resistance.136 Thus, it is plausible that these mechanisms of action could increase insulin sensitivity and metabolic control in subjects with T2DM and HF. As such, it will be of interest to rigorously determine whether ARNIs use could reduce the risk of HF progression in individuals with diabetes mellitus, particularly those at high risk for CVD and HF. Increased aldosterone signaling has been implicated in HF, diabetic cardiovascular injury including diabetic cardiomyopathy and may also play a role in the pathophysiology of insulin resistance.137 Inhibition of aldosterone receptor signaling with eplerenone may reduce indices of inflammation and markers of insulin resistance in HIV-infected subjects.138 Thus, it would be of interest to determine metabolic and cardiovascular outcomes (including HF incidence) in high-risk subjects with diabetes mellitus treated with aldosterone receptor antagonists. Other targets for modulating the RAAS are in development that could also impact glucose metabolism in addition to their cardiovascular effects.

    Aliskiren a renin inhibitor has been successful in reducing blood pressure by reducing Ang II generation.139 One potential concern is that aliskiren increases renin levels that could signal through the (P) RR (prorenin receptor).140 Blocking (P) RR may be more efficacious than blocking renin alone. To date, only one (P) RR agent has been developed called handle region peptide. Animal models have demonstrated promising results as recently reviewed141 and may have benefits in high prorenin disease states such as diabetes mellitus. A novel approach to antagonize Ang II, is stimulation/activation of ACE2, which degrades Ang II to generate Ang 1–7. Animal models of ACE2 deficiency have demonstrated cardiac dysfunction.142 Several experimental studies have suggested Ang 1–7 infusion may ameliorate diabetic cardiomyopathy, by improving LV hypertrophy, fibrosis and inflammation, and increasing cardiac output.143 Despite the complex regulation of RAAS, a case can be made for further exploration of approaches to reduce Ang II and its adverse consequences while increasing the activity of beneficial pathways such as ACE2 or Ang 1–7 administration as a plausible therapeutic approach for improving cardiovascular outcomes and reducing HF risk in diabetes mellitus.

    Lipid-Lowering Agents

    Dyslipidemia is a major risk factor for CVD in T2DM. The characteristics of diabetic dyslipidemia include high plasma TG, high LDL (low-density lipoproteins), and low HDL (high-density lipoproteins). These changes can be attributed to increased FA flux secondary to insulin resistance in adipocytes, in concert with altered hepatic lipid metabolism. While several classes of pharmacological agents are used to treat dyslipidemia, the CORONA trail (Controlled Rosuvastatin Multinational Trial in Heart Failure) suggested a reduction in the risk of hospitalization for HF by 15% to 20% in patients on rosuvastatin.144 The mechanism for the reduction in HF is not clear, but could represent reduced ischemic events or direct effects of the statin on endothelial or microvascular function. Many studies confirm that statin treatment of individuals with diabetes mellitus will reduce cardiovascular events linked to myocardial ischemia.145 However, the specific question of cholesterol lowering in a diabetic population with HF as the prespecified end point to our knowledge remains to be addressed in a clinical trial. Fibrates are PPAR-α agonists that lower TGs, LDL, and raise HDL. They may also improve insulin sensitivity.146 Fibrate therapy reduced CVD risk factors and has been shown to reduce coronary events in a diabetic population.147 In sucrose fed insulin resistant rats, used as a model of diabetic cardiomyopathy, treatment with bezafibrate prevented metabolic abnormalities and cardiomyocyte dysfunction.148 However, it is possible that the improvement in cardiomyocyte function described in this animal study resulted from reduced lipid delivery to the heart and improved systemic metabolic homeostasis. Although, these findings suggest that PPAR-α agonists therapy could be a reasonable therapeutic target in subjects at risk for diabetic cardiomyopathy, further investigation of this question is necessary and trials examining the impact of specifically treating diabetic dyslipidemia on HF risk are warranted. A clinical trial (AleCardio) of a dual PPAR-α/PPAR-γ activation which had potent effects on reducing hypertriglyceridemia and increasing HDL, was discontinued because of increased cardiovascular mortality, including a trend toward increased risk of HF.149 It is not known if these adverse effects were the consequence of PPAR-α versus PPAR-γ stimulation.

    β-Blockade

    β-blockade is central to the management of patients with HF with reduced ejection fraction (EF). Although concerns were raised in the past about the potential increase in risk of hypoglycemia, when β-blockade is used in individuals with diabetes mellitus, there is little evidence that this is the case and contemporary clinical guidelines support the use of β-blockade in individuals with diabetes mellitus and HF.150 Meta-analyses support the prognostic benefits of β-blockade in HF patients with diabetes mellitus, although, the magnitude of benefit is attenuated in diabetes mellitus,151 perhaps because of associated autonomic dysfunction. Notably, carvedilol (a combined β1/β2 antagonist) improves both glycemic control, LVEF151,152 and decreases oxidative stress in the failing human heart153 and might be the β-blocker of choice. A role for aberrant β2 adrenergic signaling in diabetic cardiomyopathy has also been suggested in animal studies.154 In this study, hyperinsulinemia-induced phosphodiesterase 4D, by a mechanism involving IRS (insulin receptor substrate) and GRK2-dependent transactivation of a β2AR-β-arrestin-ERK (extracellular signal-regulated kinase) signaling pathway. Phosphodiesterase 4D induction reduces cAMP activity and PKA (protein kinase A) phosphorylation of its substrates which contributed to cardiac dysfunction. Genetic deletion of the β2AR or β-arrestin 2 or pharmacological inhibition of GRK2 or the β2AR reversed the obesity-related cardiac dysfunction. These observations provide a rationale for targeting β2AR or GRK2-mediated signaling as a potential therapy for diabetes mellitus associated HF.

    Pathophysiologic Mechanisms That Could be Therapeutically Targeted for Treating HF in Diabetes

    Cardiac Metabolism in Diabetes Mellitus and in HF

    Diabetes mellitus with or without HF is associated with profound changes in myocardial substrate utilization and this topic has been extensively reviewed.48,117 In brief, diabetes mellitus is associated with increased myocardial FA utilization, decreased glucose utilization (glycolysis and glucose oxidation), increased myocardial oxygen consumption and decreased cardiac efficiency. Despite increased rates of FA oxidation, TG, and other lipid metabolites such as ceramides accumulate in the diabetic heart. Cardiac metabolism in HF has also been studied by many groups and extensively reviewed.155,156 Similar to diabetes mellitus, glucose oxidation rates are generally reduced in the failing heart and changes in glycolysis are variable with glycolysis being increased early in the evolution from compensated cardiac hypertrophy to HF. However, in end stage HF, rates of glucose uptake might be reduced although the mismatch between glycolysis and glucose oxidation likely persists.157 In contrast to diabetes mellitus, FA utilization, and oxidation rates are reduced in HF, although evidence for accumulation of toxic lipid intermediates have been reported.158 Thus, the combination of HF and diabetes mellitus could potentially exacerbate lipotoxicity and further reduce cardiac contractility, as was suggested by studies combining increased myocardial lipid utilization with increased glucose delivery.159 Relatively few studies have rigorously examined myocardial substrate utilization in subjects with diabetes mellitus and HF. Animal studies have attempted to examine this issue and results are variable. For example, whereas transverse aortic constriction in high-fat fed mice was associated with reduced ventricular function and increased myocardial injury,160 recent studies in diabetic db/db mice revealed incredible resilience and preservation of myocardial energetics after transverse aortic constriction.161 Moreover, studies in animal models of HF subjected to high-fat diets suggested that high-fat feeding (which induced impaired glucose tolerance and insulin resistance) could be cardioprotective.162 Metabolic modulation as an approach to treating HF has long been considered as an approach to treating HF and has been extensively reviewed.163,164 The rationale for modulating myocardial substrate utilization in HF, includes increasing glucose utilization while reducing FA utilization in an attempt to increase cardiac efficiency. The most widely studied approach has been with trimetazidine an inhibitor of 3-ketoacylcoenzyme A thiolase (3-KAT), which would shift substrate utilization from FA to glucose oxidation. Meta-analyses of small clinical studies have revealed potential beneficial effects.165 Earlier attempts to increase PDH flux thereby increasing glucose oxidation, with dichloroacetate have yielded mixed results in small human trials. Moreover, the long-term use of dichloroacetate in humans is contraindicated because of the neuropathy associated with this drug.166 However, similar studies of metabolic modulation in HF patients with established diabetes mellitus remain to be performed.

    Recent studies have revealed that human failing hearts exhibit increased ketone body utilization.167 Ketone bodies are an energy-efficient fuel generated primarily in the liver from acetyl-coenzyme A derived from β-oxidation of FA. It remains to be shown if this increase in ketone utilization in HF represents an adaptation in the face of reduced ability of the failing hearts to use other substrates. Moreover, whether ketone bodies could improve cardiac function in HF is unknown and is now an intense area of investigation. Less is known about ketone body utilization in diabetic cardiomyopathy, although a recent human study suggested that myocardial ketone utilization might be increased.168 Studies examining ketone utilization in diabetics with HF would therefore be of great interest and could provide a strong rationale for studies designed to determine the impact of modulating myocardial ketone metabolism on the course of HF in diabetes mellitus.

    Diabetes mellitus is associated with increased flux through the hexosamine biosynthetic pathway, leading to increased generation of glucosamine that is used by the enzyme O-GlcNAc transferase to generate posttranslational modifications on a diverse array of cellular proteins via a process known as O-GlcNAcylation. The relationship between protein O-GlcNacylation and cardiac structure and function is context dependent. For example, increased protein O-GlcNAcylation has been described in rodent models of hypertrophy and HF and in failing human hearts155,169,170 which correlated with reduced cardiac mitochondrial function particularly in the context of diabetes mellitus.171 In contrast, NOX4, which is induced in the failing heart was shown to maintain myocardial FA utilization via a mechanism mediated by increased O-GLcNacylation of the FA transporter CD36.172 Moreover, O-GlcNAcylation was shown to be protective in the context of ischemia173 by inhibiting calcium overload and ROS (reactive oxygen species) generation174 or by increasing cardiac stem cell survival.175 As such, future work is needed to identify the specific targets of O-GlcNACylation in the diabetic heart to determine the impact of these changes on protein function and HF pathophysiology. This in-depth understanding would be a prerequisite to determining if pharmacological modulation of the hexosamine biosynthetic pathway or of the activity of O-GlcNAc transferase or OGlcNACase may play a role in modifying HF outcomes particularly in the context of diabetes mellitus.

    Mitochondrial Bioenergetics

    Many studies have examined mitochondrial bioenergetics either in HF or in diabetes mellitus. Both conditions are associated with impaired mitochondrial oxidative capacity and oxidative stress. However, diabetes mellitus might be more likely to be associated with increased mitochondrial uncoupling, which contributes to impaired cardiac efficiency in the diabetic heart.176 There is considerable evidence linking HF with impaired myocardial energetics.155 Reduced cardiac PCr/ATP ratio has been reported in explanted human hearts,177 in 31P magnetic resonance spectroscopy studies in humans with HF with reduced EF,178 in patients with HF with preserved EF179 and in animal models of pressure overload HF.180 Similar changes in myocardial PCr/ATP ratios have been reported in subjects with diabetes mellitus with mild diastolic impairment. Impaired mitochondrial respiration and altered mitochondrial ultrastructure have been observed in rodent models of insulin resistance and diabetes mellitus and have been previously reviewed.181 Thus, the possibility exists that the superimposition of diabetes mellitus and HF could further impair mitochondrial bioenergetics. Intriguingly, this specific question has not been widely studied. Although animal studies that have attempted to maintain expression levels of regulators of mitochondrial biogenesis such as PGC1-α have not led to preservation of myocardial function, additional mechanisms linking impaired mitochondrial bioenergetics and HF could potentially be targeted therapeutically. These include ROS-mediated mitochondrial uncoupling, a characteristic of diabetic cardiomyopathy that in animal studies could be ameliorated by treatment with antioxidants.182,183 Similar effects have been reported in animal models of HF,184,185 but few studies have examined a role for ROS-scavenging when diabetes mellitus and HF coexist. Another molecular target that is emerging as a potential treatment for HF are strategies that replete the myocardial pool of NAD+ using for example nicotinamide riboside.186 Although nicotinamide riboside has also been studied in diabetic neuropathy, a role for therapeutic manipulation of this pathway in the context of diabetes mellitus and HF remains an important question for future studies. Finally, altered E-C coupling represents an important pathophysiological mechanism that is altered both in HF and in models of diabetic cardiomyopathy. Calcium reuptake via SERCA-2 (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase-2) into the SR (sarcoplasmic reticulum) is an energy-dependent process, which is impaired in HF and in models of diabetic cardiomyopathy. For example, cardiomyocytes from ob/ob mice exhibited elevated cytosolic Ca2+, delayed removal of Ca2+ and reduced amplitudes of Ca2+ transients related to reduced SERCA-2a activity and impaired Ca2+ reuptake.187–189 Adenoviral overexpression of SERCA-2 was shown to improve E-C coupling in animal models of type 1 and T2DM.190

    Lipotoxicity and Glucotoxicity

    The systemic metabolic perturbations associated with uncontrolled diabetes mellitus presents the myocardium with a surplus of fuels such as FAs, ketones, and glucose. The inability of the heart to process these substrates stem in part from mitochondrial dysfunction leading to the accumulation of toxic byproducts of these cardiac fuels that may contribute to increased myocardial injury. The net effect of this imbalance between substrate supply and metabolic capacity and the aberrant signaling that ensues from metabolic byproducts of lipid or glucose metabolism has been termed lipotoxicity or glucotoxicity, respectively, or when their effects occur in concert, the synergistic pathological consequences have been described as glucolipotoxicity. The topic of myocardial lipotoxicity has been extensively reviewed.191,192 There is a general consensus that lipotoxicity arises from the increased availability of lipid intermediates such as ceramides, diacylglycerol, or oxidized phospholipids.48 Lipotoxic cardiomyopathy has been achieved in many animal models by increasing FA uptake.48 Excess lipid can be stored as TG and are also shunted into non-oxidative pathways, disrupting normal cellular signaling and leading to apoptosis and organ dysfunction.191 Metabolites that arise from glycolysis such as sorbitol the product of aldose reductase, the initial step in the polyol pathway has been implicated in promoting oxidative stress. O-GlcNAC modifications of proteins as discussed earlier, resulting from increased flux through the hexosamine biosynthetic pathway has variable consequences which could be cardioprotective or deleterious.193 Recent studies have also revealed that glucose or its metabolites might also impact myocardial gene expression by direct effects on transcription factors or by epigenetic mechanisms.194 Although, in the context of diabetes mellitus, adaptations develop in the heart to reduce glucose uptake, persistent hyperinsulinemia, hyperglycemia and increased circulating FAs may conspire to limit protective adaptations leading to a cumulative impact of toxic byproducts of glucose and lipid metabolism, leading to glucolipotoxicity. From a therapeutic standpoint the most effective approaches to limit glucolipotoxicity will likely be those that limit excessive substrate delivery to the heart and mitigating hyperinsulinemia. As discussed elsewhere in this review, existing glucose-lowering therapies address some but not all of these variables and might have independent effects on the myocardium, which depending on the agent may provide additional benefit (eg, SGLT2i) or generate adverse effects (eg, TZDs). A nonpharmacological approach, namely bariatric surgery which represents a treatment that is most likely to lead to diabetes mellitus reversal may come close to addressing many of the metabolic abnormalities that promote glucolipotoxicity and is discussed next.

    Obesity—Impact of Bariatric Surgery or Calorie Restriction

    Bariatric surgery has been proven to be the most effective long-term weight loss treatment, provoking changes in gut hormone physiology, the metabolic profile and improvements in insulin sensitivity.195,196 Considering the strong association between body mass index and waist circumference with HF incidence,197 bariatric surgery may be an attractive therapeutic target in both HF with reduced EF and HF with preserved EF patients. Studies addressing the impact of bariatric surgery in patients with HF have comprised small sample sizes or have been mostly retrospective analyses. Weight loss induced by either Roux-en-Y gastric bypass or adjustable gastric banding proved to be beneficial and normalized LV diastolic dysfunction in 42% of patients in 1 study.198 In patients with HF with reduced EF, Roux-en-Y gastric bypass, sleeve gastrectomy, or adjustable gastric banding was associated with significant improvements in LVEF 6 months’ postsurgery. HF symptoms improved across all the New York Heart Association classes of HF.199 Findings consistently report the positive effect of weight loss, achieved through different types of bariatric surgery on myocardial structure and function, HF and symptoms of HF. A better understanding of factors that positively mediate this clinical response is necessary to aid in the design of future interventions. Another way to achieve weight loss is calorie restriction. In a randomized control trial of obese older adults with HF with preserved EF, calorie restriction plus exercise increased peak oxygen consumption.200 Recently, de Lucia et al201 examined the impact of calorie restriction, when started after the onset of HF in MI or sham operated rats. They reported that calorie restriction using an intermittent fasting protocol over 1 year ameliorated cardiac dysfunction and improved inotropic reserve. A similar study in humans with HF has yet to be completed but if true, would provide a relatively inexpensive therapeutic modality with favorable effects in the setting of HF.

    Oxidative Stress and Pharmacological Targeting of ROS

    It is widely accepted that oxidative stress contributes importantly to the pathophysiology of diabetic cardiomyopathy and arises from mitochondrial and nonmitochondrial sources such as NADPH oxidase and xanthine oxidase.48,202–204 The association between redox abnormalities and HF in general, and its potential exacerbation by diabetes mellitus provides a rationale for targeted antioxidant therapy as an adjunct for managing HF in the context of diabetes mellitus.205,206 A large body of literature has examined the potential utility of diverse antioxidant strategies in HF. Although studies in animals have suggested utility, rigorous analysis in human clinical trials have been disappointing. For example, vitamin E (α-tocopherol) supplementation was shown to have therapeutic efficacy in animal models of HF, although this was not replicated in human clinical trials of HF.207 It has been argued that more targeted antioxidant approaches are warranted and should be selectively targeted to those circumstances where oxidative stress can be shown to be increased. Recent studies have attempted to use circulating biomarkers to estimate redox changes in the context of HF and have revealed that ≈42% of HF patients exhibit evidence of oxidative stress, whereas 41% do not. Moreover, 17% of subjects in this study revealed characteristics of a hyper-reductive state.208 A similar analysis has not yet been performed to determine whether diabetics with HF will exhibit a greater preponderance of markers consistent with myocardial oxidative stress. Thus, future studies in which antioxidants are targeted selectively only to those with evidence of increased oxidative stress are warranted. Another important consideration is the molecular target of antioxidant therapy. Given that oxidative stress in the context of diabetes mellitus related HF could derive either from mitochondrial sources or from activation of NADPH oxidases (NOX), strategies that specifically target each source, either separately or in combination will need to be examined. Agents now exist that specifically target mitochondrial ROS by accumulating in mitochondria (eg, MitoQ or mito-catalase) or by reducing ROS formation by respiratory complexes (SS-31). While preclinical trials have demonstrated amelioration of cardiac damage in response to stress,183,185,209 no clinical trial has tested the efficacy of mitochondrial ROS scavengers in the general HF population or in HF populations enriched with diabetes mellitus. The ever-evolving understanding of the complex interplay between difference sources of ROS and their effect in HF have revealed novel and attractive targets for drug therapy. Further clinical investigations are required to identify the impact of ROS targeting in HF, particularly in the context of diabetes mellitus.

    Autophagy as a Therapeutic Target in Diabetes Mellitus and HF

    Autophagy is an intracellular catabolic pathway in which long-lived proteins, ribosomes, lipids, and cellular organelles are sequestered by the autophagosome and then targeted to the lysosome for degradation.210 Basal autophagy is important in the heart to maintain normal cellular function and protein and organelle quality control.211 Autophagy is induced in response to environmental stressors such as starvation and in this context, represents an important cell survival mechanism. There is some controversy about whether or not autophagy is cardioprotective or deleterious in the context of HF, and has been recently reviewed.212 The role of autophagy in promoting cellular survival or cell death is context specific. For example, the presence of autophagic structures in dying cells has led to the hypothesis that excessive autophagy may play a causative role in stress-induced cell death. Moreover, in mice with cardiomyocyte-restricted deletion of IRS1/2 excessive autophagy contributed to accelerated HF.213 However, there are many reports indicating that induction of autophagy in animal models of pressure overload induced or postischemic HF may be protective and an inhibition in autophagy could mark a transition from compensated to decompensated HF.214,215 Conversely, while specific mechanisms might differ between models of type I and T2DM, autophagic flux is believed to be impaired in the heart in diabetes mellitus.216–218 Mechanisms for autophagic impairment include lipid-induced impairment of lysosomal function, altered insulin signaling or mTORC1 activation and impaired activation of AMPK.219,220 In animal models of T2DM, inhibition of mTOR either by AAV-mediated overexpression of PRAS40,221 rapamycin222 or in Akt2 deficient mice increased autophagy which correlated with reduced hypertrophy and improved cardiac function. Mitophagy refers to selective degradation of damaged mitochondria. Considering mitochondrial dysfunction and mitochondrial ROS production are hallmarks of diabetic cardiomyopathy, a potential approach for reducing diabetic cardiac injury could be to increase the removal of dysfunctional mitochondria as an approach to limiting mitochondrial ROS overproduction by increasing mitophagy.

    Although it is possible that either excessive or impaired autophagy may play a role in the development of HF, it is still notable that none of the current approved treatments for diabetes mellitus or HF, target autophagy as a specific mechanism of action and little is known of the impact of these agents on myocardial autophagy. AT1R (ang II type 1 receptor) blockade or AT2R stimulation was reported to modulate hypertrophy-associated cardiomyocyte autophagy.223 Chronic activation of AMPK by metformin restored cardiac autophagy in parallel with improved cardiac function in type 1 diabetic mouse hearts, an effect that was absent in diabetic AMPKα2 deficient mice.219 The polyphenol resveratrol, may promote autophagy via SIRT1224 or AMPK.225 Thus, on the basis of preclinical studies there are a number of potential therapeutic agents that could modulate myocardial autophagy, thereby providing a rationale for future studies to determine their efficacy in preventing diabetic cardiomyopathy or in modifying the course of HF in patients with HF and diabetes mellitus.

    Endoplasmic Reticulum Stress as a Therapeutic Target in Diabetes Mellitus and HF

    Activation of the endoplasmic reticulum (ER) stress response also known as the UPR (unfolded protein response), or the integrated stress response in which signaling mediators downstream of the UPR may be activated in the absence of ER stress, have been described in animal models of HF or myocardial inflammation.226–228 Hyperglycemia has been associated with ER stress induction in vascular smooth muscle cells.229 Hyperglycemia-associated increases in ER stress is correlated with oxidative stress.230 Moreover, ER stress activation has been implicated as a novel risk factor for CVD in humans.231 Few studies have investigated the impact of therapeutically modulating ER stress pathways in the context of diabetic cardiomyopathy. Genetic inhibition of CHOP (C/EBP homologous protein), which is downstream of eif2α phosphorylation, which is increased by ER stress, attenuated pressure overload cardiac hypertrophy in mice.227 Salubrinal a small molecule that prevents dephosphorylation of eif2α in neurons,232 has not yet been tested in the setting of HF. It is possible that normalizing diabetes mellitus related oxidative stress might be sufficient to normalize ER stress.230 This has not yet been formally tested in the context of diabetic cardiomyopathy. The use of chemical chaperones or overexpression of chaperone proteins have been used experimentally to attenuate ER stress.233 For example, overexpression of the chaperone GRP78 reduced cardiac dysfunction and ER stress in the context of ischemia reperfusion.234 Chemical chaperones such as sodium phenylbutyrate (PBA) and tauroursodeoxycholic acid have been shown to enhance ER protein folding ability and to improve insulin resistance in vitro and in humans,235 but no studies to date have examined the impact of modulating ER stress pathways on the course or risk of diabetic cardiomyopathy. AT1R antagonism might indirectly modulate ER stress in the heart as evidenced by CHOP inhibition when mice with pressure overloaded hearts were treated with an ARB.236 AMPK activation also reduces ER stress,237 however, it remains to be established if potential beneficial effects of AMPK activation in the context of diabetic cardiomyopathy is secondary to modulation of ER stress or to other targets of AMPK. Taken together, additional studies are warranted both to explore the contribution of aberrant ER stress in diabetes mellitus related HF and its utility as a therapeutic target.

    Inflammation as a Therapeutic Target in Diabetic Cardiomyopathy

    Proinflammatory cytokines have been implicated in the pathogenesis of HF.238 Increased circulating levels of proinflammatory cytokines and cytokine receptors correlate with mortality in patients with HF with reduced EF239,240 and HF with preserved EF.241 Both circulating and intracardiac levels of proinflammatory cytokines, primarily TNF-α (tumor necrosis factor-α), IL-6, and IL-18, are elevated in patients with HF.242 The inflammation burden in a given tissue reflects the balance between pro- and anti-inflammatory cytokines, such as IL-1RA, IL-10, and IL-13 and changes in these cytokines have also been recognized in HF.243 Cytokines implicated in cardiac remodeling can originate in the heart, that is, cardiokines,244 or originate from peripheral sites such as the spleen or bone marrow.245 Although inflammation has long been considered an important player in the pathogenesis of HF and a potential therapeutic target for HF treatment, no anti-inflammatory approaches have to date proved effective in modifying the course or prognosis of HF in clinical trials.246–248

    Myocardial inflammation has also been implicated in the pathophysiology of diabetic cardiomyopathy.247,249 In diabetes mellitus, visceral adipocytes secrete cytokines and chemokines which may contribute to low-grade inflammation in many tissues including the heart. Hyperglycemia may induce cytokine secretion from cardiac cells which promotes the recruitment of monocytes and lymphocytes, that may contribute to a chronic inflammatory state and activation of signaling pathways that contribute to cardiac hypertrophy.247,250,251 Diabetes mellitus may promote cardiac inflammation by modulating a number of signaling pathways which converge on NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells). These include activation of the RAAS, advanced glycated end-products (AGEs) and damage-associated molecular patterns, which have been reviewed in detail elsewhere.252 Toll-Like receptors are present in cardiomyocytes and are implicated in immune signaling.253 High levels of glucose and FFA (free fatty acids), activate toll-like receptor (TLR)2 and TLR4.254 Diabetic TLR2 and TLR4 deficient mice demonstrated reduced cardiomyocyte TG accumulation, reduced leukocyte infiltration and decreased NF-κB signaling.255 Hyperglycemia also induces TLR2 and TLR4 in monocytes from type 2 diabetic patients.256,257 TLR antagonists ameliorate NF-κB activation, leukocyte infiltration and myocardial contractile dysfunction in murine hearts after ischemia/reperfusion injury.258 Thus, specific targeting of TLR signaling could represent a potential therapeutic target in diabetic cardiomyopathy. Inflammasomes are multimeric protein complexes, the best characterized being NLRP3 (nucleotide-binding domain, leucine rich-containing family, pyrin domain-containing 3). NLRP3 oligomerization leads to the recruitment of procaspase-1. Active caspase-1 processes IL-1β and IL-18 precursors to enhance proinflammatory pathways. Like TLRs, NLRP3 can be activated by hyperglycemia and long chain free FAs and ceramides.259 NLRP3 inflammasome formation has been implicated as a contributor to increased systemic inflammation that is characteristic of insulin resistance and T2DM.260 NLRP3 enhances myocardial cytokine production and infiltration by macrophages.261,262 Given a potential role for the NLRP3 inflammasome in linking inflammation and metabolic heart disease, targeting the inflammasome could represent a plausible target for reducing the burden of HF in diabetes mellitus. Although targeting inflammatory pathways have been proposed as a tool to reduce CVD in general,263 evidence for a specific role in HF prevention has been lacking. However, whether or not subsets of patients with HF such as diabetics or others with a greater inflammatory burden will benefit from targeted inhibition of these inflammatory pathways remain to be determined. Although anti-inflammatory strategies might modulate the progression of insulin resistance and dysglycemia, it remains to be proven that these will translate into reducing the cardiovascular complications of diabetes mellitus or to altering the course of diabetic cardiomyopathy. It is important to note that some commonly used therapeutic agents in HF or diabetes mellitus exhibit anti-inflammatory properties. For example, both statins and valsartan, an Ang II receptor blocker may attenuate TLRs, inhibit NF-κB and reduce circulating levels of cytokines in mouse models of dilated cardiomyopathy and rat models of ischemic cardiomyopathy.264–266 Evidence linking anti-inflammasome properties of antidiabetic drugs like metformin, SUs, and GLP-1 have been recently reviewed.259 However, the extent to which these pathways are modulated when these agents are used clinically remain to be determined.

    Modulating Insulin Signaling Pathways

    A strong association exists between insulin resistance and HF.267 These 2 conditions tend to coexist and the impact of one disorder on the other results in bidirectional effects relating to causation and outcome.268 On one hand, evidence from clinical studies exist to support the notion that insulin resistance predicts the development of HF.269 Genetic mouse models with cardiomyocyte-restricted knockouts of the insulin receptor, insulin receptor substrates or the glucose transporter GLUT4, have further supported a role for altered insulin signaling in the development of HF. Together, these observations have implicated insulin resistance as a contributing factor to the development of HF.270–272 Conversely, the presence of HF may predict the development of abnormalities in glucose regulation considering 28% of non-DM HF patients developed T2DM over a 3-year follow-up.273 These findings were also supported by others who reported that HF patients developed T2DM with the largest increase in those in the most severe the New York Heart Association class for HF.274,275 It is however unclear if insulin resistance is a cause or a consequence of HF and most clinical studies were not designed to discern the relationship between antecedent insulin resistance and subsequent HF. However, the presence of either condition likely exacerbates the other.

    Defective myocardial insulin signaling in diabetic cardiomyopathy has been described in both animal models276 and humans.277 The relationship between myocardial insulin signaling, diabetes mellitus and HF is complex and has been recently reviewed in-depth.117 Briefly, hyperinsulinemia or cardiomyocyte stretch can cause hyperactivation of the insulin signaling pathway, increasing IRS1 phosphorylation and Akt activation which can exacerbate cardiac dysfunction in response to pressure overload.278 Moreover, our group has recently shown that the constitutive activation of PI3K, while it leads to compensated hypertrophy, also results in a desensitization of insulin-mediated glucose uptake.279 Interestingly, short-term Akt activation resulted in reversible hypertrophy, however, long-term Akt activation results in HF. When the Akt stimulus was reduced in these failing hearts, the rate of progression to death was accelerated.280 Hyperinsulinemic activation of Akt/mTOR signaling could also lead to LV hypertrophy by inhibiting autophagy.117 Activation of such growth promoting pathways by hyperinsulinemia that characterizes T2DM could contribute to accelerating LV remodeling. Hyperinsulinemia might also activate GRK2 signaling, which may accelerate LV remodeling. Whether or not approaches that reduce hyperinsulinemia or attenuate growth signaling in diabetes mellitus may directly modulate the outcome of HF in diabetic subjects is not known. It is interesting to speculate, however, that a potential mechanism for the robust effect of SGLT2 inhibition on HF outcomes in high-risk patients with diabetes mellitus could be the consequence of reduced hyperinsulinemia.

    A well-studied downstream mediator of insulin signaling that has been studied in the context of HF are members of the Forkhead box-containing protein, O subfamily (FOXO) of transcription factors. FOXOs have also been implicated in the pathophysiology of obesity and diabetes mellitus related HF.281,282 The phosphorylation of FOXO1 (Ser265) and FOXO3 (Thr32 and Ser235) by Akt promotes their translocation from the nucleus to the cytoplasm where they become sequestered and bound by 14-3-3, thereby reducing their transcriptional activity. Conversely, the activation of FOXOs because of the disruption of the interaction with 14-3-3 by acetylation mediated by p300283,284 or AMPK,285 or by deacetylation of FOXO1 by SIRT1286 induces its nuclear localization and increases its transcriptional activity. Nuclear localized FOXO1 or FOXO3 promotes cardiac atrophy and autophagy.287 Conversely, FOXO3 inhibition is associated with pathological hypertrophy.288 Constitutively nuclear FOXO1 has been implicated in the pathophysiology of obesity-related cardiomyopathy in mice and genetic reduction of FOXO1 signaling was cardioprotective in this context.281 At present, there are no approved targets for therapeutically targeting FOXO1. However, as these agents are identified there is a strong rationale for examining their role in diabetes mellitus associated CVD.

    Advanced Glycated End Products

    Increased formation of AGEs have been implicated to play a pathophysiological role in diabetic cardiovascular injury, including diabetic cardiomyopathy.289 Mechanistically, AGEs crosslinks with extracellular matrix proteins to increase fibrosis and impair myocardial relaxation. AGEs also transactivate their receptors (RAGE [receptor for advanced glycation end products]) to activate inflammatory signaling, increase ROS production and promote myosin isoform switching via an NF-κB signaling-dependent mechanism.290–292 Studies in animal models of diabetes mellitus have suggested that pharmacological inhibition of AGEs or RAGE signaling might ameliorate myocardial dysfunction. For example, treatment of streptozotocin (STZ)-induced diabetic rats and zucker diabetic fatty (ZDF) rats using dehydroepiandrosterone counteracted hyperglycemia-mediated oxidative stress-induced RAGE activation which normalized NF-κB signaling and reversed the MHC isoform switch.290 In another study using STZ-induced type I diabetes mellitus, AGE accumulation impaired SR Ca2+ reuptake in cardiomyocytes and long-term treatment with an AGE crosslink breaker partially normalized SR Ca2+ handling.293 RAGE gene knockdown prevented hemodynamic impairments in STZ-induced diabetic mice.294 More recently, inhibition of AGE in STZ diabetic mice using aminoguanidine alleviated or reversed diabetes mellitus induced cardiac dysfunction. Diabetes mellitus also inhibited autophagy and induced ER stress which were also reversed by inhibiting AGEs. This study suggested that AGE-induced cardiac dysfunction may be mediated through ER stress and autophagy.295 Targeting AGE/RAGE axis might thus represent another potential therapeutic approach, however, the precise cellular mechanisms underlying AGE-mediated pathogenesis of diabetic cardiomyopathy remains unknown.

    Concluding Remarks

    The pathophysiology of HF in diabetes mellitus is complex and represents a cardiovascular complication of diabetes mellitus that contributes importantly to morbidity and mortality. The recent realization that various classes of approved antihyperglycemic agents may have divergent effects on HF, and that some classes of agents might actually reduce HF risk, has led to a closer examination of the relationship between treatments and outcomes. This review has provided an overview of the current state of knowledge about the mechanisms linking approved diabetes mellitus therapies and HF. While recent data have provided a rationale for preferential use of certain agents in diabetic patients at high risk for developing CVD or HF, a rationale for therapeutic decision making in individuals with coexistent diabetes mellitus and HF is less clear and will await the results of future clinical trials designed to specifically address this question. We have also discussed additional molecular targets, the modulation of which could play a role in designing therapeutic strategies to reverse or treat this challenging condition. There are many approaches now available to achieve glycemic control in individuals with diabetes mellitus. However, as we enter an era of personalization in the management of diabetes mellitus, the next challenge will be the identification of therapeutic strategies that will not only achieve and maintain glycemic control, but that will also reverse existing complications. Given the high prevalence of HF in diabetes mellitus, there is a strong imperative to advance this agenda, with the view of identifying robust strategies that will not only improve long-term outcomes in subjects with diabetes mellitus and HF but also limit the likelihood of developing HF in the first place.

    Nonstandard Abbreviations and Acronyms

    β2AR

    β-2 adrenergic receptor

    AGE

    advanced glycated end-products

    AMPK

    AMP activated protein kinase

    AngII

    angiotensin II

    ARBs

    angiotensin receptor blocker

    ARIC

    Atherosclerosis Risk in Communities

    ARNI

    angiotensin receptor neprilysin inhibitor

    CORONA

    Controlled Rosuvastatin Multinational Trial in Heart Failure

    CVD

    cardiovascular disease

    DPP4i

    dipeptidyl peptidase 4 inhibitor

    EF

    ejection fraction

    ERK

    extracellular signal-regulated kinase

    FIGHT

    Functional Impact of GLP-1 for Heart Failure Treatment

    GLP1RA

    glucagon-like peptide 1 receptor agonist

    HDL

    high-density lipoproteins

    HF

    heart failure

    IRS

    insulin receptor substrate

    LDL

    low-density lipoproteins

    LEADER

    Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

    NF-κB

    nuclear factor κ-light-chain-enhancer of activated B cells

    NLRP3

    nucleotide-binding domain, leucine rich-containing family, pyrin domain-containing 3

    NOX

    nicotinamide adenine dinucleotide phosphate oxidase

    (P) RR

    prorenin receptor

    PKA

    protein kinase A

    PPAR

    peroxisome proliferator-activated receptor

    RAAS

    renin angiotensin aldosterone system

    SGLT2i

    sodium-glucose cotransporter 2 inhibitor

    SU

    sulfonylurea

    T2DM

    type 2 diabetes mellitus

    TG

    triglycerides

    TLR

    toll-like receptor

    TnT

    troponin T

    TNF-α

    tumor necrosis factor-α

    TZDs

    thiazolidinediones

    Acknowledgments

    Research in the Abel laboratory has been supported by grants from the National Institutes of Health (RO1HL127764, RO1HL112413, R61HL141783, RO1HL108379, RO1DK092065) and the American Heart Association (16SFRN31810000).

    Footnotes

    Correspondence to E. Dale Abel, MBBS, DPhil, Fraternal Order of Eagles Diabetes Research Center, 4312 Pappajohn Biomedical Discovery Bldg, University of Iowa, 169 Newton Rd, Iowa City, IA 52242. Email

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