Heart Failure in Type 2 Diabetes Mellitus: Impact of Glucose Lowering Agents, Heart Failure Therapies and Novel Therapeutic Strategies

Abstract

Patients with diabetes have greater than two-times the risk for developing heart failure (HFrEF and HFpEF). Cardiovascular outcomes, hospitalization and prognosis are worse for patients with diabetes 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 the high prevalence of heart failure persists. This, therefore, raises the possibility that additional factors beyond glycemia might contribute to the increased HF risk in diabetes. This review summarizes the state of knowledge regarding the impact of existing anti-hyperglycemic therapies on heart failure and discusses potential mechanisms for beneficial or deleterious effects. Second, we review currently approved pharmacological therapies for heart failure and review evidence that addresses their efficacy in the context of diabetes. 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 (ER) 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 g-protein receptor kinase (GRK) signaling, renin angiotensin aldosterone signaling and beta2 adrenergic receptor signaling. These pathophysiological pathways might be amenable to pharmacological therapy to reduce the risk of heart failure in the context of type 2 diabetes. Successful targeting of these pathways could alter the prognosis and risk of heart failure beyond what is currently achieved using existing antihyperglycemic and heart failure therapeutics.