Potentiation of Insulin Signaling Contributes to Heart Failure in Type 2 Diabetes: A Hypothesis Supported by Both Mechanistic Studies and Clinical Trials

The heightened risk of heart failure in type 2 diabetes cannot be explained by the occurrence of clinically overt myocardial ischemic events or hyperglycemia. Experimentally, insulin exerts detrimental effects on the heart, vasculature, kidneys, and adipose tissue that can lead to heart failure. In both randomized clinical trials and observational studies, antihyperglycemic drugs that act through insulin signaling (i.e., sulfonylureas, thiazolidinediones, and incretins) increase the risk or worsen the clinical course of heart failure, whereas drugs that ameliorate hyperinsulinemia and do not signal through insulin (i.e., metformin and sodium-glucose cotransporter 2 inhibitors) reduce the risk of heart failure.