Differential Pathophysiological Mechanisms in Heart Failure With a Reduced or Preserved Ejection Fraction in Diabetes

State-of-the-art Review

Milton Packer, MD


JACC Heart Fail. 2021;9(7):535-549. 

In This Article

Differences Between Type 1 and 2 Diabetes and the Risk of Heart Failure

Type 2 diabetes increases the incidence of heart failure 2- to 3-fold, and this increased risk cannot be attributed to the association of diabetes with known cardiovascular risk factors, such as hyperlipidemia or to interval events (ie, myocardial infarction).[1] In contrast, in the only prospective study in type 1 diabetes that measured ventricular function and biomarkers of heart failure, the incidence of heart failure over a 7-year follow-up period was low, unless patients developed hypertension or coronary artery disease.[2] Differences in the cardiac effects of types 1 and 2 diabetes have also been observed in animal models of the 2 diseases.[3] Rodent models of type 2 diabetes exhibit mitochondrial abnormalities, oxidative stress, and neurohormonal activation, which were accompanied by ventricular hypertrophy and fibrosis and systolic and diastolic dysfunction. In contrast, animal models of type 1 diabetes do not exhibit hypertrophy, fibrosis, inflammation, or oxidative stress; their hearts are smaller than those of control animals.[4]

The major distinction between type 1 and 2 diabetes is the presence of hyperinsulinemia in the latter, but not in the former. Although the likelihood of heart failure increases as the level of glycated hemoglobin rises,[1] this observation may not be related to an adverse effect of hyperglycemia on the heart, but may instead be attributable to a deleterious action of hyperinsulinemia that is seen in type 2 diabetes.[3] The hyperinsulinemia of prediabetes has been linked to an increase in the risk of heart failure, even though blood glucose is increased only modestly.[5] Interestingly, insulin levels predict adverse ventricular remodeling and poor outcomes following an acute myocardial infarction in patients without diabetes.[6]

A seminal role of hyperinsulinemia (and enhanced cardiac and renal insulin signaling) in the pathogenesis of heart failure has been confirmed by examining the effects of interventions that influence insulin levels and blood glucose in opposite directions. Metformin and sodium-glucose cotransporter 2 (SGLT2) inhibitors exert antihyperglycemic effects that are not mediated through insulin and are typically accompanied by a decrease in insulin levels. The use of metformin has been associated with a decreased risk of heart failure in observational studies,[7] and SGLT2 inhibitors have reduced the risk of cardiovascular death and hospitalizations for heart failure in large-scale randomized trials (Supplemental Appendix). In contrast, antihyperglycemic medications that stimulate the release or augment the actions of insulin increase the risk of heart failure.[3] The use of insulin is independently associated with an increased risk of heart failure and adverse outcomes in patients with established heart failure, despite improved glycemic control.[8,9] Thiazolidinediones promote insulin signaling and have been shown to increase the risk of heart failure in randomized controlled trials. Incretins (glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) stimulate the release of insulin from the pancreas, and it is noteworthy that liraglutide increases the clinical instability of patients with HFrEF,[10] and treatment with saxagliptin, alogliptin, and vildagliptin have been associated with adverse ventricular remodeling and an increased risk of worsening heart failure events in patients with type 2 diabetes.[11] Sulfonylureas are insulin secretagogues, and their use has also been associated with an increased risk of heart failure.[12]

Insulin signaling not only increases the risk of heart failure in patients with diabetes without symptoms of left ventricular (LV) dysfunction, but it also worsens the clinical course of patients with diabetes with established heart failure. In observational studies, diabetic patients with heart failure whose levels of glycated hemoglobin were maintained at ≤7.0% had a worse survival than those with levels of 7.0% to 8.0%.[13] Interestingly, this relationship was observed only in patients whose diabetes was treated with insulin, sulfonylureas, and thiazolidinediones and not in those who were managed only with diet, indicating that the poor outcomes of patients with excellent glycemic control was related to the use of insulin-signaling medications.

These observations strongly suggest that hyperinsulinemia (rather than hyperglycemia) drives the pathogenesis of heart failure in patients with type 2 (but not type 1) diabetes.