Is Type 2 Diabetes a Modifiable Risk Factor for the Evolution and Progression of Heart Failure With a Preserved Ejection Fraction?

Abstract

Background: Type 2 diabetes is associated with an increased risk of heart failure with a preserved ejection fraction (HFpEF), but it is not clear whether this metabolic disorder is causal or represents a modifiable risk factor. Mechanisms by which diabetes may be associated with HFpEF can be grouped into the following: 1) those related to hyperglycemia and amenable to antihyperglycemic drugs; and 2) those related to the association of type 2 diabetes with obesity and visceral adiposity, and thus, treatable with interventions that reduce adipose tissue mass or improve adipocyte biology.

Evidence against a role for hyperglycemia: Experimentally, acute and chronic hyperglycemia caused by islet cell destruction can lead to cardiac dysfunction, but these models resemble type 1 (not type 2) diabetes. Heightened levels of environmental glucose can cause enzymatic or nonenzymatic modification of proteins and signaling through the polyol pathway, but interference with these mechanisms has not produce clinical benefits in patients with heart disease and type 2 diabetes. Furthermore, lowering of blood glucose in type 2 diabetes with insulin, sulfonylureas, dipeptidyl peptidase-4 inhibitors and thiazolidinediones has not reduced the risk of heart failure.

Evidence for a mediating role for adiposity: In marked contrast, experimental models that link type 2 diabetes to HFpEF are typically accompanied by excess adiposity. Epidemiological studies demonstrate that the association between type 2 diabetes and HFpEF is mediated primarily through a common link with central obesity and an expanded visceral fat mass. Changes in the biology of adipocytes as a result of visceral adiposity are sufficient to cause systemic insulin resistance and diabetes. Interestingly, the primary metabolic defect in the diabetic heart is lipid overload, not an impairment in glucose uptake or insulin resistance. Adiposity can promote HFpEF through the secretion of proinflammatory adipokines that lead to sodium retention and cardiac steatosis and fibrosis. Additionally, excess adiposity can drive the production of and enhance cardiac sensitivity to advanced glycation end products. Glucagon-like peptide receptor agonists and sodium-glucose cotransporter reduce the risk or progression of HFpEF, but this benefit is not related by the presence of diabetes or to the glucose-lowering effects of these drugs. Instead, their favorable cardiac effects may be mediated by their action to induce or mimic a state of caloric deprivation, thus restoring adipokine balance and alleviating the state of cardiac steatosis. Similarly, bariatric surgery alleviates both visceral adiposity and type 2 diabetes and reduces the risk of HFpEF.

Conclusions: Taken together, these findings suggest that diabetes-associated HFpEF is mediated primarily through its association with excess adiposity. Diabetes is a modifiable risk factor if treatment is directed toward adiposity rather than hyperglycemia.