Reconceptualization of the Molecular Mechanism by Which Sodium-Glucose Cotransporter 2 Inhibitors Reduce the Risk of Heart Failure Events.

August 6, 2019 443 Milton Packer, MD Two sodium-glucose cotransporter 2 (SGLT2) inhibitors (ie, empagliflozin and canagliflozin) are currently approved by the Food and Drug Administration to reduce cardiovascular death or major adverse thromboembolic events in patients with type 2 diabetes mellitus. Yet, the current labeling for this class of drugs is misleading. The Food and Drug Administration indication reflects certain design features of the major cardiovascular outcome safety trials with these drugs, but it does not accurately describe the most important efficacy findings of these studies. In none of the 3 major cardiovascular trials did SGLT2 inhibitors reduce the risk of myocardial infarction and stroke.1 Instead, the primary benefit of SGLT2 inhibitors was a 25% to 35% decrease in the risk of heart failure hospitalizations, which was seen consistently across the trials. The additional benefit of empagliflozin to decrease the risk of cardiovascular death is primarily driven by an effect on pump failure deaths and sudden deaths: the 2 most common modes of death in patients with heart failure.1 How can inhibition of glucose transport in the proximal renal tubule lead to such a striking decrease in the risk of heart failure events? The effect of these drugs to block glucose reabsorption is accompanied by a lowering of hemoglobin A1c, body weight, and blood pressure. However, the magnitude of these effects is modest, and these changes are not well correlated with the observed decrease in the risk of heart failure deaths or hospitalizations. Furthermore, most drugs that lower blood glucose, body weight, and blood pressure do not have beneficial effects on, and they often adversely influence, the course of heart failure. Inhibition of SGLT2 in the proximal renal tubule causes a meaningful natriuresis, and the resulting decrease in plasma volume could conceivably lead to a decrease in cardiac dimensions and pressures, resulting in favorable effects on ventricular remodeling. However, it is difficult to ascribe the benefits of these drugs primarily to an increase in urinary sodium excretion, because the reduction in heart failure events was seen in patients already receiving diuretics. Intensification of diuretic therapy has not led to a dramatic decrease in cardiovascular mortality or sudden death in patients with heart failure. Similarly, the increase in hemoglobin (that is typically seen with SGLT2 inhibitors) does not lead to clinical benefits in patients with heart failure. Important insights into the potential mechanism of benefit of SGLT2 inhibitors in heart failure have recently been provided by a post hoc analysis of the DECLARETIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58), which evaluated patients with type 2 diabetes mellitus who were enriched for atherosclerotic cardiovascular disease.2 The investigators retrospectively collected information on ejection fraction measured before randomization to determine which phenotype of heart failure (ie, heart failure with a reduced ejection fraction [HFrEF] or heart failure with a preserved ejection fraction [HFpEF]) was more likely to experience a reduction in heart failure events with dapagliflozin. The investigators found that, although heart failure hospitalizations were reduced © 2019 American Heart Association, Inc. ON MY MIND