Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease | 2021
SGLT2 Inhibition on Cardiac Mitochondrial Function: Searching for a Sweet Spot
Abstract
The cardiometabolic landscape was transformed by the unexpected cardiovascular benefits seen in the landmark EMPAREG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), in which sodium glucose cotransporter 2 (SGLT2) inhibition with empagliflozin reduced major adverse cardiovascular events, cardiovascular death, allcause mortality, and heart failure hospitalizations.1 The benefit of SGLT2 inhibition was extended to heart failure outcomes in both people with and without diabetes mellitus in CANVAS (Canagliflozin in Diabetics with Cardiovascular Disease), DECLARETIMI 58 (Dapagliflozin in Diabetics with Cardiovascular Disease or at High Cardiovascular Risk), DAPAHF (Dapagliflozin in Heart Failure with Reduced Ejection Fraction [HFrEF]), EMPERORReduced (Empagliflozin in HFrEF), and VERTISCV (Ertugliflozin in Diabetics with Cardiovascular Disease).2– 6 Ongoing trials are now evaluating SGLT2 inhibition on outcomes in heart failure with preserved ejection fraction: EMPERORPreserved (NCT03057951; empagliflozin) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; NCT03619213; dapagliflozin). Although the benefit of SGLT2 inhibition on cardiovascular outcomes including heart failure is clear, the mechanisms by which this benefit is realized are debated. SGLT2 inhibitors lower glucose by acting on the SLC5A2 gene encoding the SGLT2 to promote glucosuria and natriuresis. Although SLC5A2 gene expression is highly restricted to the kidney, the magnitude of cardiovascular benefit with SGLT2 inhibitors supports action beyond this kidney. Moreover historically, glucoselowering therapies on their own have not improved cardiovascular outcomes. Furthermore, specific agents such as thiazolidinediones have worsened outcomes.7,8 Although the diuretic effect of SGLT2 inhibitors is also thought to contribute to its cardiovascular effectiveness, diuretics for volume unloading do not provide a cardiovascular mortality benefit.9 Several additional mechanisms of action for SGLT2 inhibitors are now being explored at the myocardial level (Figure), and one very intriguing area is the modulation of cardiac mitochondrial function and metabolism. Mitochondrial dysfunction occurs in both the diabetic and failing heart, but no current therapeutics directly target cardiac mitochondria.10 There is evidence that SGLT2 inhibition improves cardiac mitochondrial function in animal models unrelated to diabetes mellitus status. In nondiabetic pigs with ischemic cardiomyopathy, empagliflozin reduced pathological cardiac remodeling and associated with increased myocardial oxidation of fatty acids, ketone