Type 2 diabetes mellitus causes excessive morbidity and premature cardiovascular (CV) mortality. Although tight glycemic control improves microvascular complications, its effects on macrovascular complications are unclear. The recent publication of the EMPA-REG OUTCOME study documenting impressive benefits with empagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) on CV and all-cause mortality and hospitalization for heart failure without any effects on classic atherothrombotic events is puzzling. More puzzling is that the curves for heart failure hospitalization, renal outcomes, and CV mortality begin to separate widely within 3 months and are maintained for >3 years. Modest improvements in glycemic, lipid, or blood pressure control unlikely contributed significantly to the beneficial cardiorenal outcomes within 3 months. Other known effects of SGLT2 inhibitors on visceral adiposity, vascular endothelium, natriuresis, and neurohormonal mechanisms are also unlikely major contributors to the CV/renal benefits. We postulate that the cardiorenal benefits of empagliflozin are due to a shift in myocardial and renal fuel metabolism away from fat and glucose oxidation, which are energy inefficient in the setting of the type 2 diabetic heart and kidney, toward an energy-efficient super fuel like ketone bodies, which improve myocardial/renal work efficiency and function. Even small beneficial changes in energetics minute to minute translate into large differences in efficiency, and improved cardiorenal outcomes over weeks to months continue to be sustained. Well-planned physiologic and imaging studies need to be done to characterize fuel energeticsbased mechanisms for the CV/renal benefits.Type 2 diabetes mellitus (T2DM) is a chronic debilitating disease that leads to excessive morbidity and premature cardiovascular (CV) mortality worldwide. Although studies have documented the benefits of optimal glycemic control on microvascular complications, the effect of tight glycemic control on macrovascular complications is unclear (1). In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, tight glycemic control increased CV and all-cause mortality (2). Glitazones and saxagliptin (a dipeptidyl peptidase 4 inhibitor) increase the risk of hospitalization for heart failure (HF) (3,4). In this context, the recent publication of the EMPA-REG OUTCOME study documenting impressive benefits with empagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) on CV/all-cause mortality and hospitalization for HF is a game changer, and if replicated, it may lead to a

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