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      Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis.

      1 , 2 , 2

      Diabetes care

      American Diabetes Association

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          Abstract

          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 energetics-based mechanisms for the CV/renal benefits.

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          Author and article information

          Journal
          Diabetes Care
          Diabetes care
          American Diabetes Association
          1935-5548
          0149-5992
          Jul 2016
          : 39
          : 7
          Affiliations
          [1 ] Veterans Affairs Medical Center and University of California, San Diego School of Medicine, San Diego, CA smudaliar@vapop.ucsd.edu.
          [2 ] Veterans Affairs Medical Center and University of California, San Diego School of Medicine, San Diego, CA.
          Article
          dc16-0542
          10.2337/dc16-0542
          27289124

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