Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis.
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.
Veterans Affairs Medical Center and University of California, San Diego School of Medicine, San Diego, CA smudaliar@vapop.ucsd.edu.
Sunder
S
Mudaliar
Veterans Affairs Medical Center and University of California, San Diego School of Medicine, San Diego, CA.
Sindura
S
Alloju
Veterans Affairs Medical Center and University of California, San Diego School of Medicine, San Diego, CA.
Robert R
RR
Henry
D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D002986:Clinical Trials as Topic / Q000379:methods; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D004734:Energy Metabolism / Q000187:drug effects*; D005960:Glucosides / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008954:Models, Biological; D012107:Research Design; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016896:Treatment Outcome
D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin