CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis - PubMed (original) (raw)

. 2016 Jul;39(7):1108-14.

doi: 10.2337/dc16-0330.

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CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis

Ele Ferrannini et al. Diabetes Care. 2016 Jul.

Abstract

The striking and unexpected relative risk reductions in cardiovascular (CV) mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) observed in the EMPA-REG OUTCOME trial using an inhibitor of sodium-glucose cotransporter 2 (SGLT2) in patients with type 2 diabetes and high CV risk have raised the possibility that mechanisms other than those observed in the trial-modest improvement in glycemic control, small decrease in body weight, and persistent reductions in blood pressure and uric acid level-may be at play. We hypothesize that under conditions of mild, persistent hyperketonemia, such as those that prevail during treatment with SGLT2 inhibitors, β-hydroxybutyrate is freely taken up by the heart (among other organs) and oxidized in preference to fatty acids. This fuel selection improves the transduction of oxygen consumption into work efficiency at the mitochondrial level. In addition, the hemoconcentration that typically follows SGLT2 inhibition enhances oxygen release to the tissues, thereby establishing a powerful synergy with the metabolic substrate shift. These mechanisms would cooperate with other SGLT2 inhibition-induced changes (chiefly, enhanced diuresis and reduced blood pressure) to achieve the degree of cardioprotection revealed in the EMPA-REG OUTCOME trial. This hypothesis opens up new lines of investigation into the pathogenesis and treatment of diabetic and nondiabetic heart disease.

© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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