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

TLDR

The EMPA‑REG OUTCOME trial showed unexpectedly large reductions in cardiovascular mortality, heart‑failure hospitalisation, and all‑cause death with empagliflozin, beyond what could be explained by modest improvements in glycaemia, weight, blood pressure, and uric acid. The authors hypothesise that mild, persistent hyperketonemia induced by SGLT2 inhibition causes the heart to preferentially oxidise β‑hydroxybutyrate over fatty acids, thereby improving cardiac efficiency. This metabolic shift, together with hemoconcentration‑driven oxygen delivery and diuretic‑induced blood‑pressure reduction, enhances mitochondrial oxygen utilisation and work efficiency, accounting for the observed cardioprotection.

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.