SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

Abstract

Three cardiovascular outcome trials of sodium glucose cotransporter 2 (SGLT2) inhibitors, including the EMPA-REG OUTCOME trial, CANVAS Program, and DECLARE TIMI 58 trial, revealed that SGLT2 inhibitors were superior to a matching placebo in reducing cardiovascular events, including mortality and hospitalization for heart failure, in patients with type 2 diabetes. However, the detailed mechanism underlying the beneficial effects that SGLT2 inhibitors exert on cardiovascular diseases remains to be elucidated. We herein review the latest findings of the salutary mechanisms of SGLT2 inhibitors in cardiomyocytes, especially focusing on their mitochondrial function-mediated beneficial effects. The administration of SGLT2 inhibitors leads to the elevation of plasma levels of ketone bodies, which are an efficient energy source in the failing heart, by promoting oxidation of the mitochondrial coenzyme Q couple and enhancing the free energy of cytosolic ATP hydrolysis. SGLT2 inhibitors also promote sodium metabolism-mediated cardioprotective effects. These compounds could reduce the intracellular sodium overload to improve mitochondrial energetics and oxidative defense in the heart through binding with NHE and/or SMIT1. Furthermore, SGLT2 inhibitors could modulate mitochondrial dynamics by regulating the fusion and fission of mitochondria. Together with ongoing large-scale clinical trials to evaluate the efficacy of SGLT2 inhibitors in patients with heart failure, intensive investigations regarding the mechanism through which SGLT2 inhibitors promote the restoration in cases of heart failure would lead to the establishment of these drugs as potent anti-heart failure drugs.

Empagliflozin Decreases Lactate Generation in an NHE-1 Dependent Fashion and Increases α-Ketoglutarate Synthesis From Palmitate in Type II Diabetic Mouse Hearts

“…A similar NHE-1 inhibition by empagliflozin was recently observed for human failing heart cardiomyocytes (12). SGLT2i inhibition of NHE results in intracellular ion changes of Na + and Ca 2+ (5,6) that may precipitate in changes in mitochondrial function (13) and can reprogram cardiac metabolism (14). Therefore, as a secondary goal, we examined whether possible SGLT2i effects on cardiac glucose metabolism are mediated through NHE-1 inhibition, by also studying SGLT2i effects in the presence of an NHE-1 inhibitor.…”

“…However, EMPA did specifically decrease cardiac lactate labeling in the 13 C glucose perfusions ( 13 C labeling of lactate: 58 ± 2% vs. 50 ± 3%, for vehicle and EMPA, respectively; P = 0.02), without changes in other glucose metabolic pathways. In contrast, EMPA increased cardiac labeling in α-ketoglutarate derived from 13 C palmitate perfusions ( 13 C labeling of α-KG: 79 ± 1% vs. 86 ± 1% for vehicle and EMPA, respectively; P = 0.01). Inhibition of the NHE by Cariporide abolished EMPA effects on lactate labeling from 13 C glucose.…”

“…In contrast, EMPA increased cardiac labeling in α-ketoglutarate derived from 13 C palmitate perfusions ( 13 C labeling of α-KG: 79 ± 1% vs. 86 ± 1% for vehicle and EMPA, respectively; P = 0.01). Inhibition of the NHE by Cariporide abolished EMPA effects on lactate labeling from 13 C glucose.…”

“…Analysis of total lactate in the effluent of the hearts revealed no effect of Empa (0.98±0.02 mM vs. 0.96±0.01 mM, for DMSO vs. EMPA, respectively; p = NS). Perfusion with 13 C glucose resulted in ∼25% labeling of TCA intermediates, indicating glucose contribution to TCA cycle in these db/db hearts. However, EMPA was without effect on 13 C glucose labeling of acetylCoA and TCA intermediates, suggesting that Empa was without a direct and acute overall effect on glucose oxidation in the diabetic heart.…”

“…Perfusion with 13 C glucose resulted in ∼25% labeling of TCA intermediates, indicating glucose contribution to TCA cycle in these db/db hearts. However, EMPA was without effect on 13 C glucose labeling of acetylCoA and TCA intermediates, suggesting that Empa was without a direct and acute overall effect on glucose oxidation in the diabetic heart. Phosphorylation status of pyruvate dehydrogenase, a crucial control point regulation glucose going into acetylCoA, was unaffected by EMPA treatment (Supplementary Figure 1).…”