Metabolic reprogramming synergy: CoQ10 and SGLT2 inhibitors combination in heart failure - a narrative review

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have fundamentally changed the treatment landscape of heart failure (HF), demonstrating cardiovascular benefit across the full ejection fraction spectrum. Among proposed mechanisms, the "ketone hypothesis" has drawn particular attention: SGLT2i raise circulating ketone bodies, shifting myocardial substrate utilization toward ketone oxidation, a more oxygen-efficient fuel for the energy-deprived failing heart. In parallel, coenzyme Q10 (CoQ10), an essential electron carrier in the mitochondrial electron transport chain (ETC), has shown efficacy in reducing mortality and hospitalization in HF. Despite the complementary nature of these two metabolic interventions, SGLT2i enhancing ketone oxidation and thereby increasing NADH flow into the ETC, and CoQ10 facilitating electron transfer from Complexes I and II to Complex III, no clinical study has investigated their combination. This narrative review examines the mechanistic basis for a potential synergistic interaction, proposing that CoQ10 may relieve the ETC bottleneck created by increased NADH delivery during SGLT2i-induced ketosis, optimizing mitochondrial energetics while reducing electron flow stress and reactive oxygen species production. We synthesize current evidence, identify critical knowledge gaps, and propose a framework for future investigation of this novel metabolic combination strategy. The CoQ10-SGLT2i combination represents a promising, mechanistically grounded approach that warrants preclinical and clinical evaluation.