SGLT2 Inhibitors as Mitochondrial Therapies in Heart Failure: A Bioenergetic Revolution in Cardiometabolic Medicine

Introduction: SGLT2 inhibitors improve outcomes in heart failure (HF), yet mechanisms beyond glycemic control remain debated. We synthesize evidence positioning mitochondrial bioenergetics as the central unifying mechanism through which SGLT2 inhibitors exert cardioprotective effects, reframing them as mitochondrial therapies with systemic metabolic benefits. Methods: Narrative critical synthesis of preclinical, translational, and clinical data. Sources were identified through database searches (2010–2025) and screened to include studies linking SGLT2 inhibitors to mitochondrial pathways and HF outcomes. Results: Preclinical studies show improved oxidative phosphorylation, reduced reactive oxygen species, enhanced mitophagy, and a shift toward ketone oxidation. Translational data suggest AMPK/PGC-1α activation and improved myocardial energetics, while randomized trials consistently reduce HF hospitalizations across phenotypes (HFrEF/HFpEF), with early benefits independent of glycemia. Discussion: Evidence supports a bioenergetic framework in which SGLT2 inhibitors enhance mitochondrial efficiency and systemic metabolic resilience. Nonetheless, human myocardial data remain limited and heterogeneous, warranting further mechanistic trials with imaging or biopsy endpoints. Conclusion: The cardioprotective actions of SGLT2 inhibitors are plausibly mediated, in part, by mitochondrial modulation. This reframes HF as an energy-deficit syndrome and motivates targeted translational studies to validate mitochondrial endpoints and refine patient selection.