SGLT2 Inhibitors in Hypertrophic Cardiomyopathy: Emerging Evidence and Putative Mechanisms.

Hypertrophic cardiomyopathy (HCM) is the most common inherited myocardial disorder and a major cause of heart failure (HF) and sudden cardiac death. Although sarcomeric gene mutations initiate the disease, increasing evidence identifies oxidative stress, mitochondrial dysfunction, and maladaptive nutrient signaling as key drivers of disease progression. Enhanced reactive oxygen species (ROS) production in HCM promotes energetic impairment, calcium mishandling, fibrosis, and the activation of pro-hypertrophic pathways, while disrupting protein quality control and endothelial function. Despite recent therapeutic advances, effective disease-modifying strategies targeting these molecular mechanisms remain limited. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), originally developed for type 2 diabetes, have demonstrated robust cardioprotective effects in HF independent of glycemic control. Beyond their renal actions, SGLT2i modulate myocardial metabolism, reduce oxidative stress, improve mitochondrial function, restore sodium and calcium homeostasis, and attenuate inflammation and maladaptive mTOR activation. Emerging preclinical and translational data suggest that these pleiotropic mechanisms may counteract key pathophysiological processes underlying HCM. This review summarizes the molecular interplay between oxidative stress and hypertrophic remodeling in HCM and explores the rationale for SGLT2 inhibition as a potential disease-modifying therapeutic strategy.