Mitochondrial function is a central determinant of cardiomyocyte survival, yet mitochondrial pharmacology remains under-integrated into cardiovascular and antidiabetic drug classification, safety assessment, and therapeutic decision-making. Many cardiometabolic drugs exert direct or indirect effects on mitochondrial bioenergetics, redox balance, calcium handling, quality control, and genome stability effects that can confer protection in some contexts while precipitating toxicity in others. In diseased myocardium, where mitochondrial reserve is constrained by ischemia, metabolic stress, ageing, or heart failure, these drug-mitochondria interactions frequently dictate clinical benefit or harm beyond the nominal drug class. This review synthesises the mitochondrial actions of widely used cardiovascular and antidiabetic therapies, including statins, renin-angiotensin-aldosterone system inhibitors, β-blockers, metformin, sodium-glucose cotransporter-2 inhibitors, and incretin-based agents, across acute and chronic exposure windows. We integrate key mechanistic domains encompassing electron transport chain modulation, redox and cofactor reprogramming, calcium permeability transition coupling, mitochondrial dynamics, mitophagy, and stress signalling, and relate these signatures to clinically relevant cardiometabolic disease contexts. We propose a unifying framework in which mitochondrial reserve capacity and quality control competence function as the central decision node determining whether pharmacologic mitochondrial engagement is adaptive or injurious. Finally, we outline principles for mitochondria-conscious prescribing, risk stratification, and drug development, and propose that systematic incorporation of mitochondrial endpoints into clinical trials and safety pipelines is essential for advancing precision cardiometabolic therapy.
