Effects of Antidiabetic Drugs on Longevity and Healthspan: Evidence and Controversies From Glucose-Lowering Therapy to Anti-Aging Intervention

Diabetes provides a clinically visible model of accelerated biological aging. Sustained hyperglycemia, insulin resistance, chronic low-grade inflammation, mitochondrial stress, and endothelial injury converge to increase the burden of cardiovascular disease, chronic kidney disease, neurodegeneration, sarcopenia, and frailty, thereby compressing both survival time and years lived with preserved function. For this reason, evaluation of glucose-lowering drugs can no longer be restricted to HbA1c reduction alone. Mortality, cardiovascular death, heart failure hospitalization, kidney failure, cognition, frailty, and quality of life (QoL) have become central outcomes, although adequate glycemic control remains indispensable for preventing microvascular disease. Among available agents, metformin has attracted the greatest attention as a possible gerotherapeutic drug because it intersects with AMPK/mTOR signaling, mitochondrial complex I activity, and the gut microbiome; nevertheless, randomized evidence in people without diabetes is still lacking, and much of the supportive human literature is observational. SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists provide stronger trial-based evidence for cardiorenal protection and, in selected populations, mortality-related benefit. Their contribution to healthspan is most plausibly explained by prevention of heart failure, kidney failure, and atherosclerotic events, rather than by proven slowing of intrinsic aging. DPP-4 inhibitors are largely cardiovascular-neutral; insulin and sulfonylureas remain necessary in specific clinical settings but carry hypoglycemia and weight-gain liabilities, and acarbose or pioglitazone remain mechanistically interesting but incompletely translated. Future studies should use healthspan-centered endpoints, aging biomarkers, equitable access frameworks, and lifestyle comparators to distinguish glucose-lowering, disease modification, and true geroprotection.