Metformin, SGLT2 Inhibitors, and Intermittent Fasting: Convergent Pathways to Healthspan Extension, Cardiovascular Longevity, and Cancer Prevention—A Narrative Review

The biology of aging and the epidemiology of cardiovascular disease share a common molecular pathway expressed through nutrient-sensing kinases, mitochondrial redox state, and chronic inflammation. Three interventions have independently emerged as translators of that interconnection into clinical benefit: metformin, a biguanide that has evolved from a first-line anti-diabetic into the world’s most extensively studied putative geroprotector; the sodium–glucose cotransporter-2 inhibitors (SGLT2is), pharmacological generators of a fasting-mimetic state that has reshaped heart failure outcomes across the ejection-fraction spectrum; and intermittent fasting (IF), the evolutionary archetype from which both agents partially derive their effects on longevity. Based on the synthetized evidence, we propose a stage-stratified clinical framework for integrated deployment. To find the manuscripts relevant for our narrative review, we searched the medical literature by using key words (“metformin”; “SGLT2i”; “intermittent fasting”; “health span”; “cardiovascular longevity”; “cancer chemoprevention”; “gut microbiome”; “geroprotection”; “heart failure”) combined through Boolean operators (AND/OR). This narrative review integrates preclinical mechanistic evidence, landmark randomized controlled trial data, and emerging data on cancer chemoprevention and gut microbiome remodeling to provide a rigorous, side-by-side analysis of all three strategies. We delineate molecular convergence on adenosine monophosphate kinase (AMPK) activation, mechanistic target of rapamycin complex 1 (mTORC1) suppression, enhanced autophagy, mitochondrial renewal, inflammatory responses, and anti-cancer biology, while mapping critical divergences in specific populations, lifespan timing, combinability, and safety. Our proposed framework has to be treated with caution, as it is based on the current evidence base, which lacks dedicated outcome trials for IF and published randomized clinical trial data for metformin in non-diabetic adults.