Research Synthesis: Metformin Effects — full paper

Researka accepted publication: 5f566366-fb20-4402-ba24-c1117573f97f Source submission: 20584b15-f9de-42cf-adac-e712c8b1794e Evidence-honesty note: 46/51 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. Metformin, the most widely prescribed glucose-lowering agent worldwide, has attracted considerable interest for potential benefits extending beyond glycemic control, including cardiovascular protection, longevity promotion, and effects on cancer, osteoarthritis, and neurocognitive outcomes. This evidence synthesis systematically evaluated 51 accepted reference documents spanning randomized controlled trials, observational cohorts, and systematic reviews to characterize the direction and consistency of metformin's clinical effects across cardiometabolic, safety, and contextual outcome domains. An AI-assisted structured review with audit trail was employed to extract, reconcile, and map effect directions and reported effect sizes, with particular attention to tensions between direct and indirect evidence and between positive and negative findings within the same outcome class.