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Although its early development was hindered by the toxicity issues associated with other guanidine derivatives and the rise of insulin therapies, it ultimately established its position as a first\u2010line oral hypoglycemic agent for addressing insulin resistance and managing hyperglycemia through extensive clinical validation. With a nearly 70\u2010year history in diabetes treatment, the mechanisms by which metformin modulates blood glucose have been widely studied and refined. Recent investigations into combination therapies, fixed\u2010dose formulations, and novel applications underscores a broader therapeutic potential beyond glycemic control. This paper aims to review the development trajectory of metformin, consolidate the latest evidence for its clinical benefits, and critically appraise its future directions and constraints.\n                  <\/jats:p>","DOI":"10.1002\/dmrr.70171","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T16:42:26Z","timestamp":1777480946000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Metformin: Historical Origins, Mechanisms of Action, and Emerging Clinical Applications"],"prefix":"10.1002","volume":"42","author":[{"given":"Ye","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Endocrinology Geriatric Medicine Center Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)  Hangzhou 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