{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:03:39Z","timestamp":1791821019691,"version":"4.3.4"},"reference-count":112,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCDD"],"abstract":"<jats:p>Metformin, the most widely prescribed oral antihyperglycemic agent, is established as the first-line therapy for type 2 diabetes mellitus (T2DM) owing to its efficacy, affordability, and safety. Increasing evidence indicates that its benefits extend beyond glycemic control, encompassing cardiovascular protection and diabetes prevention in individuals at elevated cardiometabolic risk. Mechanistic studies demonstrate that metformin exerts pleiotropic effects through activation of AMP-activated protein kinase, modulation of the gut microbiota, inhibition of pro-inflammatory and oxidative stress pathways, and improvements in endothelial function, lipid metabolism, and insulin sensitivity. These actions address core drivers of atherosclerosis and metabolic dysfunction, many of which occur independently of glucose lowering. In patients with T2DM, the cardiovascular benefits of metformin are well recognized, including reductions in all-cause mortality and cardiovascular events. In individuals without diabetes but at high cardiovascular risk\u2014such as those with prediabetes, obesity, or metabolic syndrome\u2014evidence is more limited, as most data are derived from subgroup analyses or trials with surrogate endpoints. Nonetheless, consistent signals suggest that metformin may delay the progression from prediabetes to overt diabetes and potentially confer vascular protection, particularly in carefully selected high-risk populations. Clinical trials and meta-analyses have demonstrated that metformin reduces incident diabetes by approximately one quarter in high-risk adults, with stronger effects observed in younger, overweight individuals, women with prior gestational diabetes, and those treated for longer durations. However, uncertainties remain regarding its long-term cost-effectiveness, optimal dosing strategies, and cardiovascular benefits in non-diabetic populations. The ongoing VA-IMPACT trial (NCT02915198) is expected to clarify whether metformin reduces major cardiovascular events in prediabetic patients with atherosclerotic disease. Taken together, metformin represents more than an antidiabetic drug. Its pleiotropic mechanisms, favorable safety profile, and low cost support its potential integration into broader cardiometabolic prevention strategies, including primary prevention. Expanding its role beyond diabetes management may offer a cost-effective, widely accessible intervention with significant public health impact.<\/jats:p>","DOI":"10.3390\/jcdd13010033","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T13:49:46Z","timestamp":1767707386000},"page":"33","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Metformin Beyond Glycemic Control: Cardiovascular Protection and Diabetes Prevention"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4444-0967","authenticated-orcid":false,"given":"Georgios E.","family":"Zakynthinos","sequence":"first","affiliation":[{"name":"3rd Department of Cardiology, \u201cSotiria\u201d Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1071-750X","authenticated-orcid":false,"given":"Georgios I.","family":"Tsironikos","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Ioannina, University Campus, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8079-0599","authenticated-orcid":false,"given":"Evangelos","family":"Oikonomou","sequence":"additional","affiliation":[{"name":"3rd Department of Cardiology, \u201cSotiria\u201d Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2036-6192","authenticated-orcid":false,"given":"Konstantinos","family":"Kalogeras","sequence":"additional","affiliation":[{"name":"3rd Department of Cardiology, \u201cSotiria\u201d Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerasimos","family":"Siasos","sequence":"additional","affiliation":[{"name":"3rd Department of Cardiology, \u201cSotiria\u201d Chest Diseases Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"},{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2412-5388","authenticated-orcid":false,"given":"Vasiliki","family":"Tsolaki","sequence":"additional","affiliation":[{"name":"Critical Care Department, University Hospital of Larissa, Faculty of Medicine, University of Thessaly, Mezourlo, 41335 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"ref_1","first-page":"575","article-title":"Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms","volume":"34","author":"Petrie","year":"2018","journal-title":"Can. 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