{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:57:50Z","timestamp":1790618270074,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Objective: This study investigated the effects of metformin on clinical outcomes after acute ischemic stroke in patients with type 2 diabetes mellitus (T2DM). Methods: PubMed, Embase, Web of Science, and the Cochrane Library were systematically searched for relevant English articles published from database inception to 6 April 2026. Moreover, the reference lists of eligible articles were searched. Studies were included if they focused on patients with T2DM and acute ischemic stroke, indicated whether the patients used metformin before stroke onset, and reported the patients\u2019 modified Rankin Scale (mRS) scores after stroke onset. Studies lacking adequate outcome data were excluded. Two reviewers independently extracted relevant data\u2014for example, study details, clinicodemographic characteristics, and poststroke outcomes (mRS scores, National Institutes of Health Stroke Scale [NIHSS] scores, symptomatic intracranial hemorrhage [sICH], and mortality). A senior reviewer was consulted in cases of between-reviewer disagreements. The primary outcome was poststroke mRS score (functional outcome), and the secondary outcomes were poststroke NIHSS scores (neurological severity), sICH, and mortality. Results: Eleven studies met the inclusion criteria. Most studies reported better functional outcomes (mRS scores) and lower NIHSS scores for metformin users than for nonusers. Some studies indicated reduced rates of sICH and mortality among metformin users than among nonusers. Sensitivity analyses generally supported the benefits of metformin. Caution should be exercised when interpreting these findings because the results might have been influenced by variations in study designs, stroke classifications, and renal function reporting. Conclusions: In patients with T2DM, metformin may reduce stroke severity and improve poststroke functional outcomes. To the best of our knowledge, this meta-analysis is the first to investigate the association between metformin use and neurological severity, estimate adjusted ORs for favorable functional outcomes, and highlight publication bias on this topic.<\/jats:p>","DOI":"10.3390\/jcm15197532","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:50:54Z","timestamp":1790614254000},"page":"7532","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of Metformin on Clinical Outcomes After Acute Ischemic Stroke in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"15","author":[{"given":"Ting-Yen","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chi","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3143-3357","authenticated-orcid":false,"given":"Yu-Ching","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan"},{"name":"Department of Physical Medicine and Rehabilitation, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e025579","DOI":"10.1136\/bmjopen-2018-025579","article-title":"Predicting the risk of stroke among patients with type 2 diabetes: A systematic review and meta-analysis of C-statistics","volume":"9","author":"Chowdhury","year":"2019","journal-title":"BMJ Open"},{"key":"ref_2","first-page":"330","article-title":"Coronary artery disease and diabetes mellitus","volume":"11","author":"Ismail","year":"2016","journal-title":"J. Taibah Univ. Med. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/s12020-016-1014-6","article-title":"Diabetes mellitus as a risk factor for incident chronic kidney disease and end-stage renal disease in women compared with men: A systematic review and meta-analysis","volume":"55","author":"Shen","year":"2017","journal-title":"Endocrine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.cmet.2014.09.018","article-title":"Metformin: From mechanisms of action to therapies","volume":"20","author":"Foretz","year":"2014","journal-title":"Cell Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.amjms.2016.01.011","article-title":"Diabetes and stroke: Epidemiology, pathophysiology, pharmaceuticals and outcomes","volume":"351","author":"Chen","year":"2016","journal-title":"Am. J. Med. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S1474-4422(21)00252-0","article-title":"Global, regional, and national burden of stroke and its risk factors, 1990\u20132019: A systematic analysis for the Global Burden of Disease Study 2019","volume":"20","author":"Feigin","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3661","DOI":"10.1002\/sim.6607","article-title":"Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies","volume":"34","author":"Austin","year":"2015","journal-title":"Stat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Vandenbroucke, J.P., von Elm, E., Altman, D.G., G\u00f8tzsche, P.C., Mulrow, C.D., Pocock, S.J., Poole, C., Schlesselman, J.J., Egger, M., and Strobe Initiative (2007). Strengthening the reporting of observational studies in epidemiology (STROBE): Explanation and elaboration. PLoS Med., 4.","DOI":"10.1371\/journal.pmed.0040297"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"American Diabetes Association (2019). Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes\u20142020. Diabetes Care, 43, S98\u2013S110.","DOI":"10.2337\/dc20-S009"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1161\/CIRCULATIONAHA.117.031735","article-title":"Repurposing metformin for cardiovascular disease","volume":"137","author":"Rena","year":"2018","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Lv, Z., and Guo, Y. (2020). Metformin and its benefits for various diseases. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00191"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e024954","DOI":"10.1136\/bmjopen-2018-024954","article-title":"Effect of metformin on neurodegenerative disease among elderly adult US veterans with type 2 diabetes mellitus","volume":"9","author":"Shi","year":"2019","journal-title":"BMJ Open"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejim.2017.09.019","article-title":"Antidiabetic drugs and stroke risk. Current evidence","volume":"48","year":"2018","journal-title":"Eur. J. Intern. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"173418","DOI":"10.1016\/j.ejphar.2020.173418","article-title":"Acute administration of metformin prior to cardiac ischemia\/reperfusion injury protects brain injury","volume":"885","author":"Leech","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"165893","DOI":"10.1016\/j.bbadis.2020.165893","article-title":"Metformin preferentially provides neuroprotection following cardiac ischemia\/reperfusion in non-diabetic rats","volume":"1866","author":"Benjanuwattra","year":"2020","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"eaax1912","DOI":"10.1126\/sciadv.aax1912","article-title":"Age- and sex-dependent effects of metformin on neural precursor cells and cognitive recovery in a model of neonatal stroke","volume":"5","author":"Ruddy","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"389","DOI":"10.2174\/1570159X13666150205143555","article-title":"Neuropharmacological actions of metformin in stroke","volume":"13","author":"Jia","year":"2015","journal-title":"Curr. Neuropharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s12933-016-0408-3","article-title":"Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK\/eNOS pathway in diabetic mice","volume":"15","author":"Yu","year":"2016","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_19","first-page":"9756429","article-title":"To use or not to use metformin in cerebral ischemia: A review of the application of metformin in stroke rodents","volume":"2017","author":"Palacios","year":"2017","journal-title":"Stroke Res. Treat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"107716","DOI":"10.1016\/j.jstrokecerebrovasdis.2024.107716","article-title":"The impact of pre-stroke metformin use on clinical outcomes after acute ischemic stroke: A systematic review and meta-analysis","volume":"33","author":"Pakkam","year":"2024","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"76","DOI":"10.14740\/jocmr6159","article-title":"Impact of prior metformin use on stroke outcomes: A systematic review and updated meta-analysis","volume":"17","author":"Elgenidy","year":"2025","journal-title":"J. Clin. Med. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1097\/WNF.0000000000000625","article-title":"Neuroprotective effects of metformin in stroke patients: A systematic review and meta-analysis of cohort studies","volume":"48","author":"Mohammadi","year":"2025","journal-title":"Clin. Neuropharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2520","DOI":"10.1177\/0962280219889080","article-title":"Estimating the sample mean and standard deviation from commonly reported quantiles in meta-analysis","volume":"29","author":"McGrath","year":"2020","journal-title":"Stat. Methods Med. Res."},{"key":"ref_25","first-page":"7","article-title":"Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: What are they and which is better?","volume":"7","author":"Ma","year":"2020","journal-title":"Mil. Med. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Weir, C.J., Butcher, I., Assi, V., Lewis, S.C., Murray, G.D., Langhorne, P., and Brady, M.C. (2018). Dealing with missing standard deviation and mean values in meta-analysis of continuous outcomes: A systematic review. BMC Med. Res. Methodol., 18.","DOI":"10.1186\/s12874-018-0483-0"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.medcli.2013.06.013","article-title":"Metaan\u00e1lisis de ensayos cl\u00ednicos aleatorizados, heterogeneidad e intervalos de predicci\u00f3n","volume":"142","year":"2014","journal-title":"Med. Clin."},{"key":"ref_28","first-page":"270","article-title":"Investigation of publication bias in meta-analyses of diagnostic test accuracy: A meta-epidemiological study","volume":"14","author":"Ochodo","year":"2014","journal-title":"BMC Med. Res. Methodol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1001\/jama.295.6.676","article-title":"Comparison of two methods to detect publication bias in meta-analysis","volume":"295","author":"Peters","year":"2006","journal-title":"JAMA"},{"key":"ref_30","first-page":"e978","article-title":"Three-month modified rankin scale as a determinant of 5-year cumulative costs after ischemic stroke","volume":"94","author":"Kim","year":"2020","journal-title":"Neurology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.jclinepi.2010.07.017","article-title":"GRADE guidelines: 4. Rating the quality of evidence\u2014Study limitations (risk of bias)","volume":"64","author":"Guyatt","year":"2011","journal-title":"J. Clin. Epidemiol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Akhtar, N., Singh, R., Kamran, S., Babu, B., Sivasankaran, S., Joseph, S., Morgan, D., and Shuaib, A. (2022). Diabetes: Chronic metformin treatment and outcome following acute stroke. Front. Neurol., 13.","DOI":"10.3389\/fneur.2022.849607"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"122812","DOI":"10.1016\/j.jns.2023.122812","article-title":"Neuroprotective effects of oral metformin before stroke on cerebral small-vessel disease","volume":"456","author":"Akiyama","year":"2024","journal-title":"J. Neurol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4335","DOI":"10.1007\/s10072-022-05935-x","article-title":"Ischemic stroke and reperfusion therapies in diabetic patients","volume":"43","author":"Fiume","year":"2022","journal-title":"Neurol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1007\/s10072-022-06491-0","article-title":"Metformin treatment and acute ischemic stroke outcomes in patients with type 2 diabetes: A retrospective cohort study","volume":"44","author":"Jian","year":"2023","journal-title":"Neurol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"106648","DOI":"10.1016\/j.jstrokecerebrovasdis.2022.106648","article-title":"Effect of metformin on outcome after acute ischemic stroke in patients with type 2 diabetes mellitus","volume":"31","author":"Kersten","year":"2022","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kim, C., Kim, Y., Sohn, J.-H., Sung, J.H., Han, S.-W., Lee, M., Kim, Y., Lee, J.J., Mo, H.J., and Yu, K.-H. (2024). Effects of prior metformin use on stroke outcomes in diabetes patients with acute ischemic stroke receiving endovascular treatment. Biomedicines, 12.","DOI":"10.3390\/biomedicines12040745"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.jstrokecerebrovasdis.2015.10.016","article-title":"Impact of metformin on the severity and outcomes of acute ischemic stroke in patients with type 2 diabetes mellitus","volume":"25","author":"Mima","year":"2016","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"20406223221076894","DOI":"10.1177\/20406223221076894","article-title":"Metformin use is associated with low risk of case fatality and disability rates in first-ever stroke patients with type 2 diabetes","volume":"13","author":"Tu","year":"2022","journal-title":"Ther. Adv. Chronic Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e362","DOI":"10.1212\/WNL.0000000000009951","article-title":"Association of prestroke metformin use, stroke severity, and thrombolysis outcome","volume":"95","author":"Westphal","year":"2020","journal-title":"Neurology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e70004","DOI":"10.1111\/cns.70004","article-title":"Effectiveness of metformin pretreatment for stroke severity: A propensity score matching study","volume":"30","author":"Zhang","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"256","DOI":"10.5505\/tbdhd.2020.75768","article-title":"The effect of metformin therapy on severity and prognosis in acute ischemic stroke","volume":"26","author":"Allahverdiyev","year":"2020","journal-title":"Turk. J. Cerebrovasc. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e2335","DOI":"10.1002\/brb3.2335","article-title":"Neuroprotective effects of metformin on cerebral ischemia-reperfusion injury by regulating PI3K\/Akt pathway","volume":"11","author":"Ruan","year":"2021","journal-title":"Brain Behav."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1093\/brain\/awad366","article-title":"Metformin in elderly type 2 diabetes mellitus: Dose-dependent dementia risk reduction","volume":"147","author":"Sun","year":"2024","journal-title":"Brain"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1007\/s11606-018-4425-7","article-title":"Empirical comparison of publication bias tests in meta-analysis","volume":"33","author":"Lin","year":"2018","journal-title":"J. Gen. Intern. Med."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/19\/7532\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:19:40Z","timestamp":1790615980000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/19\/7532"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":45,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["jcm15197532"],"URL":"https:\/\/doi.org\/10.3390\/jcm15197532","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]}}}