{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T22:57:03Z","timestamp":1793314623974,"version":"4.5.0"},"reference-count":33,"publisher":"American Medical Association (AMA)","issue":"20","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2025,5,27]]},"abstract":"<jats:sec><jats:title>Importance<\/jats:title><jats:p>Preclinical and preliminary human evidence suggests that metformin, a first-line treatment for type 2 diabetes, reduces inflammation, preserves cartilage, and improves knee pain in knee osteoarthritis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To evaluate the effects of metformin on knee pain at 6 months in participants with symptomatic knee osteoarthritis and overweight or obesity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>Community-based randomized, parallel-group, double-blind, placebo-controlled clinical trial that used telemedicine to recruit and follow up participants remotely. Individuals with knee pain for 6 months or longer, a pain score greater than 40 mm on a 100-mm visual analog scale (VAS), and body mass index of 25 or higher were recruited from the community through local and social media advertisements in Victoria, Australia, between June 16, 2021, and August 1, 2023. Final follow-up occurred on February 8, 2024.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interventions<\/jats:title><jats:p>Participants were randomly assigned to receive either oral metformin, 2000 mg\/d (n\u2009=\u200954), or identical placebo (n\u2009=\u200953) for 6 months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>The primary outcome was change in knee pain, measured using a 100-mm VAS (score range, 0-100; 100\u2009=\u2009worst; minimum clinically important difference\u2009=\u200915) at 6 months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of 225 participants assessed for eligibility, 107 (48%) were randomized (mean age, 58.8 [SD, 9.5] years; 68% female) and assigned to receive metformin or placebo. Eighty-eight participants (82%) completed the trial. At 6 months, the mean change in VAS pain was \u221231.3 mm in the metformin group and \u221218.9 mm in the placebo group (between-group difference, \u221211.4 mm; 95% CI, \u221220.1 to \u22122.6 mm; <jats:italic>P<\/jats:italic>\u2009=\u2009.01), corresponding to an effect size (standardized mean difference) of 0.43 (95% CI, 0.02-0.83). The most common adverse events were diarrhea (8 [15%] in the metformin group and 4 [8%] in the placebo group) and abdominal discomfort (7 [13%] in the metformin group and 5 [9%] in the placebo group).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Relevance<\/jats:title><jats:p>These results support use of metformin for treatment of symptomatic knee osteoarthritis in people with overweight or obesity. Because of the modest sample size, confirmation in a larger clinical trial is warranted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p>ANZCTR Identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/anzctr.org.au\/Trial\/Registration\/TrialReview.aspx?id=381914&amp;amp;amp;isReview=true\">ACTRN12621000710820<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jama.2025.3471","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T00:30:18Z","timestamp":1745541018000},"page":"1804","source":"Crossref","is-referenced-by-count":88,"title":["Metformin for Knee Osteoarthritis in Patients With Overweight or Obesity"],"prefix":"10.1001","volume":"333","author":[{"given":"Feng","family":"Pan","sequence":"first","affiliation":[{"name":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"},{"name":"Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan Z.","family":"Lim","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"},{"name":"Department of Rheumatology, Alfred Hospital, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna M.","family":"Urquhart","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahnuma Mahfuz","family":"Estee","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita E.","family":"Wluka","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"},{"name":"Department of Rheumatology, Alfred Hospital, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory","family":"Wolfe","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia M.","family":"Cicuttini","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"},{"name":"Department of Rheumatology, Alfred Hospital, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"7","key":"jpc250001r1","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1002\/art.42089","article-title":"Prevalence trends of site-specific osteoarthritis from 1990 to 2019: findings from the Global Burden of Disease Study 2019.","volume":"74","author":"Long","year":"2022","journal-title":"Arthritis Rheumatol"},{"issue":"11","key":"jpc250001r2","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1002\/acr.20571","article-title":"Identification of phenotypes with different clinical outcomes in knee osteoarthritis: data from the Osteoarthritis Initiative.","volume":"63","author":"Knoop","year":"2011","journal-title":"Arthritis Care Res (Hoboken)"},{"issue":"1","key":"jpc250001r3","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1186\/s12891-016-1286-2","article-title":"Identification of clinical phenotypes in knee osteoarthritis: a systematic review of the literature.","volume":"17","author":"Dell\u2019Isola","year":"2016","journal-title":"BMC Musculoskelet Disord"},{"issue":"12","key":"jpc250001r4","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.1016\/j.joca.2017.08.009","article-title":"Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review.","volume":"25","author":"Deveza","year":"2017","journal-title":"Osteoarthritis Cartilage"},{"issue":"4","key":"jpc250001r5","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1093\/rheumatology\/keu464","article-title":"Obesity and osteoarthritis, more than just wear and tear: pivotal roles for inflamed adipose tissue and dyslipidaemia in obesity-induced osteoarthritis.","volume":"54","author":"Thijssen","year":"2015","journal-title":"Rheumatology (Oxford)"},{"issue":"4","key":"jpc250001r6","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1016\/j.joca.2021.06.013","article-title":"Fundamentals of OA: an initiative of Osteoarthritis and Cartilage: obesity and metabolic factors in OA.","volume":"30","author":"Batushansky","year":"2022","journal-title":"Osteoarthritis Cartilage"},{"issue":"1","key":"jpc250001r7","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1038\/s41413-023-00301-9","article-title":"Risk of metabolic abnormalities in osteoarthritis: a new perspective to understand its pathological mechanisms.","volume":"11","author":"Wei","year":"2023","journal-title":"Bone Res"},{"issue":"3","key":"jpc250001r8","doi-asserted-by":"publisher","first-page":"196","DOI":"10.2174\/1871530315666150316124019","article-title":"Metformin and inflammation: its potential beyond glucose-lowering effect.","volume":"15","author":"Saisho","year":"2015","journal-title":"Endocr Metab Immune Disord Drug Targets"},{"issue":"1","key":"jpc250001r9","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1758-5996-5-6","article-title":"Metformin: an old but still the best treatment for type 2 diabetes.","volume":"5","author":"Rojas","year":"2013","journal-title":"Diabetol Metab Syndr"},{"issue":"2","key":"jpc250001r10","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1007\/s13679-019-00335-3","article-title":"Metformin: mechanisms in human obesity and weight loss.","volume":"8","author":"Yerevanian","year":"2019","journal-title":"Curr Obes Rep"},{"key":"jpc250001r11","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.952560","article-title":"The effects of metformin in the treatment of osteoarthritis: current perspectives.","volume":"13","author":"Song","year":"2022","journal-title":"Front Pharmacol"},{"issue":"12","key":"jpc250001r12","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2023-079489","article-title":"Metformin for knee osteoarthritis with obesity: study protocol for a randomised, double-blind, placebo-controlled trial.","volume":"13","author":"Lim","year":"2023","journal-title":"BMJ Open"},{"key":"jpc250001r13","doi-asserted-by":"publisher","first-page":"c869","DOI":"10.1136\/bmj.c869","article-title":"CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials.","volume":"340","author":"Moher","year":"2010","journal-title":"BMJ"},{"issue":"8","key":"jpc250001r14","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1002\/art.1780290816","article-title":"Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee.","volume":"29","author":"Altman","year":"1986","journal-title":"Arthritis Rheum"},{"issue":"11","key":"jpc250001r15","doi-asserted-by":"publisher","first-page":"1699","DOI":"10.1002\/acr.21747","article-title":"Minimum clinically important improvement and patient acceptable symptom state in pain and function in rheumatoid arthritis, ankylosing spondylitis, chronic back pain, hand osteoarthritis, and hip and knee osteoarthritis: results from a prospective multinational study.","volume":"64","author":"Tubach","year":"2012","journal-title":"Arthritis Care Res (Hoboken)"},{"issue":"4","key":"jpc250001r16","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1002\/1529-0131(200108)45:4<384::AID-ART352>3.0.CO;2-0","article-title":"Smallest detectable and minimal clinically important differences of rehabilitation intervention with their implications for required sample sizes using WOMAC and SF-36 quality of life measurement instruments in patients with osteoarthritis of the lower extremities.","volume":"45","author":"Angst","year":"2001","journal-title":"Arthritis Rheum"},{"issue":"12","key":"jpc250001r17","first-page":"1833","article-title":"Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee.","volume":"15","author":"Bellamy","year":"1988","journal-title":"J Rheumatol"},{"issue":"2","key":"jpc250001r18","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/S0895-4356(02)00601-7","article-title":"Quality of life assessment in the community-dwelling elderly: validation of the Assessment of Quality of Life (AQoL) instrument and comparison with the SF-36.","volume":"56","author":"Osborne","year":"2003","journal-title":"J Clin Epidemiol"},{"issue":"5","key":"jpc250001r19","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.joca.2004.02.001","article-title":"OMERACT-OARSI initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited.","volume":"12","author":"Pham","year":"2004","journal-title":"Osteoarthritis Cartilage"},{"issue":"10","key":"jpc250001r20","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1001\/jama.2016.1961","article-title":"Effect of vitamin D supplementation on tibial cartilage volume and knee pain among patients with symptomatic knee osteoarthritis: a randomized clinical trial.","volume":"315","author":"Jin","year":"2016","journal-title":"JAMA"},{"key":"jpc250001r21","doi-asserted-by":"crossref","first-page":"A1","DOI":"10.1016\/j.joca.2006.11.009","article-title":"Atlas of individual radiographic features in osteoarthritis, revised.","volume":"15","author":"Altman","year":"2007","journal-title":"Osteoarthritis Cartilage"},{"issue":"20","key":"jpc250001r22","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1001\/jama.2021.19415","article-title":"Effect of intra-articular platelet-rich plasma vs placebo injection on pain and medial tibial cartilage volume in patients with knee osteoarthritis: the RESTORE randomized clinical trial.","volume":"326","author":"Bennell","year":"2021","journal-title":"JAMA"},{"key":"jpc250001r23","doi-asserted-by":"crossref","DOI":"10.1177\/1759720X19880054","article-title":"Zoledronic acid plus methylprednisolone versus zoledronic acid or placebo in symptomatic knee osteoarthritis: a randomized controlled trial.","volume":"11","author":"Cai","year":"2019","journal-title":"Ther Adv Musculoskelet Dis"},{"issue":"15","key":"jpc250001r24","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1001\/jama.2020.2938","article-title":"Effect of intravenous zoledronic acid on tibiofemoral cartilage volume among patients with knee osteoarthritis with bone marrow lesions: a randomized clinical trial.","volume":"323","author":"Cai","year":"2020","journal-title":"JAMA"},{"issue":"3","key":"jpc250001r25","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1136\/emj.18.3.205","article-title":"The minimum clinically significant difference in visual analogue scale pain score does not differ with severity of pain.","volume":"18","author":"Kelly","year":"2001","journal-title":"Emerg Med J"},{"issue":"5","key":"jpc250001r26","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1016\/j.bja.2021.11.032","article-title":"Utility of unidimensional and functional pain assessment tools in adult postoperative patients: a systematic review.","volume":"128","author":"Baamer","year":"2022","journal-title":"Br J Anaesth"},{"issue":"1","key":"jpc250001r27","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s13075-019-1915-x","article-title":"Association between metformin use and disease progression in obese people with knee osteoarthritis: data from the Osteoarthritis Initiative\u2014a prospective cohort study.","volume":"21","author":"Wang","year":"2019","journal-title":"Arthritis Res Ther"},{"issue":"1","key":"jpc250001r28","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0191242","article-title":"Combination COX-2 inhibitor and metformin attenuate rate of joint replacement in osteoarthritis with diabetes: a nationwide, retrospective, matched-cohort study in Taiwan.","volume":"13","author":"Lu","year":"2018","journal-title":"PLoS One"},{"issue":"3","key":"jpc250001r29","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2023.3646","article-title":"Development of osteoarthritis in adults with type 2 diabetes treated with metformin vs a sulfonylurea.","volume":"6","author":"Baker","year":"2023","journal-title":"JAMA Netw Open"},{"issue":"6","key":"jpc250001r30","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1017\/S1463423617000287","article-title":"Does metformin protect against osteoarthritis? an electronic health record cohort study.","volume":"18","author":"Barnett","year":"2017","journal-title":"Prim Health Care Res Dev"},{"issue":"1","key":"jpc250001r31","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13075-023-03025-7","article-title":"Metformin attenuates symptoms of osteoarthritis: role of genetic diversity of Bcl2 and CXCL16 in OA.","volume":"25","author":"Alimoradi","year":"2023","journal-title":"Arthritis Res Ther"},{"issue":"9","key":"jpc250001r32","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.joca.2007.06.014","article-title":"OARSI recommendations for the management of hip and knee osteoarthritis, I: critical appraisal of existing treatment guidelines and systematic review of current research evidence.","volume":"15","author":"Zhang","year":"2007","journal-title":"Osteoarthritis Cartilage"},{"issue":"11","key":"jpc250001r33","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1016\/j.joca.2022.05.005","article-title":"Metformin as a potential disease-modifying drug in osteoarthritis: a systematic review of pre-clinical and human studies.","volume":"30","author":"Lim","year":"2022","journal-title":"Osteoarthritis Cartilage"}],"container-title":["JAMA"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jama\/articlepdf\/2833338\/jama_pan_2025_pc_250001_1747333559.19047.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T15:00:37Z","timestamp":1748358037000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jama\/fullarticle\/2833338"}},"subtitle":["A Randomized Clinical Trial"],"short-title":[],"issued":{"date-parts":[[2025,5,27]]},"references-count":33,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2025,5,27]]}},"URL":"https:\/\/doi.org\/10.1001\/jama.2025.3471","relation":{},"ISSN":["0098-7484"],"issn-type":[{"value":"0098-7484","type":"print"}],"subject":[],"published":{"date-parts":[[2025,5,27]]}}}