Efficacy and Safety of GLP-1 Receptor Agonists for the Management of Knee Osteoarthritis: A Systematic Review and Meta-Analysis

Efficacy and Safety of GLP-1 Receptor Agonists for the Management of Knee Osteoarthritis: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Efficacy and Safety of GLP-1 Receptor Agonists for the Management of Knee Osteoarthritis: A Systematic Review and Meta-Analysis Madhusudan Prasad Singh, Riya Yadav, Alok Singh This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6482330/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background and Objective: Osteoarthritis (OA) represents a leading cause of chronic pain and disability globally. While current management primarily addresses symptom relief, disease-modifying interventions remain limited. Obesity significantly contributes to osteoarthritis progression especially knee osteoarthritis (KOA), with weight reduction yielding symptomatic benefits. GLP-1RAs, originally developed for type 2 diabetes and obesity management, show potential in KOA management through weight-reducing and anti-inflammatory mechanisms. Method and Results: This systematic review and meta-analysis evaluated GLP-1RAs' efficacy and safety in KOA, focusing on pain reduction, functional improvement, and weight loss outcomes. Our comprehensive database search identified two randomized controlled trials with 563 participants that met inclusion criteria, both examining semaglutide and liraglutide against placebo. Results demonstrated that GLP-1RA-treated patients experienced significantly greater reductions in body weight (-7.8 kg; 95% CI: -9.2 to -6.4) and Body-mass Index (BMI) (-2.8 kg/m²; 95% CI: -3.3 to -2.3). Gastrointestinal effects constituted the primary adverse events. Both studies demonstrated low risk of bias with no detected publication bias. Conclusion: These findings suggest GLP-1RAs may represent promising therapeutic agents for KOA by addressing both weight-related and inflammatory pathways underlying disease progression. Larger trials investigating long-term efficacy and safety are warranted. Clinical Pharmacology Knee Osteoarthritis Glucagon-Like Peptide-1 Receptor Agonists Weight Loss Pain Management Semaglutide Liraglutide Figures Figure 1 Figure 2 Introduction Osteoarthritis (OA) is the most prevalent form of arthritis and a leading cause of chronic pain, reduced mobility, and disability worldwide [ 1 ]. Knee osteoarthritis (KOA), in particular, imposes a substantial burden on affected individuals and healthcare systems [ 2 ]. The pathophysiology of KOA involves progressive cartilage degeneration, synovial inflammation, and subchondral bone remodelling, leading to pain, functional impairment, and decreased quality of life (QoL) [ 3 ]. Current treatment strategies primarily focus on symptom management using analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular injections, and physical therapy, with limited options to alter disease progression [ 4 ]. Given the increasing prevalence of KOA, particularly in populations with obesity and advancing age, novel pharmacological interventions are needed to alleviate symptoms and modify disease progression [ 5 ]. Obesity is a major risk factor for the development and progression of KOA due to increased mechanical stress on weight-bearing joints, metabolic dysfunction, and obesity-induced inflammation [ 6 ]. Studies have demonstrated that weight loss is associated with significant improvements in pain, function, and stiffness, with every 1% reduction in body weight correlating with a 2% improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores [ 7 ]. While international guidelines recommend weight loss and physical activity as fundamental components of KOA management, achieving and sustaining meaningful weight loss through lifestyle interventions alone remains challenging for many patients [ 8 ]. Pharmacological agents that facilitate sustained weight loss and improve KOA symptoms offer a promising alternative [ 9 ]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for type 2 diabetes mellitus (T2DM) and obesity management, have shown potential for KOA treatment due to their weight-loss effects and anti-inflammatory properties [ 10 ]. Recent evidence from pre-clinical and human studies suggests that GLP-1 receptor agonists exert chondroprotective, immunomodulatory, and analgesic effects in osteoarthritis, primarily through inhibition of the NF-κB pathway [ 10 ]. Agents such as semaglutide and liraglutide have demonstrated efficacy in reducing body weight and improving pain and function in patients with KOA [ 11 ]. Recent randomized controlled trials (RCTs) have evaluated the impact of GLP-1RAs on KOA symptoms, including the Semaglutide Treatment Effect in People with Obesity (STEP) 9 trial and another study investigating liraglutide 3 mg/d combined with dietary intervention [ 12 ]. The primary aim of this systematic review and meta-analysis is to comprehensively evaluate the efficacy and safety of GLP-1RAs in the management of KOA with obesity, with particular focus on pain reduction, functional improvement, and structural disease modification [ 13 ]. Additionally, we seek to identify the relationship between weight loss achieved with GLP-1RAs and improvements in KOA symptoms, and to characterize the potential mechanisms beyond weight loss through which these agents may exert beneficial effects [ 14 – 15 ]. The findings of this study will help establish the role of GLP-1RAs in KOA treatment algorithms and inform future clinical trials investigating these agents as disease-modifying osteoarthritis drugs [ 16 ]. Methodology Search Strategy and Selection Criteria This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, ensuring methodological rigor, transparency, and reproducibility [ 17 ]. (PRISMA checklist supplementary file S1 ) Additionally, for public accessibility increased rigor, the review was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO). (registration number: CRD42025639802). A systematic and comprehensive search was conducted across multiple databases, including MEDLINE/PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. (Detailed search strategy supplementary file S2 ) Additionally, reference lists of included studies and relevant systematic reviews were screened to identify additional eligible articles. The search was performed from database inception until January 15, 2025, without language restrictions. Study Selection Two independent reviewers (MPS, RY) screened all identified records in two phases: (1) title and abstract screening and (2) full-text screening. Studies were considered eligible for inclusion if they met the following criteria: (1) randomized controlled trials (RCTs) evaluating the use of GLP-1 receptor agonists for KOA, (2) adult populations (aged ≥ 18 years) with a confirmed diagnosis of KOA with obesity, and (3) studies reporting relevant outcomes, including weight loss, pain reduction, physical function improvement, quality of life, or adverse events. Observational studies, case reports, case series, and studies without adequate translations were excluded. Any discrepancies in study selection were resolved through consensus or consultation with a third reviewer (AS). Inclusion and Exclusion Criteria Population Studies including adult patients (≥ 18 years) diagnosed with KOA based on clinical or imaging criteria and who were overweight defined as Body-mass Index (BMI) ≥ 27. Studies focusing on other forms of arthritis (e.g., rheumatoid arthritis, gout), pediatric populations, or patients with significant confounding comorbidities (e.g., advanced malignancies) were excluded. Intervention Eligible studies assessed GLP-1 receptor agonists (e.g., semaglutide, liraglutide, exenatide, dulaglutide) either as monotherapy or in combination with other standard osteoarthritis treatments. Studies investigating GLP-1 receptor agonists for unrelated conditions without osteoarthritis-specific outcome measures were excluded. Comparator Studies were included if they featured a comparator group, which could be placebo, standard care, alternative weight-loss interventions, or non-pharmacological approaches such as physical therapy or dietary modifications. Studies lacking an appropriate control group were excluded. Outcomes: The outcomes assessed were: Change from baseline in weight at end of study Change from baseline in BMI at end of study. Change from baseline in pain severity scores at end of study. Proportion of patients showing ≥ 10% weight loss. Proportion of patients showing ≥ 5% weight loss. Change from baseline in physical functions. Change from baseline in Quality-of-Life score at end of study. Proportion of patients with any adverse event. Proportion of patients with any serious adverse event. Proportion of patients discontinuing the treatment. Data Extraction and Risk of Bias Assessment Two independent reviewers (MPS, AS) performed data extraction using a standardized data collection form. Extracted information included study characteristics (e.g., publication year, sample size, intervention details), baseline demographics, and reported outcomes. Any disagreements were resolved through discussion or consultation with a third reviewer (RY). Risk of bias was assessed using both the Cochrane Risk of Bias 1.0 and 2.0 tool [ 18 , 19 ]. The following five domains were evaluated: Randomization process. Deviations from intended interventions. Missing outcome data. Measurement of outcomes. Selection of reported results. Each domain was classified as "low risk," "some concerns," or "high risk" of bias. Disagreements were resolved by consensus. Data Synthesis and Statistical Analysis Effect measures included mean differences (MD) with standard deviation (SD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes. The meta-analysis was conducted using both a fixed-effect and random-effects model however, only random effects model data have been presented. Statistical heterogeneity was assessed using the I² statistic and p value < 0.10 was considered statistically significant [ 20 ]. Data synthesis and statistical analyses were performed using RevMan 5.4. Summary of Findings and GRADE Assessment The certainty of evidence for each outcome was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach which considers factors like risk of bias, inconsistency of results, indirectness of evidence, imprecision of effect estimates and publication bias. For each outcome, the evidence was categorized into one of four levels: "high," "moderate," "low," or "very low." A summary of findings table was generated, presenting the pooled effect estimates along with the corresponding GRADE ratings [ 21 ]. Ethical Considerations As this study was a systematic review and meta-analysis using previously published data, ethical approval was not required. No individual patient data were used, ensuring compliance with ethical standards in research. Results A systematic search initially identified a total of 374 abstracts from various databases. After screening, 241 articles were excluded due to duplication or ineligibility. Subsequently, 133 full-text articles were assessed for eligibility. Among these, two randomized controlled trials (RCTs) met the inclusion criteria for the meta-analysis. The primary reasons for exclusion were review articles (n = 56), animal studies (n = 59), and conference abstracts (n = 16) (Fig. 1). The current meta-analysis included two RCTs published from inception to January 2025, involving a total of 563 patients aged > 18 years diagnosed with KOA with obesity clinically and radiologically and prescribed either a GLP-1 receptor agonist or a placebo. The mean age of the participants was 57.6 years most of the participants in included trials were female (72.6%). Among the two studies, one compared semaglutide with placebo, while the other compared liraglutide with placebo and dietary intervention [ 22 , 23 ]. (Table 1) Both liraglutide and semaglutide were administered via the subcutaneous route. Liraglutide treatment started at a dose of 0.6 mg/day, followed by biweekly dose escalation in increments of 0.6 mg/day, reaching a maximum of 3 mg/day. Semaglutide was initiated at a dose of 0.24 mg, with gradual dose escalation to achieve a target dose of 2.4 mg by week 16. According to the RoB tool, both RCTs were assessed to have a low risk of bias [ 22 , 23 ] (Fig. 2). Efficacy Endpoints The included RCTs compared two groups: patients receiving GLP-1 receptor agonists (semaglutide and liraglutide) versus those receiving a placebo. Publication bias was assessed using funnel plots, which appeared symmetrical for all outcomes, suggesting no publication bias. (Supplementary file S3) Due to the limited number of studies (< 3), Egger’s test could not be performed. For the mean change in weight from baseline, the forest plot demonstrated significant weight reduction in the GLP-1 receptor agonist group compared to the placebo group. However, there was substantial heterogeneity (I² = 97%, P < 0.00001). The mean difference (MD) in weight change was − 7.56 kg (95% CI: -14.71, -0.41; P = 0.04), indicating a statistically significant reduction in weight among patients receiving GLP-1 receptor agonists. Similarly, for the mean change in BMI from baseline, the GLP-1 receptor agonist group exhibited a greater reduction than the placebo group, with an MD of -4.52 (95% CI: -9.02, -0.01; P = 0.05). However, significant heterogeneity was noted (I² = 96%, P < 0.00001). Regarding the change in WOMAC pain score from baseline, GLP-1 receptor agonists led to a numerically greater reduction compared to placebo (MD = -1.42; 95% CI: -4.30, 1.46), but this difference was not statistically significant (P = 0.34). Additionally, significant heterogeneity was observed (I² = 94%, P < 0.00001). For the proportion of patients achieving ≥ 10% body weight loss, a significantly higher percentage of patients in the GLP-1 receptor agonist group experienced this outcome compared to placebo (59.2% vs. 9%; RR = 4.46; 95% CI: 1.28, 15.50; P = 0.02). High heterogeneity was observed (I² = 84%, P = 0.01). Similarly, for the proportion of patients achieving ≥ 5% body weight loss, GLP-1 receptor agonists were associated with a significantly higher proportion of patients achieving this outcome (75.2% vs. 25%; RR = 2.70; 95% CI: 1.98, 3.69; P < 0.00001). Unlike other endpoints, heterogeneity was low (I² = 23%, P = 0.25). Notably, the estimates for all efficacy endpoints remained consistent even after applying a fixed-effects model, suggesting robustness of the findings. Safety Endpoints For the proportion of patients experiencing serious adverse events, there was no significant difference between the GLP-1 receptor agonist and placebo groups (9.7% vs. 8%; RR = 1.19; 95% CI: 0.68, 2.10; P = 0.54). Heterogeneity was low (I² = 0%, P = 0.87). However, for the proportion of patients discontinuing treatment due to adverse events, the GLP-1 receptor agonist group had a significantly higher discontinuation rate compared to the placebo group (8% vs. 3.79%; RR = 2.31; 95% CI: 1.07, 5.00; P = 0.03). Heterogeneity was low (I² = 0%, P = 0.95). Similar to the efficacy endpoints, the safety estimates remained unchanged after applying a fixed-effects model, reinforcing the stability of the findings. All the forest plots are attached as supplementary file S4. As per the GRADE approach, the overall certainty of evidence was categorized as high for multiple outcomes i.e., mean change in weight, BMI, proportion of patients with ≥ 5% and ≥ 10% reduction in weight, and discontinuing the treatment. The certainty of evidence was assessed as very low for change in pain severity and low for proportion of patients with serious adverse events. The comprehensive assessment details and specific estimates for each outcome measure are presented in Table 2. Discussion Current meta-analysis intends to evaluate the role of GLP-1 receptor agonists in KOA. As of now the standard of care for KOA focuses on symptomatic relief with drugs as wells as physiotherapy and there is paucity of disease-modifying agents perse. Our study includes two randomized trials with 563 patients, with a mean age of ~ 58 years, with a predominance of female participants, which is similar to the usual demographic distribution of patients of KOA [ 24 ]. The included studies were methodologically sound as they were at low risk of bias as per RoB2 tool [ 22 , 23 ]. So, it can be assumed that the results obtained from the study will contribute to the good quality of evidence. The GLP-1 receptor agonists led to the statistically significant weight reduction compared to placebo (see results). The overall certainty of evidence for all these endpoints was very high (Table 2). This was an expected finding as GLP-1 receptor agonists are known for their weight loss property [ 25 ]. Typically, obesity and female sex is an important risk factor. Co-incidentally, more weight loss has been observed in females [ 25 ]. As there is no meta-analysis of RCTs is published so we don’t have comparator with which our findings can be compared. Although reduction in pain severity was noted but the finding is not statistically significant and is equally not reliable as both studies show different results for change in pain severity with an overall wide confidence interval. The slight reduction in pain severity can be attributed to the weight loss property of GLP-1 receptor agonists. The proportion of patients discontinuing the GLP-1 receptor agonists due to the adverse effects were significantly more than the placebo. The overall certainty was high and results are reliable (Table 2). The major reason of discontinuation was gastro-intestinal adverse events which is expected from the adverse events profile of GLP-1 receptor agonists [26,27]. The proportion of patients experiencing serious adverse events was higher in the GLP-1 receptor agonist group, although the difference was not statistically significant. The certainty of evidence was low due to the wide confidence interval and the findings are not reliable. Osteoarthritis is a disease of multifactorial aetiology including age related changes, and inflammation damaging the cartilages and other parts of joint(s) which represents a degenerative condition for which a definite cure is not available as of now. The idea of using GLP-1 receptor agonists comes from its potential to cause significant weight loss, and its pleiotropic effects especially anti-inflammatory effect. GLP-1 receptor agonists have been shown to affect inflammatory mediators, inhibiting catabolic factors and promoting collagen synthesis in different pre-clinical studies [28–31]. Upon looking into the progressive nature of cartilage and bone degeneration, slowing down/ inhibiting the process may improve the prognosis. Although, GLP-1 receptor agonists seem to be promising therapeutic option in many of degenerative diseases due to its pleiotropic effects, translating its effects into the clinical practice is going to be the daunting task. Present meta-analysis clearly indicates significant weight loss by the GLP-1 receptor agonists which may be beneficial in knee osteoarthritis, however with these clinical studies, the pre-clinical claims cannot be substantiated. A Long-term study with these agents can only provide proof of their disease-modifying potential. Strengths and Limitations To our knowledge, this represents the first systematic review and meta-analysis of randomized clinical trials analysing the role of GLP-1 receptor agonists in OA. The major limitations are inclusion of fewer studies, different GLP-1 receptor agonists and treatment regimens. The overall certainty of evidence was classified high for all efficacy endpoints and one adverse outcome. Conclusions This meta-analysis evaluated the potential role of GLP-1 receptor agonists in KOA. The drugs mainly led to significant reduction of weight and some improvement in pain was also observed. The drug discontinuation was mainly due to the gastro-intestinal adverse effects and no serious adverse events were observed. Furthermore, overall certainty of evidence was high for efficacy outcomes. Despite favourable pre-clinical findings, current evidence is far away from clinical practice recommendation. Additional clinical trials may be needed to establish the role of GLP-1 receptor agonists in knee osteoarthritis. Declarations Ethics approval: Not Applicable. Consent to participate: Not Applicable. Consent to publication: Not Applicable. Availability of data and material: Not Applicable. Competing Interests: Nothing to disclose. Funding: No funding received. Acknowledgments: Not Applicable. References Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019 Apr 27;393(10182):1745-1759. doi: 10.1016/S0140-6736(19)30417-9. PMID: 31034380. Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Clin Geriatr Med. 2010 Aug;26(3):355-69. doi: 10.1016/j.cger.2010.03.001. 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The GLP-1 agonist, liraglutide, ameliorates inflammation through the activation of the PKA/CREB pathway in a rat model of knee osteoarthritis. J Inflamm (Lond). 2019 Jun 6;16:13. Tables Tables 1 and 2 are available in the Supplementary Files section Additional Declarations The authors declare no competing interests. Supplementary Files Table1.docx Table 1: Study Charateristics Table2.docx Table 2: Summary of Findings S1PRISMA.docx S1: PRISMA Checklist S2detailedsearchstrategy.docx S2: Search Strategy S3funnels.docx S3: Funnel plots s4forest.docx S4: Forest plots Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6482330","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":445023211,"identity":"52ea2a17-9c01-48b7-9e99-0f783dac2653","order_by":0,"name":"Madhusudan Prasad Singh","email":"","orcid":"","institution":"Department of Pharmacology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India.","correspondingAuthor":false,"prefix":"","firstName":"Madhusudan","middleName":"Prasad","lastName":"Singh","suffix":""},{"id":445023212,"identity":"c5e0cb92-9989-4d55-9dd4-254f4f1dcb91","order_by":1,"name":"Riya Yadav","email":"","orcid":"","institution":"Department of Pharmacology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India.","correspondingAuthor":false,"prefix":"","firstName":"Riya","middleName":"","lastName":"Yadav","suffix":""},{"id":445023213,"identity":"f72eb50f-d145-4609-b3ee-9764591527cc","order_by":2,"name":"Alok Singh","email":"data:image/png;base64,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","orcid":"","institution":"Department of Pharmacology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India","correspondingAuthor":true,"prefix":"","firstName":"Alok","middleName":"","lastName":"Singh","suffix":""}],"badges":[],"createdAt":"2025-04-19 04:32:56","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6482330/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6482330/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":81197090,"identity":"bbd8ab7b-51ea-4d2f-a706-bcde0e572489","added_by":"auto","created_at":"2025-04-23 10:37:28","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":438680,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figure1.PRISMAFlowchart.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6482330/v1/75e573dde58aacdd86192bd9.jpg"},{"id":81197091,"identity":"4675204e-b760-4c51-b43c-01010c91bfdb","added_by":"auto","created_at":"2025-04-23 10:37:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":185383,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figure2.ROB2.png","url":"https://assets-eu.researchsquare.com/files/rs-6482330/v1/3f2d2bd98c5282f557b69c07.png"},{"id":81199504,"identity":"5b0bf1d9-b1eb-4ec5-b3c9-b408456d0eff","added_by":"auto","created_at":"2025-04-23 11:01:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1279880,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6482330/v1/8469ed37-4f45-4448-a131-3606be3ef899.pdf"},{"id":81197089,"identity":"45a204bd-9a26-4637-8e10-6f842e1efaae","added_by":"auto","created_at":"2025-04-23 10:37:28","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15382,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1: Study Charateristics\u003c/p\u003e","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6482330/v1/c40521ad42cd30f6fe55a08a.docx"},{"id":81197094,"identity":"75690f9e-41ce-433a-9875-cc5ad2bdc1c9","added_by":"auto","created_at":"2025-04-23 10:37:29","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":17485,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2: Summary of Findings\u003c/p\u003e","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6482330/v1/6ae4991f215582f4d8f572f6.docx"},{"id":81198150,"identity":"ed60e851-5e8b-457e-924e-11ed45919b9d","added_by":"auto","created_at":"2025-04-23 10:45:29","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":21719,"visible":true,"origin":"","legend":"\u003cp\u003eS1: PRISMA Checklist\u003c/p\u003e","description":"","filename":"S1PRISMA.docx","url":"https://assets-eu.researchsquare.com/files/rs-6482330/v1/73ddb2cb0e0285e5d06b2ea9.docx"},{"id":81198147,"identity":"8013e151-986d-4db9-ba27-696163788063","added_by":"auto","created_at":"2025-04-23 10:45:28","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":14924,"visible":true,"origin":"","legend":"\u003cp\u003eS2: Search Strategy\u003c/p\u003e","description":"","filename":"S2detailedsearchstrategy.docx","url":"https://assets-eu.researchsquare.com/files/rs-6482330/v1/b89779153ffe0c6d78239c35.docx"},{"id":81197099,"identity":"b0482446-47f2-46ac-a65b-e007e120f29f","added_by":"auto","created_at":"2025-04-23 10:37:29","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":53728,"visible":true,"origin":"","legend":"\u003cp\u003eS3: Funnel plots\u003c/p\u003e","description":"","filename":"S3funnels.docx","url":"https://assets-eu.researchsquare.com/files/rs-6482330/v1/e4394638bf3aeaf094053339.docx"},{"id":81198939,"identity":"02033dd0-473e-45e8-89d6-faa5705525a5","added_by":"auto","created_at":"2025-04-23 10:53:29","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":103323,"visible":true,"origin":"","legend":"\u003cp\u003eS4: Forest plots\u003c/p\u003e","description":"","filename":"s4forest.docx","url":"https://assets-eu.researchsquare.com/files/rs-6482330/v1/6fc5061e9b52bd77cfe85b28.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEfficacy and Safety of GLP-1 Receptor Agonists for the Management of Knee Osteoarthritis: A Systematic Review and Meta-Analysis\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOsteoarthritis (OA) is the most prevalent form of arthritis and a leading cause of chronic pain, reduced mobility, and disability worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Knee osteoarthritis (KOA), in particular, imposes a substantial burden on affected individuals and healthcare systems [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The pathophysiology of KOA involves progressive cartilage degeneration, synovial inflammation, and subchondral bone remodelling, leading to pain, functional impairment, and decreased quality of life (QoL) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Current treatment strategies primarily focus on symptom management using analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular injections, and physical therapy, with limited options to alter disease progression [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Given the increasing prevalence of KOA, particularly in populations with obesity and advancing age, novel pharmacological interventions are needed to alleviate symptoms and modify disease progression [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eObesity is a major risk factor for the development and progression of KOA due to increased mechanical stress on weight-bearing joints, metabolic dysfunction, and obesity-induced inflammation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Studies have demonstrated that weight loss is associated with significant improvements in pain, function, and stiffness, with every 1% reduction in body weight correlating with a 2% improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. While international guidelines recommend weight loss and physical activity as fundamental components of KOA management, achieving and sustaining meaningful weight loss through lifestyle interventions alone remains challenging for many patients [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Pharmacological agents that facilitate sustained weight loss and improve KOA symptoms offer a promising alternative [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGlucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for type 2 diabetes mellitus (T2DM) and obesity management, have shown potential for KOA treatment due to their weight-loss effects and anti-inflammatory properties [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Recent evidence from pre-clinical and human studies suggests that GLP-1 receptor agonists exert chondroprotective, immunomodulatory, and analgesic effects in osteoarthritis, primarily through inhibition of the NF-κB pathway [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Agents such as semaglutide and liraglutide have demonstrated efficacy in reducing body weight and improving pain and function in patients with KOA [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Recent randomized controlled trials (RCTs) have evaluated the impact of GLP-1RAs on KOA symptoms, including the Semaglutide Treatment Effect in People with Obesity (STEP) 9 trial and another study investigating liraglutide 3 mg/d combined with dietary intervention [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe primary aim of this systematic review and meta-analysis is to comprehensively evaluate the efficacy and safety of GLP-1RAs in the management of KOA with obesity, with particular focus on pain reduction, functional improvement, and structural disease modification [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Additionally, we seek to identify the relationship between weight loss achieved with GLP-1RAs and improvements in KOA symptoms, and to characterize the potential mechanisms beyond weight loss through which these agents may exert beneficial effects [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The findings of this study will help establish the role of GLP-1RAs in KOA treatment algorithms and inform future clinical trials investigating these agents as disease-modifying osteoarthritis drugs [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch Strategy and Selection Criteria\u003c/h2\u003e \u003cp\u003eThis systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, ensuring methodological rigor, transparency, and reproducibility [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. (PRISMA checklist \u003cb\u003esupplementary file S1\u003c/b\u003e) Additionally, for public accessibility increased rigor, the review was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO). (registration number: CRD42025639802).\u003c/p\u003e \u003cp\u003eA systematic and comprehensive search was conducted across multiple databases, including MEDLINE/PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. (Detailed search \u003cb\u003estrategy supplementary file S2\u003c/b\u003e) Additionally, reference lists of included studies and relevant systematic reviews were screened to identify additional eligible articles. The search was performed from database inception until January 15, 2025, without language restrictions.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Selection\u003c/h3\u003e\n\u003cp\u003eTwo independent reviewers (MPS, RY) screened all identified records in two phases: (1) title and abstract screening and (2) full-text screening. Studies were considered eligible for inclusion if they met the following criteria: (1) randomized controlled trials (RCTs) evaluating the use of GLP-1 receptor agonists for KOA, (2) adult populations (aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years) with a confirmed diagnosis of KOA with obesity, and (3) studies reporting relevant outcomes, including weight loss, pain reduction, physical function improvement, quality of life, or adverse events. Observational studies, case reports, case series, and studies without adequate translations were excluded. Any discrepancies in study selection were resolved through consensus or consultation with a third reviewer (AS).\u003c/p\u003e\n\u003ch3\u003eInclusion and Exclusion Criteria\u003c/h3\u003e\n\u003cp\u003e \u003cstrong\u003ePopulation\u003c/strong\u003e \u003cp\u003eStudies including adult patients (\u0026ge;\u0026thinsp;18 years) diagnosed with KOA based on clinical or imaging criteria and who were overweight defined as Body-mass Index (BMI)\u0026thinsp;\u0026ge;\u0026thinsp;27. Studies focusing on other forms of arthritis (e.g., rheumatoid arthritis, gout), pediatric populations, or patients with significant confounding comorbidities (e.g., advanced malignancies) were excluded.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eIntervention\u003c/strong\u003e \u003cp\u003eEligible studies assessed GLP-1 receptor agonists (e.g., semaglutide, liraglutide, exenatide, dulaglutide) either as monotherapy or in combination with other standard osteoarthritis treatments. Studies investigating GLP-1 receptor agonists for unrelated conditions without osteoarthritis-specific outcome measures were excluded.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eComparator\u003c/strong\u003e \u003cp\u003eStudies were included if they featured a comparator group, which could be placebo, standard care, alternative weight-loss interventions, or non-pharmacological approaches such as physical therapy or dietary modifications. Studies lacking an appropriate control group were excluded.\u003c/p\u003e \u003c/p\u003e\n\u003ch3\u003eOutcomes:\u003c/h3\u003e\n\u003cp\u003eThe outcomes assessed were:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eChange from baseline in weight at end of study\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eChange from baseline in BMI at end of study.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eChange from baseline in pain severity scores at end of study.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eProportion of patients showing\u0026thinsp;\u0026ge;\u0026thinsp;10% weight loss.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eProportion of patients showing\u0026thinsp;\u0026ge;\u0026thinsp;5% weight loss.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eChange from baseline in physical functions.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eChange from baseline in Quality-of-Life score at end of study.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eProportion of patients with any adverse event.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eProportion of patients with any serious adverse event.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eProportion of patients discontinuing the treatment.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e\n\u003ch3\u003eData Extraction and Risk of Bias Assessment\u003c/h3\u003e\n\u003cp\u003eTwo independent reviewers (MPS, AS) performed data extraction using a standardized data collection form. Extracted information included study characteristics (e.g., publication year, sample size, intervention details), baseline demographics, and reported outcomes. Any disagreements were resolved through discussion or consultation with a third reviewer (RY).\u003c/p\u003e \u003cp\u003eRisk of bias was assessed using both the Cochrane Risk of Bias 1.0 and 2.0 tool [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The following five domains were evaluated:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eRandomization process.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDeviations from intended interventions.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eMissing outcome data.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eMeasurement of outcomes.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSelection of reported results.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eEach domain was classified as \"low risk,\" \"some concerns,\" or \"high risk\" of bias. Disagreements were resolved by consensus.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData Synthesis and Statistical Analysis\u003c/h2\u003e \u003cp\u003eEffect measures included mean differences (MD) with standard deviation (SD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes. The meta-analysis was conducted using both a fixed-effect and random-effects model however, only random effects model data have been presented. Statistical heterogeneity was assessed using the I\u0026sup2; statistic and p value\u0026thinsp;\u0026lt;\u0026thinsp;0.10 was considered statistically significant [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Data synthesis and statistical analyses were performed using RevMan 5.4.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSummary of Findings and GRADE Assessment\u003c/h3\u003e\n\u003cp\u003eThe certainty of evidence for each outcome was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach which considers factors like risk of bias, inconsistency of results, indirectness of evidence, imprecision of effect estimates and publication bias. For each outcome, the evidence was categorized into one of four levels: \"high,\" \"moderate,\" \"low,\" or \"very low.\" A summary of findings table was generated, presenting the pooled effect estimates along with the corresponding GRADE ratings [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eEthical Considerations\u003c/h3\u003e\n\u003cp\u003eAs this study was a systematic review and meta-analysis using previously published data, ethical approval was not required. No individual patient data were used, ensuring compliance with ethical standards in research.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA systematic search initially identified a total of 374 abstracts from various databases. After screening, 241 articles were excluded due to duplication or ineligibility. Subsequently, 133 full-text articles were assessed for eligibility. Among these, two randomized controlled trials (RCTs) met the inclusion criteria for the meta-analysis. The primary reasons for exclusion were review articles (n\u0026thinsp;=\u0026thinsp;56), animal studies (n\u0026thinsp;=\u0026thinsp;59), and conference abstracts (n\u0026thinsp;=\u0026thinsp;16) \u003cb\u003e(Fig.\u0026nbsp;1).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe current meta-analysis included two RCTs published from inception to January 2025, involving a total of 563 patients aged\u0026thinsp;\u0026gt;\u0026thinsp;18 years diagnosed with KOA with obesity clinically and radiologically and prescribed either a GLP-1 receptor agonist or a placebo. The mean age of the participants was 57.6 years most of the participants in included trials were female (72.6%). Among the two studies, one compared semaglutide with placebo, while the other compared liraglutide with placebo and dietary intervention [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. \u003cb\u003e(Table\u0026nbsp;1)\u003c/b\u003e Both liraglutide and semaglutide were administered via the subcutaneous route. Liraglutide treatment started at a dose of 0.6 mg/day, followed by biweekly dose escalation in increments of 0.6 mg/day, reaching a maximum of 3 mg/day. Semaglutide was initiated at a dose of 0.24 mg, with gradual dose escalation to achieve a target dose of 2.4 mg by week 16. According to the RoB tool, both RCTs were assessed to have a low risk of bias [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] \u003cb\u003e(Fig.\u0026nbsp;2).\u003c/b\u003e\u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy Endpoints\u003c/h2\u003e \u003cp\u003eThe included RCTs compared two groups: patients receiving GLP-1 receptor agonists (semaglutide and liraglutide) versus those receiving a placebo. Publication bias was assessed using funnel plots, which appeared symmetrical for all outcomes, suggesting no publication bias. \u003cb\u003e(Supplementary file S3)\u003c/b\u003e Due to the limited number of studies (\u0026lt;\u0026thinsp;3), Egger\u0026rsquo;s test could not be performed. For the mean change in weight from baseline, the forest plot demonstrated significant weight reduction in the GLP-1 receptor agonist group compared to the placebo group. However, there was substantial heterogeneity (I\u0026sup2; = 97%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001). The mean difference (MD) in weight change was \u0026minus;\u0026thinsp;7.56 kg (95% CI: -14.71, -0.41; P\u0026thinsp;=\u0026thinsp;0.04), indicating a statistically significant reduction in weight among patients receiving GLP-1 receptor agonists. Similarly, for the mean change in BMI from baseline, the GLP-1 receptor agonist group exhibited a greater reduction than the placebo group, with an MD of -4.52 (95% CI: -9.02, -0.01; P\u0026thinsp;=\u0026thinsp;0.05). However, significant heterogeneity was noted (I\u0026sup2; = 96%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001).\u003c/p\u003e \u003cp\u003eRegarding the change in WOMAC pain score from baseline, GLP-1 receptor agonists led to a numerically greater reduction compared to placebo (MD = -1.42; 95% CI: -4.30, 1.46), but this difference was not statistically significant (P\u0026thinsp;=\u0026thinsp;0.34). Additionally, significant heterogeneity was observed (I\u0026sup2; = 94%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001). For the proportion of patients achieving\u0026thinsp;\u0026ge;\u0026thinsp;10% body weight loss, a significantly higher percentage of patients in the GLP-1 receptor agonist group experienced this outcome compared to placebo (59.2% vs. 9%; RR\u0026thinsp;=\u0026thinsp;4.46; 95% CI: 1.28, 15.50; P\u0026thinsp;=\u0026thinsp;0.02). High heterogeneity was observed (I\u0026sup2; = 84%, P\u0026thinsp;=\u0026thinsp;0.01). Similarly, for the proportion of patients achieving\u0026thinsp;\u0026ge;\u0026thinsp;5% body weight loss, GLP-1 receptor agonists were associated with a significantly higher proportion of patients achieving this outcome (75.2% vs. 25%; RR\u0026thinsp;=\u0026thinsp;2.70; 95% CI: 1.98, 3.69; P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001). Unlike other endpoints, heterogeneity was low (I\u0026sup2; = 23%, P\u0026thinsp;=\u0026thinsp;0.25). Notably, the estimates for all efficacy endpoints remained consistent even after applying a fixed-effects model, suggesting robustness of the findings.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSafety Endpoints\u003c/h2\u003e \u003cp\u003eFor the proportion of patients experiencing serious adverse events, there was no significant difference between the GLP-1 receptor agonist and placebo groups (9.7% vs. 8%; RR\u0026thinsp;=\u0026thinsp;1.19; 95% CI: 0.68, 2.10; P\u0026thinsp;=\u0026thinsp;0.54). Heterogeneity was low (I\u0026sup2; = 0%, P\u0026thinsp;=\u0026thinsp;0.87). However, for the proportion of patients discontinuing treatment due to adverse events, the GLP-1 receptor agonist group had a significantly higher discontinuation rate compared to the placebo group (8% vs. 3.79%; RR\u0026thinsp;=\u0026thinsp;2.31; 95% CI: 1.07, 5.00; P\u0026thinsp;=\u0026thinsp;0.03). Heterogeneity was low (I\u0026sup2; = 0%, P\u0026thinsp;=\u0026thinsp;0.95). Similar to the efficacy endpoints, the safety estimates remained unchanged after applying a fixed-effects model, reinforcing the stability of the findings. All the forest plots are\u003c/p\u003e \u003cp\u003eattached as \u003cb\u003esupplementary file S4.\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAs per the GRADE approach, the overall certainty of evidence was categorized as \u003cem\u003ehigh\u003c/em\u003e for multiple outcomes i.e., mean change in weight, BMI, proportion of patients with \u0026ge;\u0026thinsp;5% and \u0026ge;\u0026thinsp;10% reduction in weight, and discontinuing the treatment. The certainty of evidence was assessed as \u003cem\u003every low\u003c/em\u003e for change in pain severity and \u003cem\u003elow\u003c/em\u003e for proportion of patients with serious adverse events. The comprehensive assessment details and specific estimates for each outcome measure are presented in \u003cb\u003eTable\u0026nbsp;2.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eCurrent meta-analysis intends to evaluate the role of GLP-1 receptor agonists in KOA. As of now the standard of care for KOA focuses on symptomatic relief with drugs as wells as physiotherapy and there is paucity of disease-modifying agents \u003cem\u003eperse.\u003c/em\u003e Our study includes two randomized trials with 563 patients, with a mean age of ~\u0026thinsp;58 years, with a predominance of female participants, which is similar to the usual demographic distribution of patients of KOA [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The included studies were methodologically sound as they were at low risk of bias as per RoB2 tool [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. So, it can be assumed that the results obtained from the study will contribute to the good quality of evidence.\u003c/p\u003e \u003cp\u003eThe GLP-1 receptor agonists led to the statistically significant weight reduction compared to placebo (see results). The overall certainty of evidence for all these endpoints was very high \u003cb\u003e(Table\u0026nbsp;2).\u003c/b\u003e This was an expected finding as GLP-1 receptor agonists are known for their weight loss property [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Typically, obesity and female sex is an important risk factor. Co-incidentally, more weight loss has been observed in females [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. As there is no meta-analysis of RCTs is published so we don\u0026rsquo;t have comparator with which our findings can be compared. Although reduction in pain severity was noted but the finding is not statistically significant and is equally not reliable as both studies show different results for change in pain severity with an overall wide confidence interval. The slight reduction in pain severity can be attributed to the weight loss property of GLP-1 receptor agonists.\u003c/p\u003e \u003cp\u003eThe proportion of patients discontinuing the GLP-1 receptor agonists due to the adverse effects were significantly more than the placebo. The overall certainty was high and results are reliable \u003cb\u003e(Table\u0026nbsp;2).\u003c/b\u003e The major reason of discontinuation was gastro-intestinal adverse events which is expected from the adverse events profile of GLP-1 receptor agonists [26,27]. The proportion of patients experiencing serious adverse events was higher in the GLP-1 receptor agonist group, although the difference was not statistically significant. The certainty of evidence was low due to the wide confidence interval and the findings are not reliable.\u003c/p\u003e \u003cp\u003eOsteoarthritis is a disease of multifactorial aetiology including age related changes, and inflammation damaging the cartilages and other parts of joint(s) which represents a degenerative condition for which a definite cure is not available as of now. The idea of using GLP-1 receptor agonists comes from its potential to cause significant weight loss, and its pleiotropic effects especially anti-inflammatory effect. GLP-1 receptor agonists have been shown to affect inflammatory mediators, inhibiting catabolic factors and promoting collagen synthesis in different pre-clinical studies [28\u0026ndash;31]. Upon looking into the progressive nature of cartilage and bone degeneration, slowing down/ inhibiting the process may improve the prognosis. Although, GLP-1 receptor agonists seem to be promising therapeutic option in many of degenerative diseases due to its pleiotropic effects, translating its effects into the clinical practice is going to be the daunting task. Present meta-analysis clearly indicates significant weight loss by the GLP-1 receptor agonists which may be beneficial in knee osteoarthritis, however with these clinical studies, the pre-clinical claims cannot be substantiated. A Long-term study with these agents can only provide proof of their disease-modifying potential.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and Limitations\u003c/h2\u003e \u003cp\u003eTo our knowledge, this represents the first systematic review and meta-analysis of randomized clinical trials analysing the role of GLP-1 receptor agonists in OA. The major limitations are inclusion of fewer studies, different GLP-1 receptor agonists and treatment regimens. The overall certainty of evidence was classified high for all efficacy endpoints and one adverse outcome.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis meta-analysis evaluated the potential role of GLP-1 receptor agonists in KOA. The drugs mainly led to significant reduction of weight and some improvement in pain was also observed. The drug discontinuation was mainly due to the gastro-intestinal adverse effects and no serious adverse events were observed. Furthermore, overall certainty of evidence was high for efficacy outcomes. Despite favourable pre-clinical findings, current evidence is far away from clinical practice recommendation. Additional clinical trials may be needed to establish the role of GLP-1 receptor agonists in knee osteoarthritis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval: Not Applicable.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate: Not Applicable.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publication: Not Applicable.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material: Not Applicable.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests: Nothing to disclose.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding: No funding received.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments: Not Applicable.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019 Apr 27;393(10182):1745-1759. doi: 10.1016/S0140-6736(19)30417-9. PMID: 31034380.\u003c/li\u003e\n\u003cli\u003eZhang Y, Jordan JM. Epidemiology of osteoarthritis. Clin Geriatr Med. 2010 Aug;26(3):355-69. doi: 10.1016/j.cger.2010.03.001.\u003c/li\u003e\n\u003cli\u003eMessier SP, Loeser RF, Miller GD, Morgan TM, Rejeski WJ, Sevick MA, Ettinger WH Jr, Pahor M, Williamson JD. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial. Arthritis Rheum. 2004 May;50(5):1501-10. doi: 10.1002/art.20256. \u003c/li\u003e\n\u003cli\u003eChristensen R, Bartels EM, Astrup A, Bliddal H. Effect of weight reduction in obese patients diagnosed with knee osteoarthritis: a systematic review and meta-analysis. 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Prevalence of cardiovascular disease risk factors among US adults with self-reported osteoarthritis: data from the Third National Health and Nutrition Examination Survey. Am J Manag Care. 2002 Oct;8(15 Suppl):S383-91.\u003c/li\u003e\n\u003cli\u003eBannuru RR, Osani MC, Vaysbrot EE, Arden NK, Bennell K, Bierma-Zeinstra SMA, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019 Nov;27(11):1578-1589. doi: 10.1016/j.joca.2019.06.011. \u003c/li\u003e\n\u003cli\u003eBliddal H, Leeds AR, Christensen R. Osteoarthritis, obesity and weight loss: evidence, hypotheses and horizons - a scoping review. Obes Rev. 2014 Jul;15(7):578-86. doi: 10.1111/obr.12173.\u003c/li\u003e\n\u003cli\u003eFelson DT, Zhang Y, Anthony JM, Naimark A, Anderson JJ. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. The Framingham Study. 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System Rev 2015; 4: 1.\u003c/li\u003e\n\u003cli\u003eAssessing risk of bias in a randomized trial. https://training.cochrane.org/handbook/current/chapter-08.\u003c/li\u003e\n\u003cli\u003eSterne JAC, Savović J, Page MJ, et al. Rob 2: A revised tool for assessing the risk of bias in randomized trials. BMJ 2019; 366:l4898.\u003c/li\u003e\n\u003cli\u003eIdentifying and measuring heterogeneity.https://handbook-5-1.cochrane.org/chapter_9/9_5_2_identifying_and_measuring_heterogeneity.htm \u003c/li\u003e\n\u003cli\u003eSch\u0026uuml;nemann HJ, Higgins JPT, Vist GE, et al. Chapter 14: Completing \u0026lsquo;Summary of findings\u0026rsquo; tables and grading the certainty of the evidence. In: Higgins JPT, Thomas J, Chandler J, et al., editors. Cochrane Handbook for Systematic Reviews of Interventions. Version 6.4 (updated August 2023). Cochrane, 2023. www.training.cochrane.org/handbook.\u003c/li\u003e\n\u003cli\u003eBliddal H, Bays H, Czernichow S, Udd\u0026eacute;n Hemmingsson J, Hjelmes\u0026aelig;th J, Hoffmann Morville T, et al. Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis. N Engl J Med. 2024 Oct 31;391(17):1573-1583. doi: 10.1056/NEJMoa2403664.\u003c/li\u003e\n\u003cli\u003eGudbergsen H, Overgaard A, Henriksen M, W\u0026aelig;hrens EE, Bliddal H, Christensen R, et al Liraglutide after diet-induced weight loss for pain and weight control in knee osteoarthritis: a randomized controlled trial. Am J Clin Nutr. 2021 Feb 2;113(2):314-323. doi: 10.1093/ajcn/nqaa328. \u003c/li\u003e\n\u003cli\u003eHonvo G, Reginster JY, Rabenda V, Geerinck A, Mkinsi O, Charles A, et al. Safety of Symptomatic Slow-Acting Drugs for Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis. Drugs Aging. 2019 Apr;36(Suppl 1):65-99. \u003c/li\u003e\n\u003cli\u003eYang Y, He L, Han S, Yang N, Liu Y, Wang X, et al. Sex Differences in the Efficacy of Glucagon-Like Peptide-1 Receptor Agonists for Weight Reduction: A Systematic Review and Meta-Analysis. J Diabetes. 2025 Mar;17(3):e70063. \u003c/li\u003e\n\u003cli\u003eHIGHLIGHTS OF PRESCRIBING INFORMATION (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022341s027lbl.pdf. Accessed 19\u003csup\u003eth\u003c/sup\u003e March 2025.\u003c/li\u003e\n\u003cli\u003eHIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf Accessed 19th March 2025.\u003c/li\u003e\n\u003cli\u003eZhang X, Jiang J, Xu J, Chen J, Gu Y, Wu G. Liraglutide, a glucagon-like peptide-1 receptor agonist, ameliorates inflammation and apoptosis via inhibition of receptor for advanced glycation end products signaling in AGEs induced chondrocytes. BMC Musculoskelet Disord. 2024 Jul 30;25(1):601.\u003c/li\u003e\n\u003cli\u003eMeurot C, Martin C, Sudre L, Breton J, Bougault C, Rattenbach R, et al. Liraglutide, a glucagon-like peptide 1 receptor agonist, exerts analgesic, anti-inflammatory and anti-degradative actions in osteoarthritis. Sci Rep. 2022 Jan 28;12(1):1567.\u003c/li\u003e\n\u003cli\u003eLi H, Chen J, Li B, Fang X. The protective effects of dulaglutide against advanced glycation end products (AGEs)-induced degradation of type Ⅱ collagen and aggrecan in human SW1353 chondrocytes. Chem Biol Interact. 2020 May 1;322:108968. \u003c/li\u003e\n\u003cli\u003eQue Q, Guo X, Zhan L, Chen S, Zhang Z, Ni X, Ye B, Wan S. The GLP-1 agonist, liraglutide, ameliorates inflammation through the activation of the PKA/CREB pathway in a rat model of knee osteoarthritis. J Inflamm (Lond). 2019 Jun 6;16:13.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"All India Institute of Medical Sciences, Raipur, Chhattisgarh, India","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Knee Osteoarthritis, Glucagon-Like Peptide-1 Receptor Agonists, Weight Loss, Pain Management, Semaglutide, Liraglutide","lastPublishedDoi":"10.21203/rs.3.rs-6482330/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6482330/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and Objective:\u003c/strong\u003e Osteoarthritis (OA) represents a leading cause of chronic pain and disability globally. While current management primarily addresses symptom relief, disease-modifying interventions remain limited. Obesity significantly contributes to osteoarthritis progression especially knee osteoarthritis (KOA), with weight reduction yielding symptomatic benefits. GLP-1RAs, originally developed for type 2 diabetes and obesity management, show potential in KOA management through weight-reducing and anti-inflammatory mechanisms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod and Results:\u003c/strong\u003eThis systematic review and meta-analysis evaluated GLP-1RAs' efficacy and safety in KOA, focusing on pain reduction, functional improvement, and weight loss outcomes. Our comprehensive database search identified two randomized controlled trials with 563 participants that met inclusion criteria, both examining semaglutide and liraglutide against placebo. Results demonstrated that GLP-1RA-treated patients experienced significantly greater reductions in body weight (-7.8 kg; 95% CI: -9.2 to -6.4) and Body-mass Index (BMI) (-2.8 kg/m²; 95% CI: -3.3 to -2.3). Gastrointestinal effects constituted the primary adverse events. Both studies demonstrated low risk of bias with no detected publication bias.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003eThese findings suggest GLP-1RAs may represent promising therapeutic agents for KOA by addressing both weight-related and inflammatory pathways underlying disease progression. Larger trials investigating long-term efficacy and safety are warranted.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of GLP-1 Receptor Agonists for the Management of Knee Osteoarthritis: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-23 10:37:24","doi":"10.21203/rs.3.rs-6482330/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"85c50b1d-4616-472b-b028-238ba85cd98f","owner":[],"postedDate":"April 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47499017,"name":"Clinical Pharmacology"}],"tags":[],"updatedAt":"2025-04-23T10:37:24+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-23 10:37:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6482330","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6482330","identity":"rs-6482330","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}