If the evidence is there, why are GLP-1 receptor agonists not on-label for hip and knee osteoarthritis in overweight patients?

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have rapidly emerged as highly effective pharmacological tools for weight management, with additional cardiometabolic benefits extending beyond obesity and diabetes. Despite compelling evidence, their potential role in osteoarthritis (OA) remains unrecognized in current regulatory frameworks. Hip and knee OA, leading causes of disability and healthcare burden worldwide, are strongly influenced by both biomechanical overload and systemic metabolic-inflammatory pathways. Increasing data support the dual capacity of GLP-1 RAs to achieve clinically meaningful weight reduction and to exert direct anti-inflammatory and chondroprotective effects within the joint. The STEP 9 trial and complementary real-world evidence demonstrate substantial improvements in OA symptoms, paralleled by reductions in surgical risk, while ongoing trials such as STOP-KNEE OA will further clarify their structural impact. Importantly, patients with a body mass index (BMI) of 27–29.9 kg/m²—currently excluded from GLP-1 RA eligibility unless additional comorbidities are present—may particularly benefit, as weight loss beyond 7–10% appears necessary to meaningfully alter OA trajectories. Recognizing symptomatic hip and knee OA as weight-related comorbidities would align regulatory labels with emerging science, expand therapeutic access, and foster integrated management of musculoskeletal and metabolic diseases. This Viewpoint argues that failure to acknowledge OA as an on-label indication for GLP-1 RAs represents a missed opportunity for patients, clinicians, and health systems.

Despite growing clinical interest and a rapidly accumulating evidence, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) remain absent from the therapy options for hip and knee osteoarthritis (OA).¹ These agents—semaglutide, liraglutide and tirzepatide—are authorised in Europe and the USA for weight reduction in people with a body mass index (BMI) of ≥30 kg/m² or ≥27 kg/m² when accompanied by weight-related comorbidities, including type 2 diabetes, hypertension, dyslipidaemia and sleep apnoea.2,4 However, symptomatic knee and hip OA—conditions that cause significant disability, opioid use and healthcare consumption—are excluded from qualifying indications, despite robust scientific and clinical rationale.⁵

This omission has concrete consequences. Patients with a BMI <30 but ≥27 kg/m² are denied access to highly effective treatments that could change the trajectory of OA.^{1 5 6} However, in our view, the available evidence supports the formal recognition of OA as a weight-related comorbidity justifying access to GLP-1 RAs, particularly in overweight individuals with a BMI between 27 kg/m² and 29.9 kg/m².

Although excessive mechanical stress has historically been acknowledged as a factor in OA, emerging research reframes OA as a metabolically modifiable condition. In addition to biomechanical stress, persistent low-grade inflammation, adipokine dysregulation and lipotoxicity resulting from impaired adipose tissue contribute to cartilage degradation and synovitis.^{1 7 8} The heightened expression of intricate inflammatory biomarkers, such as neutrophil gelatinase-associated lipocalin, further substantiates this reclassification.⁹ GLP-1 RAs, through both weight-dependent and weight-independent pathways, are distinctly positioned to address this pathophysiology.

Mendelian randomisation studies and twin analyses indicate that the association between obesity, OA and cardiovascular disease (CVD) may arise from a common genetic and inflammatory predisposition, regardless of BMI or lifestyle factors.^{10 11} A comprehensive twin study conducted by Magnusson et al suggested that genetic overlap may explain up to 100% of the phenotypic correlation between OA and CVD.¹¹ OA and CVD may therefore be parallel manifestations of a broader metabolic-inflammatory disease framework.

Clinical guidelines consistently advocate for weight reduction as a fundamental aspect of OA therapy. The OA Research Society International (OARSI) and the American College of Rheumatology (ACR) recommend weight loss in all overweight or obese patients suffering from knee and hip OA.^{12 13} Nevertheless, the OARSI and ACR guidelines do not mention GLP-1 RAs as therapeutic choices. This reflects the timing of their development, as a significant portion of the supportive clinical and mechanistic evidence for the use of GLP-1 RAs in OA has emerged after the publication of the latest OARSI and ACR guidelines.^{12 13}

A 2025 network meta-analysis established a therapeutic threshold around 7%–10% weight loss as necessary for meaningful symptom improvement in knee OA.⁶ Prospective results corroborate this threshold, indicating substantial reductions in the risk of undergoing total knee replacement only with weight loss exceeding 7.5% in overweight or obese adults.¹⁴ Similarly, real-world evidence in hip OA demonstrates a dose-dependent improvement in pain, function and quality of life, with the most significant benefits observed in individuals who lose more than 7.5% of their total weight.¹⁵ Collectively, these findings suggest that the modest 5% target commonly advised by obesity recommendations may be insufficient to maximise musculoskeletal outcomes in OA.^{16 17} While lifestyle strategies based on psychological, dietary and exercise programmes remain the gold standard, real-world implementation is limited by adherence and long-term sustainability.⁶ For individuals with longstanding obesity, lifestyle modification alone is frequently insufficient to produce or maintain the degree of weight loss needed to alleviate OA symptoms.¹⁶ Against this backdrop of limited efficacy, pharmacologic interventions may emerge to complement lifestyle strategies to help patients achieve and sustain the degree of weight loss required.

The strongest evidence for GLP-1 RAs in OA comes from the STEP 9 trial, conducted across 11 countries, which enrolled 407 patients with obesity and moderate-to-severe knee OA.⁵ Participants were randomised 2:1 to receive semaglutide 2.4 mg once weekly (n=271; mean baseline BMI 40.5 kg/m²) or placebo (n=136; mean baseline BMI 40.0 kg/m²), alongside standardised lifestyle counselling. By week 68, patients in the treatment arm achieved an average 13.7% weight loss, compared with 3.2% in the control group. The Western Ontario and McMaster Universities Osteoarthritis Index pain scores improved by 41.7 points (on a 0–100 scale) in the semaglutide group and by 27.5 points in the placebo group, yielding a difference of 14.1 points (p<0.001). Significant between-group differences were also observed in function scores.⁵ Such improvements are comparable to or exceed those reported with widely accepted OA therapies, including non-steroidal anti-inflammatory drugs (NSAIDs), structured physical therapy programmes and intra-articular injections.18,21 For instance, a network meta-analysis published in 2017 showed that two of the most effective NSAIDs—etoricoxib 60 mg/day and diclofenac 150 mg/day—produced a standardised mean difference in pain of –0.58 and –0.57 compared with placebo, respectively, corresponding to improvements of approximately 14 mm on a 100 mm Visual Analogue Scale.¹⁸ In the STEP 9 trial, semaglutide resulted in a comparable clinical benefit.⁵

This evidence aligns with observational findings from the Shanghai Osteoarthritis Cohort, including 1807 patients with knee OA and type 2 diabetes.²² The 233 users of GLP-1 RAs (liraglutide and semaglutide) experienced a larger weight loss compared with the 1574 non-users and showed a significantly lower incidence of knee surgeries. Additionally, in a subcohort of patients with serial MRI scans, the cartilage loss rate in the medial femorotibial joint was significantly reduced in those treated with GLP-1 RAs after adjusting for baseline characteristics.²²

Importantly, this beneficial impact might not be exclusive to liraglutide and semaglutide. An ongoing randomised controlled trial is currently investigating tirzepatide, which combines GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonism, in knee OA, evaluating not only symptoms but also structural outcomes by MRI (STOP-KNEE OA trial; ClinicalTrials.gov ID: NCT06191848). Real-world data have already shown a more significant reduction in OA incidence with tirzepatide compared with other GLP-1 RAs, consistent with its superior efficacy for weight loss observed in comparative trials.^{16 23}

While the STEP 9 and STOP-KNEE OA trials focus on patients with obesity (BMI ≥30 kg/m²), the efficacy of GLP-1 RAs in OA patients with overweight (BMI 27–29.9 kg/m²) has not been systematically examined.⁵ However, extensive weight management literature offers substantial evidence supporting the effectiveness of GLP-1 RAs for individuals in this BMI category. Beyond OA-specific trials, pooled analyses of the SCALE trials demonstrated that liraglutide resulted in clinically significant and sustained weight loss in overweight individuals with at least one weight-related comorbidity, accompanied by improvements in blood pressure, glycaemic control and lipid profiles.^{24 25} In the STEP 1 and STEP 3 trials, semaglutide resulted in over 10% body weight reduction in overweight or obese individuals without diabetes.^{26 27} The SELECT trial, which enrolled 17 604 adults with a BMI ≥27 kg/m² and established CVD but no previous diagnosis of diabetes, demonstrated that semaglutide reduced the risk of a composite of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke by 20%.²⁸ These findings highlight the extensive therapeutic advantages of GLP-1 RAs in groups at metabolic risk—advantages that likely extend to patients with symptomatic OA yet remain inaccessible to many due to regulatory restrictions. Although there are currently no OA-specific randomised trials involving the overweight OA population (BMI 27–29.9 kg/m²), there is no data indicating that GLP-1 RAs would exhibit a distinct safety profile in these patients compared with other overweight populations that have been thoroughly investigated.

Adding further support to the redefinition of OA as a metabolically driven disease, a pivotal study by Yang et al published in Science described a gut–brain–joint axis in which intestinal farnesoid X receptor signalling promotes the release of GLP-1, mitigating cartilage loss in murine OA models.²⁹ This experimental pathway links bile acid metabolism to joint homeostasis and supports the concept of OA as a systemically modifiable disease, not merely a consequence of mechanical overload. Importantly, this hormonal circuit is already pharmacologically actionable in humans via GLP-1 RAs, whose mechanisms seem to coincide with the anti-inflammatory and chondroprotective benefits shown in the preclinical model.

From a mechanistic point of view, preclinical, in vitro and in vivo studies demonstrate that liraglutide exerts anti-inflammatory and chondroprotective effects in OA. This agent suppresses the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and downstream cytokines, such as IL-1β, IL-6 and TNF-α; attenuates oxidative stress and downregulates cartilage-degrading enzymes, such as matrix metalloproteinase-1 (MMP-1), MMP-3, MMP-13 and A disintegrin and metalloproteinase with thrombospondin motifs-4 and -5 (ADAMTS-4/5), while promoting anabolic repair via enhanced type II collagen and aggrecan synthesis.^{1 7 22 30 31} The effects are partially mediated by AMP-activated protein kinase (AMPK) activation, which antagonises proinflammatory and catabolic signals.³² In human chondrocytes and murine models of OA, these pathways result in structural benefits, such as decreased cartilage degradation, reduced synovitis, improved OARSI histological scores and amelioration of pain-related outcomes.^{7 30 31} The immunomodulatory effects in the synovium, including M2 macrophage polarisation, prevention of leucocyte infiltration and decreased release of inflammatory mediators, further amplify these results.³⁰ Although these studies mainly involve liraglutide, the shared GLP-1 receptor-mediated pathways imply that similar effects might apply to the other GLP-1 RAs. Therefore, GLP-1 RAs may also act directly on cartilage degradation pathways, providing a glimpse of a possible disease-modifying role.^{7 30} Human evidence is limited but suggests positive biomarker modulation, while ongoing MRI-based trials (eg, STOP-KNEE OA) will elucidate potential structural consequences.^{1 22} These mechanisms support a twofold benefit of GLP-1 RAs in OA: metabolic balance and weight reduction, alongside local anti-inflammatory and chondroprotective benefits. Collectively, these studies contest the belief that OA is beyond pharmaceutical intervention and imply that GLP-1 RAs may provide more than symptomatic relief.

The advantages of significant weight reduction in mild to moderate OA are well documented; nevertheless, there is also a compelling rationale for rigorous weight management in patients with severe OA who are awaiting joint replacement surgery. A 2024 systematic review of randomised controlled trials assessing preoperative weight loss therapies prior to total hip and knee arthroplasty indicated significant reductions in postoperative complication rates associated with average weight losses of approximately 10.2 kg or 3.5 kg/m² in BMI.³³ While these studies predominantly used nutritional or surgical methods, their results highlight the extensive therapeutic significance of attaining substantial preoperative weight loss. GLP-1 RAs demonstrate significant efficacy in achieving and sustaining comparable or superior weight loss, suggesting their potential utility not only in the initial phases of OA but also as preoperative adjunctive therapy for patients with advanced disease, which may improve surgical outcomes and mitigate complication risks across the full spectrum of OA severity.

Finally, there is a clear regulatory rationale for the inclusion of OA as a formal indication for the use of GLP-1 RAs in patients who are overweight with a BMI between 27 kg/m² and 29.9 kg/m². Current European Medicines Agency and Food and Drug Administration labels for GLP-1 RAs list comorbidities with arguably less profound impact on quality of life and healthcare burden compared with symptomatic knee and hip OA. Excluding OA from this list appears increasingly difficult to justify on clinical or epidemiological grounds.

Although data suggest that a significant proportion of patients with symptomatic knee or hip OA may exhibit at least one weight-related comorbidity, qualifying them for GLP-1 RAs therapy, the literature does not provide accurate estimates of the number of individuals within the BMI range of 27–29.9 kg/m² who do not have any of the comorbidities specified in prescribing labels.34,36 The lack of these data complicates the attempt to assess the number of OA patients potentially excluded under existing regulatory frameworks. Despite this gap, we believe the inclusion of OA is clinically and mechanistically justified. Rather than viewing OA merely as a passive consequence of obesity, it should be reframed as an active, treatable metabolic disease. This paradigm shift acknowledges OA as the product of systemic metabolic dysregulation responsive to GLP-1 therapies, not just through weight loss but via direct modulation of inflammatory and metabolic pathways central to OA pathology. Recognising OA as a metabolic condition would enable earlier, more comprehensive intervention, potentially slowing disease progression and enhancing quality of life far beyond the scope of traditional joint-focused therapies.

Incorporating symptomatic OA into the list of weight-related comorbidities that qualify overweight individuals within the BMI range of 27–29.9 kg/m² for GLP-1 RA therapy would align labels with current evidence, integrate musculoskeletal and cardiometabolic care and improve cost-effectiveness. It would also shield prescribers in high-litigation contexts. In Italy, where we write, approximately 34 000 malpractice claims are filed every year, one of the highest per capita rates in Europe, fostering a climate of defensive medicine that deters doctors from using GLP-1 RAs off-label despite evident benefits.³⁷ Without label support, clinicians may hesitate to prescribe GLP-1 RAs, hence perpetuating therapeutic inertia.

It is therefore time for regulatory authorities, guideline developers and payers to explicitly include symptomatic hip and knee OA among the weight-related comorbidities that qualify individuals with a BMI between 27 kg/m² and 29.9 kg/m² for GLP-1 RA therapy. Doing so would align clinical practice with contemporary science, increase access to effective therapies and promote an integrated approach for managing obesity-related disorders.