GLP-1 receptor agonists in obesity-related knee osteoarthritis: from weight loss to therapeutic pathway reconstruction

Obesity is a major modifiable contributor to knee osteoarthritis (KOA), but excess adiposity has often been managed as a background risk factor rather than as a therapeutic target. In obesity-related KOA, adiposity may aggravate pain and disability through increased joint loading, low-grade inflammation, metabolic dysfunction, impaired physical activity, and reduced rehabilitation tolerance. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have created a new opportunity to achieve clinically meaningful weight loss in selected patients with obesity-related KOA. However, current evidence should be interpreted cautiously. Human data most strongly support weight-loss-mediated improvements in pain, function, and rehabilitation feasibility, whereas direct cartilage-, synovium-, subchondral bone-, or structure-modifying effects remain unproven. In this narrative review, we summarize the rationale, receptor biology, pharmacological mechanisms, inflammatory signaling hypotheses, clinical evidence, safety concerns, and implementation challenges related to GLP-1RA use in obesity-related KOA. We also position GLP-1RAs within a broader obesity-treatment continuum that includes lifestyle intervention, exercise-based rehabilitation, multidisciplinary weight management, other anti-obesity medications, bariatric surgery, symptom-bridging treatments, and arthroplasty when indicated. Particular attention is given to gastrointestinal intolerance, dehydration, gallbladder and pancreatitis-related concerns, lean-mass loss, perioperative management, treatment discontinuation, affordability, access, and long-term adherence. Overall, GLP-1RAs may become a useful component of integrated obesity-directed KOA care, but they should be regarded as part of a proposed framework rather than as validated disease-modifying therapy.