Chen_2026_Ther.Adv.Musculoskelet.Dis_18_1759720x261434279

BACKGROUND: Osteoarthritis (OA) is the most prevalent form of arthritis. Currently, no disease-modifying OA drugs are available. Increasing interest has focused on repurposing antidiabetic medications to prevent OA. Preclinical studies showed that dipeptidyl-peptidase 4 inhibitors (DPP-4is) may protect against cartilage degeneration via anti-inflammatory and anti-senescent mechanisms. OBJECTIVES: To evaluate whether DPP-4i use is associated with a decreased risk of incident OA and joint replacement in patients with type 2 diabetes mellitus (T2DM). DESIGN: A nationwide, population-based, matched new-user, retrospective cohort study. METHODS: Using Taiwan's National Health Insurance Research Database (2008-2018), adult patients with newly diagnosed T2DM prescribed with DPP-4is were matched 1:1 to non-users based on age, sex, index year, and Diabetes Complications and Severity Index score. The primary endpoint was incident OA, while the secondary endpoints were total hip replacement (THR) and total knee replacement (TKR) attributed to OA. Cox proportional hazards models were used to estimate the adjusted hazard ratio (aHR) for comorbidities and concurrent medications. RESULTS: In a sample of 1,282,796 patients with newly diagnosed T2DM, 165,333 pairs were matched for treatment with or without DPP-4is. Among 165,333 matched pairs (mean age: 58.6 years; 56.2% male), DPP-4i use was associated with lower risks of OA (aHR: 0.42; 95% confidence interval (CI): 0.41-0.44), THR (aHR: 0.38; 95% CI: 0.30-0.48), and TKR (aHR: 0.42; 95% CI: 0.37-0.46), with benefits increasing with dosage. Moreover, DPP-4i use was associated with a significantly lower cumulative incidence of OA, THR, and TKR. CONCLUSION: In this first nationwide cohort study, DPP-4is were associated with decreased OA incidence and fewer joint replacement surgeries among patients with T2DM. These findings indicate the joint-protective effects of DPP-4is, highlighting their relevance to drug repurposing and clinical decision-making in patients at high risk of OA.