Use of Dipeptidyl Peptidase-4 Inhibitors and New-onset Rheumatoid Arthritis in Patients with Type 2 Diabetes

Antonios Douros, Devin Abrahami, Hui Yin, Oriana Hoi Yun Yu, Christel Renoux, Marie Hudson, Laurent Azoulay

Case reports have suggested a link between dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic drugs used as second- to third-line treatments, and incidence of rheumatoid arthritis. Since the DPP-4 enzyme is involved in several immunologic processes and possibly in the pathophysiology of rheumatoid arthritis, further research is warranted. This population-based study aimed to determine whether use of DPP-4 inhibitors is associated with incidence of rheumatoid arthritis. Using the United Kingdom Clinical Practice Research Datalink, we conducted a cohort study among 144,603 patients with type 2 diabetes initiating antidiabetic drugs between 2007 and 2016. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for incident rheumatoid arthritis using time-dependent Cox proportional hazards models, comparing use of DPP-4 inhibitors with use of other antidiabetic drugs. We imposed a 6-month exposure lag period for latency and diagnostic delays. Secondary analyses included assessment of the duration response relation and comparison with other second-line antidiabetic drugs, among others. During 567,169 person-years of follow-up, 464 patients were newly diagnosed with rheumatoid arthritis (crude incidence rate: 82 per 100,000/year). Compared with use of other antidiabetic drugs, use of DPP-4 inhibitors was not associated with an increased risk of rheumatoid arthritis (82 versus 79 per 100,000/year; HR: 1.0, 95% CI: 0.8, 1.3), with no evidence of duration-response relation. The results did not change after using second-line antidiabetic drugs as the comparator group. In this large population-based study, use of DPP-4 inhibitors was not associated with an increased risk of incident rheumatoid arthritis.