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

Douros, Antoniosa,b,c; Abrahami, Devina,b; Yin, Huia; Yu, Oriana Hoi Yuna,d; Renoux, Christela,b,e; Hudson, Mariea,f,g; Azoulay, Laurenta,b,h

doi: 10.1097/EDE.0000000000000891

Background: 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. Because 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.

Methods: 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.

Results: 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 vs. 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.

Conclusions: In this large population-based study, use of DPP-4 inhibitors was not associated with an increased risk of incident rheumatoid arthritis.

From the aCentre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada

bDepartment of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada

cInstitute of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

dDivision of Endocrinology, Jewish General Hospital, Montreal, Canada

eDepartment of Neurology and Neurosurgery, McGill University, Montreal, Canada

fDivision of Rheumatology, Jewish General Hospital, Montreal, Canada

gDepartment of Medicine, McGill University, Montréal, Canada

hGerald Bronfman Department of Oncology, McGill University, Montreal, Canada.

Submitted December 12, 2017; accepted July 10, 2018.

Availability of data and code: No additional data are available because it is not permitted according to agreements with the data custodians.

This study was funded by a Foundation Scheme grant from the Canadian Institutes of Health Research. The sponsors were not directly involved in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.

The authors report no conflicts of interest.

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Correspondence: Laurent Azoulay, Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Cote Sainte-Catherine Road, H425.1, Montreal, Quebec H3T 1E2, Canada. E-mail:

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