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Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study

BMJ 2018; 360 doi: (Published 21 March 2018) Cite this as: BMJ 2018;360:k872
  1. Devin Abrahami, graduate student1 2,
  2. Antonios Douros, post-doctoral fellow1 2 3,
  3. Hui Yin, statistician1,
  4. Oriana Hoi Yun Yu, endocrinologist1 4,
  5. Christel Renoux, assistant professor of neurology and neurosurgery1 2 5,
  6. Alain Bitton, gastroenterologist6 7,
  7. Laurent Azoulay, associate professor of epidemiology and oncology1 2 8
  1. 1Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada H3T 1E2
  2. 2Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada
  3. 3Institute of Clinical Pharmacology and Toxicology, Charité – Universitätsmedizin Berlin, Berlin, Germany
  4. 4Division of Endocrinology, Jewish General Hospital, Montreal, QC, Canada
  5. 5Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
  6. 6Division of Gastroenterology, Department of Medicine, McGill University, Montreal, QC, Canada
  7. 7McGill University Health Centre, Montreal, QC, Canada
  8. 8Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada
  1. Correspondence to: L Azoulay laurent.azoulay{at}
  • Accepted 13 February 2018


Objective To assess whether the use of dipeptidyl peptidase-4 inhibitors is associated with the incidence of inflammatory bowel disease in patients with type 2 diabetes.

Design Population based cohort study.

Setting More than 700 general practices contributing data to the United Kingdom Clinical Practice Research Datalink.

Participants A cohort of 141 170 patients, at least 18 years of age, starting antidiabetic drugs between 1 January 2007 and 31 December 2016, with follow-up until 30 June 2017.

Main outcome measures Adjusted hazard ratios for incident inflammatory bowel disease associated with use of dipeptidyl peptidase-4 inhibitors overall, by cumulative duration of use, and by time since initiation, estimated using time dependent Cox proportional hazards models. Use of dipeptidyl peptidase-4 inhibitors was modelled as a time varying variable and compared with use of other antidiabetic drugs, with exposures lagged by six months to account for latency and diagnostic delays.

Results During 552 413 person years of follow-up, 208 incident inflammatory bowel disease events occurred (crude incidence rate of 37.7 (95% confidence interval 32.7 to 43.1) per 100 000 person years). Overall, use of dipeptidyl peptidase-4 inhibitors was associated with an increased risk of inflammatory bowel disease (53.4 v 34.5 per 100 000 person years; hazard ratio 1.75, 95% confidence interval 1.22 to 2.49). Hazard ratios gradually increased with longer durations of use, reaching a peak after three to four years of use (hazard ratio 2.90, 1.31 to 6.41) and decreasing after more than four years of use (1.45, 0.44 to 4.76). A similar pattern was observed with time since starting dipeptidyl peptidase-4 inhibitors. These findings remained consistent in several sensitivity analyses.

Conclusions In this first population based study, the use of dipeptidyl peptidase-4 inhibitors was associated with an increased risk of inflammatory bowel disease. Although these findings need to be replicated, physicians should be aware of this possible association.


  • Contributors: All authors conceived and designed the study. LA acquired the data. DA, AD, HY, and LA did the statistical analyses. All authors analysed and interpreted the data. DA wrote the manuscript, and all authors critically revised it. All authors approved the final version of the manuscript and agree to be accountable for the accuracy of the work. LA supervised the study and is the guarantor.

  • Funding: This study was funded by a foundation scheme grant from the Canadian Institutes of Health Research. The sponsor had no influence on design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. AD is the recipient of a research fellowship from the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG). LA holds a Chercheur-Boursier junior 2 award from the Fonds de Recherche du Québec - Santé and is the recipient of a William Dawson scholar award from McGill University.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: this study was funded by the Canadian Institutes of Health Research; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: The study protocol was approved by the Independent Scientific Advisory Committee of the Clinical Practice Research Datalink (protocol number 17_165R) and by the Research Ethics Board of Jewish General Hospital, Montreal, Quebec, Canada.

  • Data sharing: No additional data available.

  • Transparency: The guarantor (LA) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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