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Examining the risk of depression or self-harm associated with incretin-based therapies used to manage hyperglycaemia in patients with type 2 diabetes: a cohort study using the UK Clinical Practice Research Datalink
  1. John-Michael Gamble1,2,
  2. Eugene Chibrikov1,2,3,
  3. William K Midodzi3,
  4. Laurie K Twells2,3,
  5. Sumit R Majumdar4
  1. 1 School of Pharmacy, Faculty of Science, University of Waterloo, Waterloo, Ontario, Canada
  2. 2 School of Pharmacy, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
  3. 3 Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
  4. 4 Division of General Internal Medicine, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
  1. Correspondence to Dr John-Michael Gamble; jm.gamble{at}


Objectives To compare population-based incidence rates of new-onset depression or self-harm in patients initiating incretin-based therapies with that of sulfonylureas (SU) and other glucose-lowering agents.

Design Population-based cohort study.

Setting Patients attending primary care practices registered with the UK-based Clinical Practice Research Datalink (CPRD).

Participants Using the UK-based CPRD, we identified two incretin-based therapies cohorts: (1) dipeptidyl peptidase-4 inhibitor (DPP-4i)-cohort, consisting of new users of DPP-4i and SU and (2) glucagon-like peptide-1 receptor agonists (GLP-1RA)-cohort, consisting of new users of GLP-1RA and SU, between January 2007 and January 2016. Patients with a prior history of depression, self-harm and other serious psychiatric conditions were excluded.

Main outcome measures The primary study outcome comprised a composite of new-onset depression or self-harm. Unadjusted and adjusted Cox proportional hazards regression was used to quantify the association between incretin-based therapies and depression or self-harm. Deciles of High-Dimensional Propensity Scores and concurrent number of glucose-lowering agents were used to adjust for potential confounding.

Results We identified new users of 6206 DPP-4i and 22 128 SU in the DPP-4i-cohort, and 501 GLP-1RA and 16 409 SU new users in the GLP-1RA-cohort. The incidence of depression or self-harm was 8.2 vs 11.7 events/1000 person-years in the DPP-4i-cohort and 18.2 vs 13.6 events/1000 person-years in the GLP-1RA-cohort for incretin-based therapies versus SU, respectively. Incretin-based therapies were not associated with an increased or decreased incidence of depression or self-harm compared with SU (DPP-4i-cohort: unadjusted HR 0.70, 95% CI 0.51 to 0.96; adjusted HR 0.80, 95% CI 0.57 to 1.13; GLP-1RA-cohort: unadjusted HR 1.36, 95% CI 0.72 to 2.58; adjusted HR 1.25, 95% CI 0.63 to 2.50). Consistent results were observed for other glucose-lowering comparators including insulin and thiazolidinediones.

Conclusions Our findings suggest that the two incretin-based therapies are not associated with an increased or decreased risk of depression or self-harm.

  • cohort study
  • type 2 diabetes
  • dipeptidyl-peptidase 4 inhibitors
  • glucagon-like receptor 1 agonists
  • depression
  • suicide
  • self-harm

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  • Contributors J-MG, EC, WKM, LKT and SRM were involved in the concept and design of the study. J-MG was responsible for drafting the first version of the manuscript. All authors contributed to the interpretation of data. J-MG, EC, WKM and LKT provided revisions to the manuscript. J-MG will act as guarantor for the study.

  • Funding This work was supported by an operating grant from the Canadian Institute for Health Research (FRN173599-287647).

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval Our study protocol was approved by the Independent Scientific Advisory Committee (ISAC 15_016RARA, August 2017) and received approval from the Health Research Ethics Board at Memorial University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional data are available.

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