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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

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Gamble, John-Michael, Chibrikov, Eugene, Midodzi, William K, Twells, Laurie K, Majumdar, Sumit R·2018·BMJ Open
DOI 10.1136/bmjopen-2018-023830PMC PMC6194463
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Abstract

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.

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  • DPP-4 inhibitors are not associated with the outcome and are used at a similar disease stage to GLP-1 receptor agonists.

    “We selected DPP-4 inhibitors as the comparator because they are not associated with the outcome and are used at a similar disease stage to GLP-1 receptor agonists1 6 8 27; furthermore, DPP-4 inhibitors and GLP-1 receptor agonists entered the UK market in the same year.”

    From Glucagon-like peptide-1 receptor agonists and risk of suicidality among patients with type 2 diabetes: active comparator, new user cohort study (2025) · cites this paper as [8]

    The Results (DPP-4 inhibitor cohort; page unavailable) report no significant adjusted association between DPP-4 inhibitor use and depression or self-harm. The paper studies DPP-4 inhibitors and GLP-1 receptor agonists in separate cohorts, but does not establish that they are used at a similar disease stage. (LLM, conf=0.84)

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  • Several observational studies have generated varied findings on the effect of GLP-1 receptor agonists on the risk of suicidal ideation, self-harm, and suicide, which may be a result of methodological limitations in these studies.

    “whereas several observational studies have generated varied findings on of the effect of GLP-1 receptor agonists on the risk of suicidal ideation, self-harm, and suicide, which may be a result of methodological limitations in these studies.8 9 10 11 12 13”

    From Glucagon-like peptide-1 receptor agonists and risk of suicidality among patients with type 2 diabetes: active comparator, new user cohort study (2025) · cites this paper as [8]

    The Methods define a composite outcome that includes self-harm, suicide and suicidal ideation, and the Discussion identifies limitations of this observational cohort, including confounding, limited follow-up and few self-harm events. The GLP-1 receptor agonist results report no statistically significant association with the composite outcome. This paper does not establish that several observational studies produced varied findings or that methodological limitations explain differences among them. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
Gamble, J.-M., Chibrikov, E., Midodzi, W. K., Twells, L. K., & Majumdar, S. R.
Affiliations
  • Memorial University of Newfoundland (CA)
  • University of Alberta (CA)
Corresponding author
Gamble, John-Michael
ORCID
Venue
BMJ Open
Publisher
BMJ
Published
2018-10
Volume
8
Issue
10
Pages
e023830
ISSN
2044-6055 (ISSN-L)
DOI
10.1136/bmjopen-2018-023830
PMC
PMC6194463
OpenAlex
W2896549191
Cited by
52
References
7
Citations by year
2026: 10 · 2025: 18 · 2024: 9 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 3
FWCI
1.39
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • BMJ Open (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
Canadian Institutes of Health Research
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Education
Keywords
depression, self-harm, incretin-based therapy, type 2 diabetes, DPP-4 inhibitors, GLP-1 receptor agonists, sulfonylureas, hyperglycemia, psychiatric adverse events, drug safety, glucose-lowering agents, propensity score adjustment, primary care patients, incidence rates, risk factors for depression, antidepressant use, antipsychotic use
MeSH terms
Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Depression, Diabetes Mellitus, Type 2, Female, United Kingdom, Humans, Hypoglycemic Agents, Male, Middle Aged, Primary Health Care, Cohort Studies, Incidence, Self-Injurious Behavior, Dipeptidyl-Peptidase IV Inhibitors

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