Glucagon-Like Peptide-1 Receptor Agonists and Risk for Depression in Older Adults With Type 2 Diabetes : A Target Trial Emulation Study

Abstract

Background: Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential antidepressant effects, population studies yield inconsistent results.

Objective: To compare the risk for depression in older adults with type 2 diabetes (T2D) initiating treatment with GLP-1RAs versus sodium-glucose cotransporter-2 inhibitors (SGLT2is) or dipeptidyl peptidase-4 inhibitors (DPP4is).

Design: Target trial emulation study.

Setting: U.S. National Medicare administrative data from January 2014 to December 2020.

Patients: Adults aged 66 years or older with T2D initiating treatment with a GLP-1RA were matched 1:1 on propensity score with those initiating treatment with either an SGLT2i or a DPP4i.

Measurements: The primary end point was incident depression. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) with 95% CI within matched groups.

Results: A total of 14 665 matched pairs of older adults were included in the cohort for GLP-1RAs versus SGLT2is; the rate difference of depression between GLP-1RA users and SGLT2i users was 3.48 (95% CI, -0.81 to 7.78) per 1000 person-years, with an HR of 1.07 (CI, 0.98 to 1.18). In the cohort for GLP-1RAs versus DPP4is (13 711 matched pairs), the rate difference was -5.78 (CI, -10.49 to -1.07) per 1000 person-years, with an HR of 0.90 (CI, 0.82 to 0.98).

Limitation: Unmeasured confounders (such as hemoglobin A_1c levels and body mass index), outcome misclassification, and limited generalizability to all GLP-1RA users (for example, younger populations or those without T2D receiving the drug for obesity treatment).

Conclusion: Among older adults with T2D, the incidence of depression was relatively low. Use of GLP-1RAs was associated with a modestly lower risk for depression compared with use of DPP4is, but not SGLT2is.

Primary funding source: National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

Figure 1.

Study flow diagram. DPP4i = dipeptidyl peptidase-4 inhibitor; GLP-1RA = glucagon-like peptide-1 receptor agonist; PS= propensity score; SGLT2i = sodium–glucose cotransporter-2 inhibitor; T2D = type 2 diabetes. * Before 2016, we accessed a 5% random sample of Medicare; from 2016 onward, we assessed a 15% random sample that included the previous 5% sample.

Figure 2.

Kaplan–Meier plots showing the cumulative incidence of depression in the 1:1 PS-matched cohorts for GLP-1RAs vs. SGLT2is (top) and GLP-1RAs vs. DPP4is (bottom). DPP4i = dipeptidyl peptidase-4 inhibitor; GLP-1RA = glucagon-like peptide-1 receptor agonist; PS= propensity score; SGLT2i = sodium–glucose cotransporter-2 inhibitor.

Figure 3.

Overall and subgroup analyses of the association between GLP-1RAs, compared with SGLT2is (top) or DPP4is (bottom), and risk for depression. DPP4i = dipeptidyl peptidase-4 inhibitor; GLP-1RA = glucagon-like peptide-1 receptor agonist; HR = hazard ratio; IR = incidence rate; SGLT2i = sodium–glucose cotransporter-2 inhibitor.