Date of Award
2026
Degree Type
Thesis
Degree Name
Master of Science in Pharmaceutical Sciences
Department
Pharmacy Practice and Clinical Research
First Advisor
Xuerong Wen
Abstract
Background: The widespread use of newer pharmacologic therapies for chronic conditions has raised concerns regarding potential psychiatric and cognitive safety outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have rapidly increased in use in the United States, yet their association with psychiatric disorders remains uncertain. Similarly, mineralocorticoid receptor agonists (MRAs), commonly used in hypertension and heart failure, have unclear effects on cognitive outcomes.
Objective: To evaluate the associations of GLP-1 RAs with psychiatric outcomes among patients with type 2 diabetes mellitus and MRAs with cognitive impairment in real-world clinical practice compared with alternative standard therapies.
Methods: Two target trial emulations were conducted using a U.S. administrative claims database. In the first study, GLP-1 RA initiators were compared with dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), with a composite psychiatric outcome including major depressive disorder, anxiety disorder, and suicide attempt or ideation. In the second study, MRA initiators were compared with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), with a composite outcome of cognitive impairment, including dementia, Alzheimer’s disease, vascular dementia, and mild cognitive impairment. Propensity score fine stratification was used to balance baseline covariates. Cox proportional hazards models with robust sandwich variance estimators were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Sensitivity and subgroup analyses were performed to assess robustness.
Results: In the GLP-1 RA study, 8,143 patients were included (3,638 GLP-1 RA, 2,115 DPP-4i, 2,390 SGLT2i). GLP-1 RA initiation was associated with a higher risk of any psychiatric event compared with DPP-4i or SGLT2i (HR, 1.48; 95% CI, 1.27-1.73), including major depressive disorder (HR, 1.55; 95% CI, 1.26-1.90) and anxiety disorder (HR, 1.58; 95% CI, 1.32-1.89). In agent-specific analyses, dulaglutide and liraglutide were associated with increased risks of depression and anxiety, exenatide with depression and suicide-related outcomes, and semaglutide with anxiety. In the MRA study, 2,851 MRA initiators were compared with 47,125 ACEI initiators, and 2,866 were compared with 12,122 ARB initiators. MRA use was not associated with a statistically significant difference in risk of cognitive impairment compared with ACEI (HR, 1.27; 95% CI, 0.93-1.72) or ARB (HR, 1.03; 95% CI, 0.70-1.50). Subgroup analyses showed consistent findings across sex, hypertension status, and heart failure status without evidence of heterogeneity. Conclusion: In two target trial emulations using U.S. claims data, GLP-1 RA initiation was associated with increased hazards of psychiatric outcomes, whereas MRA use was not associated with a statistically significant difference in risk of cognitive impairment compared with ACEI or ARB. These findings highlight potential psychiatric safety signals for GLP-1 RAs and a neutral cognitive safety profile for MRAs, although residual confounding cannot be excluded. Further studies are warranted to clarify causality and identify high-risk subgroups.
Recommended Citation
Yusuf, Hafizan, "TARGET TRIAL EMULATION FOR COMPARATIVE SAFETY OF GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONIST USE IN PATIENTS WITH TYPE 2 DIABETES MELLITUS AND MINERALOCORTICOID RECEPTOR ANTAGONIST USE IN REAL-WORLD CLINICAL PRACTICE" (2026). Open Access Master's Theses. Paper 2699.
https://digitalcommons.uri.edu/theses/2699