Background/Purpose: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for type 2 diabetes mellitus (T2DM) and obesity due to their beneficial metabolic effects. However, real-world evidence on whether GLP-1 RAs affect the incidence of immune-mediated inflammatory diseases (IMIDs), neurologic conditions, psychiatric disorders, or other safety outcomes remains limited. This study evaluated the associations of initiating GLP-1 RAs with the incidence of IMIDs and various clinically important outcomes, including gout, osteoarthritis, and neurodegenerative disorders (dementia, Parkinson disease) in adults with T2DM or obesity.

Methods: We conducted a propensity score-matched retrospective cohort study utilizing data from the global TriNetX federated electronic health records network. Two separate analyses were performed: adults with T2DM (n=793,873) and non-diabetic adults with obesity or overweight (N&#3f79,148). Patients initiating GLP-1 RAs (≥3 prescriptions) were matched 1:1 to comparable patients initiating non-GLP-1 medications based on demographics, BMI, comorbidities, and medication history. Outcomes assessed were new-onset IMIDs, gout, osteoarthritis, and neurodegenerative diseases (dementia, Parkinson’s disease). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression. Kaplan-Meier analyses and E-values assessed robustness, and multiple comparison corrections were applied using Bonferroni and False Discovery Rate (FDR).

Results: GLP-1 RA initiation was not associated with increased risk of IMIDs, and musculoskeletal diseases (gout or osteoarthritis) in either cohort. Notably, GLP-1 RA use was associated with significantly lower incidence of all-cause mortality in both T2DM (HR 0.38, 95% CI 0.36-0.40; p< 0.001; E-value=4.70) and obesity cohorts (HR 0.23, 95% CI 0.18-0.30; p< 0.001; E-value=8.16) lower dementia incidence in both T2DM (HR 0.51, 95% CI 0.47–0.55; p< 0.001; E-value=3.33) and obesity cohorts (HR 0.21, 95% CI 0.12–0.36; p< 0.001; E-value=9.99). Parkinson’s disease incidence was significantly lower only in the obesity cohort (HR 0.27, 95% CI 0.12–0.58; p< 0.001), but not after adjustment in the T2DM cohort. Use of GLP1 RA was also associated with a lower risk of cardiovascular diseases (heart failure, cerebral infarction and pulmonary embolism/deep vein thrombosis in both T2DM and obesity cohorts.

Conclusion: In patients with T2DM or with overweight/obesity, real-world initiation of GLP-1 receptor agonist therapy was not associated with an increased risk of autoimmune or inflammatory diseases. We found no signal that GLP-1 RAs precipitate IMIDs such as RA, lupus, or IBD. Conversely, GLP-1 RA use was linked to significant reductions in all-cause mortality, heart failure, stroke, chronic kidney disease, severe infections, and even dementia, without new safety concerns.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/risk-of-immune-mediated-inflammatory-diseases-and-other-safety-outcomes-in-patients-with-t2dm-and-obesity-initiating-glp-1-ra-a-propensity-score-matched-multi-center-study-using-the-trinetx-global-ne/