GLP-1 Receptor Agonists and Cardiovascular Events in Adults with Obesity and Autoimmune Disease: A Target Trial Emulation

Importance Obesity and autoimmune diseases (AID) are each associated with elevated risk of cardiovascular and thromboembolic events due to chronic systemic inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated cardiovascular and metabolic benefits in patients with type 2 diabetes and obesity, but their effects in patients with obesity and comorbid AID remain uncertain.

To evaluate the association between GLP-1RA use and the risk of major adverse cardiovascular and thromboembolic events among adults with obesity and AID eligible for anti-obesity medication (AOM) therapy. Design This retrospective cohort study emulated a target trial using 2014-2024 electronic health record data from the OneFlorida+ network, which includes 21 million individuals across Florida, Georgia, and Alabama. Adults with obesity and AID who met AOM eligibility criteria were included. Propensity score matching (1:1) was applied using a time-dependent framework to balance baseline covariates between GLP-1RA users and non-users. Participants AID Adults (≥18 years) who were eligible for AOM treatment. Exposure GLP-1RA use versus non-use. Main Outcomes and Measures The primary outcomes were myocardial infarction, stroke or transient ischemic attack (TIA), pulmonary embolism (PE), venous thromboembolism (VTE), and coronary revascularization. Secondary outcomes included hospitalization, emergency department (ED) visits, and all-cause mortality.

The matched cohort included 13,204 GLP-1RA users and 13,204 non-users (mean age, 54.7 ± 14.5 years; 73.4% female; mean BMI, 37 kg/m²). Compared with non-users, GLP-1RA users had lower incidence rates (per 1000 person-years) of PE (6.4 vs 9.5), VTE (16.6 vs 20.4), and mortality (9.5 vs 16.9). GLP-1RA use was associated with lower hazard of stroke/TIA (HR, 0.87 [95% CI, 0.76-0.99]; P = .039), PE (HR, 0.69 [95% CI, 0.56-0.86]; P = .001), VTE (HR, 0.83 [95% CI, 0.72-0.95]; P = .007), ED visits (HR, 0.79 [95% CI, 0.75-0.83]; P = .000), and mortality (HR, 0.56 [95% CI, 0.47-0.66]; P = .000).

and Relevance Among adults with obesity and AID, GLP-1RA use was associated with reduced thromboembolic events, lower emergency department utilization, and decreased mortality. These findings suggest potential cardiovascular and survival benefits of GLP-1RAs in a high-risk, understudied population. Question Is the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) associated with cardiovascular and thromboembolic outcomes among adults with obesity and autoimmune disease (AID)? Findings In this target trial emulation using 2014-2024 electronic health record data from the OneFlorida+ network, 13,204 GLP-1RA users were compared with 13,204 matched non-users. GLP-1RA use was associated with significantly lower risks of pulmonary embolism, venous thromboembolism, emergency department visits, and all-cause mortality, with marginal associations for stroke or transient ischemic attack. Meaning Among adults with obesity and AID, GLP-1RA therapy may confer thromboembolic and survival benefits without increasing cardiovascular risk. Competing Interest Statement The authors have declared no competing interest. Funding Statement The study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) R01DK133465. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved and exempted of consent by the University of Florida Institutional Review Board. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Funding source: NIH/NIDDK R01DK133465 Conflict of interest: None Data Availability Data set Available through OneFlorida+ Clinical Research Network (email, oneFloridaOperations{at}health.ufl.edu)