Antecedent glucagon-like peptide-1 receptor agonist use and risk of sepsis-induced cardiomyopathy in type 2 diabetes: a United States real-world active-comparator cohort study

Background Sepsis-induced cardiomyopathy (SICM) is an important cardiovascular complication of infection and sepsis, particularly in patients with type 2 diabetes mellitus (T2DM). Whether antecedent glucagon-like peptide-1 receptor agonist (GLP-1 RA) use is associated with lower SICM risk remains unclear. Methods We conducted a retrospective active-comparator cohort study using the TriNetX United States federated electronic health record network from 1 January 2010, to 30 November 2025. Adults with T2DM and documented infection were classified according to antecedent GLP-1 RA or dipeptidyl peptidase-4 inhibitor (DPP-4i) exposure before the index infection date and matched 1:1 by propensity score. The primary outcome was 1-year EHR-ascertained SICM or SICM-related cardiac dysfunction, defined using diagnostic codes for acute pulmonary edema, heart failure, cardiogenic shock, or cardiomyopathy, or objective cardiac dysfunction. Results Among 189,156 eligible patients, propensity-score matching yielded 62,267 patients in each group. Over 1 year, EHR-ascertained SICM or SICM-related cardiac dysfunction occurred in 2,503 patients (4.0%) in the GLP-1 RA group and 3,059 patients (4.9%) in the DPP-4i group (HR 0.82, 95% CI 0.78–0.87; P < 0.001; E-value 1.7). GLP-1 RA use was also associated with lower risks of surrogate cardiac dysfunction (HR 0.70, 95% CI 0.64–0.76), systolic SICM (HR 0.85, 95% CI 0.77–0.93), diastolic SICM (HR 0.88, 95% CI 0.81–0.95), hyperdynamic SICM (HR 0.82, 95% CI 0.71–0.95), new-onset heart failure (HR 0.85, 95% CI 0.80–0.89), and all-cause mortality (HR 0.64, 95% CI 0.60–0.68), but not right ventricular dysfunction SICM. Negative control outcomes showed null associations, and landmark analyses were consistent. Conclusion In this United States real-world active-comparator cohort study, antecedent GLP-1 RA exposure was associated with a lower 1-year risk of EHR-ascertained SICM or SICM-related cardiac dysfunction compared with antecedent DPP-4i exposure. These findings were consistent across sensitivity analyses and support further prospective investigation into the relationship between antecedent GLP-1 RA exposure and cardiovascular vulnerability after infection.