Combination GLP-1 Receptor Agonist and SGLT2 Inhibitor Therapy Versus GLP-1 Receptor Agonist Monotherapy on Arrhythmia Outcomes in Non-Diabetic Obese Patients: A Real-World Time-Dependent Analysis

Background:Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have established cardiometabolic benefits and are increasingly used in combination, including in patients without diabetes. Although both drug classes have been studied extensively for metabolic and cardiovascular outcomes, their effects on cardiac arrhythmias, particularly in non-diabetic obese patients, remain poorly defined. Objective:To compare arrhythmia outcomes in non-diabetic obese patients receiving combined GLP-1RA and SGLT2i therapy versus GLP-1RA alone, with particular focus on time-dependent changes in atrial and ventricular arrhythmia risk. Methods:We performed a retrospective real-world cohort study of non-diabetic obese adults treated with either combined GLP-1RA and SGLT2i therapy or GLP-1RA alone. Cohorts were balanced through propensity score matching. The primary outcome was composite arrhythmia. Secondary outcomes included atrial fibrillation/flutter, ventricular tachycardia, and ventricular fibrillation. Outcomes were assessed at 60 months, with additional longitudinal analyses from 6 months through 96 months to better define the timing of benefit and the evolution of arrhythmia risk. Results:At 60 months, combination therapy was associated with 17.5% lower odds of composite arrhythmia compared with GLP-1RA alone, OR 0.825 (0.731-0.932). This benefit emerged by 24 months and persisted through 96 months. The reduction in the primary outcome was driven mainly by lower atrial arrhythmia burden, with atrial fibrillation/flutter occurring 17.9% less often in the combination group at 60 months, OR 0.821 (0.722-0.934); this benefit became apparent by 18 months and remained present through 96 months. In contrast, ventricular tachycardia was more frequent in the combination group during earlier follow-up intervals, including 6, 12, 18, and 24 months, but this difference was not sustained and became similar between groups around 60 months, OR 1.186 (0.943-1.491), and persisted through 96 months. Ventricular fibrillation remained comparable between groups throughout the follow-up period. Conclusions:In non-diabetic obese patients, combined GLP-1RA and SGLT2i therapy was associated with lower long-term odds of composite arrhythmia compared with GLP-1RA alone, largely driven by a reduction in atrial fibrillation/flutter. An increased ventricular tachycardia risk with combination therapy appeared to diminish over time, while ventricular fibrillation remained unchanged. These findings suggest that combination therapy may have a favorable long-term electrophysiologic profile in non-diabetic obesity and highlight the importance of time-dependent analysis when evaluating arrhythmia outcomes with cardiometabolic therapies.