MDP1524 - Glucagon-Like Peptide-1 Receptor Agonists versus Metformin for Glycemic Control and Cardiovascular Risk Reduction in Adults with Prediabetes and Obesity

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Author Block:  Vinicius de Sousa Barzon Serra, Mayo Clinic, Scottsdale, AZ; Ramzi Ibrahim, Mayo Clinic, Phoenix, AZ; Julia Zanco, Mayo Clinic, Scottsdale, AZ; Allah Dad, Abdelrahman Hafez, Hoang Nhat Pham, Juan Farina, Mayo Clinic, Phoenix, AZ; Steven Lester, Mayo Clinic Scottsdale, Scottsdale, AZ; Said Alsidawi, Hari P Chaliki, Chadi Ayoub, Luis R. P. Scott, Reza Arsanjani, Mayo Clinic, Scottsdale, AZ
Disclosure Block:  V. de Sousa Barzon Serra: None.

Background: Prediabetes affects approximately 40% of US adults and substantially increases risk of progression to diabetes mellitus and cardiovascular disease, particularly among individuals with obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) demonstrate metabolic benefits beyond those of metformin, yet direct comparative effectiveness data for glycemic and cardiovascular outcomes in prediabetes remain limited. Hypothesis: We hypothesized that GLP-1RA therapy would be associated with higher rates of normoglycemia reversion and lower rates of diabetes progression and major cardiovascular events compared with metformin in a propensity score-matched cohort of adults with prediabetes and obesity. Methods: We conducted a retrospective cohort study using the TriNetX global multi-center electronic health record network spanning 104 institutions (January 1, 2010-December 31, 2023). Adults aged ≥18 years with prediabetes and obesity initiating GLP-1RA therapy (semaglutide, tirzepatide, liraglutide, or dulaglutide) or metformin were included. Patients with prior diabetes, stroke, heart failure, atrial fibrillation, or ischemic heart disease were excluded. Cohorts underwent 1:1 propensity score matching for demographics, comorbidities, medications, and laboratory values. Primary outcomes were reversion to normoglycemia and progression to diabetes. Secondary outcomes included all-cause mortality and major cardiovascular events. Hazard ratios (HR) with 95% confidence intervals were estimated using Cox proportional hazards models. Results: After matching, 256,492 patients were included (128,846 per cohort; mean age 52.4 years; 76.1% female; mean BMI 39.5 vs 38.5 kg/m²). Reversion to normoglycemia occurred in 37.3% of GLP-1RA recipients versus 29.3% of metformin users (HR 1.53, 95% CI 1.51-1.55; p<0.001). Progression to diabetes occurred in 25.1% versus 37.0% (HR 0.69, 95% CI 0.68-0.70; p<0.001). GLP-1RA therapy was associated with lower all-cause mortality (HR 0.59, 95% CI 0.55-0.63), acute heart failure (HR 0.74), ischemic stroke (HR 0.80), acute myocardial infarction (HR 0.84), cardiac arrest (HR 0.58), and atrial fibrillation (HR 0.92; all p<0.05). Ventricular tachycardia risk did not differ (HR 1.00; p=0.978). Conclusions: Among adults with prediabetes and obesity, GLP-1RA therapy was associated with improved glycemic outcomes and lower risk of major cardiovascular events and all-cause mortality compared with metformin. These findings support an expanding role for GLP-1RAs in diabetes prevention and cardiovascular risk reduction, though prospective randomized trials are needed to confirm causality.