GLP-1 RAs vs metformin: 37.3% vs 29.3% reverted to normoglycemia in retrospective cohort

Glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy, compared with metformin, was associated with higher rates of reversion to normoglycemia and lower risk of diabetes progression, cardiovascular events and all-cause mortality in adults with prediabetes and obesity. The results were presented at the American Heart Association (AHA) Scientific Sessions 2026 in Chicago, held from November 6 to 9, 2026, and reported by thecardiologyadvisor.com thecardiologyadvisor.comthecardiologyadvisor.comthecardiologyadvisor.comOpen source ↗.

Prediabetes affects roughly 40% of US adults and raises the risk of diabetes and cardiovascular disease in people with obesity. Comparative data on GLP-1 RAs and metformin for glycemic and cardiovascular outcomes in this group were limited, which the researchers set out to address.

Study design and cohort

This was a retrospective cohort study based on the TriNetX global electronic health record network, which covers 104 institutions. It compared adults with prediabetes and obesity who started GLP-1 RA therapy or metformin between January 2010 and December 2023. The GLP-1-based therapies included semaglutide, tirzepatide, liraglutide and dulaglutide. Patients with a history of diabetes, stroke, heart failure, atrial fibrillation or ischemic heart disease were excluded.

After 1:1 propensity score matching, the analysis included 256,492 patients, 128,846 in each group. The mean age was 52.4 years and 76.1% were women. Mean body mass index was 39.5 in the GLP-1 RA group and 38.5 in the metformin group.

Glycemic and cardiovascular outcomes

Reversion to normoglycemia occurred in 37.3% of patients on GLP-1 RAs and in 29.3% of those on metformin (hazard ratio [HR], 1.53). Progression to diabetes occurred in 25.1% and 37.0% respectively, a 31% lower relative hazard (HR, 0.69) thecardiologyadvisor.comthecardiologyadvisor.comthecardiologyadvisor.comOpen source ↗.

Among secondary outcomes, the GLP-1 RA group had a 26% lower hazard of acute heart failure (HR, 0.74), a 20% lower hazard of ischemic stroke (HR, 0.80) and a 16% lower hazard of acute myocardial infarction (HR, 0.84). Risk of cardiac arrest (HR, 0.58) and atrial fibrillation (HR, 0.92) was also lower. All-cause mortality was 41% lower (HR, 0.59). Ventricular tachycardia risk did not differ significantly between the groups (HR, 1.00).

The authors concluded that the findings support an expanding role for GLP-1 RAs in diabetes prevention and cardiovascular risk reduction, and noted that prospective randomized trials are needed to confirm causality.