Oral Semaglutide CV Benefits in SOUL Trial Tied to Higher Baseline HbA1c, Not BMI

Individuals with Type 2 Diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) or chronic kidney disease (CKD) face a significantly elevated risk of major adverse cardiovascular events (MACE). While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) like semaglutide are known to reduce CV risk, it has been unclear how baseline glycemic control (measured by HbA1c) or body mass index (BMI), or changes in these parameters during treatment, influence these protective effects. Understanding these associations can help identify patient subgroups who might derive the most benefit from oral semaglutide.

This was a post-hoc analysis of the SOUL trial, a double-blind, placebo-controlled study. Researchers randomized 9650 adults (aged ≥50 years) with Type 2 Diabetes and established ASCVD and/or CKD 1:1 to receive either oral semaglutide or placebo. Participants were followed for a median of 47.5 months. The primary outcome measure was 3-point MACE (CV death, nonfatal myocardial infarction, or nonfatal stroke). The analysis evaluated MACE benefits based on baseline HbA1c and BMI categories, as well as in-trial changes in HbA1c and BMI at Weeks 13 and 52.

In the SOUL trial, the cardiovascular benefits of oral semaglutide were significantly modulated by baseline glycemic status. MACE benefits from oral semaglutide were significantly different across baseline HbA1c categories (P-interaction = .04), indicating a greater risk reduction for participants with higher baseline HbA1c levels. Conversely, these benefits were consistent across all baseline BMI categories. The in-trial reductions in HbA1c were strongly associated with larger decreases in MACE risk with oral semaglutide, with significant P-interactions observed at Week 13 (P-interaction = .005) and Week 52 (P-interaction < .001). This suggests that achieving greater glycemic control with oral semaglutide directly correlates with enhanced CV protection. In contrast, in-trial changes in BMI did not significantly influence MACE benefits, showing consistency across categories (P-interactions .88 and .64, respectively).