Oral Semaglutide and CV Benefits in the SOUL Trial: How Do Baseline or Changes in HbA1c or BMI Affect Clinical Outcomes?

CONTEXT: In the SOUL trial (NCT03914326), oral semaglutide reduced risk of major adverse cardiovascular (CV) events (MACE) by 14%. Whether baseline or changes in HbA1c or BMI are associated with these CV benefits is not known. OBJECTIVE: We evaluated whether CV benefits of oral semaglutide are associated with baseline or in-trial reductions in HbA1c or BMI. DESIGN: Post hoc analysis of SOUL, a double-blind, placebo-controlled trial (2019‒2024). SETTING: International, 444 sites. PARTICIPANTS: Adults aged ≥50 years, with type 2 diabetes and atherosclerotic CV disease and/or chronic kidney disease. INTERVENTION(S): Oral semaglutide or placebo. MAIN OUTCOME MEASURES: 3-point MACE (CV death, nonfatal myocardial infarction, or nonfatal stroke) analyzed by baseline and in-trial changes in HbA1c and BMI (Weeks 13; 52). RESULTS: 9650 adults randomized 1:1 to oral semaglutide or placebo were followed for 47.5 months. Median (IQR) age was 66 (61-72) years, mean (±SD) HbA1c 8.0 (1.1)% (63.5±12.5 mmol/mol) and BMI 31.1 (5.8) kg/m2. MACE benefits from oral semaglutide were significantly different across baseline HbA1c categories (P-interaction = .04), suggesting greater risk reduction at higher baseline HbA1c, but were consistent across baseline BMI categories. Greater in-trial HbA1c reductions were associated with larger decreases in MACE risk with oral semaglutide at 13 and 52 weeks (P-interactions .005 and < .001, respectively), whereas BMI changes showed consistency (P-interactions .88 and .64, respectively). CONCLUSIONS: In SOUL, CV benefits of oral semaglutide appeared more pronounced among participants with higher baseline HbA1c and greater HbA1c reductions, but were consistent across baseline or changes in BMI.