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.