Oral Semaglutide and CV Benefits in the SOUL Trial: How Do Baseline or Changes in HbA1c or BMI Affect Clinical Outcomes? — VialBase Research
A post-hoc SOUL analysis shows oral semaglutide's 14% MACE reduction tracks with glycemic control, not weight loss — cardiovascular benefit scaled with baseline and in-trial HbA1c but was independent of BMI.
- In SOUL (NCT03914326), oral semaglutide reduced the risk of 3-point major adverse cardiovascular events (MACE) by 14% versus placebo.
- MACE benefit differed significantly across baseline HbA1c categories (P-interaction = .04), suggesting greater risk reduction at higher baseline HbA1c, but was consistent across baseline BMI categories.
- Greater in-trial HbA1c reductions were associated with larger decreases in MACE risk at both 13 and 52 weeks (P-interactions .005 and <.001, respectively).
- In-trial BMI changes showed no such interaction (P-interactions .88 at 13 weeks and .64 at 52 weeks).
- The trial randomized 9,650 adults (aged >=50 with type 2 diabetes and atherosclerotic CV disease and/or CKD) 1:1 and followed them for 47.5 months; median age 66 years, mean HbA1c 8.0%, mean BMI 31.1 kg/m2.
Summary
SOUL was a double-blind, placebo-controlled trial (2019-2024) testing oral semaglutide against placebo in 9,650 adults aged 50 or older with type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease, across 444 international sites. The parent trial found oral semaglutide reduced major adverse cardiovascular events (MACE) by 14%. This post-hoc analysis asked whether that cardiovascular benefit was tied to baseline levels of, or in-trial changes in, HbA1c or BMI. The benefit tracked with glycemia — it was larger at higher baseline HbA1c and with greater in-trial HbA1c reductions — but was consistent regardless of baseline BMI or weight change.
Key Findings
- Oral semaglutide reduced 3-point MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) by 14% versus placebo in SOUL.
- MACE benefit was significantly different across baseline HbA1c categories (P-interaction = .04), suggesting greater risk reduction at higher baseline HbA1c, but was consistent across baseline BMI categories.
- Greater in-trial HbA1c reductions were associated with larger decreases in MACE risk at 13 and 52 weeks (P-interactions .005 and <.001, respectively).
- In-trial BMI changes showed no interaction with MACE benefit (P-interactions .88 at 13 weeks and .64 at 52 weeks).
- Population: 9,650 adults randomized 1:1, followed 47.5 months; median (IQR) age 66 (61-72) years, mean HbA1c 8.0 (1.1)% (63.5 mmol/mol), mean BMI 31.1 (5.8) kg/m2.
Relevance to Semaglutide
This analysis speaks to the mechanism behind semaglutide’s cardiovascular protection. In an oral-semaglutide population with established cardiovascular or kidney disease, the MACE benefit scaled with glycemic control — larger at higher baseline HbA1c and with deeper in-trial HbA1c reductions — while being independent of baseline weight or weight change. That pattern suggests glycemic improvement, rather than weight loss per se, is more closely aligned with the cardiovascular benefit in this higher-risk diabetic cohort. It complements the weight-centric framing of GLP-1 agents such as Tirzepatide and adds nuance to how semaglutide’s CV effect should be understood in type 2 diabetes.
Citation
Inzucchi SE, Abdul Ghani R, Deanfield J, et al. Oral Semaglutide and CV Benefits in the SOUL Trial: How Do Baseline or Changes in HbA1c or BMI Affect Clinical Outcomes? The Journal of clinical endocrinology and metabolism. 2026. doi:10.1210/clinem/dgag290.
See Also
- Parent compound: Semaglutide
- Tirzepatide
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