A post hoc secondary analysis of the SOUL trial has found that once-daily oral semaglutide is associated with early and sustained improvements in multiple cardiovascular (CV) risk factors in high-risk patients with type 2 diabetes (T2D).¹ These findings help to explain the mechanisms behind the primary trial results, which showed a 14% reduction in major adverse cardiovascular events (MACE) with the drug.²
Methodology
This analysis used data from the SOUL (A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes; NCT03914326) trial, a double-blind, multicentre, randomised clinical trial.¹ The study included 9,650 adults with T2D and established atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD) who were receiving standard of care.
Participants were randomised 1:1 to receive either once-daily oral semaglutide (maximum dose 14 mg) or a matching placebo. This post hoc analysis evaluated the association of treatment on glycated haemoglobin (HbA1c), body weight, blood pressure (BP), high-sensitivity C-reactive protein (hsCRP), and lipid levels over a median follow-up of 47.5 months.
Results
Treatment with oral semaglutide led to significant improvements in most CV risk factors versus placebo, which were observed as early as 13 weeks and sustained for the trial duration.
At week 156, the estimated treatment differences (ETDs) in favour of oral semaglutide were:
- HbA1c: -0.47 percentage points (95% CI, -0.52 to -0.42)
- Body weight: -3.26 percentage points (95% CI, -3.55 to -2.98)
- Systolic BP: -1.83 mmHg (95% CI, -2.47 to -1.18)
- Pulse pressure: -2.17 mmHg (95% CI, -2.72 to -1.61)
Significant estimated treatment ratios (ETRs) were also seen for hsCRP (0.77; 95% CI, 0.74–0.81 at week 104), total cholesterol (0.99; 95% CI, 0.98–1.00), non-HDL-C (0.98; 95% CI, 0.97–0.99), HDL-C (1.01; 95% CI, 1.01–1.02), and triglycerides (0.94; 95% CI, 0.93–0.96). No significant treatment differences were observed for diastolic BP or LDL-C at week 156.
In Practice
These findings demonstrate that oral semaglutide provides broad benefits across a range of CV risk factors, incremental to standard of care. The study authors concluded that "these risk factor benefits may contribute to the overall benefit of oral semaglutide on outcomes for major adverse cardiovascular events, providing supporting evidence for the use of oral semaglutide in cardiovascular risk reduction."¹
Next Steps
The authors noted that further analyses are warranted to determine the influence of glycaemic control and other individual baseline CV risk factors on MACE outcomes.
This study was funded by Novo Nordisk A/S.
Disclaimer
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References
1. Mulvagh SL, Inzucchi SE, Marx N, et al. Oral Semaglutide and Change in Cardiovascular Risk Factors in High-Risk Type 2 Diabetes: A Post Hoc Secondary Analysis of the SOUL Randomized Clinical Trial. _JAMA Cardiol._ Published online March 25, 2026. https://doi.org/10.1001/jamacardio.2026.0245
2. McGuire DK, Marx N, Mulvagh SL, et al. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. _N Engl J Med_. 2025;392(20):2001-2012. https://doi.org/10.1056/NEJMoa2501006