Individuals with type 2 diabetes (T2D) face a high risk of atherosclerotic cardiovascular disease (ASCVD). The SOUL trial (NCT03914326) previously demonstrated that oral semaglutide reduced major adverse cardiovascular events (MACE).² A new post hoc secondary analysis of this trial now provides insight into the mechanisms behind this benefit, detailing the drug's association with changes in key cardiovascular (CV) risk factors.¹
Methodology
This analysis examined data from the SOUL trial, a double-blind, multicenter, randomized clinical trial.¹ The study included 9,650 adults with T2D and established ASCVD and/or chronic kidney disease (CKD) who were already receiving standard of care (SoC). Participants were randomized 1:1 to receive either once-daily oral semaglutide (maximum dose 14 mg) or a placebo. This post hoc analysis evaluated the association of treatment with changes in glycated haemoglobin (HbA1c), body weight, blood pressure (BP), high-sensitivity C-reactive protein (hsCRP), and lipid profiles over a median follow-up of 47.5 months.¹
Results
Treatment with oral semaglutide was associated with early and sustained improvements in multiple CV risk factors compared with placebo. At 13 weeks, significant reductions were observed in HbA1c (–0.87 percentage points), body weight (–2.54%), systolic BP (SBP; –3.84 mm Hg), and hsCRP (–18.08%).¹
These benefits were largely sustained. At week 156, the estimated treatment differences (ETDs) in favour of oral semaglutide were –0.47 percentage points for HbA1c, –3.26 percentage points for body weight, –1.83 mm Hg for SBP, and –2.17 mm Hg for pulse pressure. Significant estimated treatment ratios (ETRs) were also seen for hsCRP (0.77), total cholesterol (0.99), non-high-density lipoprotein cholesterol (non-HDL-C; 0.98), and triglycerides (0.94). HDL-C levels were modestly increased (ETR: 1.01). No significant treatment differences were found for diastolic BP or low-density lipoprotein cholesterol at week 156. These findings were consistent across subgroups of patients with ASCVD only, CKD only, or both.¹
Interpretation
The findings from this analysis suggest that the MACE reduction observed in the SOUL trial may be attributable to the collective impact of oral semaglutide on a range of CV risk factors, incremental to SoC.¹˒² The early and sustained improvements in glycaemic control, body weight, SBP, and markers of inflammation and dyslipidaemia provide supporting evidence for the role of oral semaglutide in comprehensive CV risk reduction for high-risk patients with T2D.
Next Steps
The authors note that further analyses are warranted to determine the specific influence of glycaemic control and other individual baseline CV risk factors on MACE outcomes.¹
This study was funded by Novo Nordisk A/S.
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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; SOUL Study Group. 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