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

QuestionWhat is the association between oral semaglutide and recognized cardiovascular risk factors vs placebo in the SOUL randomized clinical trial?FindingsIn this post hoc secondary analysis of the SOUL randomized clinical trial, oral semaglutide was associated with sustained improvements in multiple cardiovascular risk factors in high-risk participants with type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease receiving standard of care.MeaningThese 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.ImportanceIndividuals with type 2 diabetes (T2D) are at high risk of atherosclerotic cardiovascular disease (ASCVD). In the SOUL randomized clinical trial, once-daily oral semaglutide reduced risk of major adverse cardiovascular (CV) events by 14% vs placebo in people with T2D and ASCVD and/or chronic kidney disease (CKD) receiving standard of care (SoC); however, whether oral semaglutide modifies recognized CV risk factors in the long term is unclear.ObjectiveTo investigate whether treatment with oral semaglutide was associated with changes in ASCVD risk factors vs placebo.Design, Setting, and ParticipantsThis secondary analysis comprises post hoc intention-to-treat analyses of the SOUL (A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes) double-blind multicenter randomized clinical trial (randomization 1:1 to oral semaglutide or placebo) among adults with T2D and ASCVD and/or CKD receiving SoC. Participants underwent randomization from June 2019 to March 2021, with a mean (SD) of 47.5 (10.9) months of follow-up, and data were analyzed from February to December 2025.Intervention(s)Participants were treated with either once-daily oral semaglutide (maximum dose, 14 mg) or placebo, in addition to standard care.Main Outcomes and MeasuresThe primary outcome was the association of oral semaglutide vs placebo with glycated hemoglobin (HbA1c), body weight, and blood pressure (BP) using estimated treatment differences (ETDs) and with high-sensitivity C-reactive protein (hsCRP) and lipid plasma levels using estimated treatment ratios (ETRs).ResultsOf 9650 randomized participants (mean [SD] age, 66.1 (7.6) years; 2790 female participants [28.9%]), 9495 participants (98.4%) completed the trial. Early (13 weeks) improvements in HbA1c (-0.87 percentage points), body weight (-2.54%), systolic BP (SBP, -3.84 mm Hg), pulse pressure (-3.81 mm Hg), hsCRP (-18.08%), total cholesterol (TC, -7.00%), non-high-density lipoprotein cholesterol (non-HDL-C, -8.02%), HDL-C (-4.49%), and triglycerides (-8.15%) were observed with oral semaglutide vs placebo and sustained over the trial duration. Body weight reductions were gradual across both groups. At week 156, in favor of oral semaglutide were ETDs for 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), SBP (-1.83 mm Hg; 95% CI, -2.47 to -1.18), and pulse pressure (-2.17 mm Hg; 95% CI, -2.72 to -1.61) and ETRs for hsCRP (0.77; 95% CI, 0.74-0.81), TC (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 low-density lipoprotein cholesterol or diastolic BP.Conclusions and RelevanceIn this post hoc secondary analysis of the SOUL randomized clinical trial, oral semaglutide was associated with early and sustained improvements vs placebo in multiple ASCVD risk factors in high-risk participants with T2D and ASCVD and/or CKD, incremental to SoC.Trial RegistrationClinicalTrials.gov Identifier: NCT03914326This post hoc secondary analysis of the SOUL randomized clinical trial investigates whether treatment with oral semaglutide was associated with changes in atherosclerotic cardiovascular disease risk factors vs placebo among participants with type 2 diabetes.