Oral Semaglutide Improves Cardiovascular Risk Factors in Type 2 Diabetes

Once-daily oral semaglutide not only reduces major adverse cardiovascular events (MACE) but also delivers early and sustained improvements in key atherosclerotic cardiovascular disease (ASCVD) risk factors, including glycemic control, body weight, blood pressure (BP), inflammation, and select lipid markers, in adults with type 2 diabetes (T2D) receiving standard care, according to new findings.¹

This post hoc analysis is published in JAMA Cardiology.

“Individuals with T2D are at high risk of ASCVD,” the researchers of the study wrote. “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.”

Last year, the FDA expanded the label for oral semaglutide (Rybelsus; Novo Nordisk) 7 mg and 14 mg tablets to include reduction of MACE in adults with T2D at elevated cardiovascular risk, including those without a prior heart attack or stroke.² Supported by findings from the phase 3b SOUL trial (NCT03914326), the approval made it the first and only oral GLP‑1 receptor agonist indicated for cardiovascular risk reduction.

The trial enrolled adults with T2D and established ASCVD or chronic kidney disease (CKD).¹ Participants were randomized 1:1 between June 2019 and March 2021 to receive once-daily oral semaglutide up to 14 mg or placebo, in addition to standard of care, and were followed for a mean (SD) of 47.5 (10.9) months.

This secondary analysis evaluated changes in key cardiovascular risk factors over time, including glycated hemoglobin A_1c (HbA_1c), body weight, and BP, using estimated treatment differences, as well as inflammatory and lipid markers, such as high-sensitivity C-reactive protein (hsCRP) and cholesterol parameters, using estimated treatment ratios. Data were analyzed between February and December 2025.

Among 9650 randomized participants, 98.4% completed the trial. At 13 weeks, significant reductions were observed in HbA_1c (−0.87 percentage points), body weight (−2.54%), systolic BP (−3.84 mm Hg), pulse pressure (−3.81 mm Hg), hsCRP (−18.08%), total cholesterol (−7.00%), non–high-density lipoprotein (HDL) cholesterol (−8.02%), and triglycerides (−8.15%).

These benefits were maintained through 156 weeks, with estimated treatment differences favoring semaglutide for HbA_1c (−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 mm Hg; 95% CI, −2.47 to −1.18), and pulse pressure (−2.17 mm Hg; 95% CI, −2.72 to −1.61).

Improvements were also seen in inflammatory and lipid markers, including hsCRP (ratio, 0.77; 95% CI, 0.74-0.81), total cholesterol (0.99; 95% CI, 0.98-1.00), non–HDL cholesterol (0.98; 95% CI, 0.97-0.99), and triglycerides (0.94; 95% CI, 0.93-0.96), although no significant differences were observed for low-density lipoprotein cholesterol or diastolic blood pressure.

However, the researchers acknowledged some limitations, including a lack of demographic diversity and incomplete capture of background therapies, which may have affected generalizability and interpretation. Additionally, the link between improvements in risk factors and cardiovascular outcomes was unclear, and the findings may not apply to patients with less advanced T2D.

Despite these limitations, the researchers said they believe the study supports oral semaglutide’s ability to lower cardiovascular risk, particularly in patients with T2D and ASCVD or CKD.

“Although the observed beneficial changes were relatively small in magnitude when assessed individually, these risk factor benefits may collectively contribute to the overall benefit of oral semaglutide on MACE outcomes,” the researchers wrote. “These findings thus substantiate the evolving evidence for the use of oral semaglutide in CV risk reduction.”

References

1. Mulvagh SL, Inzucchi SE, Marx N, et al. Oral semaglutide and change in cardiovascular risk factors in high-risk type 2 diabetes. JAMA Cardiol. Published online March 25, 2026. doi:10.1001/jamacardio.2026.0245

2. Klein H. FDA expands semaglutide label to reduce cardiovascular risk in adults with type 2 diabetes. AJMC^®. October 20, 2025. Accessed March 25, 2026. https://www.ajmc.com/view/fda-expands-semaglutide-label-to-reduce-cardiovascular-risk-in-adults-with-type-2-diabetes