Oral Semaglutide and Cardiovascular Risk Factor Changes in High-Risk Type 2 Diabetes

Background

Type 2 diabetes is closely linked to a higher risk of atherosclerotic cardiovascular disease, including heart attack, stroke, and other major vascular events. People with diabetes often have multiple risk factors at the same time, such as elevated blood glucose, excess body weight, high blood pressure, abnormal cholesterol levels, and low-grade inflammation. Even when standard care is optimized, this risk remains substantial.

Oral semaglutide is a once-daily glucagon-like peptide-1 receptor agonist (GLP-1 RA). It improves glucose control and supports weight loss, and it has also been shown to reduce major adverse cardiovascular events in high-risk patients. The SOUL randomized clinical trial previously demonstrated that oral semaglutide lowered the risk of major cardiovascular events by 14% compared with placebo in adults with type 2 diabetes and established cardiovascular disease and/or chronic kidney disease who were receiving usual care.

This secondary analysis asked a more specific question: beyond reducing clinical cardiovascular events, does oral semaglutide also improve recognized cardiovascular risk factors over the long term? Understanding this matters because many cardiovascular therapies work not only by preventing events directly, but also by improving the underlying risk profile over time.

Study Design

This was a post hoc secondary analysis of the SOUL trial, a double-blind, multicenter, randomized clinical trial. Adults with type 2 diabetes and either atherosclerotic cardiovascular disease, chronic kidney disease, or both were randomized 1:1 to receive once-daily oral semaglutide, up to 14 mg, or placebo, in addition to standard care.

The trial enrolled 9,650 participants between June 2019 and March 2021. The mean age was 66.1 years, and 28.9% were female. Nearly all participants completed follow-up, with 9,495 individuals (98.4%) finishing the trial. Mean follow-up was 47.5 months.

Researchers evaluated changes in several risk factors over time. These included glycated hemoglobin (HbA1c), body weight, blood pressure, high-sensitivity C-reactive protein (hsCRP), and lipid measures such as total cholesterol, LDL cholesterol, HDL cholesterol, non-HDL cholesterol, and triglycerides. For HbA1c, weight, and blood pressure, the investigators used estimated treatment differences. For hsCRP and lipids, they used estimated treatment ratios.

Key Findings

Oral semaglutide produced early improvements in several cardiovascular risk factors, and these benefits were generally maintained throughout the trial.

By 13 weeks, compared with placebo, oral semaglutide was associated with:
– A reduction in HbA1c of 0.87 percentage points
– A reduction in body weight of 2.54%
– A reduction in systolic blood pressure of 3.84 mm Hg
– A reduction in pulse pressure of 3.81 mm Hg
– A reduction in hsCRP of 18.08%
– A reduction in total cholesterol of 7.00%
– A reduction in non-HDL cholesterol of 8.02%
– A reduction in HDL cholesterol of 4.49%
– A reduction in triglycerides of 8.15%

Body weight loss occurred gradually in both groups, but the semaglutide group consistently achieved greater reductions. The early effects on blood pressure, glucose, inflammation, and several lipid markers suggest that the medication influences multiple pathways linked to cardiovascular risk.

At week 156, the treatment differences still favored oral semaglutide. The estimated treatment differences were:
– HbA1c: -0.47 percentage points
– Body weight: -3.26%
– Systolic blood pressure: -1.83 mm Hg
– Pulse pressure: -2.17 mm Hg

The estimated treatment ratios at week 156 were:
– hsCRP: 0.77
– Total cholesterol: 0.99
– Non-HDL cholesterol: 0.98
– HDL cholesterol: 1.01
– Triglycerides: 0.94

No significant differences were seen for LDL cholesterol or diastolic blood pressure.

What These Results Mean

These findings suggest that oral semaglutide does more than lower blood sugar. It appears to improve several important cardiovascular risk markers in people with high-risk type 2 diabetes, especially in those who already have cardiovascular disease or chronic kidney disease.

The sustained reduction in HbA1c is clinically meaningful because long-term glucose control helps reduce microvascular complications and may contribute to better overall cardiometabolic health. The reduction in body weight is also important, since excess weight is associated with insulin resistance, hypertension, dyslipidemia, and inflammation.

Blood pressure reductions, even if modest, can have meaningful public health impact over time, particularly in patients who already have high baseline cardiovascular risk. The decrease in hsCRP is notable because hsCRP is a marker of systemic inflammation, and inflammation is increasingly recognized as a contributor to atherosclerosis and plaque instability.

The lipid changes were more mixed. Total cholesterol, non-HDL cholesterol, and triglycerides improved modestly, while LDL cholesterol did not change significantly. This pattern suggests that the cardiovascular benefit of oral semaglutide is not explained by cholesterol lowering alone. Instead, the therapy likely works through a combination of mechanisms, including weight loss, improved glycemic control, lower blood pressure, and reduced inflammation.

Clinical Context

For clinicians managing patients with type 2 diabetes, these results reinforce the role of GLP-1 receptor agonists as cardiometabolic therapies, not just glucose-lowering drugs. Oral semaglutide may be especially useful for patients who prefer tablets over injections, or for whom adherence to injectable therapies is difficult.

In practice, treatment selection should still be individualized. Factors such as kidney function, established cardiovascular disease, weight goals, other glucose-lowering therapies, gastrointestinal tolerability, and patient preference all matter. Oral semaglutide can cause nausea, vomiting, diarrhea, or decreased appetite, particularly when starting treatment or increasing the dose. As with other GLP-1 receptor agonists, careful counseling and gradual dose escalation are important.

It is also important to remember that oral semaglutide is an addition to, not a replacement for, standard cardiovascular prevention. Blood pressure control, statin therapy when indicated, smoking cessation, physical activity, nutrition, and kidney-protective care remain essential parts of management.

Strengths and Limitations

This analysis has several strengths. It was based on a large, international, randomized, double-blind trial with long follow-up and excellent completion rates. The consistency of the findings across multiple risk factors strengthens confidence that the observed benefits are real.

However, there are also limitations. Because this was a post hoc secondary analysis, the comparisons of risk factors were not the original primary endpoint of the trial. That means the results should be interpreted as supportive and hypothesis-generating, rather than as a separately powered definitive trial for each biomarker. In addition, some of the lipid changes were modest, and the clinical meaning of small numerical differences should be considered in the context of the whole risk profile.

Another important point is that the trial population was already high risk and receiving standard care. Therefore, the findings are most directly applicable to patients with type 2 diabetes plus established ASCVD and/or CKD, rather than to lower-risk populations.

Bottom Line

In high-risk adults with type 2 diabetes, once-daily oral semaglutide was associated with early and sustained improvements in several cardiovascular risk factors compared with placebo. These included better glycemic control, greater weight loss, lower systolic blood pressure, reduced inflammation, and favorable changes in some lipid measures. The results help explain how oral semaglutide may contribute to long-term cardiovascular protection on top of standard care.

Reference

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 Cardiology. 2026;11(5):427-437. PMID: 41879791.