Oral Semaglutide Show Promise as New Benchmark for Diabetes Care, Cardiovascular Protection

The landscape of type 2 diabetes (T2D) management has undergone a profound shift with the recent FDA approval of oral semaglutide (Rybelsus) for reducing the risk of major adverse cardiovascular events (MACE). This approval marks a significant advancement, establishing this drug—the only oral glucagon-like peptide-1 (GLP-1) medication—as a frontline defense against some of the most serious complications associated with T2D, including cardiovascular (CV) death, nonfatal myocardial infarction, and stroke.^1,2

The inherent connection between T2D and heart health underscores the importance of this development. Adults living with diabetes face a risk of cardiovascular disease that is 2 to 4 times higher than those without the condition, and they are more likely to develop and die from conditions like heart attack or stroke. This elevated risk exists even for adults who have not previously experienced a heart attack or stroke.^1,3

“Even in the absence of a previous heart attack or stroke, adults with type 2 diabetes face an increased risk of cardiovascular events, underscoring the need for therapies that go beyond managing blood sugar,” John B. Buse, MD, PhD, distinguished professor of medicine and director of the University of North Carolina Diabetes Care Center, said in a news release.¹ “Having an oral GLP-1 therapy to help improve glycemic control was an innovation in and of itself. This new indication, based on the SOUL data, marks even further advancement and showcases the versatility of semaglutide while expanding options for millions of people.”

The Landmark SOUL Trial: Evidence for Cardiovascular Reduction

The FDA’s decision was underpinned by compelling findings from the Semaglutide Cardiovascular Outcomes Trial, known as SOUL (NCT03914326). This double-blind, placebo-controlled superiority trial rigorously examined the drug’s effects on heart disease over a median follow-up period of 49.5 months. The SOUL trial included 9650 participants 50 or older who had T2D with elevated blood glucose (A_1C between 6.5% and 10.0%). Crucially, all participants were considered high risk, either possessing known atherosclerotic cardiovascular disease, chronic kidney disease, or both.^4,5

The primary end point was the occurrence of a first MACE, encompassing cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The results demonstrated meaningful cardiovascular benefits, showing a 14% reduction in MACE for patients receiving oral semaglutide compared to placebo. Specifically, 12.0% of patients in the oral semaglutide group experienced a primary outcome event (3.1 events per 100 person-years), compared with 13.8% in the placebo group (3.7 events per 100 person-years), translating to an absolute risk reduction of 2 percentage points.^3-5

When looking at specific outcomes, 6.2% of the oral semaglutide group died from cardiovascular causes, compared to 6.6% in the placebo group. Nonfatal myocardial infarction occurred in 4% of the semaglutide group versus 5.2% of the placebo group, and nonfatal stroke occurred in 3% versus 3.3%, respectively.⁵

Beyond its primary cardiovascular focus, the SOUL trial also examined confirmatory secondary outcomes related to major kidney disease events. While the initial published results indicated that the confirmatory secondary outcomes did not significantly differ between the 2 groups, some renal benefits were suggested, with events occurring in 8.4% of the semaglutide group compared to 9% in the placebo group.^3-5

Broadening Therapeutic Options

The availability of a GLP-1 therapy in an oral tablet form represents a major logistical improvement for patients. By eliminating the need for injections, oral semaglutide has the potential to improve patient adherence and support the earlier initiation of critical therapy, thereby broadening access to cardiovascular protection for individuals who might otherwise delay or avoid treatment due to reluctance toward injectable medications.^1,3

“As the only FDA-approved GLP-1 therapy in a pill, now recognized for its proven cardiovascular benefits, a new benchmark has been set for future oral innovations,” Dave Moore, executive vice president of US Operations at Novo Nordisk, said in the news release.¹ “The semaglutide molecule has consistently demonstrated robust outcomes across multiple, large-scale trials, further reinforcing the already established cardiovascular profile it delivers for patients.

Improvements in Glycemic Control and Cardiometabolic Markers

In addition to the SOUL trial’s findings in high-risk patients with T2D, analyses focusing on weight management have further illuminated the drug’s cardiometabolic effects. Data from the phase 3 OASIS 4 (NCT05564117) trial showed that once daily oral semaglutide 25 mg provided significant improvements in glycemic parameters, including hemoglobin A_1c, fasting plasma glucose, and fasting serum insulin, in patients struggling with overweight or obesity. Furthermore, the drug improved cardiovascular risk factors such as C-reactive protein and serum triglycerides.⁶

The OASIS 4 trial demonstrated substantial weight loss efficacy, with an estimated mean reduction in body weight of approximately -13.6% for patients receiving semaglutide versus -2.2% for the placebo group. Importantly, improvements in glycemic parameters and CV risk factors were observed regardless of the total weight lost, although the benefits were most pronounced in patients who achieved greater than 15% weight loss. Supporting these findings, the STEP UP (NCT05646706) phase 3b trial showed that an investigational higher dose of 7.2 mg helped patients reach target body mass index levels and waist-to-height ratios, along with healthy levels for 2 or more cardiovascular risk factors like cholesterol and blood pressure.^7,8

Consideration for Use and Safety Profile

Oral semaglutide is generally used alongside diet and exercise to control blood sugar and lower CV risk in appropriate high-risk patients with T2D. Proper administration is crucial, according to the safety information. The tablet must be taken on an empty stomach in the morning with a small amount of water (up to 4 ounces), at least 30 minutes before consuming food, drinks, or other oral medications. Patients are advised to swallow the tablet whole without splitting, crushing, or chewing it.²

The safety profile of oral semaglutide in these trials was consistent with previous investigations. The most common serious adverse events (AEs) reported included cardiac disorders and infections or infestations. Gastrointestinal AEs are common, with 74% of patients in the OASIS 4 semaglutide group reporting them, compared to 42.2% in the placebo group. In the SOUL trial, the incidence of serious AEs was 47.9% in the semaglutide group versus 50.3% in the placebo group, with gastrointestinal disorders occurring in 5.0% and 4.4%, respectively.^1,3,5,6

The collective evidence from recent large-scale trials confirms that oral semaglutide is not just an innovation in T2D treatment—it is a powerful tool in protecting the cardiovascular health of high-risk patients. This oral GLP-1 therapy offers a pathway to comprehensive cardiometabolic improvement, representing a versatile option for millions of people managing complex conditions.¹

REFERENCES

1. FDA approves Novo Nordisk’s oral semaglutide for cardiovascular (CV) risk reduction in adults with type 2 diabetes who are at high risk, including those who have not had a prior CV event. News release. Novo Nordisk. October 17, 2025. Accessed October 20, 2025. https://www.novonordisk-us.com/media/news-archive/news-details.html?id=916435

2. Mayo Clinic. Semaglutide (oral route). Updated November 1, 2025. Accessed November 14, 2025. https://www.mayoclinic.org/drugssupplements/semaglutide-oral-route/description/drg-20492085

3. Oral semaglutide significantly improves cardiovascular outcomes in individuals with type 2 diabetes. News release. American Diabetes Association. June 22, 2025. Accessed November 14, 2025. https://diabetes.org/newsroom/press-releases/oral-semaglutidesignificantly-improves-cardiovascular-outcomes-individuals

4. A heart disease study of semaglutide in patients with type 2 diabetes (SOUL). ClinicalTrials.gov. September 24, 2025. Accessed October 20, 2025. https://clinicaltrials.gov/study/NCT03914326

5. 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. doi:10.1056/NEJMoa2501006

6. Novo Nordisk presents 4 new analyses on oral semaglutide 25 mg (Wegovy in a pill) at ObesityWeek 2025, including demonstrated reductions in cardiovascular risk factors. News release. November 5, 2025. Accessed November 7, 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916447

7. Wharton S, Lingvay I, Bogdanski P, et al. Oral semaglutide at a dose of 25 mg in adults with overweight or obesity. N Engl J Med. 2025;393(11):1077-1087. doi:10.1056/NEJMoa2500969

8. Novo Nordisk Wegovy users achieved waist and BMI targets linked to improved health and low risk of obesity-related complications. News release. November 5, 2025. Accessed November 7, 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916449