Oral Semaglutide Approved to Reduce the Risk of Cardiovascular Events

Oral semaglutide (Rybelsus; Novo Nordisk) is the first and only oral glucagon-like peptide-1 (GLP-1) receptor agonist available on the market. It is approved for the treatment of type 2 diabetes (T2D) in adults and works in the pancreas to reduce glucagon secretion and increase insulin secretion in a glucose-dependent manner.¹ In addition to hemoglobin A1c lowering, oral semaglutide also has weight loss benefits owing to its effects on slowing gastric emptying in the stomach and increasing satiety in the brain. It is currently available in 2 formulations (R1 and R2) with 3 strengths available for each formulation (3 mg, 7 mg, and 14 mg and 1.5 mg, 4 mg, and 9 mg, respectively).¹

GLP-1s and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists are one of the first-line treatment options for adults with T2D.² In addition to lowering A1c, many of the injectable GLP-1 and dual GLP-1/GIP receptor agonists carry additional indications, including cardiovascular risk reduction (injectable semaglutide, dulaglutide, and liraglutide), obesity (injectable semaglutide, liraglutide, and tirzepatide), chronic kidney disease (CKD) (injectable semaglutide), obstructive sleep apnea (tirzepatide), and metabolic dysfunction-associated steatohepatitis (injectable semaglutide).^3-9

In October 2025, the FDA approved oral semaglutide (R1 formulation) for the reduction of major adverse cardiovascular events (MACE) in adult patients with T2D with or without established cardiovascular disease based on the results of the Semaglutide Cardiovascular Outcomes (SOUL) trial.^10,11 This approval allows for oral semaglutide to be a competitive treatment option specifically in patients who are unwilling or reluctant to initiate injectables.

Summary of Trial

The SOUL trial was a double-blind, placebo-controlled, event-driven, superiority trial conducted to assess the efficacy of oral semaglutide in patients with T2D and atherosclerotic cardiovascular disease (ASCVD), CKD, or both.¹¹ The primary outcome was MACE (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and the secondary outcomes were major kidney disease events (a composite of death from cardiovascular causes, death from kidney-related causes, a persistent reduction from baseline in the eGFR of >50%, a persistent eGFR of <15 mL/min/1.73 m, the initiation of long-term kidney-replacement therapy with either dialysis or transplant), death from cardiovascular causes, and major adverse limb events, which were tested in a time-to-first event hierarchical order.

The study was conducted from June 2019 to March 2021. Adults aged 50 years or older with T2D, an A1c of 6.5% to 10%, and at least one of the following conditions: coronary artery disease, cerebrovascular disease, symptomatic peripheral artery disease, or CKD (eGFR <60 mL/min/1.73 m), were included. Participants were randomly assigned in a 1-to-1 ratio to receive once-daily oral semaglutide or a matching placebo, in addition to standard of care. For participants receiving oral semaglutide, the dose was initiated at 3 mg and was escalated to 7 mg and then 14 mg, which was maintained until the end of the trial. Both treatment groups were instructed to take one tablet in the morning on an empty stomach with up to 120 mL of water and to wait at least 30 minutes before taking food, drink, or other oral medications.

A total of 9650 participants were randomly assigned to the treatment groups (4825 in each group). The mean age of the participants was 66.1+7.6 years, and 28.9% were women. Additionally, 70.7% had a history of cardiovascular disease, and 42.4% had a history of CKD. The mean follow-up was 47.5+10.9 months, and a total of 9495 participants (98.4%) completed the trial.

The primary outcome occurred in 579 participants (3.1 events per 100 person-years) in the oral semaglutide group versus 668 (3.7 events per 100 person-years) in the placebo group (95% confidence interval (CI), 0.77 to 0.96; p=0.006). Death from cardiovascular causes (95% CI, 0.80 to 1.09) and nonfatal stroke (95% CI, 0.70 to 1.11) failed to show statistical significance; however, nonfatal myocardial infarction occurred in 4% of the oral semaglutide group versus 5.3% in placebo (95% CI, 0.61 to 0.89), which was statistically significant. The first secondary outcome in the hierarchy (major adverse kidney disease events) occurred in 403 participants (2.1 events per 100 person-years) in the semaglutide group and 435 participants (2.3 events per 100 person-years) in the placebo group (95% CI, 0.80 to 1.05; p=0.19). Since the first secondary endpoint was not statistically significant, additional outcomes in the hierarchy were not tested for significance. No new safety concerns were identified during the trial.

Place in Therapy for Oral GLP-1

It is well known that T2D is an independent risk factor for ASCVD and that managing this risk factor can lead to the prevention or slowing of ASCVD in this population.² The current GLP-1 and GLP-1/GIP agonists with efficacy in both A1c and ASCVD reduction are only available in injectable form, which limits the potential patient population that would benefit from this therapy option. An oral option for patients with T2D with efficacy in ASCVD risk reduction regardless of existing ASCVD is preferable to those who are needle phobic and may relieve concerns from prescribers about injection administration, especially in patients with dexterity issues or other neurologic conditions that may limit mobility.¹¹ Furthermore, patients typically prefer once-daily oral treatment versus once-weekly injectables, regardless of the frequency of administration.¹² This can be further highlighted by recent data showing that the discontinuation rates of oral semaglutide are lower than for patients taking injectable semaglutide and adherence rates are higher.¹³

While oral semaglutide offers a favorable option to patients who are averse to injections, it is not without its limitations. The most notable is that it must be taken with no more than 4 ounces of water, on an empty stomach at least 30 minutes prior to any food or beverage, and separated from other medications.¹ Patients who take other medications that have similar guidance would have difficulty maintaining this regimen (ie thyroid medications, bisphosphonates, and PPIs) and would need additional education on maintaining the appropriate administration for each medication.

With the recent update regarding oral semaglutide, there may be an increase in patients being switched from the injectable GLP-1 and GLP-1/GIP formulations. Current guidance for patients who have initiated treatment on injectable semaglutide at a dose of 0.5 mg can be transitioned to oral treatment with the R1 formulation at 7 or 14 mg starting one week after their last dose. ¹ Alternative injectable GLPs may be transitioned to oral semaglutide based off comparative doses gathered from indirect comparisons of studies.¹⁴ Further data is needed to determine whether the R2 formulation of oral semaglutide will show similar benefits.

REFERENCES

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10. PR Newswire. 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. PR Newswire. October 17,2025. Accessed October 29, 2025. https://www.prnewswire.com/news-releases/fda-approves-novo-nordisks-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-302588022.html

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12. Boye K, Ross M, Mody R, Konig M, Gelhorn H. Patients' preferences for once-daily oral versus once-weekly injectable diabetes medications: The REVISE study. Diabetes Obes Metab. 2021;23(2):508-519. doi:10.1111/dom.14244

13. Horii T, Masudo C, Takayanagi Y, Oikawa Y, Shimada A, Mihara K. Adherence and treatment discontinuation of oral semaglutide and once-weekly semaglutide injection at 12 month follow-up: Japanese real-world data. J Diabetes Investig. 2024;15(11):1578-1584. doi:10.1111/jdi.14265

14. Whitley HP, Trujillo JM, Neumiller JJ. Special Report: Potential Strategies for Addressing GLP-1 and Dual GLP-1/GIP Receptor Agonist Shortages. Clin Diabetes. 2023; 41(3): 467-473. doi: 10.2337/cd23-0023