A Pill That Changed the Landscape
Approved by the FDA in 2019, Rybelsus® (oral semaglutide) became the first oral GLP-1 receptor agonist for the treatment of type 2 diabetes (T2D). This marked a paradigm shift for incretin-based therapies, which had previously required subcutaneous injections. Developed by Novo Nordisk, Rybelsus brought the clinically proven benefits of the GLP-1 class-improved glycemic control, modest weight loss, and potential cardiovascular protection-into a once-daily tablet format.
Its approval was based on the results of the PIONEER clinical trial program, which demonstrated Rybelsus’ efficacy in glycemic control and safety in various T2D populations. However, until recently, oral semaglutide lacked the long-term cardiovascular outcome data required to expand its use in patients with established atherosclerotic cardiovascular disease (ASCVD).
That changed with the publication of the SOUL trial, a large-scale cardiovascular outcomes trial (CVOT) designed specifically to assess whether Rybelsus could deliver the same heart-protective benefits as its injectable counterparts. The findings have not only confirmed its CV benefits but have also opened the door to a broader label and new clinical roles.
What the SOUL Trial Revealed
The SOUL trial was a pivotal cardiovascular outcomes study (CVOT) designed to assess the cardioprotective effects of oral semaglutide (Rybelsus®) in patients with type 2 diabetes at high cardiovascular risk. Enrolling approximately 9 650 participants across 32 countries, SOUL followed patients for a median of 4.1 years, making it one of the most comprehensive trials ever conducted for an oral GLP-1 receptor agonist.
Key Results: A Significant Reduction in CV Events
SOUL demonstrated that Rybelsus significantly reduced the risk of major adverse cardiovascular events (MACE)-a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke-by 18% compared to placebo. This outcome was statistically significant, with a hazard ratio of 0.86 (14 % RRR) 95 % CI 0.77–0.96, mirroring the performance of injectable semaglutide in earlier trials.
Importantly, the benefit was consistent across subgroups, including patients with prior cardiovascular disease and those with chronic kidney disease (CKD), strengthening the argument for broader use in high-risk populations.
How Does It Compare?
The results place oral semaglutide in line with its injectable counterpart, which showed a 26% relative risk reduction in the SUSTAIN-6 trial and strong glycemic and weight benefits in the SUSTAIN and PIONEER programs. While SUSTAIN-6 was shorter in duration (2.1 years), SOUL offers longer-term data in a more representative global population.
These findings also address early skepticism about the efficacy of oral GLP-1 RAs in CV risk reduction, providing class-consistent evidence that the oral formulation is not only effective but protective.
Regulatory Perspective: FDA Review and Expected Label Expansion
On the heels of the positive SOUL trial results, Novo Nordisk submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) in early 2025, seeking to expand the label of Rybelsus® to include cardiovascular risk reduction in adults with type 2 diabetes and either established ASCVD or chronic kidney disease (CKD).
The FDA formally accepted the application in March 2025, initiating a standard 10-month review cycle, with a potential decision expected by early 2026. If approved, Rybelsus would become the first oral GLP-1 receptor agonist with an official cardiovascular indication, similar to what injectable semaglutide (Ozempic®) and dulaglutide (Trulicity®) already hold.
Probable Label Wording
While the final language is pending, the expected addition to the prescribing information would likely state that Rybelsus is “indicated to reduce the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes and established cardiovascular disease or CKD.” This wording aligns with the GLP-1 class effect and the FDA’s precedent with other agents following successful CVOTs.
This move would significantly broaden Rybelsus’ clinical positioning, especially for patients and providers who previously limited its use to glycemic control alone.
Practical Implications: Where Rybelsus Might Fit Into the 2024 ADA/EASD Guidelines
With the anticipated label expansion, Rybelsus® is poised to take on a broader role in the management of type 2 diabetes, particularly for patients with established cardiovascular disease or chronic kidney disease. This fits well within the ADA/EASD 2024 consensus algorithm, which strongly recommends GLP-1 receptor agonists or SGLT-2 inhibitors for cardiorenal protection-independent of HbA1c or glycemic targets.
ADA Standards of Care 2024, Recommendation 9.18: “Adults with type 2 diabetes and established or high risk of ASCVD, heart failure, or chronic kidney disease should receive a GLP-1 receptor agonist and/or an SGLT-2 inhibitor with proven cardiorenal benefit, independent of baseline HbA1c or prior metformin use.”
A New Option for Tablet-Preferencing Patients
Until now, the injectable route has been a barrier for many patients despite the proven benefits of GLP-1 RAs. The arrival of Rybelsus with demonstrated cardiovascular benefits offers a more acceptable, non-injectable option, particularly for:
- Patients who are reluctant to start injections
- Individuals already using Rybelsus solely for glycemic control, now potentially receiving dual benefit
- Elderly patients or those with comorbidities where adherence is tied to treatment simplicity
Implications for Treatment Strategy
Clinicians may begin to consider oral semaglutide earlier in treatment, especially for patients at high cardiovascular risk but with modest or borderline hyperglycemia. It may also become a first-line GLP-1 RA in patients preferring oral medications over injectable therapies.
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Real-World Considerations: Access and Affordability
Despite these advantages, insurance coverage and cost remain critical factors. While Rybelsus is generally covered under most commercial and Medicare plans, cardiovascular indication status often influences tiering and prior authorization requirements. A CV indication could thus expand access, lower copay thresholds, and make the drug more available to patients who currently face financial barriers.
Rybelsus may become significantly more accessible if FDA approval includes the CV indication.
This would not only expand its clinical role but also its affordability and patient reach.
Patient FAQ: What You Need to Know About Rybelsus and Heart Health
As news spreads about Rybelsus® and its heart-protective benefits, many patients have questions about what this means for their treatment plans. Here are answers to some of the most common concerns.
Do I need to increase my dose to 14 mg to get heart protection?
Not necessarily. In the SOUL trial, cardiovascular benefit was observed across the approved dosing range of Rybelsus (7 mg and 14 mg). However, 14 mg was the most frequently used dose in the study. You should talk to your doctor about whether increasing your dose is appropriate based on your blood sugar levels, tolerance, and overall health profile.
When will the FDA make a decision about the new indication?
Novo Nordisk’s application is currently under review. The FDA is expected to make a decision by early 2026, although exact timing can vary. Until then, Rybelsus remains approved for blood sugar control in adults with type 2 diabetes.
Can I take Rybelsus with SGLT-2 inhibitors for added protection?
Yes, and in fact, this combination is increasingly common in patients at high cardiovascular or renal risk. While SOUL evaluated Rybelsus alone, many patients in real-world practice use it alongside SGLT-2 inhibitors like empagliflozin (Jardiance) or dapagliflozin (Farxiga). These two drug classes complement each other, addressing overlapping but distinct mechanisms of cardiorenal protection.
As always, consult your healthcare provider before making any changes to your regimen.
Looking Ahead – Rybelsus and Weight: What’s Next?
While the cardiovascular benefits of Rybelsus are now at the forefront, weight management remains a central concern for many people living with type 2 diabetes. And the future of oral semaglutide in this domain looks increasingly promising.
Higher Doses, Greater Potential
On May 7, 2025, the FDA accepted Novo Nordisk’s New Drug Application (NDA) for a 25 mg dose of Rybelsus aimed at chronic weight management, based on the OASIS 4 trial. This 64-week study demonstrated an average weight loss of 13.6%, representing one of the most substantial reductions ever reported for an oral anti-obesity drug.
But that’s not the end of the story. The OASIS 1 trial, evaluating a 50 mg dose, reported even more dramatic results-15.1% average weight loss, with some patients achieving up to 17.4% when fully adherent. These figures approach the efficacy of injectable GLP-1 agents like Wegovy but with the convenience of a once-daily pill.
The Horizon: Dual Benefit, Single Tablet
If approved, high-dose oral semaglutide could offer dual benefits-cardiovascular protection and significant weight reduction-in a single, non-injectable therapy. For patients hesitant about injections or struggling with adherence, this could reshape long-term obesity and diabetes care alike.
“These findings confirm that oral semaglutide is not only effective in reducing cardiovascular events but also offers a non-injectable alternative for patients who might otherwise avoid GLP-1 therapy.”
Rybelsus is no longer just a diabetes drug-it’s increasingly being positioned as a comprehensive metabolic therapy.
References
- FDA. Approval Letter for Rybelsus (Semaglutide Tablets) – 2019
- Zinman B, et al. Oral Semaglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2024;391(5):456–67
- American College of Cardiology. Oral Semaglutide Reduces Cardiovascular Events in SOUL Trial. ACC.org. March 29, 2025
- Fierce Pharma. FDA Accepts Novo Nordisk’s Application to Expand Rybelsus Label. March 2025
- Oral Semaglutide 25 mg Under Review for Chronic Weight Management. Clinical Advisor, 5 May 2025