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Rybelsus Gets FDA Approval to Reduce Heart Risk in Adults with Diabetes

Key Takeaways

  • FDA approved oral semaglutide (Rybelsus) as the first oral GLP-1 receptor agonist to reduce major adverse cardiovascular events in adults with type 2 diabetes at high risk.
  • The SOUL trial demonstrated a 14% reduction in cardiovascular risk over almost 4 years when compared to placebo.
  • This approval expands Rybelsus beyond blood sugar control to include cardiovascular protection for high-risk patients.
  • Available in 7mg and 14mg doses, offering an oral alternative to injectable GLP-1 therapies for heart disease prevention.
  • Gastrointestinal side effects remain the most common adverse events.

The FDA has granted approval that could change cardiovascular care for millions of Americans with type 2 diabetes. Rybelsus (oral semaglutide) became the first oral GLP-1 receptor agonist approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes who are at high cardiovascular risk. This historic milestone represents a significant advancement beyond managing blood sugar, offering proven cardiovascular benefits through an oral formulation that expands treatment options for patients who prefer taking medications by mouth over injections.

FDA Approval Details and Significance

The FDA approved Novo Nordisk’s oral semaglutide Rybelsus for a new indication that goes beyond its original purpose of improving glycemic control in type 2 diabetes. This approval makes Rybelsus the first oral GLP-1 therapy approved specifically for reducing cardiovascular risk, marking an even further advancement in diabetes.

The new indication covers adults with type 2 diabetes at an increased risk for cardiovascular events, including both patients with established cardiovascular disease and those with chronic kidney disease.

John B. Buse, MD, PhD, steering committee co-chair for cardiovascular outcome studies and director of the UNC Diabetes Care Center, emphasized the significance: “This approval showcases the versatility of semaglutide while expanding options for millions of people with diabetes who may benefit from cardiovascular protection but prefer oral medications.”

The established cardiovascular profile of GLP-1 receptor agonist medications has been well-documented with injectable formulations, but this represents the first time an oral GLP-1 receptor agonist has received FDA approval for cardiovascular risk reduction. Novo Nordisk’s development of oral semaglutide addresses a need for patients who are unable or unwilling to use injectable GLP-1s.

SOUL Trial: Pivotal Evidence for Approval

The FDA approval was based on consistently demonstrated robust outcomes from the SOUL trial, a large-scale randomized, double-blind, placebo-controlled cardiovascular outcome study that enrolled 9,650 adults with type 2 diabetes and established cardiovascular disease or chronic kidney disease. This clinical trial provided evidence demonstrating that oral semaglutide can reduce the risk of major adverse cardiovascular events.

The trial design included patients receiving oral semaglutide at doses up to 14mg once daily compared to placebo, with both groups receiving standard cardiovascular care. The primary endpoint focused on the time to first occurrence of major adverse cardiovascular events (MACE), which includes cardiovascular death, nonfatal myocardial infarction (heart attack), and nonfatal stroke.

Over a mean follow-up period of almost 4 years, the SOUL data mark even more significant progress in oral GLP-1 therapy. The trial demonstrated that patients receiving oral semaglutide experienced a statistically significant 14% reduction in MACE risk compared to the placebo group.

Breakdown of Cardiovascular Benefits

The cardiovascular benefits observed in the SOUL trial were demonstrated by a reduction in nonfatal myocardial infarction rates. Patients taking oral semaglutide experienced a 26% reduction in heart attack risk compared to those in the placebo group.

The overall MACE event rates were 12.0% in the semaglutide group versus 13.8% in the placebo group. This translates to a number needed to treat of approximately 50 patients over 3 years to prevent one cardiovascular event, making this an effective intervention for reducing the risk of cardiovascular events in high-risk diabetes patients.

The SOUL data’s consistency with other semaglutide cardiovascular outcome trials reinforces the already established cardiovascular profile of this GLP-1 receptor agonist across different formulations. Previous studies with injectable semaglutide had already demonstrated similar benefits, and this trial confirmed that the oral formulation also decreases the risk of MACE (major adverse cardiovascular events).

Safety Profile and Adverse Events

The SOUL trial revealed that oral semaglutide is generally well-tolerated and safe. Fewer serious adverse events occurred in the semaglutide group (47.9%) compared to the placebo group (50.3%), indicating that the medication did not increase overall risks.

However, gastrointestinal disorders were more common with semaglutide treatment, affecting 5.0% of patients compared to 4.4% in the placebo group. These side effects are consistent with the known profile of GLP-1 receptor agonist medications and typically include nausea, vomiting, and diarrhea. Most of the adverse events were mild to moderate and improved as patients took the medication.

Drug discontinuation rates due to adverse events were higher in the semaglutide group (15.5%) compared to placebo (11.6%). This was primarily due to gastrointestinal (GI) side effects. However, this discontinuation rate is consistent with other GLP-1 therapy trials and can often be helped with dose titration and patient counseling.

Importantly, rates of acute pancreatitis were equal between the semaglutide and placebo groups (0.4% each), addressing a key safety concern that has been associated with GLP-1 receptor agonists. The trial also monitored for medullary thyroid carcinoma and other serious adverse events, with no significant differences observed between treatment groups. And other serious adverse events were slightly lower in the Rybelsus group compared to placebo, with cardiac disorders and infections/infestations being the most common.

Dosing and Administration Considerations

Rybelsus is available in 7mg and 14mg tablets for once-daily administration. The dosing for heart protection follows the same titration schedule used for glycemic control, starting with 3mg daily for 30 days, then increasing to 7mg daily. If additional glycemic control is needed after at least 30 days on the 7mg dose, the dose can be increased to 14mg daily.

You should take Rybelsus with plain water, then wait at least 30 minutes before eating, drinking, or taking other oral medications. This is important because food, beverages other than water, and other medications can significantly reduce how effective oral semaglutide is.

Contraindications for Rybelsus include a personal or family history of medullary thyroid carcinoma, patients with Multiple Endocrine Neoplasia syndrome type 2, and known hypersensitivity to semaglutide. Healthcare providers should also exercise caution in patients with a history of pancreatitis or severe gastrointestinal problems.

The medication can be used alone or in combination with other diabetes medications, though dose adjustments of insulin or insulin secretagogues may be necessary to reduce the risk of hypoglycemia. Regular monitoring of blood glucose, HbA1c, and cardiovascular risk factors should continue throughout treatment.

Frequently Asked Questions

How does oral semaglutide compare to injectable GLP-1 medications for heart protection?

Oral semaglutide demonstrated similar cardiovascular benefits to injectable GLP-1 receptor agonists in clinical trials. The SOUL trial showed a 14% reduction in major adverse cardiovascular events, which is comparable to results seen with injectable semaglutide and other GLP-1 medications. The main advantage of the oral formulation is convenience and increased patient compliance, as many patients prefer oral medications over injections.

What specific criteria determine if a diabetes patient is at “high cardiovascular risk” for this treatment?

Patients are considered at high cardiovascular risk if they have established atherosclerotic cardiovascular disease (such as a previous heart attack, stroke, or coronary artery disease) or chronic kidney disease. This includes both primary prevention (patients without prior CV event but with risk factors) and secondary prevention (patients with established cardiovascular disease). Healthcare providers will determine your risk factors, including age, blood pressure, cholesterol levels, smoking status, and duration of diabetes, to determine if you qualify for this indication.

Can Rybelsus be used in patients who haven’t tried other diabetes medications first?

While Rybelsus can be used as monotherapy, clinical guidelines typically recommend starting with metformin as first-line therapy for type 2 diabetes unless contraindicated. However, for patients at high cardiovascular risk, GLP-1 receptor agonists like Rybelsus may be considered earlier due to their proven cardiovascular benefits. The decision should be individualized based on patient factors, cardiovascular risk profile, and treatment goals.

What should patients do if they experience gastrointestinal side effects when starting Rybelsus?

Gastrointestinal (GI) side effects like nausea, vomiting, and diarrhea are common when starting Rybelsus but often improve over time. You should take the medication exactly as prescribed, eat smaller meals, avoid high-fat foods, and stay well-hydrated. If side effects are severe or persistent, contact your healthcare provider, who may recommend slowing the dose increases or providing additional care. In some cases, temporary dose reduction may be necessary, but you should never stop or adjust your dose without medical supervision.

How long does it typically take to see cardiovascular benefits after starting oral semaglutide therapy?

The cardiovascular benefits of once daily oral semaglutide develop gradually over time. In the SOUL trial, this was seen after approximately 12-18 months of treatment, with continued benefit throughout the 4-year study period. However, improvements in blood sugar control and other factors may be seen within weeks to months of starting treatment. You should continue taking the medication as prescribed, even if you don’t immediately feel any difference, as the cardiovascular protection is a long-term benefit that reduces future risk of heart attack or stroke rather than providing immediate symptomatic relief.

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