Oral Semaglutide: A Game-Changer for Cardiovascular Risk in Type 2 Diabetes

Oral Semaglutide Reduces Cardiovascular Risk in Patients with Type 2 Diabetes and Comorbidities

In a groundbreaking new study presented at the 2025 American College of Cardiology (ACC) Scientific Session, researchers have demonstrated that oral semaglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, significantly reduces the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes (T2D) and concomitant cardiovascular disease (CVD) or chronic kidney disease (CKD). The SOUL trial, an international phase 3b placebo-controlled study, evaluated the effectiveness of this oral formulation of semaglutide and confirmed its potential to enhance treatment options for patients who struggle with injections.

For patients with type 2 diabetes and cardiovascular or kidney disease, managing the risk of major adverse cardiovascular events has always been a key therapeutic goal. The positive results from this trial indicate that oral semaglutide could play a crucial role in achieving better cardiovascular outcomes for this high-risk population.

The SOUL Trial: A New Era in Treatment

The SOUL trial, a double-blind, randomized controlled study, enrolled 9,650 patients aged 50 or older who had established cardiovascular disease, cerebrovascular disease, symptomatic peripheral artery disease, or chronic kidney disease (eGFR < 60 mL/min/1.73 m²). These patients were randomized to receive either oral semaglutide or a placebo. The primary endpoint of the trial was a composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke.

After a median follow-up of 49.5 months, oral semaglutide demonstrated a 14% relative reduction in the primary endpoint, with a hazard ratio (HR) of 0.86 (P = 0.006). This result was consistent across subgroups and showed a robust benefit in preventing major adverse cardiovascular events in patients with T2D and comorbid conditions, underscoring the potential of oral GLP-1 receptor agonists in clinical practice.

Addressing an Unmet Need: Oral GLP-1 Receptor Agonists

The results of the SOUL trial are particularly significant because they address an unmet clinical need for patients with type 2 diabetes and cardiovascular comorbidities who are reluctant to use injectable GLP-1 receptor agonists. Many patients are hesitant to take injections due to discomfort or fear, and this has limited the widespread adoption of GLP-1 receptor agonists, despite their known benefits for glycemic control, weight loss, and cardiovascular risk reduction.

As Dr. Darren K. McGuire, the principal investigator of the study and distinguished chair in cardiovascular science at the University of Texas Southwestern Medical Center, explained during the presentation, "I’m going to guess that over half of people who are eligible will refuse a GLP-1 receptor agonist just because they don't want to take an injection." The introduction of an oral version of semaglutide is a game-changer, offering a more accessible treatment option for these patients.

Kidney Protection: A Missed Opportunity

While the primary outcome demonstrated clear cardiovascular benefits, the study did not find statistically significant evidence for kidney protection in the oral semaglutide group. The secondary endpoint of kidney disease-related events, such as progression to severe kidney compromise (eGFR < 15 mL/min/1.73 m²), did not reach statistical significance (HR, 0.91; P = 0.0967).

However, the numerical trend in favor of kidney protection was directionally consistent with previous findings from the FLOW trial, which evaluated subcutaneous semaglutide. The FLOW trial demonstrated a 24% reduction in a composite endpoint of kidney disease events and death from either cardiovascular or kidney-related causes (HR, 0.76; P = 0.0003). This discrepancy may be attributed to the higher baseline renal function in the SOUL trial population compared to the FLOW cohort.

Secondary Outcomes: Favorable Trends

In addition to the primary endpoint, several secondary outcomes favored the oral semaglutide group. For instance, while the reduction in nonfatal stroke did not reach statistical significance (HR, 0.88; 95% CI, 0.70–1.11), a significant reduction in major adverse limb events (HR, 0.71; 95% CI, 0.52–0.96) was observed in patients receiving oral semaglutide. These findings suggest that oral semaglutide may provide broader cardiovascular benefits beyond the primary outcome of MACE.

Additionally, the study assessed the effects of combining oral semaglutide with sodium-glucose cotransporter-2 (SGLT2) inhibitors, a class of medications that has been shown to provide additional cardiovascular and renal benefits in patients with type 2 diabetes. The results revealed no significant difference in the effectiveness of oral semaglutide whether patients were taking an SGLT2 inhibitor or not, further confirming the versatility of oral semaglutide in improving cardiovascular outcomes.

Expanding Treatment Options for Patients with Type 2 Diabetes

The SOUL trial's results mark a significant advancement in the management of patients with type 2 diabetes and cardiovascular or kidney disease. Dr. Anuradha Lala, associate professor of cardiovascular medicine at the Icahn School of Medicine at Mount Sinai in New York City, who discussed the trial at the ACC session, emphasized the value of these findings. "We now have expanded options, which is a thrilling development," she said.

The ability to prescribe oral semaglutide in patients with type 2 diabetes and concomitant cardiovascular disease provides clinicians with an additional treatment option, especially for those who may be hesitant or unable to use injectable GLP-1 receptor agonists. The challenge, however, remains determining where oral semaglutide fits into the broader treatment armamentarium for patients with type 2 diabetes and comorbid cardiovascular or kidney disease.

Dr. McGuire further clarified that injectable semaglutide remains the preferred option, as it is 100% bioavailable, while the oral formulation has lower bioavailability. However, he acknowledged that the reality is that many patients are unwilling to take injections, even when needles are small and virtually painless. "It's not that they hurt very much. You simply cannot feel it going into the skin," he said, pointing out that many patients would likely be willing to try injections if they had the opportunity.

Conclusion: A New Era in Diabetes and Cardiovascular Care

The SOUL trial provides strong evidence supporting the use of oral semaglutide as a treatment option for patients with type 2 diabetes and established cardiovascular or kidney disease. By offering a convenient oral option, semaglutide may overcome barriers to treatment adherence and reduce the risk of major adverse cardiovascular events in this high-risk population. As research continues, clinicians will have to weigh the benefits of oral versus injectable semaglutide based on patient preferences, bioavailability, and overall treatment goals.