Heart Health
Sonya Collins
Last year, FDA approved injectable semaglutide (Wegovy) to reduce the risk of cardiovascular death, heart attack, and stroke in people with CVD and obesity or overweight. Less was known about the cardiovascular benefits of oral semaglutide (Rybelsus) in this population.
The Semaglutide Cardiovascular Outcomes (SOUL) Trial, a randomized controlled clinical trial, found that oral semaglutide significantly lowered risk for major adverse cardiovascular events in people with T2D and atherosclerotic CVD and/or CKD. The findings were published in the May 29, 2025, issue of NEJM.
“Participants achieved cardiovascular risk reduction of 14%, which is precisely the pooled analysis of injectables,” said Darren McGuire, MD, a study coauthor and the Jere H. Mitchell, M.D. Distinguished Chair in Cardiovascular Science at UT Southwestern Medical Center in Dallas. “This puts the tablet squarely in the GLP-1 receptor agonist space and tells us that a large population can take the tablet appropriately over a long period of time.”
The SOUL trial
The SOUL trial enrolled 9,650 adults aged 50 years and older who had T2D with an A1C of 6.5% to 10% and either atherosclerotic CVD, CKD, or both. Participants were randomized to receive either once-daily oral semaglutide or placebo. The trial followed the study participants for about 4 years to track the primary outcome of major adverse cardiovascular events, including death from cardiovascular causes, nonfatal heart attack and nonfatal stroke, and the secondary outcome of major kidney disease events.
During 4 years of follow up, 12% of those in the semaglutide group had a major cardiovascular event compared with 13.8% of those in the placebo group. There was no difference in kidney disease-related events between the two groups.
“We also had cardiometabolic readouts demonstrating, on average, that weight, A1C and C-reactive protein were reduced,” McGuire said. “We were able to achieve pharmacologic dosing exposure with a tablet that mimics much of the long-term, long acting injectables.”
Injection is still best
The SOUL trial demonstrated that oral semaglutide is a viable option with comparable health benefits for those who cannot use the injectable form of the drug.
“Some patients believe that once they inject themselves with a medication for type 2 diabetes that their disease is much worse than it is,” McGuire said. “It’s a holdover from the fear of needing insulin as a last resort.”
That said, injectable semaglutide is still preferable to the tablet. The injection is more bioavailable than the oral formulation, though the oral dose is nearly 100 times that of the injection. At the 1 mg/week injectable dose, patients get a little more exposure than they do from 14 mg/day by tablet.
“If there’s any dose dependency to any of the benefits,” McGuire said, “the tablet’s only, on average, 0.8% bioavailable.”
Nevertheless, it is a feat, he added, that this drug can be delivered orally.
“This is the first time in the history of medicine we’ve been able to deliver a peptide through the GI tract. It’s revolutionary.”
Tell your patients
For patients who would never consider injectable semaglutide, pharmacists can recommend the oral formulation as equally safe and effective. For those who want to switch from injectable to oral, however, McGuire says he would discourage it. “The needle is so small, you can’t feel it under the skin, so that fear is something we can overcome.”
For patients who are starting oral semaglutide, pharmacists can stress that the drug must be taken on an empty stomach with no more than 4 ounces of water and the patient must not eat or drink for 30 minutes after their dose.
The tablet is made with an absorption enhancer that makes it sticky in the acidic environment of the stomach. Once it reaches the stomach, it sticks to the gastric mucosa. That point of contact is the only place that the medication is delivered, and food or drink would interrupt that absorption.
“The pharmacist will really help us to reinforce this—that you have to take it a little bit differently than other tablets.” ■