SAN DIEGO – Higher doses of oral semaglutide than the 14-mg/day dose that is currently approved for type 2 diabetes may be additional options for patients with prediabetes or diabetes and obesity, according to the results of two new Phase 3 clinical trials.
The two trials, OASIS in patients with overweight or obesity without diabetes and PIONEER PLUS in patients with inadequately controlled type 2 diabetes, were presented here at the American Diabetes Association (ADA) 83rd Scientific Sessions and simultaneously published in The Lancet.
Filip K. Knop, MD, PhD, University of Copenhagen, Denmark, presented highlights of the OASIS-1 results, and Vanita R. Aroda, MD, Brigham and Women's Hospital and Harvard University, Boston, Massachusetts, presented key findings of PIONEER PLUS, during a press briefing prior to the ADA session.
OASIS-1 showed that "oral semaglutide 50 mg may represent an effective option for the treatment of obesity, particularly in patients who prefer oral administration," Knop summarized.
And "the PIONEER PLUS trial showed superior glycemic control and body-weight loss and improvement in cardiometabolic risk factors, with higher doses of once-daily oral semaglutide (25 mg and 50 mg) compared with the currently [highest] approved 14-mg dose," said Aroda.
Session Chair Marion Pragnell, PhD, vice president of research & science at ADA, told Medscape Medical News there is a need for multiple treatment options, as different patients respond differently to individual drugs. The oral dose of semaglutide has to be higher than that approved for subcutaneous injection (as Ozempic or Wegovy) due to bioavailability, but small molecule research is advancing such that in future lower doses of oral drugs may have the same effect as the current lower subcutaneous doses of the drug.
The oral version of semaglutide (Rybelsus) was approved in the US for type 2 diabetes in doses of 7 mg or 14 mg per day in 2019; it has not been approved for use in obesity.
Knop remarked that in his clinical practice, about 25% of patients with type 2 diabetes prefer daily oral semaglutide and the rest prefer weekly injected semaglutide.
"Having an oral formulation of semaglutide in addition to the subcutaneous, or injectable, formula available will allow people who struggle to lose weight with diet and physical activity alone to take this effective medication in a way that best suits them," he added.
Participants in OASIS and PIONEER PLUS were instructed to take the once-daily study drug tablet in the morning, in the fasting state, with up to half a glass of water (120 mL) at least 30 minutes before intake of any other food, beverage, or oral medication.
Sean Wharton, MD, PharmD, the assigned discussant and last speaker in the packed room at the ADA session where the results were revealed, said: "OASIS 1 and PIONEER PLUS introduce the world to a medication that is oral, relatively easy to administer, scalable, and effective, with a similar magnitude of efficacy as injectable semaglutide," a 15% weight loss at 52 weeks.
Wharton is an assistant professor at the University of Toronto, Ontario, Canada, and lead author of the 2020 Canadian obesity guidelines. He was not involved with either trial.
OASIS: 50-mg Daily Pill in Adults With Overweight or Obesity
Knop and colleagues say that, to their knowledge, OASIS is "the first trial to assess the bodyweight-lowering effect of an oral GLP-1 agonist (semaglutide 50 mg taken once per day) in adults with overweight or obesity, without type 2 diabetes."
The 50-mg dose induced clinically meaningful reductions in bodyweight, with accompanying improvements in cardiometabolic risk factors, consistent with results reported for subcutaneous semaglutide 2.4 mg once weekly (Wegovy) in a similar population.
As an adjunct to diet and physical activity, oral semaglutide 50 mg led to a mean bodyweight reduction of 15.1% compared with 2.4% in the placebo group, and greater percentages of participants reaching bodyweight reduction targets of at least 5%, 10%, 15%, and 20%.
Body-weight reductions were accompanied by significant improvements in cardiometabolic risk factors compared with placebo.
"These results indicate that oral semaglutide 50 mg could provide an effective, future option for people with overweight or obesity who would benefit from a GLP-1 receptor agonist," they conclude.
PIONEER PLUS: Inadequately Controlled Type 2 Diabetes
Reporting the PIONEER PLUS data, Aroda and colleagues say: "For people with inadequately controlled type 2 diabetes on a stable dose of one to three oral glucose-lowering drugs, higher doses (25 mg and 50 mg) of once-daily oral semaglutide provided more effective glycemic control and greater bodyweight loss than 14-mg semaglutide, without additional safety concerns."
PIONEER PLUS is the first study to indicate that these bigger doses of semaglutide might provide a highly effective oral option to improve both glycemic control and weight loss in type 2 diabetes.
"This trial provides compelling evidence that the availability of a wider range of doses of oral semaglutide will allow for individualized dosing to the desired effect, and the ability to intensify treatment as needed," said Aroda. "We are hopeful that these results encourage earlier effective management of type 2 diabetes and allow for broader management in the primary care setting."
In an accompanying editorial, Christina H. Sherrill, PharmD, and Andrew Y. Hwang, PharmD, write: "This expansion in dosing titration might provide clinicians with more opportunities to obtain the maximum efficacy of this oral GLP-1 agonist."
But additional investigations "to establish whether the superior glycemic reduction seen at these higher doses translates into cardiovascular risk reduction" are needed, say Sherrill, High Point University, North Carolina, and Hwang, Massachusetts College of Pharmacy and Health Sciences University, Boston.
Such investigations "would further elucidate the place in therapy of high-dose oral semaglutide," they conclude.
Aroda and colleagues agree: "Future real-world studies will be needed to investigate the clinical impact of the availability of higher doses of oral semaglutide."
Where Would Oral Semaglutide Fit in Clinical Practice?
During his discussion, Wharton said the current "landscape" includes rapid weight management medication development ("like whiplash"), high demand, lack of availability of injectables, and a "Hollywood phenomenon," where people take these medications off-label to lose a few pounds.
"Oral semaglutide 25 mg and 50 mg are effective," he summarized. The magnitude of mean weight loss in these trials (15%) is the same with the oral medication as for 2.4 mg subcutaneous semaglutide. For both formulations, a third of patients lose over 20% of their initial weight.
Wharton pointed out that injectable GLP-1 receptor agonists are unavailable to many people in the world with obesity. Meanwhile, the three countries that have launched injectable semaglutide 2.4 mg (Wegovy) — Norway, Denmark, and the United States — are among the richest in the world.
A pill might have a larger global reach and increase access to care. Semaglutide 50 mg may be a long-term solution for obesity, with reduced associated comorbidities, he said.
What is striking about these trials is that "the company was able to produce a sensational molecule that many people did not think would have such a significant impact," Wharton told Medscape Medical News.
"For those who can afford it, who can take it," he said, "it has a very nice place in overall therapy to give additional options that are similar in efficacy. I also believe it is possible we have the chance of getting equity in getting newer meds to other people."
The trials were funded by Novo Nordisk.
ADA 2023 Scientific Sessions. Presented June 24, 2023.
Lancet. Published online June 25, 2023. OASIS Study, PIONEER PLUS Study, Editorial
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Lead Image: Novo Nordisk
Medscape Medical News © 2023
Cite this: OASIS and PIONEER PLUS Support High-Dose Oral Semaglutide - Medscape - Jun 25, 2023.
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