Weight loss with high-dose oral semaglutide in obese nondiabetics

A higher dose of oral semaglutide than the currently approved 14 mg/day dose may be the next option for overweight or obese patients wanting to lose pounds.

In the phase III OASIS 1 trial presented at the American Diabetes Association (ADA) 83rd Scientific Sessions (ADA 2023), semaglutide 50 mg once daily brought significant reductions in body weight among obese or overweight adults without diabetes.  At week 68, mean weight loss from baseline was 15.1 percent with semaglutide vs 2.4 percent with placebo, for a difference of 12.7 percent (p<0.0001). [Lancet 2023;S0140-6736(23)01185-6]

Approximately 85 percent of patients in the semaglutide group lost at least 5 percent of their body weight vs 26 percent in the placebo group (odds ratio [OR], 12.6; p<0.0001).

“This went down to 69 percent and 12 percent, respectively, when restricted to patients who lost 10 percent of their body weight (OR, 14), and further dropped to 34 percent and 3 percent, respectively, in those who lost at least 20 percent of their weight (OR, 18.5),” said lead investigator Professor Filip Knop from the Centre for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen in Hellerup, Denmark.

OASIS  1 a first-of-a-kind study

“OASIS 1 was the first trial to assess the weight-lowering effect of an oral glucagon-like peptide-1 (GLP-1) analogue in adults with overweight or obesity, but without type 2 diabetes [T2D],” he told ADA 2023 attendees. “In this population, oral semaglutide induced clinically meaningful reductions in body weight, with accompanying improvements in cardiometabolic risk factors.”

Patients were randomly assigned to semaglutide or a matching placebo. Semaglutide was initiated at 3 mg and escalated every 4 weeks (or more, as needed) until it reached the 50 mg maintenance dose by week 16.

The safety profile was in line with those reported for subcutaneous semaglutide and for GLP-1 receptor agonist class in general. Gastrointestinal-related adverse events, including gastroesophageal reflux disease and dyspepsia, were more frequent with semaglutide than placebo (268 vs 154), typically occurring during the dose-escalation period.

“The weight loss achieved and the safety profile observed in the study support a role for oral semaglutide,” said Knop. “Oral semaglutide 50 mg therefore represents an effective option for the treatment of obesity.”

Bariatric surgery may take a back seat

Commenting on the study, Dr Pam Taub from the UC San Diego Health, La Jolla, California, US said the flurry of attention and research being devoted to new agents in the weight loss space is quite encouraging. “This system of modulating the GLP axis is very potent, and we may be seeing a lot more powerful drugs emerge in the future,” she predicted. “I think it’s going to negate the need for bariatric surgery because the magnitude of weight loss is so profound.”

Taub said it would be nice to have another tool in the doctors’ armamentarium for weight loss. Meantime, she looks forward to trials of semaglutide 50 mg in T2D to identify the most efficient way to control both blood sugar and weight. “I would also like to see if the glycaemic reduction seen with this higher dose can translate into cardiovascular risk reduction.”

“I just want to clarify that GLP-1 receptor agonists are not only for people who want to fit into a new bikini or lose weight,” added Knop. “These drugs are transformative as they make people lose so much weight, but they also have other pleiotropic effects which seem to improve cardiovascular health.”

In OASIS, cardiac biomarkers all headed in the right direction with semaglutide. Blood pressure, glucose levels, high-sensitivity C-reactive protein levels, and lipid parameters all improved on semaglutide vs placebo. “This was not the same as reducing the hard endpoints,” acknowledged Knop. “But it’s a good starting point.”

Inadequately controlled T2D

A separate trial of oral semaglutide 25 mg and 50 mg (PIONEER PLUS) in patients with inadequately controlled T2D showed superior glycaemic control and weight loss, on top of improvement in cardiometabolic risk factors. This was relative to the currently highest approved dose of 14 mg. [Lancet 2023;S0140-6736(23)01127-3]

“PIONEER PLUS provides compelling evidence that the availability of a wider range of doses of oral semaglutide will allow for individualized dosing to the desired treatment effect, and the ability to intensify treatment as needed,” said study author Dr Vanita Aroda from the Brigham and Women’s Hospital and Harvard University, Boston, Massachusetts, US during a press briefing prior to the ADA session.

“We are hopeful that these results would encourage earlier effective management of T2D and allow for broader management in the primary care setting,” she added.

Oral semaglutide (7 mg or 14 mg doses daily) is US FDA-approved for T2D in adults. Subcutaneous semaglutide (0.25 mg to 0.5 mg once weekly), on the other hand, is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with T2D. The higher subcutaneous dosing (2.4 mg once weekly) is approved for chronic weight management in overweight or obese adults with at least one cardiometabolic risk.

The symmetry between trials

“OASIS 1 and PIONEER PLUS introduced the world to a medication that is oral, relatively easy to administer, scalable, and effective, with a similar magnitude of efficacy as injectable semaglutide,” commented discussant Dr Sean Wharton from the University of Toronto, Ontario, Canada, who was not involved in the studies.