Oral, Daily Semaglutide Cuts Pounds in Nondiabetic Patients: OASIS 1

An oral formulation of semaglutide produces significant reductions in body weight compared with placebo, investigators for the phase III OASIS 1 trial reported this week.

The news joins other developments in the exploding glucagon-like peptide (GLP) sphere that have been making headlines around the world and driving the popularity of the one-time diabetes drugs now making strides in weight management.

“To our knowledge, this was the first trial to assess the body weight-lowering effect of an oral glucagon-like peptide-1 (GLP-1) analogue (semaglutide 50 mg taken once per day) in adults with overweight or obesity, without type 2 diabetes,” OASIS 1 investigators reported in the Lancet this week. “In this population, oral semaglutide 50 mg induced clinically meaningful reductions in body weight, with accompanying improvements in cardiometabolic risk factors.”

The study was simultaneously released at the American Diabetes Association 2023 Scientific Sessions alongside several other presentations testing oral formulations in diabetes (PIONEER PLUS) as well as a new dual glucagon (GCG) receptor and GLP-1 receptor drug, survodutide, and the triple-targeting retatrutide, which acts on GLP-1, GCG, and glucose-dependent insulinotropic polypeptide (GIP).

Speaking with TCTMD, lead investigator Filip K. Knop, MD (University of Copenhagen, Denmark), stressed that the emerging data point to drug effects that go far beyond the weight loss mania that has made brand-name semaglutide a household name.

“I just want to make sure that cardiologists understand that GLP 1 receptor agonists are not only for people who want to fit into a new bikini and lose a little bit of weight. These drugs are transformative in the way that they make people lose so much weight, but they also have other pleiotropic effects which all seem to improve cardiovascular health,” he said.

I just want to make sure that cardiologists understand that GLP 1 receptor agonists are not only for people who want to fit into a new bikini and lose a little bit of weight. Filip K. Knop

Commenting on the study for TCTMD, Pam Taub, MD (UC San Diego Health, La Jolla, CA), called the flurry of research into new agents in this space encouraging. “This system of modulating the GLP axis is very potent and we're going to see a lot more, even more powerful drugs emerge,” she predicted. “I think it's going to negate the need for bariatric surgery because the magnitude of weight loss is so profound.”

An Oral Option

Marketed as Ozempic, a 0.5-mg or 1.0-mg subcutaneous dose of semaglutide is indicated to control glucose levels in type 2 diabetes, and to reduce the risk of cardiovascular events in people with diabetes and known heart disease. Marketed as Wegovy, a 2.4-mg subcutaneous dose is approved for chronic weight management in overweight or obese adults with at least one cardiometabolic disease. Both are sold by Novo Nordisk.

A Food and Drug Administration-approved oral formulation (7 mg or 14 mg daily) is indicated for type 2 diabetes, but whether an even higher oral dose—50 mg once daily—could be effective for weight loss was unknown.

I think it's going to negate the need for bariatric surgery because the magnitude of weight loss is so profound. Pam Taub

In the meantime, both Ozempic and Wegovy are being widely plugged on social media and in mainstream magazines for helping people lose significant amounts of weight. An uptick in inappropriate prescribing Ozempic for weight loss in the absence of diabetes has contributed to recurring drug shortages in the United States.

“We haven't seen oral semaglutide, what's currently available, really take off,” Taub said. “People still continue to use the subcutaneous, once-a-week formulation of semaglutide, so it's nice to see that in this trial a much higher dose, 50 milligrams, was pretty well tolerated. It really tells us that we should be thinking about using the oral agent more in clinical practice.”

OASIS 1 in Obesity

OASIS 1 randomized 667 patients at 50 centers to semaglutide 50 mg or placebo. The drug was initiated at 3 mg and escalated every 4 weeks (or more, as needed) to reach the 50 mg maintenance dose by week 16.

At 68 weeks, mean weight loss from baseline was 15.1% in the semaglutide patients and 2.4% in placebo-treated patients (P < 0·0001). Approximately 85% of patients in the investigational group lost at least 5% of their original weight, as compared with 26% in the placebo group (OR 12.6; 95% CI 8.5-18.7), a proportion that fell to 69% and 12% when restricted to patients who lost at least 10% of their baseline weight (OR 14.7; 95% CI 9.6-22.6), and 34% and 3%, respectively, for those losing at least 20% (OR 18.5; 95% CI 8.8-38.9).

The safety profile was “generally in line with subcutaneous semaglutide,” the authors note, as well as with the GLP-1 receptor agonist class as a whole. More semaglutide patients reported gastrointestinal-related adverse events, including upper gastrointestinal events such as gastro-esophageal reflux disease and dyspepsia, with events typically occurring in the dose-escalation period

Both the weight loss achieved and the safety profile seen support a role for an oral formulation, the authors conclude. “These results were notably consistent with those previously reported for subcutaneous semaglutide 2.4 mg taken once per week in a similar population,” they say. “Oral semaglutide 50 mg therefore might represent an effective option for the treatment of obesity.”

“What's really encouraging about this study is the magnitude of weight loss with an oral agent is pretty astounding: about a 15% decrease over a 68-week period, and that’s impressive,” Taub said. “It's nice to have another tool in our armamentarium for weight loss. I would love to see this higher dose being looked at in patients with type 2 diabetes, because it would be interesting to see what this higher dose does in terms of cardiovascular outcomes.”

To TCTMD, Knop stressed that there are very good data from the diabetes trials supporting a reduction in hard cardiovascular events—MI, stroke, and CVD-death—with injectable semaglutide in the SUSTAIN-6 trial and with the oral formulation, albeit at a lower dose, in PIONEER-6.

“Of course, those studies were performed in a type 2 diabetes population, which is characterized by a much higher risk of cardiovascular events as compared to the nondiabetic overweight or obese population that was studied in OASIS 1,” he said.

What’s encouraging, however, is that cardiac biomarkers all headed in the right direction with semaglutide in OASIS 1. Systolic and diastolic blood pressures, lipid parameters, glucose levels, and high-sensitivity C-reactive protein levels all showed improvements on the study drug versus placebo. “That’s not the same as reducing the hard endpoints, but it’s a good start,” Knop said.

The field is eagerly awaiting the results from the large, placebo-controlled SELECT trial, expected to report out earlier this year, he continued, likely at the American Heart Association 2023 Scientific Sessions. The trial is randomizing more than 17,000 overweight and obese adults, without diabetes, to placebo or the once-weekly injectable dose of semaglutide.

“To me, it would be a big surprise if the SELECT study does not read out positively,” Knop said.