Oral Semaglutide: Will Injectors Switch?

With a GLP-1 in pill form for weight loss expected to be FDA-approved by year’s end, obesity medicine physicians said they are gearing up for higher demand and already answering questions about the anticipated new option.

Predictions are mixed about how many people may dump the shots in favor of the pill, and some physicians worry about misuse, mostly patients skipping or double dosing. While doctors welcome the new option, many also pointed to a host of other medications in the pipeline that they say look as good or better than the anticipated new pill.

Semaglutide in a Weight-Loss Pill

The FDA accepted the New Drug Application submission from Novo Nordisk in May for an investigational, once-daily, 25-mg oral form of Wegovy (semaglutide) for chronic weight management in adults with obesity or overweight with one or more comorbid conditions and to reduce the risk for major adverse cardiovascular events in adults with overweight or obesity and cardiovascular disease.

The decision is expected in the fourth quarter of 2025.

No information is available at this point on costs, a Novo Nordisk spokesperson said in late June.

OASIS 4 Results: 13.6% vs 2.2% Loss

The FDA filing is based on results of the phase 3 OASIS 4 trial, presented in November at Obesity Week in San Antonio.

That trial suggested that a dose of 25 mg may be the sweet spot. The double-blind, placebo-controlled 64-week multicenter trial randomized 307 participants with overweight or obesity 2:1 to the 25 mg semaglutide or to placebo. In all, 167 in the intervention group and 76 in the placebo group completed the trial.

The average age was 48 years, and body weight was 105.9 kg. The semaglutide group lost an average of 13.6% of weight vs 2.2% in the placebo group. All adverse events (AEs) were comparable between groups — 93.1% in the semaglutide group and 85.3% in the placebo group; the incidence of serious AEs was lower in the semaglutide group (3.9%) than in the placebo group (8.8%).

While 79.2% of the intervention group lost 5% or more of their body weight, 31.1% of the placebo group did so as well.

Physical functioning improved more in the semaglutide group; improvements in cardiometabolic risk factors were also greater in the semaglutide group.

Doctors Gear Up for Demand

The pill form of semaglutide for weight management will definitely be in demand, doctors told Medscape Medical News, although experts disagreed on how big that demand would be and cited unknown factors such as insurance coverage and costs that would affect people’s decisions.

“Coverage and cost are important and determine who can use the medication,” said Delilah Strother, MD, DABOM, an obesity medicine physician at Providence Swedish Weight Loss Services in Seattle.

While many people have gotten used to injecting themselves, not everyone has. “We actually have people come into our office every week to have us inject them,” said Supriya Rao, MD, DABOM, DABLM, a gastroenterology and obesity medicine physician in Lowell, Massachusetts. “They’re scared of needles. People are able to wrap their head around taking a pill.”

However, Rao thinks those on injectables and happy with them will stay on them. Yet, even then, she said, the unknown, as always, is insurance. “Already we’ve heard rumblings about some [plans] not covering injectables [for weight loss] starting next year,” she said.

While cost is an unknown, Rao predicted the pills will be cheaper than insurance and speculated: “Insurance might be more willing to take those on, as opposed to injectables.”

Doctors say they regularly get the “When’s the pill coming out?” question and have for years. “Many are curious whether the oral version will be as effective, how it compares in term of side effects, and if switching would make sense for them,” said Urvi Vyas, MD, an endocrinologist at Hoag, a healthcare system in Southern California. “There’s enthusiasm, especially among those who have struggled with the logistics or discomfort of weekly injections.”

Right now, “less than 5% of my patients are requesting oral options,” Strother said, “but once an oral option is advertised, I suspect all patients would be more interested in an oral as first line.”

Pills will be a boon for those who travel, said Tanna Donalson, PA-C, a physician assistant in Denver who directs a medical spa because popping a pill is easier than injecting. It will also help those with an issue with refrigeration. (Novo advises storing Wegovy pens in the refrigerator and discarding any that have been out of refrigeration for 28 days or more.) “It opens the door for those who wouldn’t consider GLP-1s [in injectable form],” Donalson said of the expected pill option.

Donalson said it’s difficult to guess who else will switch to oral. She suspects some may actually prefer the weekly injection. For instance, some may do an injection every Sunday, and it’s become kind of a ritual, and they just prefer to keep it that way and not have to think about remembering a dose the rest of the week. She estimates maybe 25% of people on injected GLP-1s would want to switch to a pill.

Misuse and Misconceptions Concerns?

Pill sharing probably isn’t a concern, most doctors interviewed said. Most patients are so grateful to be on the medication they’re not about to share with friends, doctors said.

But misconceptions about pills may need to be cleared up, Rao said. “People think pills don’t have as many side effects as injecting,” and that they can go on and off, which she will advise against.

Pills are easier to misuse, such as by skipping a day, and that could affect results, she said.

Setting Expectations

In the phase 3 trial, patients lost an average of 13.6% of body weight.

“That’s a substantial amount and is comparable to results seen with injectable GLP-1 medications,” said Vyas. “Of course, real-world results can vary depending on individual factors like adherence, diet, physical activity, and metabolic profile.” She emphasizes to patients the medications are part of an overall strategy for health.

Coming Up

Numerous other medications are in development for both weight loss and diabetes. Two that doctors often mentioned they are tracking:

• Orforglipron: Studied in a phase 3 trial to reduce A1C, Lilly’s small-molecule GLP-1 lowered A1C by an average of 1.3%-1.6% from a baseline of 8%. In a secondary endpoint, those randomly assigned to orforglipron lost an average of 16 lb, or 7.9% of weight, at the highest dose at 40 weeks, and the weight loss had not plateaued when the study ended. Lilly is studying it in the ATTAIN trial as a weight-loss medication for people with obesity or overweight; results are expected late in 2025.
• Amycretin: In early-stage research, Novo Nordisk’s obesity medication includes subcutaneous and oral formulations; results were published here and here.

“I do believe there will be quite a host of different medicines coming out that will be able to benefit our patients,” Rao said. Her hope, shared by other physicians and patients hoping to benefit, is that insurance will understand those benefits and put them within reach.

Strother, Vyas, Donalson, and Rao reported having no disclosures.