番茄社区

SAN DIEGO -- Once-daily oral semaglutide proved effective for weight loss in people with obesity, according to the phase III OASIS 1 trial.

When added to lifestyle intervention over 68 weeks, patients taking 50 mg of oral semaglutide lost 15.1% of their weight compared with a loss of 2.4% among those on placebo (estimated treatment difference -12.7 percentage points, 95% CI -14.2 to -11.3), reported Filip Knop, MD, PhD, of the Center for Clinical Metabolic Research at Gentofte Hospital at the University of Copenhagen in Denmark, and colleagues.

This translated to a 15.5 kg (34.2 lb) drop in body weight for those treated with semaglutide versus a 2.5 kg (5.5 lb) loss among those on placebo, Knop noted during the American Diabetes Association (ADA) Scientific Sessions.

The findings were also published in .

"These data are very similar to the STEP 1 trial investigating the effect of injectable semaglutide, Wegovy. No big differences," Knop pointed out at a press conference. "Oral semaglutide thus may represent an effective option for the treatment of obesity, particularly for patients who prefer an oral formulation over injectable formulation, but also for clinicians to help them tailor the perfect obesity treatment for their patients."

In the STEP 1 trial, patients on 2.4 mg of injectable semaglutide lost an average 14.9% of baseline body weight after 68 weeks of treatment compared with only 2.4% in a placebo and lifestyle intervention group.

Significantly more people with overweight or obesity treated with high-dose semaglutide pills also achieved clinically significant weight loss versus placebo, the trial's other co-primary endpoint:

• At least 5% weight loss: 85% on semaglutide vs 26% on placebo
• At least 10% weight loss: 69% vs 12%
• At least 15% weight loss: 54% vs 6%
• At least 20% weight loss: 34% vs 3%

Semaglutide also led to an average 5.6-point drop in body mass index (BMI) versus a 0.9-point drop with placebo. They also lost an average of 13 cm around their waist compared with a 3-cm decrease in the placebo group.

Knop said from his own clinical experience with prescribing semaglutide for type 2 diabetes, an estimated 20%-25% of his patients opt for the once-daily oral form (Rybelsus, 7 mg and 14 mg) over the once-weekly injectable (Ozempic, 0.5 mg, 1 mg, 2 mg).

"There are some restrictions in the way you take oral semaglutide," he explained. "You need to be fasted in the morning, take with half a glass of water, you need to wait 30 minutes before you take your morning coffee or breakfast in order to ensure you actually absorb as much as possible of the active compound. But the other angle with the injectables, you need to get to know the pen well enough to use needles to penetrate your skin."

"So it very much depends on the dialogue you have with your patient [to determine their preference]," he said.

Overall, the safety profile was similar to the already-approved semaglutide products on the market. The most common adverse events were gastrointestinal related, including nausea, constipation, diarrhea, and vomiting. Also as expected, there was a pulse rate increase of 4.1 beats per minute.

One new adverse event that emerged was an increase in altered skin sensation, reported by 13% of semaglutide patients and 1% of placebo patients. This treatment-emergent adverse event hasn't been seen in prior GLP-1 receptor agonist trials, Knop said. "These events, for example, could be hypersensitivity of the skin or paresthesia. They were all transient and all appeared within the first 20 weeks. So they occurred while the weight loss was going on and they were typically mild in nature."

For the 50-center, 667-participant trial (73% women), those randomized to semaglutide were started on a 3-mg dose and were titrated up every 4 weeks, reaching the maximum 50-mg dose by week 16. All participants were instructed to follow a diet with a 500 daily kcal deficit and 150 minutes per week of physical activity.

For inclusion, participants had to have a BMI of at least 30 or 27 plus a weight-related comorbidity (baseline 37.5). Those with diabetes were excluded, but having prediabetes was allowed (HbA1c under 6.5%).

This higher dose of oral semaglutide was also found to be even more effective that the currently highest-approved dose of semaglutide (Rybelsus) for people with uncontrolled type 2 diabetes.

Also presented at ADA and simultaneously published in , the phase IIIb PIONEER PLUS trial showed that patients treated with 50 mg of oral semaglutide had a 2% drop in HbA1c compared with a 1.5% drop in those treated with the 14-mg dose over 52 weeks.

Even a 25-mg dose of oral semaglutide was significantly better at reducing HbA1c than the 14-mg dose (-1.8% vs -1.5%), reported Vanita R. Aroda, MD, of Brigham and Women's Hospital in Boston, and colleagues.

Significantly more patients treated with these two higher investigational doses achieved an HbA1c of 6.5% or lower: 51% on 50 mg, 40% on 25 mg, and 26% on 14 mg. The higher doses also led to a significantly higher loss of body weight (-8.0 kg for 50 mg, -6.7 kg for 25 mg, and -4.4 kg for 14 mg).

That being said, a higher proportion of patients on the 25- and 50-mg doses experienced gastrointestinal side effects, though most were mild to moderate. The most common were nausea (27% on 50 mg, 27% on 25 mg, 18% on 14 mg), vomiting (18%, 17%, 10%), and diarrhea (14%, 13%, 12%).

The altered skin sensation signal didn't come out in this trial, Aroda told 番茄社区. "However, after we saw the results of OASIS 1, we looked back with the sponsor [Novo Nordisk] and looked at the coding, and only at the high dose of 50 mg there was a little bit higher reporting of abnormal skin sensation at about 5% compared to 1% at the lower dose."

This 177-site trial enrolled 1,606 participants (58.3% men), with baseline HbA1c levels of 8%-10.5% (average 9.0%), and a BMI of 25 or higher. Most participants were also on metformin, more than half were on a sulfonylurea, 30% were on an SGLT2 inhibitor, and 25% were on a DPP-4 inhibitor. All sulfonylureas were allowed to be continued throughout the trial, though the dose was lowered to avoid hypoglycemia.

"This expansion in dosing titration might provide clinicians with more opportunities to obtain the maximum efficacy of this oral GLP-1 agonist," wrote Christina Sherrill, PharmD, of High Point University in North Carolina, and Andrew Hwang, PharmD, of MCPHS University in Boston, in an . "Additional investigations are necessary to establish whether the superior glycemic reduction seen at these higher doses translates into cardiovascular risk reduction, which would further elucidate the place in therapy of high-dose oral semaglutide."

announced plans to file for FDA approval this year, though the company noted that "global launch of oral semaglutide 50 mg is contingent on portfolio prioritizations and manufacturing capacity."