Oral GLP-1 confers up to 14.7% weight loss at 36 weeks for adults with obesity
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Key takeaways:
- Adults with obesity lost at least 9.4% of their body weight at 36 weeks with orforglipron.
- The safety profile for orforglipron was similar to other GLP-1 receptor agonists.
SAN DIEGO — Adults with obesity and without diabetes receiving the oral GLP-1 receptor agonist orforglipron lost 8.6% to 12.6% of their body weight at 26 weeks, according to a data from a phase 2 trial.
In findings presented at the American Diabetes Association Scientific Sessions and simultaneously published in The New England Journal of Medicine, most adults receiving 24 mg or more per day of the oral GLP-1 orforglipron (Eli Lilly) lost 10% or more of their body weight at 36 weeks, and weight loss approached 15% at 36 weeks in the highest dose group.
“We observed a 14.7% weight reduction at 36 weeks, and it was not yet at plateau,” Sean Wharton, MD, director of the Wharton Medical Clinic in Toronto, said during a presentation.
Efficacy was similar to approved injectable GLP-1 receptor analogs, he said.
“In my opinion, this is a medical advancement not just another study ... because this is a non-injectable, it’s a nonpeptide. It's hard to make injections. It's hard to make oral peptides for the world,” Wharton told Healio. “Obesity is on every continent, in every country, and there's no access to care. ... Making a chemical, nonpeptide, small molecule drug that you can make a billion of relatively quickly and warehouse them can [help] people access care that they need. ... That's what I think is the game changer. This is a world-changing molecule.”
Researchers conducted a phase 2 randomized controlled trial with 272 adults aged 18 to 75 years with obesity or overweight plus one weight-related comorbidity and without diabetes (mean age, 54.2 years; 59% women). Participants must have had a stable body weight for at least 3 months before enrollment. After a 2-week screening and run-in period, adults were randomly assigned to 12 mg, 24 mg, 36 mg or 45 mg orforglipron or placebo daily for 36 weeks. A 2-week follow-up period followed the 36 week trial. The trial’s primary endpoint was percent change in body weight from baseline to 26 weeks. Secondary endpoints included percent change in body weight from baseline to 36 weeks, absolute changes in body weight, BMI and waist circumference at 26 and 36 weeks, and the percentage of adults with at least a 5% and 10% weight loss at 26 and 36 weeks.
At 26 weeks, the mean weight loss was 8.6% in the 12 mg orforglipron group, 11.2% in the 24 mg orforglipron group, 12.3% in the 36 mg orforglipron group and 12.6% in the 45 mg orforglipron group compared with 2% for those receiving placebo. Mean weight loss further increased at 36 weeks for those receiving orforglipron to 9.4% with the 12 mg dose, 12.5% with the 24 mg dose, 13.5% with the 36 mg dose and 14.7% with the 45 mg dose compared with 2.3% with placebo. At 36 weeks, more than half of adults in all orforglipron groups except the 12 mg group achieved a 10% or better weight loss, with 75% of the 36 mg group losing at least 10% of their body weight.
The placebo-corrected percentage body weight loss with orforglipron ranged from 6.5% to 10.6% at 26 weeks and from 7.1% to 12.3% at 36 weeks across the dose cohorts. The placebo-corrected absolute change in body weight ranged from –6.9 kg to –11.2 kg at 26 weeks and from –7.4 kg to –13 kg at 36 weeks. For BMI, the placebo-corrected change with orforglipron ranged from –2.4 kg/m2 to –3.9 kg/m2 at 26 weeks and from –2.5 kg/m2 to –4.6 kg/m2 at 36 weeks. The change in waist circumference ranged from –4.4 cm to –8.7 cm at 26 weeks and from –5.6 cm to –9.6 cm at 36 weeks. Participants receiving orforglipron had a mean change in systolic blood pressure of –10.5 mm Hg at both 26 and 36 weeks compared with a change of –3.6 mm Hg at 26 weeks and –1.8 mm Hg at 36 weeks with placebo. There was no difference observed in diastolic BP.
The most common adverse events with orforglipron were nausea, constipation, vomiting, diarrhea and eructation. The percentage of participants receiving orforglipron who reported adverse events ranged from 86% to 90% across the dose cohorts vs. 76% with placebo. Serious adverse events were reported by seven adults receiving orforglipron. There was no clinically relevant difference in serious adverse events between those receiving orforglipron and placebo, and the safety profile of orforglipron was consistent with other GLP-1 receptor agonists.
“Orforglipron can be taken without restriction of food, water and other medications and has a half-life [that] enables once-daily dosing,” Wharton said. “This promising data of a chemical, nonpeptide molecule supports continued development of orforglipron as an oral treatment for obesity.”
Wharton said a phase 3 trial has begun to analyze orforglipron as a treatment for chronic weight management for treatment of obesity.
Reference:
- Wharton S, et al. N Engl J Med. 2023:doi:10.1056/NEJMoa2302392.
Perspective
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Orforglipron is promising. It's very competitive with injectable GLP-1 receptor agonists, and it has the advantage of being oral. It has the same side effect profile, so we'll have to see how that stacks up. I think what this does is expand the market to people who could use a GLP-1 receptor agonist more in the primary care space.
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Wharton S, et al. 52-OR. Presented at: American Diabetes Association Scientific Sessions; June 23-26, 2023; San Diego (hybrid meeting).
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