Daily oral orforglipron leads to significant weight loss in obese/overweight people: NEJM

Adverse events seen with orforglipron, a nonpeptide GLP-1 receptor agonist, were similar to those with injectable GLP-1 receptor agonists.

Obesity is a global health problem and is a risk factor for many leading causes of illness and death. There is a need for data regarding the safety and efficacy of orforglipron, a nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist, as a once-daily oral therapy for weight reduction in obese adults in phase 2, randomized, double-masked trial.

The trial enrolled adults with overweight or obesity plus at least one weight-related coexisting condition without diabetes. Two hundred seventy-two participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. At week 26 (primary endpoint), the authors assessed the percentage change from baseline in body weight and at week 36 (secondary endpoint). At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9.

The study revealed the following findings:

• At week 26, the mean change from baseline in body weight ranged from −8.6% to −12.6% across the orforglipron dose cohorts and was −2.0% in the placebo group.
• At week 36, the mean change ranged from −9.4% to −14.7% with orforglipron and was −2.3% with placebo.
• A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, compared with 9% who received a placebo.
• The use of orforglipron improved all prespecified weight-related and cardiometabolic measures.
• The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts.
• The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class.

Currently approved GLP-1 agonists for type 2 diabetes and/or obesity are peptide-based and given orally or by subcutaneous injection. No oral GLP-1 agonists are approved for obesity, and only oral semaglutide is approved for type 2 diabetes, the authors noted.

The formulation of oral semaglutide is done with an ingredient that helps protects its degradation and enhances gastric absorption. To maximize efficacy and absorption, the doctors advise taking it in the fasting stage and not drinking or eating anything for at least 30 minutes after. The bioavailability of orally ingested semaglutide is only 1% or less.

"In contrast, Orforglipron is a small molecule that isn't a peptide, so it isn't degraded in the gastrointestinal tract and can be taken with or without food," Manige Konig, Eli Lilly, Indianapolis, IN, and colleagues concluded.

Reference:

The study, "Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity," was published in The New England Journal of Medicine.

DOI: 10.1056/NEJMoa2302392