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Small-Molecule Oral GLP-1 Receptor Agonist for Obesity

Orforglipron, a once-daily oral therapy under development for use in adults with obesity, was associated with weight reduction in a phase 2 trial. Adverse events with the agent were similar to those with injectable GLP-1 receptor agonists, report the authors. “Similar to other GLP-1 receptor agonists, orforglipron produced improvements in the blood pressure and levels of circulating lipids.,” the authors concluded. “When abnormal, these levels are cardiovascular risk factors, so such improvements may lead to cardiovascular benefits, which have been observed with the GLP-1 receptor agonist class.”

Trial participants — none of whom had diabetes — were adults with obesity or overweight and at least 1 weight-related comorbidity. They were randomized to orforglipron 12, 24, 36, or 45 mg or placebo once daily for 36 weeks.

Based on the percentage change from baseline in body weight at week 26 (primary endpoint) and at week 36 (secondary endpoint), the study showed the following: “A total of 272 participants underwent randomization. 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. 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, as compared with 9% who received placebo. The use of orforglipron led to improvement in 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.”

Editorial: “There is growing recognition that obesity is a chronic health condition for which long-term multidisciplinary approaches are needed,” writes an editorialist. “Given the burden of obesity, strategies that are durable and safe and can be safely prescribed by nonspecialists would represent an important advance. Moreover, affordability of treatment and equitable access among vulnerable populations who are at high risk for obesity and related conditions, including those from historically marginalized communities, are essential to the widespread adoption of any new and effective therapeutic strategy. Whether orforglipron will fill this void is unknown, but it is never too early to address equity concerns. [This trial] is an important milestone in the development of effective oral therapeutics for obesity management that are based on a validated mechanism of action and target a pathway for which there is a long track record of clinical experience. Results of phase 3 trials will be key.”

Source: New England Journal of Medicine