Orforglipron, Oral GLP-1 drug demonstrates significance weight loss in new clinical trial

Wharton et al., 2025 (N Engl J Med): In a phase 3 multinational, randomized, double-blind trial, Orforglipron, a small-molecule, nonpeptide GLP-1 receptor agonist, was investigated as a treatment for obesity. The safety and efficacy of orforglipron at doses (mg) of 6, 12, or 36 once-daily, as compared with placebo (assigned in a 3:3:3:4 ratio) as an adjunct to healthy diet and physical activity for 72 weeks, was evaluated.  A total of 3127 patients, who had obesity without diabetes mellitus, underwent randomization. The mean change in body weight from baseline to week 72 was -7.5%  with 6 mg, -8.4% with 12 mg, and -11.2%  with 36 mg, as compared with     -2.1%  with placebo. In 36 mg group of orforglipron, 54.6% had a reduction of 10%, 36.0% had a reduction of 15% and 18.4% had a reduction of 20%. With orforglipron waist circumference, systolic blood pressure, triglyceride levels, and non-HDL cholesterol levels significantly improved. The most common adverse events with orforglipron were gastrointestinal effects, which were mostly mild to moderate. The study concluded that 72-week treatment with orforglipron led to significantly greater reductions in body weight than placebo in adults with obesity, the adverse-event profile was consistent with that of other GLP-1 receptor agonists.