Orforglipron Associated With Significant Weight Loss


As a once-daily oral treatment, orforglipron could help address barriers to injectable medications, such as semaglutide and liraglutide.

Treatment with orforglipron, an investigational nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist, was associated with significant weight loss in a phase 2 clinical trial, according to findings published in The New England Journal of Medicine.

Image credit: Siam - stock.adobe.com

Image credit: Siam - stock.adobe.com

Clinical guidelines for weight loss have advanced rapidly in recent years, now recommending treatment with weight-management medications for individuals with obesity and those with overweight and weight-related coexisting conditions. GLP-1 receptor agonists have been particularly impactful and are widely used as a component of obesity treatment.

GLP-1 receptor agonists mimic the incretin hormone GLP-1, which decreases appetite and delays gastric emptying. Trials of injectable GLP-1 receptor agonists for weight management have shown long-term efficacy and significant weight loss. To date, only 2 have been FDA-approved for weight loss: 3 mg liraglutide (Saxenda; Novo Nordisk) once daily and 2.4 mg semaglutide (Ozempic; Novo Nordisk) once weekly. An oral formulation of semaglutide has also been approved for the treatment of type 2 diabetes.

Despite their efficacy, the injectable formulations of these medications have resulted in barriers to uptake and access for patients. The oral formulation of semaglutide is only effective when taken 30 minutes before breakfast, and its lower 40 mg dose is less effective for weight reduction. Higher doses of oral semaglutide (25 and 50 mg) are under investigation for both weight management and type 2 diabetes.

Orforglipron is a once-daily oral nonpeptide GLP-1 receptor agonist in development for weight management and type 2 diabetes, and its oral formulation could improve access and adherence challenges. It is a potent partial agonist of the GLP-1 receptor that has a greater effect on cyclic AMP signaling than on b-arrestin recruitment, which may offer lower receptor desensitization than full GLP-1 receptor agonists. The drug has a half-life of 29 to 49 hours, which supports once-daily oral administration.

Investigators conducted a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. The trial included 272 participants with a mean age of 54.2 years, most of whom were female (59%) and White (91%).

Participants were randomized to receive orforglipron 12 mg, 24 mg, 36 mg, or 45 mg, or placebo once daily for 36 weeks. The 36-mg and 45-mg dose cohorts were each divided into 2 subcohorts with different starting doses and dose-escalation schemes. The primary endpoint was the percentage change from baseline in body weight at week 26, and secondary endpoints included percentage change from baseline in body weight at week 36; absolute change from baseline in body weight, body mass index (BMI), and waist circumference at weeks 26 and 36; and weight reductions of at least 5% and at least 10% by weeks 26 and 36.

At week 26, the estimated mean change from baseline in body weight was -8.6% with the 12-mg dose of orforglipron, -11.2% with the 24-mg dose, -12.3% with the 36-mg dose, -12.6% with the 45-mg dose, and -2% with placebo. At week 36, the estimated mean change from baseline in body weight was -9.4% with the 12-mg dose, -12.5% with the 24-mg dose, -13.5% with the 36-mg dose, -14.7% with the 45-mg dose, and -2.3% with placebo. Weight reductions of at least 5%, at least 10%, and at least 15% were more likely with orforglipron than with placebo.

The use of orforglipron also resulted in a continuous decrease in BMI and in the waist circumference from baseline through weeks 26 and 36. There was also a clinically meaningful change in the systolic blood pressure among participants receiving orforglipron.

The mean change from baseline in the systolic blood pressure was up to -10.5 mm Hg at week 26 and was up to -10.5 mm Hg at week 36 with orforglipron, compared with -3.6 mm Hg and -1.8 mm Hg, respectively, with placebo. The use of orforglipron was also beneficial with respect to changes in the levels of fasting lipids, including triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, low-density lipoprotein (LDL) cholesterol, and very-LDL cholesterol.

Nausea, constipation, vomiting, diarrhea, and eructation were the most common adverse events reported with orforglipron, and occurred more frequently with the investigational treatment than with placebo. The incidence of nausea ranged from 37% to 58% across the dose cohorts and was 10% in the placebo group. Most gastrointestinal events were mild to moderate in severity, occurred during dose escalation, and were transient, resolving without permanent discontinuation.

The findings could help push research on orforglipron forward as a new option for weight loss, potentially providing new, more accessible treatment options for patients.


Wharton S, Blevins T, Connery L, et al. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. New Engl J Med. 2023;389(10):877-888. doi:10.1056/NEJMoa2302392

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