Physicians' Academy for Cardiovascular Education

Oral nonpeptide GLP-1RA reduces body weight in phase 2 trial

Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity

Literature - Wharton S, Blevins T, Connery L, et al. - N Engl J Med. 2023 Jun 23 [Online ahead of print]. doi: 10.1056/NEJMoa2302392

Introduction and methods


There is a need for oral therapeutic options with weight-reduction efficacy similar to that of approved injectable GLP-1RAs (i.e., semaglutide and liraglutide). The oral nonpeptide GLP-1RA orforglipron is currently under development for weight management and treatment of T2D [2,3]. As orforglipron is a partial agonist of the GLP-1R, it may offer lower receptor desensitization than full GLP-1RAs [2].

Aim of the study

The authors evaluated the efficacy and safety of oral orforglipron once daily in adults with obesity or overweight but no diabetes.



In this multicenter, double-blind, placebo-controlled, parallel-group, phase 2 RCT, conducted in Canada, the US, and Hungary, 272 patients aged 18–74 years with either obesity (BMI ≥30 kg/m²) or overweight (27–29 kg/m²) plus ≥1 weight-related coexisting conditions (hypertension, dyslipidemia, CVD, or obstructive sleep apnea), but no diabetes, were enrolled. Participants were randomly assigned to oral orforglipron at a dose of 12, 24, 36, or 45 mg (starting dose: 2 or 3 mg) or placebo once daily for 36 weeks. The 36-mg and 45-mg dose cohorts were each divided into 2 subcohorts that had different starting doses and dose-escalation schemes. All participants also received education regarding healthy eating and exercise.


The primary endpoint was the percentage change in body weight from baseline to 26 weeks. Secondary endpoints included percentage change in body weight from baseline to 36 weeks; absolute change in body weight, BMI, and waist circumference from baseline to 26 and 36 weeks; and weight reductions of ≥5% and ≥10% at 26 and 36 weeks. Key safety endpoints included adverse events, pulse rate, and safety-related laboratory measures.

Main results




In this phase 2 trial, patients with overweight or obesity but no diabetes who were treated with oral orforglipron (12, 24, 36, or 45 mg) once daily showed a greater body weight reduction at 26 and 36 weeks than those treated with placebo. The safety profile of orforglipron was similar to that of injectable GLP-1RAs that have been approved for weight management.


Show references

Find this article online at N Engl J Med.

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