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


  • The estimated mean change in body weight from baseline to 26 weeks (primary endpoint) was −8.6% in patients treated with orforglipron 12 mg (n=44), −11.2% with orforglipron 24 mg (n=51), −12.3% with orforglipron 36 mg (n=56), −12.6% with orforglipron 45 mg (n=57), and −2.0% with placebo (n=48).
  • At 36 weeks, the estimated mean change in body weight from baseline (secondary endpoint) was −9.4% with orforglipron 12 mg, −12.5% with orforglipron 24 mg, −13.5% with orforglipron 36 mg, −14.7% with orforglipron 45 mg, and −2.3% with placebo. Weight reduction did not appear to have plateaued by week 36.
  • The placebo-corrected absolute change in body weight from baseline with orforglipron ranged from −6.9 to −11.2 kg at 26 weeks and from −7.4 to −13.0 kg at 36 weeks.
  • Orforglipron-treated patients also showed a larger decrease in BMI and waist circumference at 26 and 36 weeks compared with the placebo group.
  • At 36 weeks, a weight reduction of ≥5% was observed in 72%–92% of the orforglipron-treated patients and 24% of the placebo-treated patients, whereas a weight reduction of ≥10% occurred in 46%–75% and 9%, respectively.
  • In addition, orforglipron treatment resulted in a clinically meaningful decrease in systolic blood pressure and improved fasting lipid levels compared with placebo.


  • The rate of any adverse event was 86%–97% in the orforglipron dose cohorts and 76% in the placebo group, and the rate of any serious adverse event was 0%–10% and 0%, respectively.
  • The most common adverse events were gastrointestinal (nausea, constipation, vomiting, diarrhea, and eructation) and were more frequently seen with orforglipron than with placebo. These events were mild to moderate in severity, occurred primarily during dose escalation, and resolved without permanent discontinuation of the study drug.
  • In all orforglipron dose cohorts, the pulse rate increased up to approximately 12 weeks and decreased thereafter. At 36 weeks, the mean change in pulse rate from baseline was 3.2–7.4 bpm in orforglipron-treated patients and −1.8 bpm in those receiving placebo.
  • Overall, the safety profile of orforglipron was similar to that seen with the GLP-1RA class.


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.


1. Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: randomized clinical trial of the efficacy and safety of oral semaglutide monotherapy in comparison with placebo in patients with type 2 diabetes. Diabetes Care. 2019; 42: 1724-32.

2. Kawai T, Sun B, Yoshino H, et al. Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist. Proc Natl Acad Sci U S A. 2020; 117: 29959-67.

3. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes — state-of-the-art. Mol Metab. 2021; 46: 101102.

Find this article online at N Engl J Med.

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