The oral GLP-1 pill orforglipron produced up to 14.7% weight loss in 36 weeks, with 75% of participants on the highest dose losing at least 10% of their body weight.
−14.7% body weightMaximum weight loss achieved with the 45 mg daily oral dose of orforglipron over 36 weeks, approaching injectable GLP-1 drug results
What the researchers found
In this phase 2 NEJM trial, the oral GLP-1 pill orforglipron produced up to 14.7% body weight loss at 36 weeks in adults with obesity — compared to just 2.3% with placebo. At the highest dose (45 mg), 75% of participants lost at least 10% of their body weight. The drug also improved all prespecified cardiometabolic measures. Gastrointestinal side effects were the main issue, causing 10-17% of participants to discontinue, but these were mostly mild-to-moderate and occurred during the dose ramp-up period.
Why it matters
This is a landmark trial published in the New England Journal of Medicine — one of the first rigorous demonstrations that an oral, non-peptide GLP-1 drug can produce weight loss approaching what injectable semaglutide achieves. Because orforglipron is a small molecule (not a peptide), it doesn't need special absorption enhancers and can be taken as a simple daily pill. If confirmed in phase 3 trials, it could dramatically expand access to GLP-1-based weight loss treatment by removing the injection barrier.
How the study worked
This was a phase 2, randomized, double-blind, placebo-controlled trial. 272 adults with obesity (mean BMI 37.9, mean weight 108.7 kg) or overweight with weight-related conditions — and without diabetes — were randomized to one of four orforglipron doses (12, 24, 36, or 45 mg) or placebo, taken orally once daily for 36 weeks. The primary endpoint was percentage change in body weight at week 26, with week 36 as a secondary endpoint.
Who was studied
272 adults with obesity (BMI ≥30) or overweight (BMI ≥27) with weight-related conditions, without diabetes
What this study cannot tell us
This is a phase 2 trial with only 272 participants — large enough to establish efficacy signals but too small to detect rare adverse events. The 36-week duration doesn't address long-term safety or whether weight loss is maintained. Participants with diabetes were excluded, so results may not generalize to that population. The 10-17% discontinuation rate due to side effects across dose groups is notable.
How to read the evidence
This is a well-designed phase 2 randomized controlled trial published in the New England Journal of Medicine, with clear dose-response relationships and rigorous methodology. However, phase 2 trials are designed to establish proof-of-concept and dose selection, not definitive efficacy — larger phase 3 trials are needed.
When this study was published
Published in 2023, this was the pivotal phase 2 trial that established orforglipron as a serious contender in the oral GLP-1 space. Phase 3 results have since been reported, building on these findings.
The bigger picture
Injectable GLP-1 drugs have transformed obesity treatment, but needles remain a major barrier for many patients. Oral semaglutide (Rybelsus) exists but requires special absorption technology and fasting restrictions. Orforglipron is different — it's a small molecule, not a peptide, so it doesn't need those workarounds. This NEJM trial put orforglipron on the map as a potential game-changer: a simple daily pill that could bring GLP-1-level weight loss to the mass market. Eli Lilly has since advanced it to phase 3 trials.
Questions still open
- Will phase 3 trials with larger populations confirm these weight loss results and reveal any rare safety concerns?
- How does orforglipron's efficacy compare head-to-head with injectable semaglutide at maximally effective doses?
- Can the GI side effect profile be improved with slower dose titration or modified-release formulations?
Common questions
How is orforglipron different from oral semaglutide (Rybelsus)?
Is 14.7% weight loss as good as injectable GLP-1 drugs?
Read the original research
Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity.
The New England journal of medicine, 389(10), 877-888
Citation
Wharton, Sean; Blevins, Thomas; Connery, Lisa; Rosenstock, Julio; Raha, Sohini; Liu, Rong; Ma, Xiaosu; Mather, Kieren J; Haupt, Axel; Robins, Deborah; Pratt, Edward; Kazda, Christof; Konig, Manige. (2023). Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity.. The New England journal of medicine, 389(10), 877-888. https://doi.org/10.1056/NEJMoa2302392