Lancet (London, England)Nov 23, 2025

Orforglipron, an oral GLP-1 drug, for treating obesity in people with type 2 diabetes: a phase 3 placebo-controlled trial

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 19, 2026

Abstract

Mean bodyweight reduction with orforglipron was -9.6% for the highest dose over 72 weeks.

Orforglipron treatment led to significant bodyweight reductions of -5.1% with 6 mg, -7.0% with 12 mg, and -9.6% with 36 mg, compared to -2.5% with placebo.
Statistically significant improvements were observed in all prespecified weight and cardiometabolic measures, including HbA1c levels.
Adverse events related to orforglipron were primarily gastrointestinal and led to a higher discontinuation rate compared to placebo.
Ten deaths occurred during the study, with investigators considering most unrelated to the treatment, except for a few specific cases.

Simplified

BACKGROUND: Obesity is a chronic disease that significantly contributes to type 2 diabetes and its complications. We aimed to evaluate orforglipron, an oral small-molecule (non-peptide) GLP-1 receptor agonist, for obesity treatment in adults with type 2 diabetes.

METHODS: This 72-week, phase 3, double-blind, placebo-controlled trial was conducted across 136 sites in ten countries. Participants with a BMI of 27 kg/mor higher and glycated haemoglobin (HbA) of 7-10% (53-86 mmol/mol) were randomly assigned (1:1:1:2) to once-daily orforglipron 6 mg, 12 mg, 36 mg, or placebo. The primary endpoint was the mean percent change in bodyweight from baseline to week 72. The treatment regimen estimand (using data from all randomly assigned participants, regardless of intercurrent events) was the primary estimand, with the efficacy estimand considered supportive. Safety was assessed in all patients who received at least one dose of study drug. This trial was registered at ClinicalTrials.gov (NCT05872620) and is completed. 2 1c

FINDINGS: From June 5, 2023, to Feb 15, 2024, 2859 participants were screened, and 1613 (757 [46·9%] female) were randomly assigned, following a dose-escalation phase, to receive orforglipron 6 mg (n=329), 12 mg (n=332), 36 mg (n=322), or placebo (n=630), as an adjunct to lifestyle modification; 1444 (89·5%) completed the study. Baseline bodyweight was 101·4 kg (SD 22·5), BMI 35·6 kg/m(SD 6·6), and HbA8·05% (SD 0·75; 64·4 mmol/mol [SD 8·2]). For the treatment regimen estimand, the mean percent change in bodyweight from baseline to week 72 was -5·1% (95% CI -6·0 to -4·2) with 6 mg (estimated treatment difference [ETD] -2·7 [95% CI -3·7 to -1·6]; p<0·0001), -7·0% (-7·8 to -6·2) with 12 mg (ETD -4·5 [-5·5 to -3·6]; p<0·0001), and -9·6% (-10·5 to -8·7) with 36 mg orforglipron (ETD -7·1 [-8·2 to -6·1]; p<0·0001), versus -2·5% (-3·0 to -1·9) with placebo (all p<0·0001 compared with placebo). All prespecified weight and cardiometabolic measures including HbAstatistically significantly improved with orforglipron. Treatment discontinuations due to adverse events (mainly gastrointestinal-related) were higher for orforglipron (6·1-9·9%) versus placebo (4·1%). The most common adverse events with orforglipron were mild-to-moderate gastrointestinal events, predominantly occurring during dose escalation. Ten deaths were reported during the study: six with orforglipron and four with placebo. Investigators deemed all deaths unrelated to the study treatment, except for one case in the placebo group and one case in the 12 mg orforglipron group. For the case in the orforglipron group, no treatment-related association was reported. 2 1c1c

INTERPRETATION: In adults with obesity or overweight and type 2 diabetes, statistically superior reduction in bodyweight compared with placebo was demonstrated by once-daily orforglipron as an adjunct to lifestyle modification, with a safety profile similar to other GLP-1 receptor agonists.

FUNDING: Eli Lilly and Company.

Full Text

Full text is available at the source.

View Full Text ↗

Funding

Competing interests

Declaration of interests DBH reports consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Roche, Kailera, and Zealand Pharmaceuticals; honoraria for presentations and support for meeting attendance from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Zealand, Vindico, Haymarket, and Novo Nordisk; institutional research support from Eli Lilly, Novo Nordisk, KVK Tech, and Weight Watchers; roles in advisory boards for Eli Lilly, AstraZeneca, Amgen, Novo Nordisk, Zealand, and Boehringer Ingelheim, and in speaker bureaus for Eli Lilly and Novo Nordisk; and volunteer services for The Obesity Society, Obesity Medicine Association, and the World Obesity Federation. BA reports research grants and support for attending meetings from Eli Lilly, Novo Nordisk, Boehringer Ingelheim, and Arrowhead Pharmaceuticals. SGKim reports support for the present manuscript from Eli Lilly; grants from Abbott, Novo Nordisk, and Viatris; consulting fees from AstraZeneca, Novo Nordisk, Celltrion, and Eli Lilly; payments or honoraria from Boehringer Ingelheim, Eli Lilly, Celltrion, Viatris, Sanofi, Daewoong, and AstraZeneca; and support for attending meetings from Eli Lilly and Novo Nordisk. JA reports consulting fees from Boehringer Ingelheim, Eli Lilly, and Novo Nordisk; payments or honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk; support for attending meetings from AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk; and a role as a board member and commission speaker of the German Obesity Association. SCB reports payments or honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Dexcom, Eli Lilly, Menarini, and Novo Nordisk. DHR reports consulting fees for advisory services from AbbVie, Altimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Calibrate, Carmot/Roche, CinRx, Currax, eMedd, Epitomee, Fractyl, Gila, Eli Lilly, Nestle, Novo Nordisk, Pfizer, Regeneron, Source Bio, Structure Therapeutics, Tenvie, Wondr Health, and Zealand; payments or honoraria for presentations from Novo Nordisk, Eli Lilly, and PPD; participation on data monitoring committees for IQVIA, Eli Lilly, and CinRx; volunteer service for The Obesity Society, World Obesity Federation, Stop Obesity Alliance, and Obesity Action Coalition; and stock or stock options from Calibrate, Scientific Intake, Epitomee, Roman, and Xeno Bioscience. AS, SA, ES, QW, SGKis, and IJ are employees and stockholders of Eli Lilly and Company. YM declares no competing interests.

PubMed

Orforglipron, an oral GLP-1 drug, for treating obesity in people with type 2 diabetes: a phase 3 placebo-controlled trial

Abstract

Full Text

Funding

Competing interests

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the glp-1 therapies brief

Abstract

Full Text

Funding

Competing interests

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the glp-1 therapies brief