Evidence Grade C — Moderate human evidence. 92 published studies, 52 human. 47 registered clinical trials.
Medically reviewed by a licensed medical professional
Orforglipron is a once-daily pill in late-stage development by Eli Lilly that activates the same GLP-1 receptor targeted by injectable treatments like semaglutide and tirzepatide. It is not a peptide — it is a small molecule — but it could become the first oral non-peptide GLP-1 treatment for obesity and diabetes, potentially offering a far more convenient alternative to weekly injections with no cold-chain storage requirements.
Orforglipron is also known by these brand and alternate names:
92 published studies: 52 human, 0 animal, 0 in-vitro, 48 reviews
Orforglipron is in Phase III development (not yet approved). Phase II results (272 patients, 36 weeks) showed up to 14.7% weight loss. Phase III results (ATTAIN-1, 3,127 patients, 72 weeks) showed 11–12% weight loss, which is less than injectable GLP-1 agonists but achieved with a once-daily pill.
Orforglipron is not a peptide. Its significance is in potentially making GLP-1-based obesity treatment available in pill form without the cold-chain storage and injection requirements of current peptide-based treatments. Phase III trials for type 2 diabetes are also ongoing.
Orforglipron binds a different site on the GLP-1 receptor than peptide agonists — a hydrophobic pocket within the receptor's transmembrane domain rather than the exterior peptide-binding site. It is a partial agonist biased toward the cAMP signalling pathway, which may reduce receptor desensitisation compared to full agonists. Despite its different binding mode, it produces the same downstream metabolic effects: appetite suppression, delayed gastric emptying, and glucose-dependent insulin secretion.
Phase III results (ATTAIN-1, 3,127 patients) showed 11-12% weight loss at 72 weeks — less than injectable GLP-1 agonists but achieved with a simple daily pill. A head-to-head trial showed superiority over oral semaglutide (Rybelsus) for blood sugar control. A regulatory filing was submitted in December 2025, with potential approval in 2026. Orforglipron's weight loss is lower than injectable competitors like CagriSema (23%) and tirzepatide (22.5%), positioning it primarily as an oral-first option for patients who prefer pills over injections, or as a step before escalating to injectables. The lack of food or water restrictions (unlike oral semaglutide) and room-temperature storage are meaningful practical advantages.
PeptideTrace tracks 47 registered clinical trials for Orforglipron sourced from ClinicalTrials.gov.
A Study of Orforglipron (LY3502970) in Participants With Type 2 Diabetes Who Observe Ramadan Fasting
A Study of Orforglipron (LY3502970) on Cardiovascular Outcomes in Adults With Atherosclerotic Cardiovascular Disease and/or Chronic Kidney Disease (ATTAIN-Outcomes)
Efficacy and Safety of Orforglipron in Participants With Peripheral Artery Disease
A Study of Orforglipron in Female Participants With Stress Urinary Incontinence Who Have Obesity or Overweight
A Study of Orforglipron (LY3502970) in Participants With Obesity or Overweight and Osteoarthritis (OA) of the Knee
Orforglipron (LY3502970) is a non-peptide oral small-molecule GLP-1 receptor agonist developed by Eli Lilly, originally discovered by Chugai Pharmaceutical. NOTE: This is NOT a peptide. Molecular formula: C48H48F2N10O5; molecular weight approximately 883 Da. CAS number: 2212020-52-3. The compound has a half-life of 29-49 hours supporting once-daily oral dosing without food or water restrictions. The NDA was submitted to the FDA in December 2025 with a Commissioner's National Priority Voucher, and Lilly plans submissions in over 40 countries.
Orforglipron binds a hydrophobic pocket within the transmembrane domain of GLP-1R, distinct from the orthosteric peptide-binding site, as resolved by cryo-electron microscopy at 3.1 angstrom resolution. The compound is a partial agonist biased toward Gs/cAMP signaling with low beta-arrestin recruitment, potentially reducing receptor desensitization compared with peptide agonists. A primate-specific Trp33 residue in the receptor is essential for binding, which precluded the use of standard rodent models during early development.
Phase 2 obesity trial (N=272; NEJM September 2023): the 45 mg dose achieved -14.7% weight loss at 36 weeks with a placebo-adjusted difference of -12.3 percentage points. ATTAIN-1 Phase 3 (NCT05869903; N=3,127; NEJM September 2025): the 36 mg dose achieved -11.2% (treatment-regimen estimand) and -12.4% (efficacy estimand) at 72 weeks versus -2.1% placebo (P<0.001). Key categorical outcomes at 36 mg: at least 10% loss in 54.6%, at least 15% in 36.0%, at least 20% in 18.4%. ATTAIN-2 (T2D): -10.5% weight loss at 36 mg. ACHIEVE-3 (NCT number pending; N=1,698; Lancet 2026): orforglipron outperformed oral semaglutide on all primary and secondary endpoints. Gastrointestinal adverse events include nausea (29-36%), constipation (22-30%); discontinuation due to adverse events was 5.3-10.3%. No hepatic safety signal identified.
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Semaglutide is one of the most extensively studied peptide medications available today, with clinical trial data spanning over 50,000 patients. It is sold as Ozempic for type 2 diabetes (approved 2017), Rybelsus as an oral tablet for diabetes (approved 2019), and Wegovy for weight management (approved 2021). Wegovy has since received additional approvals for reducing heart attack and stroke risk, for use in adolescents aged 12 and older, and for liver disease related to obesity. In clinical trials, patients taking Wegovy lost an average of 14.9% of their body weight over 68 weeks, and the SELECT trial demonstrated a 20% reduction in major cardiovascular events such as heart attack and stroke. Research is now exploring its potential in early Alzheimer's disease. The main side effects are gastrointestinal, particularly nausea, and a key limitation is that most weight tends to return after stopping treatment.
Bimagrumab is in Phase II/III development (not yet approved). A Phase II trial (75 patients with type 2 diabetes and obesity) showed 20.5% fat mass reduction with 3.6% lean mass increase — essentially reshaping body composition without net appetite suppression. The BELIEVE Phase IIb trial (507 patients) showed that bimagrumab plus semaglutide achieved 22% weight loss with the weight lost being 88% fat — significantly better body composition than semaglutide alone. Bimagrumab is not a peptide. Its strategic significance is as a combination partner to address the muscle loss problem inherent in weight loss with current obesity drugs. Eli Lilly's acquisition positions it alongside tirzepatide.
Pemvidutide is in Phase II/III development (not yet approved). In the MOMENTUM Phase II trial (391 patients, 48 weeks), the 2.4 mg dose achieved 15.6% weight loss. Body composition analysis showed 78% of weight lost was fat mass, with only 22% lean mass — a favourable ratio. A Phase IIb MASH trial (212 patients) showed MASH resolution in up to 75% of patients at the highest dose. Pemvidutide's balanced receptor profile and no-titration dosing regimen represent potential practical advantages. The high rate of MASH resolution in Phase II positions it as a candidate for liver disease indications alongside obesity.
Evidence Reviews
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This content is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional before making decisions about your health.
