Orforglipron

Also known as: LY3502970, OWL833, Foundayo

Evidence: Clinical

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Overview

Small-molecule, non-peptide oral GLP-1 receptor agonist; approved by the FDA in April 2026 as Foundayo for weight management after 72-week phase 3 trials (11.2% loss at the top dose).

Orforglipron (LY3502970, OWL833) is a non-peptide GLP-1 receptor agonist reported by Chugai and Eli Lilly researchers (Kawai 2020). It is taken as a once-daily tablet with or without food. In a 36-week phase 2 trial (n=272) weight fell 9.4 to 14.7% vs 2.3% with placebo (Wharton 2023). Phase 3 ATTAIN-1 (n=3127, no diabetes) reported 7.5%, 8.4% and 11.2% loss at 6, 12 and 36 mg vs 2.1% at 72 weeks (Wharton 2025); ATTAIN-2 in type 2 diabetes reported smaller losses (Horn 2026), and ACHIEVE-1 lowered HbA1c by 1.24 to 1.48 points at 40 weeks (Rosenstock 2025). The FDA approved it on 1 April 2026 (NDA 220934, Foundayo, Eli Lilly, prescription, marketed) for weight reduction and maintenance in adults with obesity, or overweight with a weight-related condition. Labeled strengths (0.8 to 17.2 mg) differ from trial doses because the tablet is a new formulation.

Benefits

Weight loss (human phase 3 RCTs, approved indication), lower HbA1c in type 2 diabetes (human phase 3 RCT), lower waist circumference, systolic blood pressure and triglycerides (human phase 3 RCT), once-daily oral dosing without food or water restrictions (label)

Dosing reference

Research dose: 0.8 mg once daily for at least 30 days, then 2.5 mg, then 5.5 mg, with optional steps to 9, 14.5 or 17.2 mg (FDA label, Foundayo tablets; maximum 17.2 mg). Trials used an investigational formulation at 3 to 45 mg
Range: 800 to 17200 mcg, 1x daily

Oral tablet, once daily, with or without food, swallowed whole. The label escalates in steps of at least 30 days and caps the dose at 9 mg with a strong CYP3A4 inhibitor. After 7 or more missed doses the label restarts escalation at a lower dose. Because delayed gastric emptying may lower oral contraceptive absorption, the label calls for a non-oral or added barrier method for 30 days after starting and after each increase. Trial doses of the investigational formulation (6, 12, 36 mg) correspond to labeled 5.5, 9 and 17.2 mg.

Mechanism

Orforglipron is a partial agonist of the GLP-1 receptor, biased toward G-protein signalling over beta-arrestin recruitment. A cryo-EM structure shows it in a pocket of the upper helical bundle formed by the extracellular domain, extracellular loop 2 and transmembrane helices 1, 2, 3 and 7, a different binding mode from peptide agonists. Contact with the primate-specific Trp33 makes its activity species-selective, so efficacy work used humanized-receptor mice and monkeys (Kawai 2020). In people it reduces food intake, delays gastric emptying (most after the first dose) and lowers fasting glucose (label; Pratt 2023). It is cleared mainly by hepatic CYP3A4 and excreted in faeces, so strong CYP3A4 inhibitors and inducers change exposure (label).

Evidence

Clinical: at least one published human trial or an approved drug

Phase 1a, healthy adults (n=92): half-life 24.6 to 35.3 h after one dose and 48.1 to 67.5 h after 28 days; up to 5.4 kg lost in 4 weeks vs 2.4 kg with placebo (Pratt et al., 2023)
Phase 2 obesity, 36 weeks (n=272): -9.4% to -14.7% across 12 to 45 mg vs -2.3% with placebo; GI events led 10 to 17% to stop (Wharton et al., 2023)
Phase 3 ACHIEVE-1, early type 2 diabetes, 40 weeks (n=559): HbA1c -1.24 to -1.48 points vs -0.41 with placebo; weight -4.5% to -7.6% (Rosenstock et al., 2025)
Phase 3 ATTAIN-1, obesity without diabetes, 72 weeks (n=3127): -7.5% (6 mg), -8.4% (12 mg), -11.2% (36 mg) vs -2.1% with placebo (Wharton et al., 2025)
Phase 3 ATTAIN-2, obesity with type 2 diabetes, 72 weeks (n=1613): -5.1% at 6 mg, larger at higher doses, vs -2.5% with placebo (Horn et al., 2026)
Human-trial status: approved by the FDA on 2026-04-01 (Foundayo, NDA 220934, Eli Lilly) for weight management; prescription, marketed. Further phase 3 trials (ACHIEVE, ATTAIN-MAINTAIN, sleep apnoea, hypertension) continue

References

Side effects

In the pooled 72-week weight trials (3155 on drug), nausea affected 26 to 35% vs 10% on placebo, with constipation, diarrhoea, vomiting, dyspepsia and abdominal pain also common; GI events led 3 to 6% to stop vs 0.7% (FDA label). Boxed warning for thyroid C-cell tumours, a rodent finding with GLP-1 agonists of unknown human relevance; contraindicated with a personal or family history of medullary thyroid carcinoma or MEN 2. Other label warnings: pancreatitis, severe GI reactions, acute kidney injury from volume loss, hypoglycaemia with insulin or secretagogues, diabetic retinopathy complications, gallbladder disease and aspiration under anaesthesia.

Storage

Storage: Room temperature, 20 to 25°C, excursions 15 to 30°C (FDA label, tablets in bottles with desiccant)
Lyophilized: Not stated in the label; manufacturer expiry date applies

Pharmacology

Half-life: 29 to 49 h (human, oral, FDA label); 24.6 to 35.3 h single dose and 48.1 to 67.5 h at day 28 (healthy adults, phase 1a)
Bioavailability: 77% absolute (human, oral 0.8 mg tablet); tmax 4 to 8 h; food lowers AUC by 19%, not clinically relevant (FDA label)
Molecular weight: 883 Da