Oral Orforglipron for Obesity Management

On April 1, 2026, the FDA approved orforglipron (Foundayo; Eli Lilly), an oral glucagon-like peptide-1 (GLP-1) receptor agonist, for weight management in obese and overweight adults having at least one weight-related comorbidity. Orforglipron is a small molecule that activates GLP-1 receptors to regulate appetite and reduce food consumption.

Efficacy

The efficacy of orforglipron was evaluated in 2 randomized, double-blind, placebo-controlled trials, ATTAIN-1 (NCT05869903) and ATTAIN-2 (NCT05872620). In both trials, all participants received counseling on a reduced-calorie diet and a minimum of 150 minutes of physical activity per week beginning with treatment initiation. ATTAIN-1 included 3127 adults with a body mass index (BMI) greater than or equal to 27 kg/m² and at least one weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). Patients with diabetes mellitus were excluded.^1-3

ATTAIN-2 included 1613 adults with a BMI greater than or equal to 27 kg/m² and type 2 diabetes mellitus with hemoglobin A_1c between 7% and 10%. Patients treated with insulin, dipeptidyl peptidase-4 inhibitors, GLP-1 receptor agonists, or pramlintide were excluded. In both trials, participants were randomly assigned to receive orforglipron (6 mg, 12 mg, or 36 mg) or a placebo once daily for 72 weeks. The primary end point in both studies is the mean percent change in body weight at 72 weeks from baseline. In Trial 1, the mean change is –7.5% (95% CI, –8.2 to –6.8), –8.4% (–9.1 to –7.7), and –11.2% (–12.0 to –10.4) for participants taking 6 mg, 12 mg, and 36 mg, respectively, compared with –2.1% (–2.8 to –1.4). Trial 2 yielded similar results in participants with diabetes. The mean change in body weight at 72 weeks is –5.1% (–6.0 to –4.2), –7.0% (–7.8 to –6.2), and –9.6% (–10.5 to –8.7) in participants administered 6 mg, 12 mg, and 36 mg, respectively. Patients receiving placebo experienced a mean body weight reduction of –2.5% (–3.0 to –1.9). In both trials, participants receiving orforglipron at any dose had a statistically significant reduction in body weight compared with participants receiving placebo (P<.001).^1-3

Safety

In trials, the most common adverse effects observed in at least 5% of patients treated with orforglipron include nausea, constipation, diarrhea, vomiting, dyspepsia, abdominal pain, headache, abdominal distention, fatigue, eructation, gastroesophageal reflux disease, and flatulence. Nausea, vomiting, and diarrhea decreased over time and more commonly occurred during dose escalations. Orforglipron should be discontinued in patients who develop pancreatitis or severe gastrointestinal reactions. Monitor patients with diabetic retinopathy, cholecystitis symptoms, or risk of volume depletion. Dose reductions of insulin or insulin secretagogues may be required due to the reduced appetite effects of GLP-1 agonists and the increased risk of hypoglycemia. Do not administer orforglipron with strong CYP3A4 inducers and strong CYP3A4/OATP1B inhibitors. When coadministered with a strong CYP3A4 inhibitor, the maximum recommended dose of orforglipron is 9 mg daily.^1-3

Simvastatin should not exceed 20 mg daily when administered with orforglipron. Delayed gastric emptying may affect the absorption of other orally administered medications. For this reason, barrier methods of contraception are recommended for 30 days after initiation and dose escalations of orforglipron. Orforglipron is contraindicated in patients with a history or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 and is not recommended in patients with Child-Pugh class C hepatic impairment. Orforglipron may harm a fetus. Discontinue during pregnancy.¹

Administration

Foundayo is available as 0.8 mg, 2.5 mg, 5.5 mg, 9 mg, 14.5 mg, and 17.2 mg tablets. The medication is initiated at 0.8 mg once daily, increased to 2.5 mg daily after 30 days, and then to 5.5 mg after another 30 days. Based on response and tolerability, the dose may be increased every 30 days to the maximum dose of 17.2 mg daily. Foundayo may be taken with or without food. If a dose is missed, it should be taken as soon as possible, but no more than once daily. If therapy is interrupted for a week or more, reinitiate it at a lower dose. Store Foundayo at room temperature in the original container to protect the medication from light. ¹

REFERENCES

1. Foundayo. [package insert]. Lilly USA, LLC: 2026. Accessed May 5, 2026. https://pi.lilly.com/us/foundayo-uspi.pdf

2. Wharton S, Aronne LJ, Stefanski A, et al; for the ATTAIN-1 Trial Investigators. Orforglipron, an oral small-molecule GLP-1 receptor agonist for obesity treatment. N Engl J Med. 2025;393(18):1796-1806. doi:10.1056/NEJMoa2511774

3. Horn DB, Ryan DH, Kis SG, et al; ATTAIN-2 Trial Investigators. Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial. Lancet. 2026;406(10522):2927-2944.