Orforglipron

Research overview

Key studies

1. Wharton et al., N Engl J Med (ATTAIN-1) (2025)

   Phase 3, randomized, double-blind, placebo-controlled, 72 weeks
   Model: Humans (3127 adults with obesity without diabetes)

   Body-weight change -7.5%, -8.4% and -11.2% with 6, 12 and 36 mg versus -2.1% with placebo; adverse events led to discontinuation in 5.3-10.3% versus 2.7% ^4.

2. Rosenstock et al., N Engl J Med (ACHIEVE-1) (2025)

   Phase 3, randomized, double-blind, placebo-controlled, 40 weeks
   Model: Humans (559 adults with type 2 diabetes on diet and exercise)

   HbA1c change -1.24 to -1.48 percentage points versus -0.41 with placebo; no severe hypoglycemia reported ^5.

3. Rosenstock et al., Lancet (ACHIEVE-3) (2026)

   Phase 3, open-label, randomized, active-controlled, 52 weeks
   Model: Humans (1698 adults with type 2 diabetes on metformin)

   HbA1c reductions with orforglipron 12 and 36 mg were non-inferior and superior to oral semaglutide 7 and 14 mg; discontinuation for adverse events was 9-10% versus 4-5% ^6.

4. Klein et al., Lancet (ACHIEVE-4) (2026)

   Phase 3, event-driven, open-label, non-inferiority, active comparator
   Model: Humans (2749 adults with type 2 diabetes at increased cardiovascular risk)

   MACE-4 occurred in 4.2% versus 5.0% with insulin glargine (HR 0.84; 95% CI 0.59-1.20), meeting non-inferiority ^7.

5. Kawai et al., Proc Natl Acad Sci U S A (2020)

   Structural biology, pharmacology and animal efficacy studies
   Model: Cells, humanized mice and nonhuman primates

   Identified LY3502970 as a partial, G protein-biased nonpeptide GLP-1 receptor agonist with a distinct binding pocket ^3.

Dosing as stated on the FDA label

Quoted from the prescribing information for reference. Prescribing decisions belong to a licensed clinician; this is not a recommendation or instruction for use.

• For chronic weight management (FOUNDAYO): start at 0.8 mg orally once daily; after at least 30 days increase to 2.5 mg, then after at least 30 days to 5.5 mg once daily ^1.
• The dosage may be increased to the next level (9 mg, 14.5 mg or 17.2 mg once daily) after at least 30 days on the current dosage based on response and tolerability; the maximum is 17.2 mg once daily, and no more than one tablet should be taken per day ^1.
• With a strong CYP3A4 inhibitor the maximum dosage is 9 mg once daily; strong CYP3A4 inhibitors that also inhibit OATP1B and strong CYP3A4 inducers should be avoided ^1.
• If 7 or more consecutive doses are missed, the label advises reinitiating escalation at a lower dosage ^1.
• Label efficacy and safety data come from an investigational orforglipron formulation presented as equivalent FOUNDAYO dosages; the trial publications report capsule doses (for example 36 mg), which ACHIEVE-4 states is equivalent to the 17.2 mg tablet ^1,7.

Published adverse-event data

Reported in the cited trials or product labels. Frequencies apply to the stated population and do not transfer to other settings.

• Nausea
  26% (5.5 mg), 34% (9 mg), 35% (17.2 mg) versus 10% placebo
  Adults with obesity or overweight, pooled Trials 1 and 2 (up to 72 weeks) ¹ · Mostly mild or moderate GI reactions; higher during escalation
• Constipation
  20%, 27%, 24% versus 9%
  Same pooled trials ¹ · Not graded in the label table
• Diarrhea
  21%, 23%, 25% versus 11%
  Same pooled trials ¹ · Not graded in the label table
• Vomiting
  13%, 21%, 24% versus 4%
  Same pooled trials ¹ · Not graded in the label table
• Dyspepsia
  12%, 16%, 13% versus 4%
  Same pooled trials ¹ · Not graded in the label table
• Hair loss
  4%, 4%, 5% versus 2%
  Same pooled trials ¹ · Not graded in the label table
• Discontinuation due to adverse reactions
  8% overall (6%, 9%, 10%) versus 3% placebo
  Same pooled trials ¹ · Mostly gastrointestinal
• Hypoglycemia (glucose below 54 mg/dL)
  2% versus 0.2% placebo; 7% when combined with a sulfonylurea
  Adults with type 2 diabetes and BMI of 27 or more (Trial 2) ¹ · One severe event with orforglipron

What is not known: Long-term outcomes beyond the trial durations, the human relevance of the thyroid C-cell signal (untestable in rodents for this molecule), and use in pregnancy (the label advises discontinuing when pregnancy is recognized) remain open ^1. A type 2 diabetes indication was not on the label reviewed ^1.

Regulatory status

Status

FDA-approved as FOUNDAYO tablets (NDA 220934, original approval April 1, 2026) for reducing excess body weight and maintaining reduction long term in adults with obesity, or overweight with at least one weight-related comorbid condition, with diet and physical activity; the label is current as of the August 13, 2026 DailyMed version and does not include a type 2 diabetes indication ^1,2.

United States (FDA)

FDA-approved under NDA 220934 (FOUNDAYO, Eli Lilly and Co.), original approval April 1, 2026, per Drugs@FDA records retrieved 2026-10-24 ^2; label reviewed from the August 13, 2026 DailyMed version ^1.

Sport (WADA)

Orforglipron is not named in the 2026 Prohibited List text reviewed; it is not a peptide hormone and, being approved, is outside the S0 non-approved class ^8.

Status varies by country and changes over time. How we describe regulatory status.

References

1. FOUNDAYO (orforglipron) tablets, for oral use, prescribing information (DailyMed SPL version 10, published Aug 13, 2026) FDA label (DailyMed). 2026
2. Drugs@FDA application NDA 220934 (FOUNDAYO, Eli Lilly and Co; original approval 2026-04-01) via openFDA FDA (openFDA Drugs@FDA). 2026
3. Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist Proc Natl Acad Sci U S A. 2020
4. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment N Engl J Med. 2025
5. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes N Engl J Med. 2025
6. Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial Lancet. 2026
7. Cardiovascular safety of orforglipron versus insulin glargine in adults with type 2 diabetes at increased cardiovascular risk (ACHIEVE-4): a phase 3, event-driven, randomised, open-label, non-inferiority, active comparator trial Lancet. 2026
8. Tractatenblad 2026 Nr. 25: Anti-doping convention (ETS No. 135), amendment to the appendix - The 2026 Prohibited List, World Anti-Doping Code (English text; entry into force 1 January 2026) Tractatenblad van het Koninkrijk der Nederlanden (official government publication). 2026
9. PubChem compound record for orforglipron (CID 137319706) PubChem. 2026