Dr. Pep

Peptides · Oral non-peptide GLP-1 receptor agonist

Orforglipron: what the studies show

Every line below comes from a study, label or regulator record, checked by two models, with the source linked. Information, not medical advice. For adults 18+.

What it is

  • Orforglipron (LY3502970) is a once-daily pill from Eli Lilly that activates the GLP-1 receptor. It is a small molecule, not a peptide, and it can be taken without food or water restrictions. It is a different type of drug from injected semaglutide and from oral semaglutide, which is a peptide.[1][2]

Bottom line

  • In large phase 3 trials, orforglipron cut weight by about 11% at 72 weeks in adults with obesity and no diabetes (36 mg), lowered HbA1c in type 2 diabetes, and matched insulin glargine on heart-event safety. Stomach side effects were the main problem. The weight loss was smaller than that reported for injected semaglutide or tirzepatide in network analyses. It is FDA-approved for weight management as Foundayo (2026).[1][2][3][4][5]

What the human studies found

  • ATTAIN-1, a phase 3 double-blind trial funded by Eli Lilly, randomised 3,127 adults with obesity and no diabetes to orforglipron 6, 12 or 36 mg daily or placebo for 72 weeks. Weight changed by -7.5%, -8.4% and -11.2% versus -2.1% on placebo. On 36 mg, 54.6% lost 10% or more of body weight versus 12.9% on placebo.[1]
  • ATTAIN-2 randomised 1,613 adults with obesity and type 2 diabetes for 72 weeks. Weight changed by -5.1%, -7.0% and -9.6% on 6, 12 and 36 mg versus -2.5% on placebo.[6]
  • ACHIEVE-1 (559 adults with early type 2 diabetes, 40 weeks) found HbA1c fell 1.24, 1.47 and 1.48 points on 3, 12 and 36 mg versus 0.41 on placebo. ACHIEVE-3 (1,698 adults on metformin, open-label, 52 weeks) found orforglipron 12 mg and 36 mg beat oral semaglutide 7 mg and 14 mg on HbA1c (for example -1.91% on 36 mg versus -1.47% on semaglutide 14 mg).[7][2]
  • ACHIEVE-4, an event-driven trial in 2,749 adults with type 2 diabetes at high heart risk, compared orforglipron (up to 36 mg) with insulin glargine for about 2 years. Major cardiovascular events occurred in 4.2% versus 5.0% (hazard ratio 0.84, 95% CI 0.59-1.20), which met the trial's non-inferiority test. It does not show a heart benefit.[3]
  • In ATTAIN-MAINTAIN, 376 adults who had lost weight on tirzepatide or semaglutide were switched to daily orforglipron or placebo for 52 weeks. Those on orforglipron kept more of the earlier weight loss (model estimates of about 75% to 79% kept versus 38% to 49% on placebo). It had no arm that kept taking the injection.[8]
  • A population-adjusted indirect comparison (not a head-to-head trial) found oral semaglutide 25 mg gave more weight loss and fewer stops for side effects than orforglipron 36 mg.[9]

Known risks and side effects

  • Boxed warning: risk of thyroid C-cell tumours, as for the GLP-1 class. Orforglipron itself is not active in rats or mice and did not cause tumours there; whether the class effect matters in humans is unknown. Not for anyone with a personal or family history of medullary thyroid cancer or MEN 2.[5]
  • Stomach effects were the most common side effect, mostly mild to moderate. In ATTAIN-1, 5.3% to 10.3% on orforglipron stopped because of side effects versus 2.7% on placebo.[1]
  • In ACHIEVE-1, stopping because of side effects was 4.4% to 7.8% on orforglipron versus 1.4% on placebo, and no severe low blood sugar was reported.[7]
  • A pooled liver-safety analysis of seven phase 3 trials (6,920 on orforglipron, 4,300 on comparators, up to 104 weeks) found no case that met drug-induced liver injury criteria. ALT or AST at least 3x the upper limit with bilirubin at least 2x occurred in 0.1% on each side.[10]
  • A 2026 meta-analysis in adults with overweight or obesity and no diabetes found GLP-1 drugs raised heart rate, and orforglipron 36 mg had the largest rise. A network meta-analysis also found dose-linked stomach effects and higher pancreatic enzymes without clinical symptoms.[11][12]

Legal status

  • FDA-approved as Foundayo (Eli Lilly) tablets for long-term weight reduction, with a reduced-calorie diet and more activity, in adults with obesity, or with overweight and at least one weight-related condition. Label effective 2026-07-29. Using it with another GLP-1 drug is not recommended.[5]
  • FDA's Import Alert 66-80 (GLP-1 active ingredients, 2026) lists orforglipron among its product codes; the corpus text shows the list but not its rules.[13]

Sources

  1. [1] Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment.
  2. [2] 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.
  3. [3] 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.
  4. [4] Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis.
  5. [5] Foundayo (Orforglipron) Tablet, Film Coated prescribing information
  6. [6] 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.
  7. [7] Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes.
  8. [8] Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial.
  9. [9] Oral Semaglutide 25 mg Versus Orforglipron 36 mg in Obesity: A Population-Adjusted Indirect Treatment Comparison.
  10. [10] Hepatic Safety of Orforglipron in Adults With Obesity or Overweight and/or Type 2 Diabetes: A Pooled Analysis of the Orforglipron Phase 3 Clinical Trials.
  11. [11] Effect of glucagon-like peptide-1 receptor agonists on heart rate in non-diabetic individuals with overweight or obesity: a systematic review and pairwise and network meta-analysis of randomized controlled trials.
  12. [12] The Gastrointestinal Safety of Orforglipron, a GLP-1 Receptor Agonist, in Adults With or Without Type 2 Diabetes: A Network Meta-Analysis of Randomized Controlled Trials.
  13. [13] FDA: Import Alert 66-80, GLP-1 active pharmaceutical ingredients (green list)