Orforglipron

Overview

The development names LY3502970 and OWL833 refer to orforglipron. The original structural paper gives the neutral molecule as C48H48F2N10O5, with a molecular weight of 882.96 g/mol. Foundayo contains the calcium salt; its formula and molecular weight include calcium and are therefore different. Kawai and colleagues, FDA label, section 11.

The FDA indication, checked on October 15, 2026 against the July 2026 label, is reduction of excess body weight and long-term maintenance of that reduction in adults with obesity, or adults with overweight and at least one weight-related condition, together with a reduced-calorie diet and increased physical activity. That indication does not make every preparation sold under the name orforglipron an approved medicine. The clinical findings concern controlled study formulations and the product supported by FDA's review; a separately sold research powder has not been shown equivalent by those studies. FDA label, sections 1, 6.1 and 14.

Uses and research areas

Weight-management trials enrolled adults with obesity or overweight, with diabetes examined in a separate trial. The diabetes program also studied people at different stages of treatment: those managing glucose with diet and exercise alone, those taking metformin, those already receiving insulin glargine, and those with established cardiovascular or kidney disease. These populations differ in baseline risk and background medicines, which helps explain why one weight-loss percentage cannot describe every setting. ATTAIN-1, ATTAIN-2, ACHIEVE-1, ACHIEVE-2, ACHIEVE-5, ACHIEVE-4.

Another trial asked whether people who had already lost weight with injected tirzepatide or semaglutide could retain more of that loss after switching to oral orforglipron than after switching to placebo. This is a maintenance question in selected previous trial participants. It differs from starting treatment in someone who has not used those medicines. ATTAIN-MAINTAIN.

Mechanism of action

GLP-1 is a hormone whose receptor helps regulate food intake and glucose-dependent insulin release. Orforglipron binds and activates the human receptor. Structural imaging and cell experiments showed that the small molecule occupies a pocket near the receptor's outer surface and activates its G-protein signaling machinery. It produced a stronger response in this pathway than in recruitment of beta-arrestin, a protein involved in how receptors are regulated after activation. This pattern is called biased signaling; the cellular observation does not by itself quantify weight loss or establish a safety advantage. Kawai and colleagues.

Species selectivity is an unusually consequential part of this biology. A receptor amino acid found in primates helps orforglipron bind, and ordinary mouse receptors did not respond in the original assays. Researchers therefore used mice expressing the human receptor for glucose-lowering experiments and also studied nonhuman primates. This helps explain why absence of a particular effect in ordinary rodents can be difficult to interpret. Kawai and colleagues.

In people, the clinically useful outcomes are reduced body weight and blood glucose. The product label also describes decreased food intake and delayed stomach emptying, with the delay greatest after the first dose and diminishing over time. Slower stomach emptying is relevant to tolerability and absorption of other oral medicines. FDA label, sections 7.3 and 12.1–12.2.

Pharmacokinetics

After an oral dose, the blood concentration of orforglipron rises during absorption and later falls as the body eliminates it. The FDA label reports peak concentrations at 4–8 hours, an elimination half-life of approximately 29–49 hours, and steady exposure after about one week of daily administration. A half-life describes the later decline in drug concentration; it does not describe the entire rise and fall after swallowing a tablet. FDA label, section 12.3.

Two early food-effect studies included 12 and 34 healthy participants. Eating lowered total measured exposure and peak concentrations by roughly one-fifth to one-quarter relative to fasting, while the timing of the peak and elimination half-life were comparable. The investigators judged these differences unlikely to alter efficacy meaningfully; the approved product can be taken with or without food. The label also identifies CYP3A4 metabolism and clinically relevant drug interactions, so oral absorption alone does not determine exposure. Ma and colleagues, 2024, FDA label, sections 2.1, 7 and 12.3.

The formulation change was tested directly in 429 otherwise healthy adults with obesity or overweight. Researchers compared blood concentrations over 24 hours and the highest concentration reached after repeated capsule and tablet administration. The corresponding strengths met the study's predefined bioequivalence criteria: for example, the 6-, 12- and 36-mg investigational capsules corresponded to 5.5-, 9- and 17.2-mg tablets. These are findings about the tested formulations, not a general conversion rule for research products. Trial doses below retain the original publications' capsule units. Ma and colleagues, 2026.

Research findings

Weight loss in adults with and without diabetes

The phase 2 obesity trial randomized 272 adults without diabetes to orforglipron or placebo. At 36 weeks, average weight loss ranged from 9.4% to 14.7% across orforglipron groups, compared with 2.3% with placebo. Gastrointestinal symptoms frequently occurred during dose increases, and 10–17% of orforglipron participants stopped the drug because of adverse events. The trial explored several doses and escalation schedules, so its largest percentage should be read with that design in mind. Wharton and colleagues, 2023.

The larger ATTAIN-1 trial randomized 3,127 adults without diabetes and followed them for 72 weeks with diet and activity support in every group. Average weight reductions were 7.5%, 8.4% and 11.2% with the 6-, 12- and 36-mg trial formulations, compared with 2.1% with placebo. The main analysis estimated weight change across the assigned groups, including people who stopped treatment. An additional analysis estimated what would happen if participants remained on treatment, producing different percentages. Adverse events caused treatment discontinuation in 5.3–10.3% of orforglipron groups and 2.7% of the placebo group. ATTAIN-1.

ATTAIN-2 enrolled 1,613 adults with type 2 diabetes and a body mass index (BMI) of at least 27. At 72 weeks, average weight loss was 5.1%, 7.0% and 9.6% with the same three trial strengths, compared with 2.5% with placebo. At the highest strength, the estimated additional loss was 7.1 percentage points, with a 95% confidence interval from 6.1 to 8.2 points. Adverse events caused more treatment stopping with orforglipron: 6.1–9.9%, compared with 4.1%. The different populations and background treatments prevent these two trials from proving that diabetes itself caused the smaller average loss. ATTAIN-2.

Glucose control and direct comparisons

In ACHIEVE-1, 559 adults with type 2 diabetes treated only with diet and exercise were randomized to orforglipron or placebo for 40 weeks. Glycated hemoglobin, or HbA1c, reflects glucose exposure over preceding weeks. It fell by 1.24–1.48 percentage points across orforglipron groups and by 0.41 points with placebo, from an overall starting average of 8.0%. No severe hypoglycemia was reported, although more participants stopped orforglipron because of adverse events. ACHIEVE-1.

Trials with active comparators put the benefits beside different treatment burdens. Among 962 metformin-treated participants in ACHIEVE-2, HbA1c fell by 1.23–1.56 points with orforglipron versus 0.81 with dapagliflozin at 40 weeks. Gastrointestinal events were more common with orforglipron, as was stopping the study intervention. In the 1,698-person ACHIEVE-3 trial, the 36-mg orforglipron group had a 1.91-point HbA1c decrease at 52 weeks versus 1.47 points with oral semaglutide 14 mg. Gastrointestinal events occurred in 58% versus 45%, and adverse events caused treatment stopping in 10% versus 5%. This comparison concerns the tested oral semaglutide strengths in type 2 diabetes; it does not rank every semaglutide product or its obesity regimens. ACHIEVE-2, ACHIEVE-3.

In ACHIEVE-5, 546 adults whose diabetes remained inadequately controlled on insulin glargine received added orforglipron or placebo while insulin was adjusted under the trial protocol. At 40 weeks, HbA1c fell by 1.58–1.88 points with orforglipron versus 0.79 with placebo; body weight fell by 2.6–5.4% versus a 0.2% increase. The trial did not find increased clinically significant hypoglycemia with added orforglipron. This result arose within supervised insulin adjustment and does not remove the label's hypoglycemia warning when the medicines are combined. ACHIEVE-5, FDA label, section 5.5.

Maintaining previous weight loss and assessing cardiovascular safety

ATTAIN-MAINTAIN randomized 205 previous tirzepatide participants and 171 previous semaglutide participants to orforglipron or placebo. Among those whose weight had plateaued before switching, the estimated proportions of earlier weight loss retained at 52 weeks were 74.7% with orforglipron and 49.2% with placebo after tirzepatide, and 79.3% with orforglipron and 37.6% with placebo after semaglutide. These percentages describe how much of the earlier loss remained, not a new reduction of that percentage of body weight. There was no group continuing the original injectable medicine. Placebo participants could receive rescue orforglipron from week 24 after substantial regain, requiring specified statistical handling of later weights. ATTAIN-MAINTAIN.

The 2,749-person ACHIEVE-4 trial compared orforglipron with insulin glargine in adults with type 2 diabetes and established cardiovascular or kidney disease. Over a median two years, the combined outcome of cardiovascular death, nonfatal heart attack, nonfatal stroke or hospitalization for unstable angina occurred in 57 of 1,358 participants in the orforglipron analysis and 67 of 1,343 in the glargine analysis. The hazard ratio was 0.84, with a 95% confidence interval of 0.59–1.20. The trial's safety rule required the upper confidence limit to be below 1.8, ruling out an 80% or greater increase in the event rate relative to glargine under that analysis. The result met this rule, while its interval still leaves uncertainty about whether orforglipron reduces the combined outcome. Gastrointestinal events were much more common with orforglipron, while clinically significant or severe low blood glucose was less common. ACHIEVE-4.

Safety and tolerability

Nausea, vomiting, diarrhea and constipation recur across the controlled trials. Their frequency and the proportion stopping treatment matter even when most events are described as mild or moderate. The year-long ACHIEVE-J study adds experience in 401 Japanese adults with type 2 diabetes: 339 reported an adverse event, and adverse events caused treatment stopping in 5%, 8% and 14% across ascending trial-dose groups. Every participant received orforglipron, so the study cannot estimate the excess frequency compared with no orforglipron. ACHIEVE-J.

The FDA label carries a boxed warning about thyroid C-cell tumors and contraindicates Foundayo in people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Other GLP-1 agonists produced these tumors in rodents. Orforglipron did not produce rodent tumors, but it also lacks the relevant receptor activity in rats and mice; the human relevance of the class finding remains unknown. FDA label, boxed warning and section 5.1.

Other label warnings concern inflammation of the pancreas (pancreatitis), severe stomach or intestinal reactions, kidney injury from fluid loss, low blood glucose, especially when combined with insulin or medicines that stimulate insulin release, serious allergy, worsening diabetes-related eye disease, and gallbladder disease. Delayed stomach emptying also raises concern about stomach contents entering the lungs during anesthesia or deep sedation. The label does not recommend use in severe gastroparesis, a condition of markedly delayed stomach emptying, or severe liver impairment. Safety and effectiveness have not been established in children. Pregnancy and interactions with other medicines require separate attention, including the effect of delayed stomach emptying on oral hormonal contraception. Approval establishes a defined product's benefit–risk assessment for its indication; uncommon harms and experience over many years continue to require observation. FDA label, sections 5, 7 and 8.

What the research means

Orforglipron has progressed from receptor experiments to large human randomized trials and an approved oral weight-management product. The weight and glucose effects are supported by direct measurements in defined populations. Understanding the result requires retaining the studied formulation, the background treatment and the analysis being quoted. A percentage from an on-treatment analysis can differ from the main estimate that includes treatment stopping, even within the same trial. ATTAIN-1, ACHIEVE-3, formulation study.

The remaining questions are specific. The maintenance trial did not compare switching with continuing the injectable medicine. The cardiovascular trial established its prespecified safety criterion while leaving the size and direction of any additional protection uncertain. Neither result justifies assuming all GLP-1 medicines share identical clinical outcomes. The most useful reading of the evidence keeps those limits beside the demonstrated weight and glucose reductions. ATTAIN-MAINTAIN, ACHIEVE-4.

FAQs

Comparisons and related reading

The direct oral-semaglutide trial is useful when comparing glucose lowering and tolerability at its tested strengths. Wider comparisons also need to account for different molecules, routes, populations and measured outcomes. ACHIEVE-3.

• Semaglutide

  Explains peptide GLP-1 receptor agonism and oral versus injectable formulations. ACHIEVE-3 directly compared orforglipron with specific oral semaglutide strengths in type 2 diabetes.

• Tirzepatide

  Provides context for a dual GIP/GLP-1 receptor agonist and the injectable weight-loss treatment used before randomization in one ATTAIN-MAINTAIN cohort.

References

• U.S. Food and Drug Administration. FDA Approves First New Molecular Entity Under National Priority Voucher Program. April 1, 2026.

  Official announcement establishes the date and adult weight-management scope of Foundayo's US approval.

• U.S. Food and Drug Administration. FOUNDAYO (orforglipron) tablets, for oral use. Prescribing information, revised July 2026. NDA 220934; Reference ID 5842935. · dailymed.nlm.nih.gov

  The current accessed FDA label defines the calcium-salt product, adult weight-management indication, formulation bridge, pharmacokinetics, contraindications and warnings.

• Kawai T, Sun B, Yoshino H, Feng D, Suzuki Y, Fukazawa M, Nagao S, Wainscott DB, Showalter AD, Droz BA, Kobilka TS, Coghlan MP, Willard FS, Kawabe Y, Kobilka BK, Sloop KW. Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist. Proceedings of the National Academy of Sciences of the United States of America. 2020;117(47):29959–29967. doi:10.1073/pnas.2014879117. · Full text (PMC)

  The original structural and pharmacology study identifies the neutral molecule, its development aliases, receptor binding and species-selective activity.

• Pratt E, Ma X, Liu R, Robins D, Coskun T, Sloop KW, Haupt A, Benson C. Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1b, multicentre, blinded, placebo-controlled, randomized, multiple-ascending-dose study in people with type 2 diabetes. Diabetes, Obesity and Metabolism. 2023;25(9):2642–2649. doi:10.1111/dom.15150.

  A short controlled diabetes study measured human exposure and early glucose and weight responses; its observed half-life range agrees with the later label.

• Ma X, Liu R, Pratt EJ, Benson CT, Bhattachar SN, Sloop KW. Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), a Non-peptide GLP-1 Receptor Agonist. Diabetes Therapy. 2024;15(4):819–832. doi:10.1007/s13300-024-01554-1. · Full text (PMC)

  In two human studies, eating lowered total orforglipron exposure and peak concentrations relative to fasting, while peak timing and elimination half-life were comparable.

• Ma X, Li YG, Raha S, Sperry DC, Coutant DE, Bhattachar S. Pharmacokinetic Bioequivalence of Orforglipron Tablets and Capsules in Healthy Participants With Obesity or Overweight. Diabetes, Obesity and Metabolism. 2026;28(7):5803–5809. doi:10.1111/dom.70783. · dom-pubs.onlinelibrary.wiley.com

  The direct 429-person formulation study explains why the clinical-trial capsules and marketed tablets have different strengths despite comparable exposure at tested pairs.

• Wharton S, Blevins T, Connery L, Rosenstock J, Raha S, Liu R, Ma X, Mather KJ, Haupt A, Robins D, Pratt E, Kazda C, Konig M; GZGI Investigators. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. New England Journal of Medicine. 2023;389(10):877–888. doi:10.1056/NEJMoa2302392. · PubMed record

  The phase 2 obesity trial measured 26- and 36-week weight changes while exploring doses and escalation schedules, with substantial gastrointestinal treatment stopping.

• Frias JP, Hsia S, Eyde S, Liu R, Ma X, Konig M, Kazda C, Mather KJ, Haupt A, Pratt E, Robins D. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study. Lancet. 2023;402(10400):472–483. doi:10.1016/S0140-6736(23)01302-8.

  This dose-ranging diabetes trial compared orforglipron with placebo and dulaglutide and recorded both glucose lowering and gastrointestinal adverse events.

• Wharton S, Aronne LJ, Stefanski A, Alfaris NF, Ciudin A, Yokote K, Halpern B, Shukla AP, Zhou C, Macpherson L, Allen SE, Ahmad NN, Klise SR; ATTAIN-1 Trial Investigators. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment. New England Journal of Medicine. 2025;393(18):1796–1806. doi:10.1056/NEJMoa2511774.

  The pivotal 3,127-person trial supplies the main 72-week weight-loss estimates in adults without diabetes and adverse-event treatment-stopping rates.

• Horn DB, Ryan DH, Giljanovic Kis S, Alves B, Mu Y, Kim SG, Aberle J, Bain SC, Allen S, Sarker E, Wu Q, Stefanski A, Jouravskaya I; 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. Published online November 20, 2025. doi:10.1016/S0140-6736(25)02165-8.

  The 1,613-person diabetes-and-weight trial provides a separate 72-week estimate rather than borrowing the result from adults without diabetes.

• Rosenstock J, Hsia S, Nevarez Ruiz L, Eyde S, Cox D, Wu WS, Liu R, Li J, Fernández Landó L, Denning M, Ludwig L, Chen Y; ACHIEVE-1 Trial Investigators. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes. New England Journal of Medicine. 2025;393(11):1065–1076. doi:10.1056/NEJMoa2505669.

  The 40-week placebo-controlled trial measured HbA1c and weight in 559 adults whose diabetes treatment was diet and exercise alone.

• Welch M, Forst T, Jia W, Orozco Del Pino P, Denning M, Wu WS, Li J, Liu R, Eifu M, Chen Y; ACHIEVE-2 Trial Investigators. Orforglipron compared with dapagliflozin in adults with type 2 diabetes and inadequate glycaemic control with metformin (ACHIEVE-2): a multicentre, randomised, non-inferiority, open-label, phase 3 trial. Lancet. 2026;408(10550):125–140. doi:10.1016/S0140-6736(26)00800-7.

  The direct dapagliflozin comparison demonstrates glucose lowering alongside more gastrointestinal events and intervention stopping with orforglipron.

• Rosenstock J, Yabe D, Cox D, Li J, Denning M, Wu WS, Liu R, Zhao Y; ACHIEVE-3 Investigators. 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;407(10534):1147–1160. doi:10.1016/S0140-6736(26)00202-3.

  The direct oral-semaglutide trial reports greater HbA1c lowering with orforglipron at tested strengths, with more gastrointestinal events, treatment stopping and pulse increase.

• Klein KR, Wysham C, Tuttle KR, Davies MJ, Cox D, Chen J, Wu WS, Denning M, Liu R, Ludwig L, Meskimen ER. 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. Published online September 30, 2026. doi:10.1016/S0140-6736(26)01865-9.

  This event-driven trial directly examined major cardiovascular events. It met the prespecified non-inferiority criterion against insulin glargine, while the confidence interval did not establish cardiovascular superiority.

• Giorgino F, D'Souza S, Ludwig L, Kiyosue A, Ibriga H, Rha H, Denning M, Wu WS, Fernández Landó L, Tobian J. Orforglipron Added to Titrated Insulin Glargine in Type 2 Diabetes: The ACHIEVE-5 Randomized Clinical Trial. JAMA. 2026;336(5):389–399. doi:10.1001/jama.2026.9512.

  The insulin-background trial measured added glucose and weight effects under protocol-directed insulin adjustment; that context matters for its hypoglycemia result.

• Yabe D, Shiraiwa T, Ugai H, Takeuchi M, Suzuki R. Long-term safety of oral orforglipron in Japanese participants with type 2 diabetes (ACHIEVE-J): a multicentre, randomised, open-label, parallel-group phase 3 trial. Lancet Diabetes & Endocrinology. 2026;14(10):841–855. doi:10.1016/S2213-8587(26)00138-5.

  A 52-week study in Japanese adults adds safety observations and treatment-stopping frequencies, with every randomized group receiving orforglipron.

• Aronne LJ, Horn DB, le Roux CW, Chao AM, Ho W, Halpern B, Griffin R, Xie C, Gomez Valderas E, Lee CJ, Ribeiro A, Hyman DM, Glass L, Xavier N. Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial. Nature Medicine. 2026;32(7):2679–2687. doi:10.1038/s41591-026-04386-7. · PubMed record

  The randomized switch study measures retention of earlier injectable-treatment weight loss, with a plateau subgroup primary analysis, rescue treatment and no continued-injection control.

Glossary

GLP-1 receptor agonist

A compound that activates the receptor used by glucagon-like peptide-1, a hormone involved in appetite and glucose-dependent insulin release.

Nonpeptide

A compound that is not a chain of amino acids, even if it acts at a receptor normally activated by a peptide hormone.

HbA1c

Glycated hemoglobin, a blood measurement reflecting glucose exposure over preceding weeks. A change from 8% to 7% is a fall of one percentage point.

Bioequivalence

Evidence that specified formulations provide sufficiently similar drug exposure under predefined statistical criteria; it does not establish equivalence for unrelated preparations.

Elimination half-life

The time over which drug concentration falls by half during the elimination phase; it does not describe absorption or the whole concentration curve.

Hazard ratio

A comparison of event rates over follow-up. A value of 1 indicates no relative difference; its confidence interval describes uncertainty in the estimate.

Non-inferiority

A trial criterion asking whether a treatment can be ruled out as worse than its comparator by more than a specified margin. Passing it does not necessarily show that the treatment is better.

Gastrointestinal

Related to the stomach and intestines; relevant symptoms include nausea, vomiting, diarrhea and constipation.

Gastroparesis

Delayed movement of food out of the stomach because stomach emptying is impaired.

Insulin secretagogue

A medicine that stimulates insulin release, such as a sulfonylurea; combining it with another glucose-lowering medicine can increase hypoglycemia risk.