Acronyms
- GLP-1 - glucagon-like peptide-1
- MTC - medullary thyroid carcinoma
- MEN 2 - multiple endocrine neoplasia syndrome type 2
- GI - gastrointestinal
- CYP - cytochrome P450
- OATP1B - organic anion transporting polypeptide 1B
DRUGS IN CLASS
- GLP-1 analogs
FDA-APPROVED INDICATIONS
- Foundayo is indicated, in combination with a reduced-calorie diet and increased physical activity, to reduce excess body weight and maintain weight reduction long term in adults with obesity or adults with overweight in the presence of at least one weight-related comorbid condition.
- Limitations of use: Concomitant use with another GLP-1 receptor agonist is not recommended.
MECHANISM OF ACTION
- Foundayo is a GLP-1 receptor agonist that binds to and activates the human GLP-1 receptor. GLP-1 is a physiological regulator of appetite and caloric intake. GLP-1 receptors are present in brain regions that regulate appetite. In animal studies, orforglipron distributed to and activated neurons in brain regions that regulate appetite and food intake.
WEIGHT LOSS
- The effects of orforglipron on weight loss in overweight and obese adults were studied in the trials below. ATTAIN-1 enrolled adults without diabetes, and ATTAIN-2 enrolled adults with diabetes.
RCT
ATTAIN-1 - Orforglipron vs Placebo for Weight Loss in Adults with Obesity and No Diabetes, NEJM (2025) [PubMed abstract]
- The ATTAIN-1 trial enrolled 3127 adults with obesity without diabetes and randomly assigned them to three doses of orforglipron (6 mg, 12 mg, 36 mg) or matching placebo
Main inclusion criteria
- Age 18 years or older
- BMI ≥ 30 or 27 - 30 with at least one of the following:
- Hypertension
- Dyslipidemia
- Cardiovascular disease
- Obstructive sleep apnea
- At least one patient-reported unsuccessful dietary effort to lose body weight
Main exclusion criteria
- Diagnosis of diabetes mellitus
- Change in body weight (gain or loss) of more than 5 kg within 90 days before screening
Baseline characteristics
- Average age - 45 years
- Female - 64%
- Average body weight - 227 lb (103 kg)
- Average BMI - 37
- Prediabetes - 36%
Randomized treatment groups
- Group 1 (723 patients): Orforglipron 6 mg once daily
- Group 2 (725 patients): Orforglipron 12 mg once daily
- Group 3 (730 patients): Orforglipron 36 mg once daily
- Group 4 (949 patients): Matching placebo once daily
- All orforglipron groups began at 1 mg once daily, with dose increases every 4 weeks until the assigned maintenance dose was reached (6 mg at 8 weeks, 12 mg at 12 weeks, 36 mg at 20 weeks).
Primary outcome: Percent change in body weight from baseline to week 72 (treatment-regimen estimand, intention-to-treat population).
Results
| Duration: 72 weeks | |||||
| Outcome | Orf 6 mg | Orf 12 mg | Orf 36 mg | Placebo | Comparisons |
|---|---|---|---|---|---|
| Primary outcome (% weight change) | -7.5% | -8.4% | -11.2% | -2.1% | P<0.001 for all doses vs placebo |
| Patients with ≥5% weight reduction | 60.6% | 63.5% | 71.8% | 26.8% | P<0.001 vs placebo for each orforglipron dose |
| Patients with ≥10% weight reduction | 33.3% | 40.0% | 54.6% | 12.9% | P<0.001 vs placebo for each orforglipron dose |
| Patients with ≥15% weight reduction | 15.1% | 20.3% | 36.0% | 5.9% | P<0.001 vs placebo for each orforglipron dose |
| Patients with ≥20% weight reduction | 6.4% | 9.0% | 18.4% | 2.8% | P<0.001 vs placebo for each orforglipron dose |
| Any adverse event during treatment | 83.4% | 86.6% | 85.2% | 80.5% | N/A |
| Serious adverse event | 5.5% | 5.4% | 3.8% | 4.9% | N/A |
| Adverse event leading to discontinuation | 5.3% | 7.9% | 10.3% | 2.7% | N/A |
| GI disorder leading to discontinuation | 3.5% | 5.2% | 7.0% | 0.4% | N/A |
|
|||||
Findings: In adults with obesity, 72-week treatment with orforglipron led to significantly greater reductions in body weight than placebo; the adverse-event profile was consistent with that of other GLP-1 receptor agonists.
- RCTATTAIN-2 - Orforglipron vs Placebo for Weight Loss in Adults with Obesity and Type 2 Diabetes, Lancet (2025) [PubMed abstract]
- Design: Randomized, double-blind, placebo-controlled trial (N=1613 | length = 72 weeks) in adults with BMI ≥ 27 and type 2 diabetes
- Treatment: Following dose escalation, once-daily orforglipron 6 mg (n=329), 12 mg (n=332), or 36 mg (n=322) vs placebo (n=630), as an adjunct to lifestyle modification
- Primary outcome: Mean percent change in body weight from baseline to week 72 (treatment-regimen estimand; all randomly assigned participants)
- Results:
- Baseline characteristics: Mean body weight 223.5 lb (101.4 kg) and average BMI 35.6
- Primary outcome: 6 mg: −5.1% (p<0.0001 vs placebo); 12 mg: −7.0% (p<0.0001 vs placebo); 36 mg: −9.6% (p<0.0001 vs placebo); placebo: −2.5%.
- Findings: In adults with obesity or overweight and type 2 diabetes, statistically superior reduction in bodyweight compared with placebo was demonstrated by once-daily orforglipron as an adjunct to lifestyle modification, with a safety profile similar to other GLP-1 receptor agonists.
TYPE 2 DIABETES
- RCTOrforglipron vs Semaglutide in Adults with Type 2 Diabetes, Lancet (2026) [PubMed abstract]
- Design: Randomized, open-label, active-controlled trial (N=1698 | length = 52 weeks) in adults with type 2 diabetes inadequately controlled with metformin (≥1500 mg per day), HbA1c between 7.0% and 10.5%, and BMI at least 25
- Treatment: Orforglipron 12 mg once daily vs Semaglutide 7 mg once daily; Orforglipron 36 mg once daily vs Semaglutide 14 mg once daily (randomized 1:1:1:1), with up to 4-week lead-in and 52-week treatment period; all drugs oral once daily
- Primary outcome: Non-inferiority of mean change from baseline in HbA1c at week 52 for orforglipron versus the corresponding semaglutide dose (non-inferiority margin 0.3%; treatment-regimen estimand, intention-to-treat population)
- Results:
- Primary outcome: Mean change in HbA1c at week 52 from baseline 8.3%: Orforglipron 12 mg −1.71%; Orforglipron 36 mg −1.91%; Semaglutide 7 mg −1.23%; Semaglutide 14 mg −1.47%. Estimated differences: 12 mg vs 7 mg −0.48% (95% CI −0.65 to −0.31; p<0.0001); 36 mg vs 14 mg −0.44% (−0.62 to −0.26; p<0.0001).
- Findings: In individuals with type 2 diabetes inadequately controlled with metformin, orforglipron 12 mg and 36 mg was non-inferior and superior to semaglutide 7 mg and 14 mg with respect to the mean change in HbA1c from baseline to 52 weeks. Although the safety profiles of both orforglipron and semaglutide were generally consistent with the GLP-1 receptor agonist class, the incidence of gastrointestinal events, discontinuations due to adverse events, and mean increase in pulse rate were higher with orforglipron than oral semaglutide.
SIDE EFFECTS
| Gastrointestinal (GI) side effects in 72 week trials | ||||
|---|---|---|---|---|
| Side effect | Placebo (N=1,576) |
Orforglipron 5.5 mg (N=1,051) |
Orforglipron 9 mg (N=1,055) |
Orforglipron 17.2 mg (N=1,049) |
| Nausea | 10 | 26 | 34 | 35 |
| Constipation | 9 | 20 | 27 | 24 |
| Diarrhea | 11 | 21 | 23 | 25 |
| Vomiting | 4 | 13 | 21 | 24 |
| Dyspepsia | 4 | 12 | 16 | 13 |
| Abdominal pain | 7 | 13 | 14 | 14 |
| Headache | 7 | 8 | 9 | 9 |
| Abdominal distension | 3 | 7 | 9 | 8 |
| Fatigue | 4 | 6 | 7 | 9 |
| Eructation | 1 | 6 | 8 | 8 |
| Gastroesophageal reflux disease | 2 | 6 | 6 | 7 |
| Flatulence | 2 | 5 | 6 | 6 |
| Hair loss | 2 | 4 | 4 | 5 |
- Risk of thyroid C-cell tumors
- In products with GLP-1 receptor agonist activity that are pharmacologically active in rats and mice, rodent thyroid C-cell tumors (adenomas and carcinomas) have been observed at clinically relevant exposures and are considered GLP-1 receptor-dependent effects in rodents. Orforglipron is not pharmacologically active in rats or mice and did not produce tumors in rodents. While orforglipron is pharmacologically active at the human GLP-1 receptor, the human relevance of GLP-1 receptor-dependent thyroid C-cell tumors observed in rodents has not been determined. Foundayo is contraindicated in patients with a personal or family history of MTC or MEN 2. Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or thyroid ultrasound for early detection of MTC in patients treated with Foundayo is of uncertain value.
- Acute pancreatitis
- Acute pancreatitis has been reported in patients treated with Foundayo. Fatal and non-fatal hemorrhagic or necrotizing pancreatitis have been observed with GLP-1 receptor agonists. In two pooled trials, 6 adjudicated events of acute pancreatitis occurred in Foundayo-treated patients (0.14 patients per 100 patient-years of exposure) versus 2 events in 1 placebo-treated patient (0.04 patients per 100 patient-years). After initiation, observe for persistent or severe abdominal pain (sometimes radiating to the back), with or without nausea or vomiting; if pancreatitis is suspected, discontinue Foundayo and manage accordingly.
- Severe gastrointestinal reactions
- Use of Foundayo has been associated with gastrointestinal adverse reactions, sometimes severe. In clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients treated with orforglipron (approximately 3%) than among patients who received placebo (1%). Foundayo is not recommended in patients with severe gastroparesis.
- Acute kidney injury due to volume depletion
- Acute kidney injury, in some cases requiring hemodialysis, has been reported with GLP-1 receptor agonists or Foundayo. Many events occurred in the setting of GI adverse reactions leading to dehydration (e.g., nausea, vomiting, diarrhea). In two pooled trials, acute kidney injury was reported in 0.2% of Foundayo-treated patients compared with 0.05% of placebo-treated patients. Monitor renal function in patients reporting adverse reactions that could lead to volume depletion, especially during initiation and dose escalation.
- Hypoglycemia
- Foundayo lowers blood glucose and can cause hypoglycemia. In a trial involving overweight adults without type 2 diabetes, hypoglycemia (plasma glucose <54 mg/dL) was reported in 2% of orforglipron-treated patients versus 0.2% on placebo; one orforglipron-treated patient reported severe hypoglycemia. In the same trial, 7% of patients on Foundayo with concomitant sulfonylurea reported hypoglycemia versus 0.5% of those not taking a sulfonylurea. Risk is also increased with insulin. Inform patients of the signs and symptoms of hypoglycemia. In patients with diabetes, monitor glucose and consider reducing insulin or insulin secretagogue dose.
- Hypersensitivity reactions
- Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported with GLP-1 receptor agonists. In two pooled trials, hypersensitivity reactions including anaphylactic reaction occurred in 0.5% of Foundayo-treated patients versus 0.3% on placebo. If a reaction occurs, discontinue Foundayo and seek appropriate care. Use caution in patients with prior anaphylaxis or angioedema to another GLP-1 receptor agonist.
- Diabetic retinopathy complications in patients with type 2 diabetes
- Rapid improvement in glucose control can temporarily worsen diabetic retinopathy. Foundayo has not been studied in patients with diabetic retinopathy or macular edema requiring acute treatment. Monitor patients with a history of diabetic retinopathy for progression.
- Acute gallbladder disease
- In a pool of Trials 1 and 2, cholelithiasis was reported in 1% of orforglipron-treated patients and 0.7% of placebo-treated patients; acute cholecystitis was reported in 0.4% and 0.3%, respectively. Events were associated with weight reduction. If cholecystitis is suspected, obtain appropriate studies and follow-up.
CONTRAINDICATIONS
- Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2)
- Known serious hypersensitivity to orforglipron or to any excipient in Foundayo
PRECAUTIONS
- Kidney disease
- No dosage adjustment of Foundayo is recommended for patients with renal impairment, including end-stage renal disease; pharmacokinetics were not meaningfully changed in studies. Monitor renal function in patients who develop adverse reactions that could lead to volume depletion (e.g., vomiting, diarrhea).
- Liver disease
- Child-Pugh class A or B (mild or moderate hepatic impairment): No dosage modification recommended.
- Child-Pugh class C (severe hepatic impairment): Foundayo is not recommended; exposure is substantially increased in severe impairment.
- Pregnancy
- Weight loss offers no benefit during pregnancy and may cause fetal harm. When pregnancy is recognized, discontinue Foundayo.
- General anesthesia or deep sedation
- GLP-1 therapies, like Foundayo, slow gastric emptying, possibly increasing the risk of residual gastric contents and pulmonary aspiration in patients receiving anesthesia or deep sedation for procedures. Rare postmarketing cases of pulmonary aspiration from retained stomach contents have been reported in GLP-1-treated patients, even after following the recommended preoperative fast. Recommendations from the American Society of Anesthesiologists for managing GLP-1 therapies perioperatively are available here - GLP-1 therapy perioperative management recommendations.
- STUDYA small study (N=60) compared holding one preprocedure dose of a GLP-1 agonist (hold group) to not holding it (continuation group) in patients undergoing EGD with or without colonoscopy. The primary outcome was clinically significant residual gastric volume as observed during EGD. Patients in the study were receiving dulaglutide (7), semaglutide injection (27), semaglutide oral (3), and tirzepatide (23). Clinically significant residual gastric volume occurred more frequently in the continuation group (25%) than in the hold group (3%). For patients undergoing colonoscopy, who were on clear liquid diets the day prior, no clinically significant residual gastric volume was found in either group. There was no difference between the groups in the number of procedural complications or adverse events. [PMID 41837981]
DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- Strong CYP3A4 inhibitors - CYP3A4 inhibitors increase Foundayo exposure, which may increase the risk of adverse reactions. The maximum dosage of Foundayo is 9 mg once daily when used with a strong CYP3A4 inhibitor. Avoid concomitant use of Foundayo with strong CYP3A4 inhibitors that also inhibit OATP1B (e.g., ritonavir).
- Strong CYP3A4 inducers - Avoid concomitant use. CYP3A4 inducers decrease Foundayo exposure and may reduce effectiveness.
- Moderate CYP3A4 inducers - Monitor Foundayo effectiveness and escalate dosage as needed. Moderate CYP3A4 inducers decrease Foundayo exposure.
- Oral hormonal contraceptives - Because delayed gastric emptying can affect the absorption of oral drugs, advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method or add a barrier method of contraception for 30 days after initiation with Foundayo and for 30 days after each dose escalation.
- Simvastatin - Do not exceed simvastatin 20 mg once daily when used with Foundayo. Coadministration increased exposure of the active metabolite simvastatin acid approximately two-fold, which may be clinically meaningful at higher simvastatin doses.
- Insulin or insulin secretagogue (e.g., sulfonylurea) - When initiating Foundayo, consider reducing the dose of concomitant insulin or insulin secretagogues. Foundayo stimulates insulin release when glucose is elevated, which increases hypoglycemia risk in combination with these agents.
- Drugs affected by gastric emptying
- Medications are partially digested in the stomach before being emptied into the small intestine, where most drugs are absorbed. Foundayo delays gastric emptying, possibly altering the absorption of some drugs. In many cases, the overall effect on the medication's therapeutic action is not significant, but the efficacy of some drugs (see below) may be altered.
- Antibiotics: Antibiotics require rapid absorption to achieve their desired therapeutic effect
- Drugs with a narrow therapeutic index: Drugs with a narrow therapeutic index may have their steady state altered by delayed gastric emptying. Examples include:
- Carbamazepine (Tegretol®)
- Cyclosporine (Neoral®)
- Digoxin
- Levothyroxine (Synthroid®)
- Lithium
- Phenytoin (Dilantin®)
- Tacrolimus (Prograf®)
- Theophylline (Theo-24®)
- Warfarin (Coumadin®)
- Drugs that alter gastrointestinal motility - drugs that slow gastrointestinal motility may potentiate the gastric-slowing effects of Foundayo. Examples include anticholinergic medications and opioid pain medications (e.g., hydrocodone, morphine)
- Metabolism and clearance
- Orforglipron is metabolized primarily via hepatic CYP3A4 to several oxidative metabolites, which are excreted into the intestinal lumen. After a single oral dose of 2.5 mg orforglipron, 87% of the dose was recovered in feces (as metabolites) and less than 1% in urine. Mean systemic clearance is 7.15 L/hour; elimination half-life is approximately 29 to 49 hours after an oral dose. Steady state is reached after about 1 week of once-daily dosing. Maximum concentration occurs 4 to 8 hours post dose; absolute bioavailability was 77% after a 0.8 mg dose.
- In vitro, orforglipron did not inhibit or induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Orforglipron is a substrate of CYP3A4 and CYP2J2. Orforglipron is a substrate of P-glycoprotein, OATP1B1, and OATP1B3.
DOSING
- Dosage forms (tablet)
- 0.8 mg
- 2.5 mg
- 5.5 mg
- 9 mg
- 14.5 mg
- 17.2 mg
- Dosing (weight-loss in adults with obesity or overweight)
- Starting dosage is 0.8 mg once daily. After at least 30 days, increase to 2.5 mg once daily; after at least 30 days on 2.5 mg, increase to 5.5 mg once daily.
- 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 dose, based on response and tolerability. Maximum dosage is 17.2 mg once daily.
- Take once daily, with or without food. Swallow tablets whole; do not break, crush, or chew. Do not take more than one tablet per day.
- With strong CYP3A4 inhibitors: maximum recommended dose is 9 mg once daily. Avoid concomitant use with strong CYP3A4 inhibitors that also inhibit OATP1B (e.g., ritonavir).
- With strong CYP3A4 inducers: avoid concomitant use.
- With moderate CYP3A4 inducers: monitor Foundayo effectiveness and escalate the dosage as needed.
- Missed dose: Take the missed dose as soon as possible; do not double the next dose. If 7 or more consecutive doses are missed, reinitiate titration at a lower dose to reduce the risk of GI adverse reactions.
BIBLIOGRAPHY
- 1 - Foundayo (orforglipron) tablets prescribing information. Eli Lilly and Company. Revised April 2026.