II. Indications
- See GLP-1 Agonist
- Not yet FDA approved for Type 2 Diabetes as of May 2026
- Orforglipron lowers Hemoglobin A1C 1% more than Placebo
- Weight Loss
- At least 50% of weight regained on stopping GLP-1 agents
- Similar efficacy to Semaglutide 25 mg/day with 11% more weight loss than Placebo
III. Contraindications
- See GLP-1 Agonist
- Type I Diabetes Mellitus
- Medullary Thyroid Carcinoma (personal or Family History)
- Multiple Endocrine Neoplasia syndrome type 2 (active)
- Concurrent prandial Insulin (Bolus Insulin)
- Basal insulin (e.g. Lantus) may be used
- Severe Gastrointestinal Diseases or Gastroparesis
- Relative contraindication due to the high Incidence of gastrointestinal side effects with GLP-1 Agonists
IV. Mechanism
- See GLP-1 Agonist
- Oral GLP-1 (similar to Semaglutide; other GLP1 Agonists are injectable)
- Orforglipron is a unique, non-peptide small molecule agent
-
Glucagon-Like Peptide 1 (GLP-1) Agonist, an Incretin Mimetic, derived from Gila monster Saliva
- Increases Glucose dependent Insulin secretion
- Inhibits Glucagon secretion
- Delays gastric emptying
- Decreases food intake (improves satiety and decreases appetite)
- Direct effects at the Hypothalamus, Nucleus Accumbens, ventral tegmental areas and Vagus Nerve
V. Medications
- Orforglipron (Foundayo) film coated tablets: 0.8, 2.5, 5.5, 9, 14.5, 17.2 mg
- Precautions
- All GLP-1 Agonists are expensive ($600 to $1300 per month without insurance, $150 to $500 with insurance)
- GLP-1 shortages (esp. Semaglutide and Tirzepatide) have resulted in many online resellers
- Buy from only licensed pharmacies (U.S.), and appropriately accredited (e.g. compounding pharmacy)
- Certificates of analysis confirm active ingredient
VI. Dosing
- Instructions
- Take once daily with or without food (contrast with Semaglutide)
- Swallow tablets whole, and do not break, crush or chew
- Start: 0.8 mg orally daily
- Titration (>30 days between dose increase): 2.5 mg, 5.5 mg, 9 mg, 14.5 mg, 17.2 mg
- Maximum: 17.2 mg/day
VII. Adverse Effects
- See GLP-1 Agonist
- Diarrhea
- Dizziness
- Headache
-
Nausea or Vomiting
- Gastrointestinal adverse effects may be prolonged with Semaglutide Oral (Rybelsus)
- Eat smaller meals and more slowly, stopping before fullness (satiety)
- Consider short-term Ondansetron
- Consider dose reduction until tolerated
-
Hypoglycemia
- Alone, GLP-1 Agonists do not significantly increase risk of Hypoglycemia
- Avoid combination with Bolus Insulin (Mealtime Insulin) or Insulin Secretagogues (e.g. Sulfonylureas)
- Acute Pancreatitis (occurs with all GLP-1 Agonists)
- Gallbladder disease (Cholelithiasis, Cholecystitis, Choledocholithiasis)
- Increased by one in 357 patients over 3 years of medication use
- Increased with longer use, higher dose and when GLP-1 Agonist is used for weight loss
- Faillie (2016) JAMA Intern Med 176(10): 1474-81 +PMID: 27478902 [PubMed]
- Subcutaneous Fat Loss
- Desired weight loss may result in loose, sagging skin ("Ozempic face")
-
Diabetic Retinopathy complications (increased Retinal Hemorrhage)
- Increased risk of Retinopathy complications (esp. if pre-existing Retinopathy)
- GLP1-Agonist class effect (esp. Semaglutide, Liraglutide, Dulaglutide)
- Paradoxically attributed to better Blood Glucose control
- Other serious but uncommon effects (<1%)
VIII. Drug Interactions
- Strong CYP3A4 Inhibitors (e.g. Clarithromycin)
- Maximum Orforglipron dose: 9 mg
- Strong CYP3A4 Inducers (e.g. Carbamazepine)
- Discontinue strong CYP3A4 Inducers or avoid Orforglipron
IX. Safety
- See GLP1 Agonist
- Unknown safety in pregnancy and Lactation
X. Resources
XI. References
- (2026) Presc Lett 33(5): 1-2