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Orforglipron

Extensively Studied

Oral Small-Molecule GLP-1 Receptor Agonist | Weight Loss & Diabetes

Dose Start 3-6mg daily, titrate up to 12-36mg based on response
Frequency Once daily oral tablet
Cycle Long-term continuous therapy (72+ weeks in trials)
Storage Room temperature 15-30°C; no refrigeration needed
Accumulation Plotter

First oral non-peptide GLP-1 completing Phase 3 trials. Achieves substantial weight loss without injections, refrigeration, or dietary restrictions, with clinical evidence of 12.4% weight reduction at 72 weeks.

Mechanism of Action

Small-molecule GLP-1 receptor agonist with biased signaling preferentially activating G protein/cAMP pathways, enhancing insulin secretion, suppressing glucagon, delaying gastric emptying, and reducing appetite while minimizing receptor desensitization. 79.1% oral bioavailability with 29-49 hour half-life.

Key Benefits

  • Significant weight loss (up to 12.4% at 72 weeks)
  • Robust diabetes control (HbA1c reduction 1.3-1.6%)
  • Once-daily oral tablet format
  • No refrigeration or food restrictions required
  • Reduced cardiovascular risk markers
Molecular Weight
882.974 Da
Chain Length
Non-peptide small molecule
Type
Small-molecule GLP-1R agonist
Amino Acid Sequence
Not applicable - synthetic small molecule

Complex or non-standard sequence format

Weight Loss

  • Obesity Without Diabetes

    ATTAIN-1 demonstrated 12.4% weight loss (27.3 lbs) at 72 weeks with 36mg dose; 59.6% achieving ≥10% weight loss.

  • Obesity With Type 2 Diabetes

    ATTAIN-2 showed 10.5% weight loss with 72.8% achieving ≥5% weight loss.

  • Cardiometabolic Risk Reduction

    Improvements in waist circumference, systolic blood pressure (8-12 mmHg), triglycerides (-20-30%).

  • Prediabetes Prevention

    91% achieved near-normal blood sugar levels versus 42% with placebo.

Type 2 Diabetes

  • Type 2 Diabetes Management

    ACHIEVE-1 Phase 3 trial showed HbA1c reductions of 1.3-1.6% from 8.0% baseline; 76.2% achieving HbA1c <7%.

  • Insulin Resistance Improvement

    Significant improvements in insulin sensitivity indices within 4 weeks of therapy initiation.

Once-daily oral tablet requiring no reconstitution. Can be taken with or without food or water at any time of day.

GoalDoseFrequencyRoute
Type 2 diabetes initiation3mg dailyOnce daily, any timeOral tablet
Type 2 diabetes moderate control12mg dailyOnce daily, any timeOral tablet
Type 2 diabetes optimal control36mg dailyOnce daily, any timeOral tablet
Weight loss initiation6mg dailyOnce daily, any timeOral tablet
Weight loss optimization36mg dailyOnce daily, any timeOral tablet
Semaglutide

Both are GLP-1 agonists; combining increases severe hypoglycemia and excessive GI adverse effects.

avoid
Tirzepatide

Dual GIP/GLP-1 agonist overlaps with GLP-1 mechanism; combination contraindicated.

avoid
Liraglutide

Another GLP-1 agonist; concurrent use contraindicated due to overlapping mechanisms.

avoid
Insulin

Orforglipron enhances insulin sensitivity; may require significant insulin dose reduction.

monitor
Metformin

Complementary mechanisms for diabetes management; Phase 3 trials showed enhanced efficacy.

synergistic
BPC-157

No known interactions; may support gut health and potentially mitigate GI adverse effects.

compatible
Week 1-2

Appetite reduction typically within 1-3 days; mild to moderate nausea common

Week 2-4

Gradual weight loss begins (0.5-2 lbs per week); improved blood sugar control

Week 4-12

Reduced food cravings; GI adverse effects generally diminish; metabolic markers improving

Week 12-36

Continued progressive weight loss without plateau

Week 36+

Long-term therapy well-tolerated; sustained benefits at 72 weeks

Common Side Effects

  • Diarrhea (more prevalent than with injectable GLP-1s)
  • Nausea (typically improves after first month)
  • Appetite reduction

Stop Signs - Discontinue if:

  • Severe or persistent abdominal pain radiating to back (potential pancreatitis)
  • Neck lumps, hoarseness, difficulty swallowing, or neck swelling
  • Severe nausea/vomiting preventing adequate nutrition or hydration
  • Signs of severe hypoglycemia (confusion, sweating, rapid heartbeat)
  • Suicidal thoughts, severe depression, or significant mood changes
  • Vision changes or persistent eye pain

Contraindications

  • Personal or family history of medullary thyroid carcinoma
  • Multiple Endocrine Neoplasia syndrome type 2 (MEN2)
  • Pregnancy and breastfeeding

Good Signs

  • Intact tablet packaging with proper labeling, batch numbers, and expiration dates
  • Uniform tablet appearance without discoloration, chipping, or cracking
  • Proper storage at room temperature (15-30°C)

Warning Signs

  • As of late 2025, orforglipron remains investigational only; any product claiming FDA approval is fraudulent

Bad Signs

  • Discolored, crumbling, or damaged tablets indicate improper storage
  • Moisture exposure or humidity damage
  • ATTAIN-1 Phase 3 Trial (Obesity)
    (2025)

    3,127 adults; 72 weeks. 36mg dose achieved 12.4% weight loss (27.3 lbs) versus 2.1% placebo. First oral small-molecule GLP-1 completing Phase 3.

  • ATTAIN-2 Phase 3 Trial (Obesity + Type 2 Diabetes)
    (2025)

    1,613 adults; 72 weeks. 36mg dose achieved 10.5% weight loss with 72.8% achieving ≥5% weight loss.

  • ACHIEVE-1 Phase 3 Trial (Type 2 Diabetes)
    (2025)

    559 adults; 40 weeks. All doses significantly reduced HbA1c by 1.3-1.6%; 76.2% achieved HbA1c <7%.

  • Phase 2 Obesity Study
    (2023)

    272 adults; 36 weeks. Achieved up to 14.7% mean weight reduction at 36 weeks with 45mg dose.

Disclaimer

This information is for educational and research purposes only. Consult a healthcare professional before use.