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The Peptide Effect
phase 3Weight Loss & Diabetes

Orforglipron

Also known as: LY3502970, Oral GLP-1

Orforglipron is an investigational oral non-peptide GLP-1 receptor agonist developed by Eli Lilly. Unlike all currently approved GLP-1 medications (which are either injectable or peptide-based oral formulations with very low bioavailability), orforglipron is a small molecule that can be taken as a simple daily pill without the strict fasting requirements of oral semaglutide. In phase 2 trials, it demonstrated up to 14.7% weight loss, potentially bringing GLP-1 therapy to millions of injection-averse patients.

Key Facts

Mechanism
Orforglipron is a small-molecule (non-peptide) agonist of the GLP-1 receptor. Unlike peptide-based GLP-1 agonists, it is not degraded by gastric acid or peptidases, enabling high oral bioavailability without the special absorption enhancers or strict fasting protocols required by oral semaglutide (Rybelsus). It activates the same GLP-1 receptor signaling cascade — suppressing appetite through hypothalamic pathways, enhancing glucose-dependent insulin secretion, reducing glucagon, and slowing gastric emptying — but through a distinct binding site and conformational activation mechanism compared to peptide agonists.
Research Status
phase 3
Half-Life
~25-60 hours (supports daily dosing)
Molecular Formula
C₃₀H₃₂F₃N₃O₅
Primary Use
Weight Loss & Diabetes
Table of Contents

Benefits

  • Oral daily pill — no injections required, dramatically improving convenience and adherencestrong
  • Weight loss up to 14.7% body weight at 36 weeks in phase 2 trialmoderate
  • No fasting or water volume restrictions (unlike oral semaglutide/Rybelsus)preliminary
  • Improved glycemic control with HbA1c reductions of ~2.1% in T2D patientsmoderate
  • Stable at room temperature — no cold chain storage required, unlike injectable GLP-1 agentspreliminary

Dosage Protocols

RouteDosage RangeFrequencyNotes
Oral tablet (phase 2 — dose finding)12 mg, 24 mg, 36 mg, or 45 mgOnce dailyPhase 2 trial tested four dose levels with escalation. The 36 mg and 45 mg doses showed the most robust weight loss. Final dosing for commercial use will be determined by phase 3 results.
Oral tablet (phase 2 — dose escalation schedule)3 mg → 6 mg → 12 mg → target doseOnce daily, escalating every 2-4 weeksGradual titration over 8-12 weeks to minimize GI side effects. No food or fasting restrictions required.
Oral tablet (anticipated commercial)36 mg or 45 mg (expected)Once dailyAnticipated maintenance doses based on phase 2 efficacy data. Phase 3 trials (ACHIEVE program) will confirm optimal dosing. Take with or without food.

Medical disclaimer

Dosage information is provided for educational reference only. Always follow your prescriber's instructions and consult a qualified healthcare provider before starting any peptide protocol.

Side Effects

  • Nausea (dose-dependent, most common during titration)common
  • Vomitingcommon
  • Diarrheacommon
  • Decreased appetitecommon
  • Dyspepsia and abdominal discomfortcommon
  • Long-term safety profile not yet established (phase 3 ongoing)rare

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Frequently Asked Questions

When will orforglipron be available to patients?
Orforglipron is currently in phase 3 clinical trials (the ACHIEVE program). Based on typical development timelines, FDA submission could occur in 2026-2027 with potential approval in 2027-2028. However, clinical trial outcomes, FDA review timelines, and manufacturing scale-up can all affect the schedule. Monitor Eli Lilly press releases and clinicaltrials.gov for the most current information. This is speculative and not a guarantee of approval or timeline.
How does an oral GLP-1 pill compare to injectable GLP-1 medications?
Current injectable GLP-1 medications (semaglutide, tirzepatide) produce greater weight loss (15-25%) than orforglipron's phase 2 results (~14.7%). However, orforglipron offers significant practical advantages: no needles, no refrigeration, no injection site reactions, and potentially lower cost (small molecules are cheaper to manufacture than biologics). For millions of patients who refuse or cannot tolerate injections, an effective oral option could be transformative. Phase 3 data will clarify the efficacy gap.
How is orforglipron different from oral semaglutide (Rybelsus)?
Orforglipron and Rybelsus are fundamentally different molecules. Rybelsus is a peptide (semaglutide) co-formulated with an absorption enhancer (SNAC) that requires strict dosing conditions: take on an empty stomach with no more than 4 oz of water, wait 30 minutes before eating or other medications. Orforglipron is a small molecule with naturally high oral bioavailability — no fasting, no water restrictions, no absorption enhancers needed. This makes orforglipron far more convenient for real-world daily use.
Will orforglipron be cheaper than injectable GLP-1 medications?
Small-molecule drugs are significantly cheaper to manufacture than biologic peptides, which theoretically could translate to lower pricing. However, pharmaceutical pricing is driven by market dynamics, patent protection, and payer negotiations — not just manufacturing cost. Eli Lilly has not disclosed expected pricing. If priced competitively, oral GLP-1 therapy could dramatically expand access to this drug class. This is not financial advice or a guarantee of pricing.
Is orforglipron really a peptide if it is a small molecule?
Technically, orforglipron is not a peptide — it is a non-peptide small molecule that activates the same GLP-1 receptor targeted by peptide drugs like semaglutide, liraglutide, and tirzepatide. It is included in peptide reference resources because it belongs to the same GLP-1 receptor agonist drug class and will directly compete with peptide-based GLP-1 medications. Its development represents a potential paradigm shift from injectable biologics to oral small molecules in the metabolic drug space.

References

  1. 1
    Orforglipron (LY3502970), a novel oral non-peptide GLP-1 receptor agonist: a phase 2, randomised, placebo-controlled trial in obesity(2023)PubMed ↗
  2. 2
    Orforglipron, a non-peptide oral GLP-1 receptor agonist, in type 2 diabetes: a phase 2, randomised trial(2023)PubMed ↗
  3. 3
    Discovery of orforglipron (LY3502970): a novel oral non-peptide GLP-1 receptor agonist(2022)PubMed ↗
  4. 4
    Non-peptide GLP-1 receptor agonists: a new frontier in obesity and type 2 diabetes treatment(2023)PubMed ↗

Last updated: 2026-02-14