Peptides›Metabolic›Orforglipron

Orforglipron

/ Oral small-molecule GLP-1 receptor agonist (Eli Lilly, biased)

TIER 2 · TranslationalN = 0 · TESTING PENDINGMW 580.50 g·mol⁻¹

ALIAS · LY-3502970 · Orforglipron

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Research use onlyAny dose figures below describe what specific cited studies used, reported factually. Nothing on this page is guidance for human use.READ FIRST →

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§ A · Identity

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MW · 580.50CLASS · Oral small-molecule GLP-1 receptor agonist (Eli Lilly, biased)CATEGORY · Metabolic

Tier 2. Phase 2 obesity and type 2 diabetes data published (Wharton, Frias and colleagues). The ATTAIN Phase 3 obesity program and ACHIEVE-1 Phase 3 type 2 diabetes program are ongoing. Eli Lilly biased small-molecule oral GLP-1 receptor agonist; not approved.

§ B · Mechanism of action

Orforglipron is an orally bioavailable small-molecule GLP-1 receptor agonist developed by Eli Lilly. Like danuglipron, it engages the GLP-1 receptor at an allosteric site distinct from the orthosteric peptide-binding pocket. Orforglipron is designed for biased signalling (preferential cAMP over beta-arrestin coupling), with the same hypothesis as ecnoglutide: that biased pharmacology may retain insulinotropic and weight-loss efficacy while improving gastrointestinal tolerability. The oral route avoids subcutaneous injection.

§ C · Human clinical evidence

Tier 2. The Phase 2 obesity trial (Wharton and colleagues) reported dose-dependent weight reduction in adults with obesity over 36 weeks with once-daily oral orforglipron. Phase 2 type 2 diabetes data (Frias and colleagues) showed dose-dependent HbA1c reduction. The ATTAIN Phase 3 obesity program (multiple sub-studies) and ACHIEVE-1 Phase 3 T2D program are ongoing; readouts expected.

§ D · Primary literature

PubMed37351564Wharton S et al. — Daily oral GLP-1 receptor agonist orforglipron for adults with obesity · The New England Journal of Medicine · human-phase-2Once-daily oral orforglipron produced dose-dependent weight reduction (up to 14.7% mean change at 36 weeks) versus placebo in adults with obesity; gastrointestinal adverse events most common.Limitations: 36-week duration; Phase 2; smaller sample size than Phase 3 obesity trials.2023

PubMed37369232Frias JP et al. — Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study · The Lancet · human-phase-2Once-daily oral orforglipron reduced HbA1c (up to 2.10% mean change) and body weight versus placebo over 26 weeks in T2D inadequately controlled on metformin; gastrointestinal AEs dose-related.Limitations: 26-week duration; Phase 2; longer-term safety and durability not established.2023

§ F · Safety signal

Phase 2 common adverse events were nausea, vomiting, diarrhoea, and decreased appetite, broadly consistent with class effects of GLP-1 receptor agonism. Tolerability profile in published Phase 2 data has been characterised as broadly comparable to peptide GLP-1 receptor agonists; whether this holds at Phase 3 scale and longer duration remains to be established. Liver-enzyme effects observed with related small-molecule GLP-1 receptor agonists (lotiglipron, danuglipron) have not been reported as a class-defining signal for orforglipron in published Phase 2 data, but long-term safety remains to be characterised.

§ H · Regulatory status

Regulatory status

FDA status:: Not FDA-approved

§ I · Notable gaps and controversies

Orforglipron is the most-advanced oral small-molecule GLP-1 receptor agonist program as of the cutoff, after the discontinuations of lotiglipron (2023, liver findings) and danuglipron (2025, tolerability and liver enzymes). Whether ATTAIN and ACHIEVE-1 Phase 3 data demonstrate efficacy and safety supporting approval is the open question for the class. Vendor 'orforglipron' research-grade material is not interchangeable with clinical-grade compound.