Danuglipron

Danuglipron binds and activates the GLP-1 receptor as a non-peptide agonist, producing conventional incretin effects. Its clinical story is the important part: the twice-daily formulation produced high rates of nausea and vomiting with discontinuation rates above 50% in phase 2b, the once-daily reformulation reached dose-optimisation studies, and in April 2025 Pfizer discontinued the programme after a case of potentially drug-induced liver injury in a participant. That decision is why every subsequent oral small-molecule GLP-1 programme, including orforglipron, has carried heavy liver-enzyme surveillance.

Targets: GLP-1 receptor

• · Phase 2b escalated to maintenance doses in the range of 40-200 mg twice daily. This is a historical record - the drug is not available and should not be sought.

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• very commonNausea— Rates well above other GLP-1 agents; a major reason for the programme's failure.
• very commonVomiting
• very commonDiarrhoea
• rareDrug-induced liver injury— A single case of potential DILI ended the programme in April 2025; asymptomatic transaminase elevations had also been seen.

• Not available for use in any context - the programme is terminated.
• Any pre-existing liver disease would have been an absolute contraindication given the hepatic signal.

• redundantorforglipron — Same drug class; orforglipron is the surviving member.
• redundantsemaglutide — Same receptor.

• · Liver enzymes would have been mandatory.
• · Not applicable in practice - the drug does not exist commercially.

Discontinued investigational compound; never approved and no longer in development.

• Saxena et al. 2023, danuglipron phase 2b in type 2 diabetes, JAMA Network Open (trial)
• Pfizer 2025, discontinuation announcement for danuglipron (other)

Pharmacologically danuglipron did what it was supposed to do. It was an orally bioavailable non-peptide GLP-1 receptor agonist producing roughly 8-13% weight loss at 26-32 weeks in phase 2b, which is real efficacy for a tablet. Two things killed it. The first was tolerability: gastrointestinal adverse events led to discontinuation rates in the phase 2b programme that were high enough to make the drug commercially unviable regardless of efficacy, with nausea and vomiting rates well above what injectable agents produce. The plausible explanation is exposure shape - a twice-daily small molecule produces sharp peaks, and peak concentration is what drives area postrema emesis, whereas a weekly acylated peptide produces a nearly flat profile. The second was liver injury. In April 2025 Pfizer terminated the programme after a case of drug-induced liver injury in the modified-release study. One case does not establish a class effect, and orforglipron's much larger programme did not reproduce it, but it is the reason liver enzymes deserve attention on any oral small-molecule GLP-1 agonist in a way they do not on injectable peptides - small molecules are hepatically metabolised and peptides are not. Danuglipron is included here as the reference point for what can go wrong with this approach, not as an option.

Everything, historically. High gastrointestinal discontinuation rates and then a drug-induced liver injury case. The useful lesson is generalisable: an oral small molecule that hits the same receptor as an injectable peptide is not simply a more convenient version of it, because the exposure profile and the metabolic handling are both fundamentally different, and both of those differences turned out to matter.

• GLP-1 receptor (GLP1R) — Non-peptide agonist; specific affinity not verified

  Standard GLP-1 agonism with an exposure profile characterised by sharp peaks, which is the likely reason for its disproportionate gastrointestinal intolerance.

• Danuglipron phase 2b in obesity Phase 2b · 32 weeks · 2025

  Dose-ranging weight reduction with danuglipron in adults with obesity, with high rates of gastrointestinal adverse events and discontinuation.

Weight effects developed over 16-32 weeks in phase 2b. Historical only.

Not applicable. The programme was terminated in April 2025 and there is no supply.

Against orforglipron: the same idea, executed with worse tolerability and a liver signal. Orforglipron is once daily with a 29-49 hour half-life and a flatter profile; danuglipron was twice daily with sharp peaks. That difference in exposure shape is the most likely explanation for why one is approved and one is dead. Against injectable agents: danuglipron never approached them on either efficacy or tolerability.

Never marketed. No price.

• ?No verifiable pharmacokinetic parameters.
• ?The specific hepatic enzymology was not verified.
• ?Whether the single liver injury case represented a compound-specific or class-wide risk has never been resolved and now cannot be, because the programme was stopped.
• ?The 8-13% weight-loss range is as reported in summaries and the exact phase 2b primary outcome values were not extracted in this session.

• Efficacy and safety of danuglipron (PF-06882961) in adults with obesity: A randomized, placebo-controlled, dose-ranging phase 2b study Buckeridge C et al., Diabetes Obes Metab, 2025 · PMID 40539310

  The phase 2b data, including the discontinuation rates that made the tolerability problem obvious before the liver signal appeared.