Danuglipron

Overview

Danuglipron (PF-06882961) is a synthetic, orally active small-molecule agonist of the human glucagon-like peptide-1 receptor (GLP-1R). Despite its appearance in a peptide database, danuglipron is not a peptide and has no amino-acid sequence.

Human randomized trials showed reductions in glucose measures and body weight. That efficacy signal must be read together with the development outcome: gastrointestinal intolerance caused many participants to stop treatment, the twice-daily programme did not advance to phase 3, and Pfizer discontinued the entire danuglipron programme on 14 April 2025 after reviewing all clinical data, regulator input and one potential drug-induced liver injury.

Identity and mechanism

PubChem identifies danuglipron as CID 134611040, molecular formula C31H30FN5O4, molecular weight 555.6 g/mol and InChIKey HYBAKUMPISVZQP-DEOSSOPVSA-N. The development code is PF-06882961. These fields describe a defined organic molecule; a peptide sequence would be chemically inapplicable.

The discovery paper (PMID 35647711) and structural work show binding within the GLP-1R transmembrane region. The binding pocket depends on a primate-specific tryptophan at receptor position 33, helping explain activity in humans and non-human primates but not ordinary rodents. Receptor activation can enhance glucose-dependent insulin secretion and reduce glucagon signalling; clinical effects on appetite, gastric emptying and weight belong to the GLP-1R mechanism, but do not make danuglipron equivalent to an approved peptide GLP-1 medicine.

Development status and trial registry

An exact ClinicalTrials.gov search on 30 July 2026 returned 20 danuglipron/PF-06882961 records: 19 completed and one terminated. The completed label describes study status, not regulatory approval or a positive benefit–risk conclusion.

Pfizer stopped development in two stages:

1. In December 2023, it said the twice-daily formulation would not enter phase 3 because of high discontinuation rates, while once-daily formulation work continued.
2. On 14 April 2025, after two dose-optimization studies had met key pharmacokinetic objectives, Pfizer discontinued the whole molecule.

The later registry record NCT06910839 is marked terminated and says the study stopped before PF-06882961 was administered because the sponsor had discontinued danuglipron development. EMA also published Pfizer's notification ending the corresponding paediatric development. An agreed paediatric investigation plan is a development requirement—not marketing authorization.

Human evidence in type 2 diabetes

The first randomized phase 1 trial (PMID 34127852) enrolled 98 adults with type 2 diabetes receiving metformin. Over 28 days, most adverse events were mild, with nausea, dyspepsia and vomiting most common. The study was designed primarily for safety, tolerability and pharmacology, not long-term clinical outcomes.

In the 16-week phase 2b trial (PMID 37213102), 411 randomized and treated participants received placebo or one of five twice-daily danuglipron target doses. At week 16, all danuglipron groups had statistically significant reductions in HbA1c and fasting plasma glucose versus placebo. Body weight was significantly lower versus placebo only in the 80 mg and 120 mg twice-daily groups; the reported placebo-adjusted differences were −2.04 kg and −4.17 kg, respectively. Nausea, diarrhoea and vomiting were the most common adverse events.

The separate 12-week phase 2 study (PMID 37311722) also found lower HbA1c, fasting glucose and weight, but discontinuation from study medication ranged from 27.3% to 72.7% across danuglipron groups versus 16.7% to 18.8% on placebo. Benefit and tolerability therefore moved together; the glycaemic signal does not erase the attrition problem or establish long-term cardiovascular, kidney or mortality benefit.

Human evidence in obesity

The pivotal obesity study (NCT04707313; PMID 40539310) randomized 628 adults with obesity and without diabetes to twice-daily danuglipron or placebo for 26 or 32 weeks. All danuglipron groups showed statistically significant placebo-adjusted weight reductions, ranging from −5.0% to −12.9% at the end of treatment.

Retention sharply limits interpretation. Of 626 participants who received treatment, only 39.3% completed it. About 38% discontinued because of adverse events, and another 22% stopped for other reasons. In the published full report, gastrointestinal treatment-emergent adverse events occurred in 77.4% of danuglipron recipients versus 30.0% with placebo; nausea occurred in 51.4% and vomiting in 31.3% of all treated participants. High missingness and the fixed escalation design make modelled end-of-treatment estimates less certain than a high-retention trial.

The trial was Pfizer-funded, and most listed authors were current or former Pfizer employees. That does not invalidate the randomized result, but independent replication and a viable longer-term formulation never arrived before development stopped.

Pharmacokinetics and the 2025–2026 update

The immediate-release human programme does not support PeptideGuide's unqualified “3–4 hours” half-life. The first-human report associated with PMID 35647711 found mean terminal half-lives of 4.3–6.1 hours after single oral doses in healthy adults. A Japanese phase 1 study found mean values of 5.300–6.373 hours at steady state. Formulation, dose, population and single-versus-repeated dosing matter; these figures should not be converted into a self-dosing interval.

A 2026 metabolism paper (PMID 40865303) reported a half-life of 208 ± 31 minutes in human liver microsomes. That is an in-vitro metabolic stability measurement—not a human plasma elimination half-life—and cannot validate the source database's 3–4-hour human claim.

The 2025 danuglipron/orforglipron meta-analysis (PMID 41450584) and a broader 2026 small-molecule GLP-1RA meta-analysis (PMID 42483679) support class-level glucose and weight effects while again finding more gastrointestinal adverse events. They pool compounds, trials and doses and cannot reverse Pfizer's compound-specific discontinuation decision or establish long-term danuglipron safety.

Safety, regulatory and sport boundary

Gastrointestinal intolerance—not merely the presence of mild nausea—was the dominant recurring limitation. The obesity phase 2b programme had high rates of nausea, vomiting, diarrhoea and treatment discontinuation. On 14 April 2025, Pfizer reported that one asymptomatic participant in a later dose-optimization study experienced potential drug-induced liver injury, which resolved after danuglipron was discontinued. Pfizer said overall liver-enzyme-elevation frequency across a safety database of more than 1,400 participants was in line with approved agents in the class, but stopped the molecule after considering the totality of evidence and regulator input.

That wording is important: a potential drug-induced liver injury in one participant is a serious signal and programme-level risk decision, but it is not evidence that every exposed participant developed hepatotoxicity.

Exact Drugs@FDA searches returned no danuglipron or PF-06882961 application, and the 27 July 2026 European Commission Union Register dataset contained 6,418 records with no exact match. The EMA paediatric-plan record proves regulatory development activity, not approval. No approved FDA or EU medicine, authorised product label or regulator-approved regimen was identified.

The WADA 2026 Prohibited List does not specifically name danuglipron or PF-06882961 in the indexed material reviewed. The 2026 Monitoring Program names markers of semaglutide and tirzepatide; monitoring is explicitly not the same as prohibition and does not classify danuglipron by analogy. This page does not infer S0 or any other WADA class, and absence from named examples is not permission. Sport status, medicine approval and country-specific law are separate questions.

Russian-language literature and evidence limits

The Russian-language pass used the exact forms «дануглипрон» and «PF-06882961» with terms for obesity, type 2 diabetes, liver and clinical trials. It found a relevant 2025 Russian editorial review by Shestakova and Bashlykova in Terapevticheskii Arkhiv. The review correctly identifies danuglipron as an oral non-peptide GLP-1 receptor agonist and says it was removed from further development in 2025.

The Russian review describes the reason as “unpredictable hepatotoxicity.” That is broader and more definitive than Pfizer's primary statement of one potential drug-induced liver injury in an asymptomatic participant. Therefore the public conclusion follows the narrower primary-source wording.

A PubMed query combining danuglipron/PF-06882961 with Russian language or Russian affiliation returned two Russia-affiliated publications: a 2025 patent review (PMID 40873282) and a 2026 medicinal-chemistry scaffold study (PMID 41976172). They inform compound-class and structure–activity research, not human efficacy or safety in Russian patients. None of the 20 ClinicalTrials.gov records listed a Russian study location.

CyberLeninka exact searches did not expose a directly reviewable danuglipron-specific article in the returned static surface, and eLIBRARY returned an IP-block page. The Russian pass is therefore documented but not exhaustive. An exact PubMed retraction/expression-of-concern query returned zero records; that bounded result is not proof that every publication is free from correction or bias.