Danuglipron

Metabolic / Weight Loss

Also known as: PF-06882961, Pfizer Danuglipron

GLP-1 Receptor Agonists (Oral Non-Peptide)Research phase: Phase 2b (obesity and T2DM)Regulatory: Investigational. Not approved by any regulatory agency.

Mechanism

Danuglipron is an oral, non-peptide small molecule that activates the same GLP-1 receptor as injectable semaglutide. Unlike peptide-based GLP-1 drugs that must be injected or specially formulated for oral use, danuglipron is a traditional pill. It reduces appetite, improves blood sugar control, and promotes weight loss, though gastrointestinal side effects remain common.

Technical detail

Danuglipron is a non-peptide, small-molecule oral GLP-1R agonist. It binds the extracellular domain of GLP-1R and activates Gs-coupled cAMP signaling in pancreatic beta cells, promoting glucose-dependent insulin secretion. Despite being a non-peptide, it achieves full GLP-1R agonism with biased signaling profiles that may differ from native GLP-1. Oral bioavailability eliminates the need for injection or permeation enhancers required by oral semaglutide. Twice-daily dosing in current formulations.

Evidence

Efficacy and Safety of Oral Small Molecule Glucagon-Like Peptide 1 Receptor Agonist Danuglipron for Glycemic Control Among Patients With Type 2 Diabetes: A Randomized Clinical Trial.
Saxena AR et al. (2023) — JAMA Netw Open — PMID: 37213102
16-week phase 2b randomized trial in 411 adults with type 2 diabetes showed statistically significant HbA1c and fasting glucose reductions across danuglipron doses, plus body-weight loss up to 4.17 kg versus placebo at 120 mg BID; nausea, diarrhea, and vomiting were common adverse events.
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Tolerability, safety and pharmacodynamics of oral, small-molecule glucagon-like peptide-1 receptor agonist danuglipron for type 2 diabetes: A 12-week, randomized, placebo-controlled, Phase 2 study comparing different dose-escalation schemes.
Saxena AR et al. (2023) — Diabetes Obes Metab — PMID: 37311722
12-week randomized placebo-controlled phase 2 study found danuglipron reduced HbA1c by about 1.04%-1.57%, lowered fasting glucose, and reduced body weight by 1.93-5.38 kg, but with higher discontinuation and gastrointestinal adverse-event rates at higher target doses.
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Safety and efficacy of the new, oral, small-molecule, GLP-1 receptor agonists orforglipron and danuglipron for the treatment of type 2 diabetes and obesity: systematic review and meta-analysis of randomized controlled trials.
Karakasis P, Patoulias D, Pamporis K, Stachteas P, Bougioukas KI, Klisic A, Fragakis N, Rizzo M. (2023) — Metabolism — PMID: 37852529
The novel GLP-1 receptor agonists orforglipron and danuglipron led to significant reduction in HbA1c in patients with type 2 diabetes mellitus (T2DM) compared to controls, with a mean difference of -1.03% (95% CI = [-1.29, -0.77]). They also showed efficacy in weight reduction in T2DM and obesity.
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Effect of Renal Impairment on the Pharmacokinetics of a Single Oral Dose of Danuglipron in Participants With Type 2 Diabetes
(2023) — Wiley — PMID: 10.1002/jcph.2371
The study found that renal impairment had no clinically significant effect on the pharmacokinetics of danuglipron in participants with type 2 diabetes. A single 20-mg oral dose of danuglipron was generally safe and well tolerated in all participant groups.
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Danuglipron (PF-06882961) in type 2 diabetes: a randomized, placebo-controlled, multiple ascending-dose phase 1 trial.
Saxena AR et al. (2021) — Nat Med — PMID: 34127852
Multiple ascending-dose phase 1 trial in type 2 diabetes found danuglipron generally well tolerated over 28 days, with mostly mild gastrointestinal adverse events and no clinically meaningful laboratory or ECG safety signal.
moderate

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