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DanuglipronSmall moleculeNo amino acid sequence. Icon reflects category theme only.Also known as: PF-06882961
Pfizer spent years building an oral GLP-1 pill that didn't need injections, absorption enhancers, or fasting windows. Danuglipron (PF-06882961) is a non-peptide small molecule that activates the GLP-1 receptor from an allosteric binding site. Phase 2b data in 626 adults with obesity showed placebo-adjusted weight loss of 5 to 13 percent at 32 weeks. The problem was tolerability. Nausea hit up to 73 percent of participants at the highest dose arms in the obesity trial. Vomiting reached 47 percent at the highest dose arms in the obesity trial. More than half dropped out. Then a single case of drug-induced liver injury prompted Pfizer to shut down the entire program in April 2025.
Danuglipron (PF-06882961, CAS 2142440-24-2) is a small molecule GLP-1 receptor agonist, not a peptide. Pfizer developed it as an oral alternative to injectable GLP-1 drugs, and the Phase 2b obesity trial showed 8 to 13 percent placebo-adjusted weight loss. Pfizer discontinued all development in April 2025. The molecule binds an allosteric site on the GLP-1 receptor, separate from the orthosteric pocket where semaglutide and native GLP-1 attach. That distinction matters because it means the molecule is orally bioavailable without help. Oral semaglutide (Rybelsus) requires a permeation enhancer and an empty stomach. Danuglipron works with or without food. The Phase 2b obesity trial (626 participants, 26 to 32 weeks)[1] confirmed the weight loss numbers. At the highest doses, completers lost 5 to 13 percent more than placebo at 32 weeks. In type 2 diabetes trials [2], HbA1c dropped by 1.16 percent versus placebo and fasting glucose fell 33 mg/dL versus placebo. But 61 percent of obesity trial participants never finished. Thirty-eight percent quit because of side effects, mostly nausea and vomiting. That 5 to 13 percent weight loss figure reflects survivorship bias; the people who tolerated the drug did well. The short half-life of roughly 6 to 8 hours forced twice-daily dosing, and Pfizer was developing an extended-release version when a single participant in a dose-optimization study showed raised liver enzymes consistent with drug-induced liver injury. That participant recovered after stopping the drug, and overall liver enzyme rates across 1,400 participants looked similar to approved GLP-1 drugs. Pfizer discontinued all development in April 2025 anyway. The drug is not available commercially, through compounding pharmacies, or for any clinical use.
Danuglipron activates the GLP-1 receptor without touching the same binding pocket as semaglutide or native GLP-1. It is a non-peptide allosteric agonist, meaning it locks onto a different part of the receptor surface and stabilizes an active conformation from there. Once the receptor is active, the downstream signaling is familiar. Gs-protein coupling raises intracellular cAMP in pancreatic beta cells. Insulin secretion increases, but only when glucose is present. Glucagon release from alpha cells drops. Gastric emptying slows. Appetite suppression kicks in through hypothalamic and brainstem GLP-1 receptors. The molecular weight sits around 584 g/mol. That's small enough to survive proteolytic enzymes in the GI tract. Pharmacokinetic studies confirmed similar plasma exposure in fed and fasted states; food doesn't change absorption (Phase 1 MAD study)[3]. Primary metabolism runs through hepatic pathways. The short half-life, approximately 6 to 8 hours, is the defining pharmacokinetic limitation. Injectable semaglutide lasts roughly 7 days. Even liraglutide holds for about 13 hours. Danuglipron's clearance rate forced twice-daily dosing in every trial. Pfizer was working on an extended-release once-daily formulation before the program ended.
Demonstrated meaningful weight loss (−6.9% to −11.7% from baseline at 32 weeks; placebo-adjusted −8% to −13%) and HbA1c reduction (up to −1.16% vs placebo) in Phase 2b trials. Development discontinued April 14, 2025 after a single DILI case in a dose-optimization study; never reached Phase 3 or FDA approval.
Obesity Phase 2b RCT (PMID 40539310): 626 participants, 26–32 weeks; placebo-adjusted weight loss −8% to −13% at 32 weeks among completers
Only 39.3% of obesity Phase 2b participants completed treatment (38% discontinued due to AEs, 22% other reasons). Up to 73% nausea, 47% vomiting at higher doses. Single DILI case halted entire program. No Phase 3 data. Discontinued drug: no approved dosing protocol exists.
Negligible community use: drug never reached market, no compounded versions available. Discussed only as a cautionary tale and comparison point against orforglipron in GLP-1 forums.
Danuglipron never reached market or compounding availability. All data is from clinical trials (n=626 obesity, n=~415 T2D across arms). Community protocols do not exist. Science-only by default.
| Level | Dose / Injection | Frequency |
|---|---|---|
| Beginner | 10mg | 2x Daily |
| Moderate | 80mg | 2x Daily |
| Aggressive | 120mg | 2x Daily |
Danuglipron is an oral tablet. No vials, no reconstitution, no bacteriostatic water. That's the entire practical appeal and why Pfizer invested in this program. The twice-daily dosing schedule matters. The half-life is roughly 6 to 8 hours, so missing a dose creates a 12 to 16 hour gap in receptor coverage. If you're reading about this compound for research context, the clinical doses ranged from 2.5 mg BID up to 200 mg BID depending on the trial and arm. The obesity trial targeted 40 to 200 mg BID. The T2D trial tested 2.5, 10, 40, 80, and 120 mg BID. Slow titration is the only tolerability strategy that showed any benefit. The 4-week titration schedule in Cohort 3 of the obesity trial [1] produced the best efficacy data (32 weeks at target dose) and better completion rates than faster titration arms. This drug is not available from compounding pharmacies. No FDA-approved reference drug exists, which means 503A and 503B pharmacies cannot legally compound it. Research chemical suppliers carry it for lab use only; those products are explicitly not for human consumption.
Development discontinued: no approved dosing protocol exists. Phase 2b studies used continuous twice-daily dosing for 26-32 weeks with dose escalation over the first several weeks. The intended clinical use was continuous long-term treatment, similar to other GLP-1 agonists.
Danuglipron was designed for continuous long-term administration (like all GLP-1 agonists): cycling was not studied in any Phase 2b trial. However, the confirmed DILI signal makes scheduled treatment interruptions with LFT re-evaluation the rational safety framework if the drug were used. Any protocol should include structured breaks for liver enzyme normalization if elevations are detected.
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Expected: Placebo-adjusted weight loss −5% to −9.5% at 26 weeks; −8% to −13% at 32 weeks in completers (note survivorship bias: majority of participants dropped out before reaching these timepoints)
Monitor: Liver enzymes (ALT/AST) are mandatory given confirmed DILI signal. Monitor at baseline, weeks 4, 8, 12, then monthly. Also track nausea/vomiting severity, weight, heart rate.
Danuglipron was studied as an oral tablet taken twice daily, approximately 12 hours apart.
T2D trials started as low as 2.5 mg BID.
Pharmacokinetic data confirmed similar plasma exposure in fed and fasted states.
The best-tolerated approach used 4-week steps: 40 mg BID for 4 weeks, then 80 mg BID for 4 weeks, then to target dose.
Target doses ranged from 80 to 200 mg BID depending on the trial arm and tolerability.
No syringe, no reconstitution, no injection technique required. This is a pill.
Liver function tests (ALT, AST, ALP, total bilirubin) required at baseline, weeks 4, 8, 12, and monthly thereafter. Any reading above 3 times the upper limit of normal requires immediate discontinuation.
Store tablets at room temperature, 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit).
Concurrent GLP-1 receptor agonism: additive GI toxicity, increased hypoglycemia risk, no pharmacological benefit. Dual GLP-1 agonist use is contraindicated by mechanism.
Do not combineGLP-1/GIP dual agonist: overlapping GLP-1 mechanism. Additive nausea, vomiting, and hypoglycemia risk. Avoid concurrent use.
Do not combineGLP-1 receptor agonist duplication. Additive GI toxicity, nausea, and hypoglycemia risk.
Do not combineSame drug class (oral small-molecule GLP-1 agonist). Duplicate mechanism with no benefit; additive GI and potential liver enzyme concerns.
Do not combineThe GI side effect profile was severe enough to define the clinical story. Nausea reached 73 percent in the highest-dose obesity arms versus 12.5 percent on placebo [1]. Vomiting hit 47 percent. Those are not typos. Across all dose groups in the Phase 2b obesity trial, 38 percent of participants dropped out specifically because of adverse events. Total discontinuation exceeded 60 percent. For comparison, placebo dropout was around 40 percent. That gap makes the tolerability problem clear. The GI burden stacked: nausea (20 to 48 percent across T2D dose groups), vomiting (18 to 41 percent), diarrhea, dyspepsia, decreased appetite, and abdominal pain were all reported at rates well above placebo [2]. Most of these events clustered during dose escalation. Slower titration schedules (4-week steps versus 1-week steps) appeared to improve tolerability without sacrificing efficacy, but even the slowest titration arms had high dropout. The most consequential safety signal was drug-induced liver injury. A single participant in a dose-optimization study developed raised liver enzymes consistent with potential DILI. The participant was asymptomatic and recovered after stopping danuglipron. Across the broader safety database of over 1,400 participants, liver enzyme elevation rates fell within the range seen with approved GLP-1 agents. Pfizer still chose to discontinue the entire program after consulting with regulators. Heart rate increases were observed at Day 28 in Phase 1 data [3]. No serious cardiac events occurred during the trial program, but the observation is consistent with the GLP-1 class effect seen with other drugs in this category. If you're looking at this compound for any reason, liver function tests are non-negotiable. ALT and AST must be checked at baseline, at weeks 4, 8, and 12, and monthly after that. Any reading above 3 times the upper limit of normal means stop immediately. Symptoms of liver injury (jaundice, right upper quadrant pain, dark urine, unusual fatigue) require emergency evaluation. Do not restart without specialist guidance. Pregnancy safety data does not exist. GI side effects severe enough to prevent adequate hydration or nutrition are also a reason to stop.
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Danuglipron is a discontinued pharmaceutical drug with a confirmed DILI (drug-induced liver injury) signal from clinical trials. It was never approved, never reached market, and is not available as a compounded product. Only accessible as a research chemical from lab suppliers (AbMole BioScience, Selleck Chemicals, MedKoo) explicitly prohibited from human use. Self-administration carries unquantified hepatotoxicity risk with no dose guidance, no clinical oversight, and no safety monitoring infrastructure.
| Test | When | Target |
|---|---|---|
| Liver function tests (ALT, AST, ALP, total bilirubin) | Baseline before any use; weeks 4, 8, 12; monthly at steady-state dose | ALT/AST <3× ULN required to continue; any elevation above this threshold warrants immediate discontinuation |
| Fasting blood glucose and HbA1c | Baseline; every 8 weeks during treatment | FBG 70–99 mg/dL (euglycemic); HbA1c per individual glycemic targets |
| Body weight | Baseline; every 2 weeks during titration; every 4 weeks at target dose | — |
| Resting heart rate | Baseline; monthly | 60–100 bpm resting; flag sustained increase >10 bpm above individual baseline |
Confirmed DILI signal from Phase 3 dose-optimization study (single participant with elevated liver enzymes resolving after drug discontinuation). Risk is unquantified without Phase 3 safety data.
GLP-1 mechanism lowers blood glucose: relevant for anyone with T2D or metabolic syndrome. Hypoglycemia risk is elevated if combined with insulin or sulfonylureas.
Primary efficacy endpoint. Rapid weight loss (>1.5 lb/week sustained) may warrant dose assessment; plateaued weight loss at tolerable dose is the expected steady-state.
Phase 1 MAD study showed heart rate increases at Day 28: a GLP-1 class effect observed with danuglipron. Relevant for individuals with pre-existing arrhythmia or tachycardia.
Dose escalation phase starting from low doses (2.5-10 mg BID). GI side effects most pronounced during this period: nausea, vomiting, and dyspepsia were commonly reported. Modest appetite suppression may begin. Minimal weight change expected.
Escalation toward target dose (80-120 mg BID). Phase 2 T2D data showed HbA1c reductions of approximately -1% and body weight reductions of -1.9 to -5.4 kg vs placebo at 12-16 weeks. GI side effects may persist or worsen with dose increases.
Continued weight loss at target dose. Phase 2b obesity trial showed placebo-adjusted weight loss of -5% to -9.5% at 26 weeks. However, over 50% of participants had discontinued by this point in trials, primarily due to GI adverse events.
Maximum observed efficacy window in Phase 2b. Placebo-adjusted weight loss reached -8% to -13% at 32 weeks in the highest dose groups among those who remained on treatment: though this reflects a survivorship bias given the high dropout rates.
Weeks 1 to 4: Dose escalation begins at 10 to 40 mg twice daily. GI side effects peak during this window. Nausea reached 73 percent at the highest obesity trial doses, with vomiting at 47 percent. Lower starting doses had lower rates. Appetite suppression may start. Weight change is minimal this early. Weeks 5 to 12: Escalation toward target dose, typically 80 to 120 mg twice daily. T2D Phase 2b data showed HbA1c reductions around 1 percent and body weight falling 1.9 to 5.4 kg versus placebo by 12 to 16 weeks. GI symptoms may worsen with each dose step. Most trial dropouts occurred during this window. Weeks 13 to 26: Target dose maintenance. Placebo-adjusted weight loss reached 5 to 9.5 percent at 26 weeks in the obesity trial. Only 39.3 percent of participants made it this far. Liver enzyme monitoring is most important here given cumulative drug exposure. Weeks 27 to 32: Extended treatment from the longest-running arm (Cohort 3, 4-week titration). Placebo-adjusted weight loss hit 5 to 13 percent at 32 weeks in completers. That number carries serious survivorship bias; the majority of participants had already dropped out.
Dose escalation from starting dose (10–40 mg BID). GLP-1 receptor occupancy building. Appetite suppression may begin. GI adverse events are most severe during this window.
No community data: drug never marketed.
T2D Phase 2b: body weight reductions of −1.9 to −5.4 kg vs placebo emerging at 12 weeks. HbA1c begins falling. GI side effects may worsen with each dose step.
No community data.
Obesity Phase 2b (Cohorts 1&2): placebo-adjusted weight loss −5% to −9.5% at 26 weeks. T2D Phase 2b: HbA1c −1.16% vs placebo, fasting glucose −33 mg/dL vs placebo.
No community data. Only 39.3% of obesity trial participants reached this phase.
Obesity Phase 2b Cohort 3 (4-week titration schedule, 32-week treatment): placebo-adjusted weight loss −8% to −13% at 32 weeks in completers. Represents the best-case efficacy from the longest-running arm: significant survivorship bias applies.
No community data.
Source: Saxena et al. Phase 1 MAD study (PMID 34127852); ~6-8 hour terminal half-life necessitating twice-daily dosing
Loading the interactive decay curve.
Danuglipron has no FDA approval. It never completed Phase 3 trials. Pfizer discontinued all development in April 2025 after a drug-induced liver injury signal in a dose-optimization study, in consultation with regulators. The official discontinuation announcement is on Pfizer's press release page. The compound is classified as research-only. It is available from laboratory chemical suppliers (AbMole BioScience, Selleck Chemicals, MedKoo Biosciences) for in-vitro and animal research. These suppliers explicitly prohibit human use. No compounding pathway exists. Because there is no FDA-approved reference product, 503A and 503B compounding pharmacies cannot legally produce danuglipron for human use. Any product marketed as "compounded danuglipron" for human administration is unapproved and unverified. If you're seeking an oral GLP-1 option, orforglipron (approved by the FDA as Foundayo) and oral semaglutide (Rybelsus) are supervised alternatives with established safety profiles. This content is for educational and research purposes only. It does not constitute medical advice. Consult a licensed healthcare provider before making any treatment decisions.
Peptide Schedule Research TeamReviewed Apr 20267 Citations
