Tirzepatide
Human RCTMounjaro · Zepbound · LY3298176 · GIP/GLP-1 receptor agonist
Highest available evidence among curated papers: Human RCT (as of 2026-06-04).
Chemical & identity
- Molecular formula
- C225H348N48O68
- Molecular weight
- 4813 g/mol · PubChem
- PubChem CID
- 166567236 · PubChem
- SMILES
- CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CC[C@@H](C(=O)O)NC(=O)CCCCCCCCCCCCCCCCCCC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)NCC(=O)NCC(=O)N4CCC[C@H]4C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N5CCC[C@H]5C(=O)N6CCC[C@H]6C(=O)N7CCC[C@H]7C(=O)N[C@@H](CO)C(=O)N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)C(C)(C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H](CC8=CC=C(C=C8)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC9=CC=CC=C9)NC(=O)[C@H]([C@@H](C)O)NC(=O)CNC(=O)[C@H](CCC(=O)O)NC(=O)C(C)(C)NC(=O)[C@H](CC1=CC=C(C=C1)O)N
- InChIKey
- BTSOGEDATSQOAF-MCNPHUAVSA-N
- ChEMBL ID
- CHEMBL4297839 · ChEMBL
- Category
- Metabolic/GLP-1
Chemical/structural fields are auto-pulled and source-linked. ChEMBL data: ChEMBL_36, CC BY-SA 3.0.
Mechanism (curated)
Dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist.
Pharmacology & handling
- Half-life
- Approximately 5 days (~120 hours), enabling once-weekly subcutaneous dosing.
Research
Sattar N et al. · Nature medicine · 2022 · Meta-analysis
This pre-specified meta-analysis pooled data from seven randomized controlled trials (SURPASS program) lasting ≥26 weeks to evaluate tirzepatide's association with cardiovascular outcomes in type 2 diabetes. The analysis included 4,887 tirzepatide-treated and 2,328 control participants, assessing the primary endpoint of MACE-4 (cardiovascular death, myocardial infarction, stroke, hospitalized unstable angina). Tirzepatide showed a hazard ratio of 0.80 (95% CI, 0.57–1.11) for MACE-4 compared to controls, with no increased risk of major cardiovascular events. The authors concluded tirzepatide did not increase cardiovascular risk in participants with type 2 diabetes.
Nicholls SJ et al. · American heart journal · 2024 · RCT
SURPASS-CVOT is a randomized, double-blind, active-controlled cardiovascular outcomes trial comparing tirzepatide (a GIP/GLP-1 receptor agonist) to dulaglutide (a GLP-1 receptor agonist) in 13,299 people with type 2 diabetes aged ≥40 years and established atherosclerotic cardiovascular disease. The primary outcome is time to first major adverse cardiovascular event (MACE: cardiovascular death, myocardial infarction, or stroke), with the trial designed to assess noninferiority and superiority of tirzepatide versus dulaglutide. Baseline characteristics show mean age 64.1 years, diabetes duration 14.7 years, HbA1c 8.4%, and BMI 32.6 kg/m², with 65% having coronary disease and significant prior cardiovascular events. The trial is fully recruited and ongoing, intended to provide definitive evidence on the cardiovascular safety and efficacy of tirzepatide.
Heise T et al. · The lancet. Diabetes & endocrinology · 2022 · RCT
This multicentre, randomised, double-blind, phase 1 clinical trial compared tirzepatide 15 mg (n=39), semaglutide 1 mg (n=39), and placebo (n=24) in 102 adults with type 2 diabetes over 28 weeks. Tirzepatide significantly increased the clamp disposition index (a combined measure of insulin secretion and sensitivity) compared to placebo, with improvements also greater than semaglutide. Tirzepatide reduced glucose excursions and glucagon concentrations on meal tolerance testing and improved both total insulin secretion rate and insulin sensitivity versus semaglutide. Gastrointestinal adverse events (nausea, diarrhea, vomiting) were the most common side effects, with similar safety profiles between tirzepatide and semaglutide.
GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice.
Animal-onlySamms RJ et al. · The Journal of clinical investigation · 2021 · Animal study
This animal study in obese mice examined how tirzepatide, a dual GIP and GLP-1 receptor agonist, improves insulin sensitivity. Tirzepatide enhanced insulin sensitivity more than GLP-1R agonism alone, partly through GIPR agonism-mediated effects independent of weight loss. The mechanism involved enhanced glucose disposal in white adipose tissue and reduced circulating branched-chain amino acids and ketoacids, with upregulation of catabolic genes in brown adipose tissue. The findings suggest GIPR agonism contributes to tirzepatide's therapeutic effects through both weight-dependent and weight-independent pathways.
Nauck MA, D'Alessio DA · Cardiovascular diabetology · 2022 · Meta-analysis
Tirzepatide is a dual GIP/GLP-1 receptor co-agonist approved for type 2 diabetes treatment. Five clinical trials (SURPASS 1-5) in type 2 diabetic subjects showed tirzepatide at 5–15 mg weekly reduced HbA1c by 1.24–2.58% and body weight by 5.4–11.7 kg, with 23–62% reaching normal HbA1c (<5.7%) and 21–68% losing >10% baseline body weight. Tirzepatide was more effective than semaglutide (GLP-1 receptor agonist) and basal insulin, with similar adverse events (nausea, vomiting, diarrhea, constipation). Cardiovascular event analysis across the trial program showed no hazard ratios >1.0 versus pooled comparators, meeting cardiovascular safety criteria, although event numbers were low. The abstract notes that GIP's mechanisms in humans remain unclear, as previous studies suggest type 2 diabetic patients are unresponsive to GIP.
Karagiannis T et al. · Diabetologia · 2022 · Meta-analysis
This systematic review and meta-analysis included seven randomized controlled trials (6,609 participants) comparing tirzepatide (5, 10, or 15 mg once-weekly) with placebo or other glucose-lowering drugs for type 2 diabetes. Tirzepatide demonstrated dose-dependent superiority in reducing HbA1c versus all comparators, with mean differences of -17.71 to -22.35 mmol/mol versus placebo and -3.22 to -10.06 mmol/mol versus GLP-1 receptor agonists. Tirzepatide also produced greater body weight reduction than GLP-1 RAs (1.68 to 7.16 kg more) and had hypoglycemia rates similar to placebo and lower than basal insulin. The main safety concern was increased gastrointestinal adverse events with tirzepatide, including higher rates of nausea, vomiting, and diarrhea (particularly at the 15 mg dose), and a higher discontinuation rate due to adverse events at 15 mg, though serious adverse events and mortality were comparable to comparators.
Sattar N et al. · Journal of the American College of Cardiology · 2026 · RCT
This post hoc analysis of the SURMOUNT-1 randomized trial examined cardiovascular risk biomarkers in 392 participants with obesity or overweight who received once-weekly placebo or tirzepatide (5, 10, or 15 mg) for 72 weeks. At week 72, tirzepatide was associated with dose-dependent reductions in inflammatory biomarkers (high-sensitivity C-reactive protein, interleukin-6), metabolic/adiposity markers (leptin, homeostatic model assessment of insulin resistance), and selected hemostasis markers (plasminogen activator inhibitor-1), as well as increases in adiponectin and improvements in endothelial dysfunction markers. No consistent associations were observed with fibrinogen, tissue plasminogen activator, or thrombomodulin. The authors conclude tirzepatide produced comprehensive improvements across multiple cardiovascular risk biomarker pathways over the 72-week period.
Ma T et al. · Frontiers in nutrition · 2025 · Animal study
This animal study compared tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a GLP-1 receptor agonist) in male C57BL/6J mice fed a high-fat, high-fructose diet. Both drugs reduced body weight, improved lipid profiles, and enhanced insulin sensitivity. RNA sequencing of brown adipose tissue identified 40 genes modulated by tirzepatide and 467 by semaglutide, with shared targets (Cyp1a1, Hsd11b1, Atp1a3) and tirzepatide-specific targets (Tfrc, Ptger4, Il1b) identified through bioinformatic analysis.
Willard FS et al. · JCI insight · 2020 · In-vitro study
Tirzepatide (LY3298176) is a dual GIP/GLP-1 receptor agonist in development for type 2 diabetes, obesity, and nonalcoholic steatohepatitis. This in-vitro and mechanistic study establishes methods to calculate receptor occupancy at clinically efficacious doses, revealing greater engagement of the GIP receptor than the GLP-1 receptor. Signaling studies show tirzepatide mimics native GIP at the GIP receptor but exhibits bias at the GLP-1 receptor, favoring cAMP generation over β-arrestin recruitment and showing weaker GLP-1 receptor internalization compared with GLP-1 itself. Experiments in primary islets indicate β-arrestin1 limits insulin response to GLP-1 but not to GIP or tirzepatide, suggesting biased agonism may enhance insulin secretion. The authors propose that imbalanced GIP receptor engagement combined with biased GLP-1 signaling may explain tirzepatide's promising clinical efficacy.
Packer M et al. · The New England journal of medicine · 2025 · RCT
This international double-blind randomized controlled trial assigned 731 patients with heart failure with preserved ejection fraction (ejection fraction ≥50%) and obesity (BMI ≥30) to receive tirzepatide (up to 15 mg weekly) or placebo for at least 52 weeks. Tirzepatide reduced the composite outcome of cardiovascular death or worsening heart failure (9.9% vs 15.3%; hazard ratio 0.62) and improved quality of life measured by Kansas City Cardiomyopathy Questionnaire score (19.5-point vs 12.7-point improvement) at 52 weeks compared to placebo. Adverse events, mainly gastrointestinal, led to discontinuation in 6.3% of the tirzepatide group versus 1.4% of placebo.
Jastreboff AM et al. · The New England journal of medicine · 2022 · RCT
This phase 3 double-blind randomized controlled trial assigned 2539 adults with obesity (BMI ≥30 or ≥27 with weight-related complications, excluding diabetes) to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks. At week 72, tirzepatide produced mean weight reductions of -15.0%, -19.5%, and -20.9% for the 5 mg, 10 mg, and 15 mg doses respectively, compared to -3.1% with placebo (P<0.001). A substantial proportion of tirzepatide recipients achieved ≥5% weight reduction (85–91%) and ≥20% reduction (50–57%), versus 35% and 3% with placebo. The most common adverse events were gastrointestinal, predominantly mild to moderate and occurring during dose escalation, with treatment discontinuation rates of 4.3–7.1% for tirzepatide and 2.6% for placebo.
Loomba R et al. · The New England journal of medicine · 2024 · RCT
This phase 2, randomized, double-blind, placebo-controlled trial evaluated tirzepatide (a GLP-1 and GIP receptor agonist) in 190 participants with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and moderate or severe liver fibrosis. Over 52 weeks, tirzepatide at doses of 5 mg, 10 mg, and 15 mg once weekly significantly improved the primary endpoint of MASH resolution without worsening fibrosis (44%, 56%, and 62% respectively, versus 10% placebo). A key secondary endpoint of fibrosis improvement of at least one stage without worsening MASH was also met across all tirzepatide groups (55%, 51%, and 51% respectively, versus 30% placebo). The most common adverse events were gastrointestinal and mostly mild to moderate in severity.
Aronne LJ et al. · JAMA · 2024 · RCT
SURMOUNT-4 was a phase 3 randomized withdrawal trial in 670 adults with obesity or overweight (mean age 48 years, 71% women) who completed a 36-week open-label lead-in period with tirzepatide (10–15 mg subcutaneous once weekly), achieving mean weight reduction of 20.9%. Participants were then randomized to continue tirzepatide or switch to placebo for 52 weeks. From week 36 to week 88, tirzepatide recipients showed −5.5% mean weight change versus +14.0% for placebo (difference −19.4%; P < 0.001), and 89.5% of tirzepatide recipients maintained at least 80% of initial weight loss versus 16.6% on placebo. Overall weight reduction from baseline to week 88 was 25.3% with tirzepatide and 9.9% with placebo. The most common adverse events were mild to moderate gastrointestinal events, occurring more frequently with tirzepatide.
Hamarsheh S et al. · Endocrinology, diabetes & metabolism · 2026 · Meta-analysis
This network meta-analysis of 25 randomized controlled trials compared tirzepatide, semaglutide, cagrilintide, and their combination (CagriSema) for weight loss in adults with overweight or obesity. Tirzepatide 15 mg achieved the greatest percent weight reduction (−17.97%), followed by CagriSema (−17.84%) and semaglutide 7.2 mg (−14.66%). At the ≥20% weight-loss threshold, CagriSema showed the highest rate (RR 27.82), followed by tirzepatide 15 mg (RR 23.70). Gastrointestinal adverse events increased across all treatments (RR 1.33–1.91), and semaglutide 7.2 mg had the highest treatment discontinuation rate (RR 3.09), while serious adverse events remained comparable to placebo.
Acucella GA, Caponio D · Endocrinology, diabetes & metabolism · 2026 · Systematic review
This systematic review evaluated tirzepatide, a dual GIP/GLP-1 receptor agonist, as an adjunct to insulin in adults with type 1 diabetes and overweight or obesity. Eight studies were included (one small 12-week phase 2 RCT and seven observational studies), most with serious bias risk. The most consistent finding was body weight reduction: the RCT showed 10.3 kg mean reduction (8.7 kg treatment difference versus placebo, 8.8% from baseline), plus a placebo-adjusted 35.1% reduction in daily insulin dose and -0.4 percentage points HbA1c difference, though glycaemic findings were short-term and imprecise. Gastrointestinal adverse events were the most frequent safety findings. The authors concluded tirzepatide may be promising for weight reduction in this population, but evidence certainty was low or very low, and current data are insufficient to establish durable glycaemic benefit or long-term safety.
Frías JP et al. · The New England journal of medicine · 2021 · RCT
This phase 3 randomized controlled trial compared tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist, with semaglutide (a selective GLP-1 agonist) in 1,879 patients with type 2 diabetes over 40 weeks. Tirzepatide at doses of 10 mg and 15 mg achieved greater reductions in glycated hemoglobin (−2.24 and −2.30 percentage points) compared with semaglutide (−1.86 percentage points), and tirzepatide produced larger weight reductions across all doses. The most common adverse events were gastrointestinal (primarily mild to moderate), with nausea in 17–22% of tirzepatide recipients and 18% of semaglutide recipients; serious adverse events occurred in 5–7% of tirzepatide recipients and 3% of semaglutide recipients.
Malhotra A et al. · The New England journal of medicine · 2024 · RCT
Two phase 3 randomized controlled trials tested tirzepatide (10–15 mg) versus placebo in adults with moderate-to-severe obstructive sleep apnea and obesity. Trial 1 enrolled patients not receiving positive airway pressure therapy at baseline; trial 2 enrolled those already on PAP therapy. Tirzepatide reduced the apnea-hypopnea index (AHI) significantly more than placebo in both trials (treatment difference of −20.0 events/hour in trial 1 and −23.8 events/hour in trial 2, both P<0.001) and also improved body weight, hypoxic burden, C-reactive protein, systolic blood pressure, and patient-reported sleep outcomes compared to placebo. The most frequent adverse events with tirzepatide were gastrointestinal and mostly mild to moderate in severity.
Garvey WT et al. · Lancet (London, England) · 2023 · RCT
SURMOUNT-2 is a phase 3, double-blind, randomized, placebo-controlled trial of once-weekly subcutaneous tirzepatide (10 mg or 15 mg) versus placebo in 938 adults with obesity and type 2 diabetes across seven countries. Over 72 weeks, tirzepatide 10 mg and 15 mg produced mean bodyweight reductions of 12.8% and 14.7% respectively, compared to 3.2% with placebo (treatment differences of 9.6 and 11.6 percentage points). Approximately 79–83% of tirzepatide-treated participants achieved ≥5% bodyweight reduction versus 32% on placebo. The most frequent adverse events were gastrointestinal (nausea, diarrhea, vomiting), mostly mild to moderate; serious adverse events occurred in 7% overall, with two deaths in the tirzepatide 10 mg group that were not considered treatment-related.
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Regulatory status
- FDA approved
- Yes
- WADA prohibited
- No
- Compounding status
- FDA-approved (Mounjaro for type 2 diabetes; Zepbound for chronic weight management / obstructive sleep apnea).
- Notes
- FDA-approved tirzepatide (Mounjaro for type 2 diabetes; Zepbound for chronic weight management and obstructive sleep apnea) as of 2026-06-04. Not listed on the WADA prohibited list.
Legal/regulatory status varies by jurisdiction and changes over time — accurate as of last review (2026-06-04).
Data sources: Curated IDs (PubChem/UniProt/ChEMBL) + Europe PMC + ClinicalTrials.gov (2026-06-04).
Last reviewed 2026-06-04