Tirzepatide
Tirzepatide is a synthetic, fatty-acid-modified (acylated) peptide built on the sequence of native glucose-dependent insulinotropic polypeptide (GIP) and engineered to activate both the GIP receptor and the glucagon-like peptide-1 (GLP-1) receptor. The acyl modification extends its pharmacokinetic profile enough to support once-weekly subcutaneous administration in the trials that characterised it. It is the first dual GIP/GLP-1 receptor co-agonist to reach regulatory approval, cleared as an adjunct to diet and exercise for glycaemic control in adults with type 2 diabetes in the USA, the EU, Japan and other jurisdictions. Both of its target receptors mediate insulin secretion and are also expressed in brain regions that regulate food intake.
Information on this page is provided for laboratory research reference. The compound is not a drug, supplement, or medical product, and is not for human or veterinary use, ingestion, or consumption.
- #171211 · 30 mg99.845%
- #171261 · 15 mg99.685%
- #197315 · 20 mg99.647%
Each result applies to the tested sample shown, not to every catalog strength or lot.
- Aib
- α-Aminoisobutyric acid — Backbone-rigidifying methylated alanine; resists DPP-4 cleavage.
Tirzepatide activates the GIP and GLP-1 receptors together, and in mice its effect on glucose tolerance required action at both. Receptor-occupancy modelling at clinically studied doses indicates greater engagement of the GIP receptor than the GLP-1 receptor, an imbalanced profile; at the GLP-1 receptor its signalling is biased toward cAMP generation over beta-arrestin recruitment, with weaker receptor internalisation than native GLP-1. In adults with type 2 diabetes, a clamp study attributes its glucose lowering to three concurrent changes: improved beta-cell function, improved insulin sensitivity, and lower fasting and postprandial glucagon. What remains unsettled is the contribution of the GIP arm in humans specifically: GIP reduces food intake and body weight in rodents, but that effect has not been demonstrated in people, and it is not established that GIP receptor agonism improves insulin secretion in patients with type 2 diabetes, who earlier work found to be GIP-unresponsive. The proposal that imbalance toward the GIP receptor plus biased GLP-1 receptor signalling explains the drug's efficacy is a hypothesis advanced by its discovery group, not a settled result.1,2,4,5
Agonist. Tirzepatide mimics the signalling actions of native GIP at this receptor, and occupancy calculations at clinically efficacious doses show greater engagement here than at the GLP-1 receptor.1,4
Biased agonist. Favours cAMP generation over beta-arrestin recruitment and drives less receptor internalisation than native GLP-1; in primary islets, beta-arrestin1 limited the insulin response to GLP-1 but not to tirzepatide.4
Downstream effector. Produces glucose-dependent insulin secretion in mice, and in adults with type 2 diabetes raises the clamp disposition index, a change the trial attributed to greater total insulin secretion rate together with greater insulin sensitivity.1,5
Downstream effector. Lowers fasting and postprandial glucagon concentrations during meal tolerance testing in adults with type 2 diabetes.5
Proposed site of the weight effect. Both receptors are expressed in brain regions governing food intake, and appetite falls during treatment; however, measured ad libitum energy intake did not separate tirzepatide from semaglutide, so the pathway to its larger weight effect is not resolved.2,6
Metabolic & weight
In a 72-week phase 3 double-blind trial in 2,539 adults with obesity and without diabetes, mean body weight fell 15.0%, 19.5% and 20.9% in the 5, 10 and 15 mg tirzepatide groups versus 3.1% with placebo; 57% of the 15 mg group lost at least 20% of body weight versus 3% on placebo.7
In the 176-week extension of that phase 3 obesity trial, among the 1,032 participants who also had prediabetes, type 2 diabetes was diagnosed in 1.3% on tirzepatide versus 13.3% on placebo (hazard ratio 0.07, 95% CI 0.0 to 0.1); mean weight change at 176 weeks was -12.3%, -18.7% and -19.7% in the 5, 10 and 15 mg groups versus -1.3% with placebo.8
In a 72-week open-label phase 3b trial in 751 adults with obesity but without type 2 diabetes, weight fell 20.2% with tirzepatide versus 13.7% with semaglutide at their respective maximum tolerated doses, and waist circumference fell 18.4 cm versus 13.0 cm.9
In a 40-week open-label phase 3 trial in 1,879 adults with type 2 diabetes, glycated haemoglobin fell 2.01, 2.24 and 2.30 percentage points in the 5, 10 and 15 mg tirzepatide groups versus 1.86 points with semaglutide 1 mg, and weight reductions exceeded semaglutide by 1.9 kg, 3.6 kg and 5.5 kg respectively.10
In a systematic review and meta-analysis of seven randomised trials covering 6,609 adults with type 2 diabetes, tirzepatide lowered glycated haemoglobin by 0.29 to 0.92 percentage points more than GLP-1 receptor agonists and 0.70 to 1.09 points more than basal insulin regimens, with weight reductions 1.68 kg (5 mg) to 7.16 kg (15 mg) greater than GLP-1 receptor agonists.11
In a double-blind active-comparator trial in 13,165 adults with type 2 diabetes and established atherosclerotic cardiovascular disease, the composite of cardiovascular death, myocardial infarction or stroke occurred in 12.2% of the tirzepatide group and 13.1% of the dulaglutide group (hazard ratio 0.92, 95.3% CI 0.83 to 1.01), meeting the prespecified noninferiority margin but not superiority.12
In a randomised placebo-controlled trial in 731 patients with heart failure, an ejection fraction of at least 50% and a body-mass index of at least 30, cardiovascular death or a worsening heart-failure event occurred in 9.9% of the tirzepatide group versus 15.3% of the placebo group (hazard ratio 0.62, 95% CI 0.41 to 0.95) over a median 104 weeks of follow-up.13
In two 52-week phase 3 trials in adults with moderate-to-severe obstructive sleep apnoea and obesity, the apnoea-hypopnoea index fell by 25.3 events per hour with tirzepatide versus 5.3 with placebo among participants not using positive airway pressure (treatment difference -20.0 events per hour), and by 29.3 versus 5.5 events per hour among those already using it (difference -23.8), from mean baselines of 51.5 and 49.5 events per hour.14
In a 52-week phase 2 trial in 190 adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis and stage F2 or F3 fibrosis, resolution of steatohepatitis without worsening of fibrosis occurred in 44%, 56% and 62% of the 5, 10 and 15 mg tirzepatide groups versus 10% on placebo.15
In a post-hoc MRI analysis of 246 adults with type 2 diabetes, 52 weeks of tirzepatide reduced thigh muscle volume by 0.64 L and muscle fat infiltration by 0.36 percentage points; the volume loss was statistically indistinguishable from what UK Biobank data (n=2,942) predict for the same weight loss, while the fat-infiltration fall exceeded that prediction by 0.42 percentage points.16
In a 28-week phase 1 clamp study in 117 adults with type 2 diabetes, the clamp disposition index rose 1.92 pmol m-2 L min-2 kg-1 more in the tirzepatide 15 mg arm than with placebo and 0.84 more than with semaglutide 1 mg, reflecting both greater insulin secretion rate and greater insulin sensitivity.5
In a nonrandomised, propensity-matched retrospective cohort of 18,386 US adults with overweight or obesity, tirzepatide initiators were more likely than semaglutide initiators to reach at least 15% weight loss (hazard ratio 3.24, 95% CI 2.91 to 3.61), an on-treatment difference of -6.9% at 12 months; more than half of each group discontinued (55.9% versus 52.5%), so the estimates are on-treatment only.17
What investigators recorded alongside the results above, at the rates their papers state.
Gastrointestinal adverse events (nausea, vomiting, diarrhoea)10,11,17,18
The most common adverse events, reported as mild to moderate and transient. Nausea occurred in 12-18% across the tirzepatide 5, 10 and 15 mg groups versus 6% with placebo over 40 weeks in adults with type 2 diabetes (SURPASS-1), and in 17-22% versus 18% with semaglutide 1 mg over 40 weeks (SURPASS-2). Pooling seven randomised trials (6,609 participants), the 15 mg dose carried a nausea odds ratio of 5.60 (95% CI 3.12 to 10.06) versus placebo, vomiting 5.50 (95% CI 2.40 to 12.59) and diarrhoea 3.31 (95% CI 1.40 to 7.85); odds were similar to those of GLP-1 receptor agonists except diarrhoea at 10 mg (odds ratio 1.51, 95% CI 1.07 to 2.15). Outside trial conditions, in a propensity-matched retrospective cohort of 18,386 US adults with overweight or obesity, rates of gastrointestinal adverse events were similar between tirzepatide and semaglutide initiators.
Discontinuation of study drug due to adverse events7,11,13
4.3%, 7.1% and 6.2% in the 5, 10 and 15 mg groups versus 2.6% with placebo over 72 weeks in adults with obesity (SURMOUNT-1). In the meta-analysis of seven randomised trials in type 2 diabetes, the 15 mg dose raised discontinuation regardless of comparator. In adults with heart failure with preserved ejection fraction and obesity (SUMMIT), discontinuation, mainly gastrointestinal, occurred in 6.3% (23 of 364 patients) with tirzepatide versus 1.4% (5 of 367) with placebo.
Serious adverse events and overall adverse-event burden10,11,12
Serious adverse events occurred in 5-7% across the tirzepatide groups versus 3% with semaglutide 1 mg over 40 weeks in adults with type 2 diabetes (SURPASS-2). Across seven pooled randomised trials, no dose of tirzepatide increased serious adverse events or mortality relative to comparators. In the cardiovascular outcomes trial of 13,165 adults with type 2 diabetes and atherosclerotic cardiovascular disease (SURPASS-CVOT), the overall adverse-event burden was similar between groups, though gastrointestinal adverse events were more frequent with tirzepatide than with dulaglutide.
Hypoglycaemia (blood glucose below 54 mg/dL)10,11,18
0.6%, 0.2% and 1.7% in the 5, 10 and 15 mg groups versus 0.4% with semaglutide 1 mg in adults with type 2 diabetes on background therapy (SURPASS-2). As monotherapy in injectable-naive adults (SURPASS-1), no clinically significant or severe hypoglycaemia was reported with tirzepatide. Across pooled trials, hypoglycaemia incidence was similar to placebo and lower than with basal insulin.
Reduction in thigh muscle volume during weight loss16
Mean -0.64 L at 52 weeks in 246 adults with type 2 diabetes, versus a modest increase with insulin degludec. The loss was consistent with population-based expectations for the same weight change; muscle fat infiltration fell more than expected. Longer-term functional consequences were not assessed.
- 1.LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. · Molecular Metabolism · 2018 · PMID 30473097
- 2.Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. · Cardiovascular Diabetology · 2022 · PMID 36050763
- 3.Tirzepatide: A Review in Type 2 Diabetes. · Drugs · 2024 · PMID 38388874
- 4.Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. · JCI Insight · 2020 · PMID 32730231
- 5.Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial. · The Lancet Diabetes & Endocrinology · 2022 · PMID 35468322
- 6.Tirzepatide Reduces Appetite, Energy Intake, and Fat Mass in People With Type 2 Diabetes. · Diabetes Care · 2023 · PMID 36857477
- 7.Tirzepatide Once Weekly for the Treatment of Obesity. · The New England Journal of Medicine · 2022 · PMID 35658024
- 8.Tirzepatide for Obesity Treatment and Diabetes Prevention. · The New England Journal of Medicine · 2025 · PMID 39536238
- 9.Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. · The New England Journal of Medicine · 2025 · PMID 40353578
- 10.Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. · The New England Journal of Medicine · 2021 · PMID 34170647
- 11.Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. · Diabetologia · 2022 · PMID 35579691
- 12.Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. · The New England Journal of Medicine · 2025 · PMID 41406444
- 13.Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. · The New England Journal of Medicine · 2025 · PMID 39555826
- 14.Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. · The New England Journal of Medicine · 2024 · PMID 38912654
- 15.Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. · The New England Journal of Medicine · 2024 · PMID 38856224
- 16.Tirzepatide and muscle composition changes in people with type 2 diabetes (SURPASS-3 MRI): a post-hoc analysis of a randomised, open-label, parallel-group, phase 3 trial. · The Lancet Diabetes & Endocrinology · 2025 · PMID 40318682
- 17.Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity. · JAMA Internal Medicine · 2024 · PMID 38976257
- 18.Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. · Lancet · 2021 · PMID 34186022
- 19.Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. · The Lancet Diabetes & Endocrinology · 2022 · PMID 35468325