Tirzepatide
Published research and evidence base
Tirzepatide (LY3298176) is a fatty acid-modified synthetic peptide that agonises both the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors from a single molecule. Receptor pharmacology published between 2018 and 2020 characterised it as imbalanced towards the GIP receptor and biased at the GLP-1 receptor, and rodent work linked that profile to reduced food intake and body weight. Clinical development proceeded through a phase 2 trial against dulaglutide, the SURPASS glycaemic-control programme in type 2 diabetes and the SURMOUNT body-weight programme in obesity, followed by dedicated trials in obstructive sleep apnoea, metabolic dysfunction-associated steatohepatitis and heart failure with preserved ejection fraction. SURPASS-CVOT, an active-comparator cardiovascular outcomes trial in more than 13,000 patients, reported in 2025. Tirzepatide is an approved prescription medicine for type 2 diabetes and for weight management in several jurisdictions, and gastrointestinal adverse events dominate the tolerability profile reported across the programme.
- Studies cited
- 17
- Published 2023+
- 9
- Newest paper
- 2025
- Last reviewed
- Sept 2026
Recurring themes in the literature
- Dual GIP and GLP-1 receptor agonism from a single peptide
- Imbalanced receptor occupancy and biased GLP-1 receptor signalling
- Glycaemic control in type 2 diabetes (SURPASS programme)
- Dose-dependent body-weight reduction in obesity (SURMOUNT programme)
- Head-to-head comparison with selective GLP-1 receptor agonists
- Progression from prediabetes to type 2 diabetes
- Weight regain after treatment withdrawal
- Obstructive sleep apnoea and the apnoea-hypopnoea index
- Steatohepatitis resolution and hepatic fibrosis stage
- Heart failure with preserved ejection fraction and cardiovascular outcomes
- Body composition, muscle volume and muscle fat infiltration
- Gastrointestinal tolerability and gallbladder or biliary events
Compound identifiers
17 published studies.
Ordered by strength of study design, then by recency. Every entry links to its source record so the finding can be checked against the paper rather than taken on our word.
- 01Systematic review2023
Safety issues of tirzepatide (pancreatitis and gallbladder or biliary disease) in type 2 diabetes and obesity: a systematic review and meta-analysis
Zeng Q, et al. · Frontiers in Endocrinology · systematic review and meta-analysis of 9 randomised controlled trials, 9,871 participants with type 2 diabetes or obesity
Pancreatitis risk was not significantly increased relative to controls (RR 1.46, 95% CI 0.59-3.61). The composite of gallbladder or biliary disease was significantly more frequent than with placebo or basal insulin (RR 1.97, 95% CI 1.14-3.42), although the individual cholelithiasis and cholecystitis outcomes were not.
Reported safety finding. Increased composite risk of gallbladder or biliary disease versus placebo or basal insulin (RR 1.97, 95% CI 1.14-3.42)
- 02Systematic review2022
Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis
Karagiannis T, et al. · Diabetologia · systematic review and meta-analysis of 7 randomised controlled trials, 6,609 participants with type 2 diabetes
Pooled HbA1c reduction was dose-dependent and superior to placebo, to GLP-1 receptor agonists and to basal insulin, with body-weight differences versus GLP-1 receptor agonists of 1.68 kg to 7.16 kg. Hypoglycaemia was not increased relative to placebo, while nausea, vomiting and diarrhoea were more frequent.
Reported safety finding. Nausea odds ratio 5.60 (95% CI 3.12-10.06) versus placebo at the highest dose, with higher discontinuation for adverse events at that dose regardless of comparator
- 03Human clinical2025
Tirzepatide for Obesity Treatment and Diabetes Prevention
Jastreboff AM, et al. · The New England Journal of Medicine · three-year analysis of the SURMOUNT-1 phase 3 trial, 1032 participants with obesity and prediabetes, 176 weeks on treatment plus a 17-week off-treatment period
Mean weight change at 176 weeks ranged from -12.3% to -19.7% across the dose groups versus -1.3% with placebo. Type 2 diabetes was diagnosed in 1.3% of treated participants compared with 13.3% on placebo (hazard ratio 0.07), and the authors reported that no new safety signals were identified.
- 04Human clinical2025
Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity
Packer M, et al. · The New England Journal of Medicine · phase 3 double-blind placebo-controlled trial (SUMMIT), n=731 patients with heart failure with preserved ejection fraction and obesity, median follow-up 104 weeks
Cardiovascular death or a worsening heart-failure event occurred in 9.9% of treated patients versus 15.3% on placebo (hazard ratio 0.62, 95% CI 0.41-0.95). The Kansas City Cardiomyopathy Questionnaire clinical summary score improved by 19.5 points compared with 12.7 on placebo.
- 05Human clinical2025
Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes
Nicholls SJ, et al. · The New England Journal of Medicine · double-blind active-comparator non-inferiority trial (SURPASS-CVOT), 13,165 adults analysed with type 2 diabetes and atherosclerotic cardiovascular disease, dulaglutide comparator
A primary composite event 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; P=0.003 for non-inferiority, P=0.09 for superiority). Gastrointestinal adverse events were more frequent in the tirzepatide group.
- 06Human clinical2025
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
Sattar N, et al. · The Lancet Diabetes & Endocrinology · post-hoc analysis of the SURPASS-3 MRI substudy, n=246 adults with type 2 diabetes with a valid week-52 scan, insulin degludec comparator
Pooled tirzepatide was associated with reductions at 52 weeks in thigh muscle fat infiltration (-0.36 percentage points), muscle volume (-0.64 L) and muscle volume Z score (-0.22), while insulin degludec was associated with modest weight and muscle-volume gain. Observed muscle-volume change was similar to UK Biobank population-based estimates for equivalent weight loss.
Reported safety finding. Measurable loss of thigh muscle volume alongside weight reduction, with the muscle volume Z score in the highest-dose group falling more than population-based estimates predicted
- 07Human clinical2024
Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial
Aronne LJ, et al. · JAMA · phase 3 randomised-withdrawal trial, 670 adults randomised after a 36-week open-label lead-in, 52-week double-blind period
Mean weight change from week 36 to week 88 was -5.5% with continued treatment versus +14.0% after a switch to placebo (difference -19.4%). At week 88, 89.5% of those continuing treatment had maintained at least 80% of the lead-in weight loss compared with 16.6% of those withdrawn.
- 08Human clinical2024
Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity
Malhotra A, et al. · The New England Journal of Medicine · two phase 3 double-blind randomised controlled trials (SURMOUNT-OSA), adults with moderate-to-severe obstructive sleep apnoea and obesity, 52 weeks
The apnoea-hypopnoea index fell by 25.3 events per hour in the trial of participants not receiving positive airway pressure and by 29.3 events per hour among those receiving it, against reductions of roughly 5 events per hour on placebo. Hypoxic burden, high-sensitivity C-reactive protein and systolic blood pressure also improved.
- 09Human clinical2024
Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis
Loomba R, et al. · The New England Journal of Medicine · phase 2 dose-finding double-blind placebo-controlled trial (SYNERGY-NASH), n=190 adults with biopsy-confirmed MASH and stage F2 or F3 fibrosis, 52 weeks
Resolution of steatohepatitis without worsening of fibrosis was recorded in 44%, 56% and 62% of the three dose groups compared with 10% on placebo (P<0.001 for all three comparisons). The authors stated that larger and longer trials were needed to assess efficacy and safety further.
- 10Human clinical2023
Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial
Garvey WT, et al. · The Lancet · phase 3 double-blind placebo-controlled trial, n=938 adults with obesity and type 2 diabetes, 72 weeks
Least-squares mean weight change at week 72 was -12.8% with 10 mg and -14.7% with 15 mg versus -3.2% with placebo. Between 79% and 83% of treated participants reached at least 5% weight reduction, compared with 32% on placebo.
- 11Human clinical2022
Tirzepatide Once Weekly for the Treatment of Obesity
Jastreboff AM, et al. · The New England Journal of Medicine · phase 3 double-blind randomised controlled trial (SURMOUNT-1), n=2539 adults with obesity or overweight without diabetes, 72 weeks
Mean percentage weight change at week 72 was -15.0%, -19.5% and -20.9% across the three dose groups versus -3.1% with placebo (P<0.001 for all comparisons). A reduction of at least 20% of body weight was recorded in 50% and 57% of the two highest dose groups compared with 3% on placebo.
- 12Human clinical2021
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
Rosenstock J, et al. · The Lancet · phase 3 double-blind placebo-controlled monotherapy trial, n=478 adults with type 2 diabetes naive to injectable therapy, 40 weeks
Mean HbA1c fell by 1.87% to 2.07% across the three dose groups compared with a 0.04% rise on placebo (all p<0.0001). Body-weight loss was dose-dependent at 7.0 kg to 9.5 kg, and no clinically significant or severe hypoglycaemia was reported on active treatment.
- 13Human clinical2021
Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes
Frías JP, et al. · The New England Journal of Medicine · open-label phase 3 head-to-head trial, n=1879 adults with type 2 diabetes, 40 weeks, semaglutide 1 mg comparator
Estimated mean HbA1c change was -2.01, -2.24 and -2.30 percentage points across the three tirzepatide groups versus -1.86 with semaglutide, meeting both non-inferiority and superiority. Weight reduction was greater with tirzepatide, with estimated treatment differences of -1.9 kg, -3.6 kg and -5.5 kg.
- 14Human clinical2021
Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial
Del Prato S, et al. · The Lancet · open-label phase 3 trial, n=1995 adults with type 2 diabetes and established or high cardiovascular risk, 52 weeks with treatment continued to a maximum of 104 weeks
HbA1c change at 52 weeks was -2.43% with 10 mg and -2.58% with 15 mg compared with -1.44% on insulin glargine. Adjudicated four-component major adverse cardiovascular events were not increased relative to glargine (hazard ratio 0.74, 95% CI 0.51-1.08), and hypoglycaemia was less frequent.
- 15Human clinical2018
Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial
Frias JP, et al. · The Lancet · phase 2 double-blind randomised trial, n=316 adults with type 2 diabetes, 26 weeks, placebo- and dulaglutide-controlled
Mean HbA1c change at 26 weeks ranged from -1.06% to -1.94% across the four dose groups, against -0.06% with placebo and -1.21% with dulaglutide. Mean body-weight change ranged from -0.9 kg to -11.3 kg, and the incidence of gastrointestinal events was dose-related, reaching 66.0% in the highest-dose group.
Reported safety finding. Dose-related gastrointestinal adverse events rising to 66.0% at the highest dose, versus 9.8% with placebo
- 16Animal in vivo2018
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
Coskun T, et al. · Molecular Metabolism · in vitro incretin receptor signalling assays, mice, and a phase 1 single- and multiple-ascending-dose programme in healthy subjects and adults with type 2 diabetes (142 dosed)
LY3298176 activated both GIP and GLP-1 receptor signalling in vitro and improved glucose tolerance in mice, where chronic administration lowered body weight and food intake more than a selective GLP-1 receptor agonist. In the phase 1b proof-of-concept cohort the 10 mg and 15 mg doses significantly reduced fasting serum glucose compared with placebo, and gastrointestinal events were the most frequent side effects.
- 17In vitro2020
Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist
Willard FS, et al. · JCI Insight · receptor occupancy modelling and signalling assays in recombinant cell lines and primary islets
Occupancy calculations at clinically efficacious doses indicated greater engagement of the GIP receptor than of the GLP-1 receptor, described by the authors as an imbalanced mechanism of action. At the GLP-1 receptor the peptide favoured cAMP generation over beta-arrestin recruitment and drove less receptor internalisation than native GLP-1.
What this evidence does not establish.
Almost all of the pivotal literature was funded and conducted by the manufacturer, and independent replication outside that programme remains limited. SURPASS-CVOT established non-inferiority to dulaglutide for major adverse cardiovascular events but did not demonstrate superiority, and no placebo-controlled cardiovascular outcome trial has been published. Hepatic evidence rests on a phase 2 biopsy-based trial of 190 participants whose authors stated that larger and longer trials were needed. Data beyond the three-year SURMOUNT-1 analysis are not available, durability of effect after discontinuation was poor in the SURMOUNT-4 randomised-withdrawal design, and effects on all-cause mortality have not been established. Comparative evidence against other dual and triple incretin receptor agonists is sparse, muscle-composition findings come from a single post-hoc MRI substudy, and pancreatic and biliary safety estimates rest on meta-analyses with small numbers of events.
Common questions about the research.
- What is tirzepatide?
Tirzepatide (development code LY3298176) is a synthetic peptide with agonist activity at both the GIP and GLP-1 receptors. The material supplied by AKH BioLabs is a lyophilised research compound for laboratory use.
- What makes it a dual agonist rather than a GLP-1 agonist?
A GLP-1 agonist engages one incretin receptor. Tirzepatide engages two — the GIP receptor and the GLP-1 receptor — from a single molecule built on a GIP backbone, a design the cited discovery paper describes in detail.
- What does the published evidence base for tirzepatide consist of?
It spans receptor pharmacology and rodent work from 2018 to 2020, a phase 2 trial against dulaglutide, the phase 3 SURPASS programme in type 2 diabetes, the phase 3 SURMOUNT programme in obesity, dedicated outcome trials in obstructive sleep apnoea, steatohepatitis and heart failure with preserved ejection fraction, a large active-comparator cardiovascular outcomes trial, and systematic reviews pooling those randomised data.
The great majority of these trials were sponsored by the manufacturer.
- How large were the reported changes in HbA1c and body weight in the phase 3 trials?
In SURPASS-1 mean HbA1c fell by 1.87% to 2.07% across the dose groups against a 0.04% rise on placebo, and body weight fell by 7.0 kg to 9.5 kg. In SURMOUNT-1 the mean body-weight change at 72 weeks was -15.0% to -20.9% across dose groups compared with -3.1% on placebo.
Figures differ between trials because the populations, comparators and durations differ.
- Has tirzepatide been compared directly against a selective GLP-1 receptor agonist?
Yes. SURPASS-2 randomised 1,879 adults with type 2 diabetes to tirzepatide or semaglutide 1 mg over 40 weeks and reported tirzepatide as non-inferior and superior on HbA1c change, with greater weight reduction. SURPASS-CVOT used dulaglutide as the active comparator in a cardiovascular outcomes setting.
Both comparisons were open-label or active-controlled rather than placebo-controlled.
- What have the cardiovascular outcome trials reported?
SURPASS-CVOT randomised 13,299 patients with type 2 diabetes and atherosclerotic cardiovascular disease against dulaglutide and reported a primary composite event in 12.2% versus 13.1%, meeting non-inferiority but not superiority. The SUMMIT trial in heart failure with preserved ejection fraction and obesity reported a hazard ratio of 0.62 for cardiovascular death or worsening heart failure against placebo.
Neither result establishes a placebo-controlled cardiovascular benefit in the wider type 2 diabetes population.
- Which adverse events recur most consistently across the trials?
Gastrointestinal events - nausea, diarrhoea, vomiting and decreased appetite - are the most frequently reported in every programme, are dose-related, and cluster during the escalation period. A meta-analysis of nine randomised trials reported an increased composite risk of gallbladder or biliary disease relative to placebo or basal insulin, while pancreatitis risk was not significantly raised.
Hypoglycaemia was not increased relative to placebo in the pooled analyses.
- Does the literature extend beyond type 2 diabetes and obesity?
It does. Published randomised trials cover obstructive sleep apnoea with obesity, metabolic dysfunction-associated steatohepatitis with stage F2 or F3 fibrosis, heart failure with preserved ejection fraction and obesity, and progression from prediabetes to type 2 diabetes.
The steatohepatitis evidence is phase 2 and biopsy-based in 190 participants; the sleep apnoea and heart failure evidence is phase 3.
- What happened when treatment was stopped in the published trials?
SURMOUNT-4 used a randomised-withdrawal design: after a 36-week lead-in, participants switched to placebo regained weight, with a mean change of +14.0% from week 36 to week 88 against -5.5% for those who continued. In the three-year SURMOUNT-1 analysis, 2.4% of previously treated participants had type 2 diabetes after a 17-week off-treatment period versus 13.7% of the placebo group.
Durability of effect after discontinuation is therefore limited in the published record.
- What has been reported about effects on muscle mass?
A post-hoc analysis of the SURPASS-3 MRI substudy measured thigh muscle composition in 246 participants at 52 weeks and reported reductions in muscle volume, muscle volume Z score and muscle fat infiltration alongside weight loss. The observed muscle-volume change was broadly similar to UK Biobank population-based estimates for comparable weight reduction.
This remains a single exploratory analysis and has not been replicated in a prespecified trial.
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