Tirzepatide in Human Clinical Trials: Populations, Endpoints and Findings

A trial-by-trial account of the published SURPASS, SURMOUNT, SYNERGY-NASH, SUMMIT and SURPASS-CVOT programmes: populations enrolled, designs, durations, primary endpoints, results as reported, adverse events and limitations.

By Published Updated

Tirzepatide, developed under the code LY3298176, is a single synthetic peptide with agonist activity at two receptors: the glucose-dependent insulinotropic polypeptide receptor and the glucagon-like peptide-1 receptor [1]. It has the most extensive published human clinical record of any multi-receptor agonist in its family, spanning two named phase 3 programmes, three organ-specific trials and one cardiovascular outcome trial against an active comparator.

This article describes that record programme by programme. For each trial it states the population enrolled, the design, the duration, the primary endpoint as the protocol defined it, the results as the publication reports them, the adverse events described, and the limitations that remain after the paper is read. It ends with what the record still does not settle.

Two boundaries apply throughout. Everything below describes trials of a pharmaceutical investigational or approved product: material manufactured to a regulatory standard, administered under clinical supervision, in screened populations, under protocols registered before enrolment. And nothing below is guidance of any kind on handling any material, a comparison of products, or a recommendation.

The molecule these trials tested

In vitro research

Tirzepatide was characterised in 2018 as a dual agonist with activity at the GIP receptor comparable to native GIP and weaker relative activity at the GLP-1 receptor than native GLP-1 — an imbalanced profile, in the vocabulary of this field, rather than a balanced one [1]. Its backbone is stabilised against dipeptidyl peptidase-4 and carries a fatty diacid attached through a linker, which binds it reversibly to serum albumin and supports once-weekly administration.

Two cautions carry into the clinical sections. Relative potencies measured at cloned receptors in transfected cell lines do not predict proportional effects in tissue, where receptor densities differ by organ. And the albumin binding that governs the pharmacokinetics is absent from the assay that defines the receptor profile.

The SURPASS programme in type 2 diabetes

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

SURPASS-1: monotherapy against placebo

Population. 478 adults aged 18 or over with type 2 diabetes inadequately controlled by diet and exercise alone and naive to injectable diabetes therapy, recruited at 52 centres in India, Japan, Mexico and the United States between 3 June 2019 and 28 October 2020, from 705 screened. Mean baseline glycated haemoglobin was 7.9%, mean age 54.1 years, mean diabetes duration 4.7 years, mean body-mass index 31.9 kg/m²; 48% were women [2, 11].

Design, duration, endpoint. A 40-week, double-blind, randomised, placebo-controlled phase 3 trial, assignment 1:1:1:1 to once-weekly tirzepatide 5, 10 or 15 mg or placebo. The primary endpoint was mean change in glycated haemoglobin from baseline at 40 weeks.

Results as reported. Glycated haemoglobin decreased by 1.87%, 1.89% and 2.07% across the three tirzepatide groups against an increase of 0.04% with placebo, giving estimated treatment differences of −1.91%, −1.93% and −2.11%, all p<0.0001. Between 87% and 92% of tirzepatide participants reached a glycated haemoglobin below 7.0% against 20% of placebo participants. Body-weight reduction was graded with the amount administered and ranged from 7.0 to 9.5 kg [2].

Adverse events and limitations. The most frequent adverse events were mild-to-moderate transient gastrointestinal events: nausea 12–18% against 6%, diarrhoea 12–14% against 8%, vomiting 2–6% against 2%. No severe hypoglycaemia was reported with tirzepatide; one death occurred, in the placebo group. 14% discontinued study drug and 10% discontinued the study prematurely. The trial tested monotherapy in a treatment-naive population, which is the least representative setting for established diabetes and the cleanest one for a monotherapy signal [2].

SURPASS-2: against semaglutide 1 mg

Population and design. 1,879 adults with type 2 diabetes on metformin, randomly assigned 1:1:1:1 to tirzepatide 5, 10 or 15 mg or semaglutide 1 mg, in an open-label 40-week phase 3 trial. Mean baseline glycated haemoglobin was 8.28%, mean age 56.6 years, mean weight 93.7 kg. The primary endpoint was change in glycated haemoglobin at 40 weeks [3, 12].

Results as reported. Estimated mean change in glycated haemoglobin was −2.01%, −2.24% and −2.30% with tirzepatide against −1.86% with semaglutide, giving differences of −0.15% (95% CI −0.28 to −0.03; P=0.02), −0.39% (−0.51 to −0.26; P<0.001) and −0.45% (−0.57 to −0.32; P<0.001). All three tirzepatide groups met noninferiority and superiority. Estimated treatment differences in body weight against semaglutide were −1.9 kg, −3.6 kg and −5.5 kg, all P<0.001 [3].

Adverse events and limitations. Gastrointestinal events predominated in both arms and were primarily mild to moderate: nausea 17–22% against 18%, diarrhoea 13–16% against 12%, vomiting 6–10% against 8%. Serious adverse events were reported in 5–7% of tirzepatide participants and 3% of semaglutide participants. The trial was open-label, so participants and investigators knew the assignment, and the comparator was semaglutide 1 mg — the highest approved amount for type 2 diabetes at the time, and below the amounts later studied in obesity trials. A single comparator amount limits what the comparison establishes.

The SURMOUNT programme in obesity

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

SURMOUNT-1: obesity without diabetes

2,539 adults with a body-mass index of 30 or more, or 27 or more with at least one weight-related complication, diabetes excluded, were assigned 1:1:1:1 to once-weekly subcutaneous tirzepatide 5, 10 or 15 mg or placebo for 72 weeks, including a 20-week escalation period. Coprimary endpoints were percentage change in weight from baseline and a reduction of 5% or more. Mean baseline weight was 104.8 kg and mean body-mass index 38.0 [4, 13].

Mean percentage change in weight at week 72 was −15.0%, −19.5% and −20.9% against −3.1% for placebo, all P<0.001. Reductions of 5% or more occurred in 85%, 89% and 91% against 35%; reductions of 20% or more occurred in 50% and 57% of the 10 mg and 15 mg groups against 3% of placebo. Adverse events were most commonly gastrointestinal, mostly mild to moderate, and occurred primarily during escalation; they caused discontinuation in 4.3%, 7.1% and 6.2% of the tirzepatide groups against 2.6% of placebo [4].

The endpoints are anthropometric. The trial excluded diabetes, so its population is not the population of SURMOUNT-2, and 72 weeks is the whole of what it describes.

SURMOUNT-2: obesity with type 2 diabetes

938 adults with a body-mass index of 27 kg/m² or higher and glycated haemoglobin of 7–10% were randomised 1:1:1 to tirzepatide 10 mg, 15 mg or placebo for 72 weeks across seven countries, between 29 March 2021 and 10 April 2023. Mean age was 54.2 years, 51% were female, 76% were White and 60% Hispanic or Latino; mean baseline weight was 100.7 kg and mean glycated haemoglobin 8.02%. Coprimary endpoints were percentage change in body weight and a reduction of 5% or more [5, 14].

Least-squares mean change in body weight at week 72 was −12.8% and −14.7% against −3.2% for placebo, giving treatment differences of −9.6 and −11.6 percentage points, both p<0.0001. Between 79% and 83% of tirzepatide participants met the 5% threshold against 32% of placebo participants. Gastrointestinal events were again the most frequent, mostly mild to moderate, with fewer than 5% discontinuing for adverse events. Serious adverse events were reported in 7% overall, and two deaths occurred in the 10 mg group, neither considered related to study treatment by the investigator [5].

The comparison is against placebo only, and the effect sizes are smaller than in SURMOUNT-1 — a consistent observation across this drug family in populations with diabetes, and one the trial documents rather than explains.

SURMOUNT-5: against semaglutide in obesity

751 adults with obesity and without type 2 diabetes were randomly assigned 1:1 to the maximum tolerated amount of tirzepatide (10 or 15 mg) or the maximum tolerated amount of semaglutide (1.7 or 2.4 mg), once weekly for 72 weeks, in an open-label phase 3b trial. The primary endpoint was percentage change in weight to week 72 [9, 17].

Least-squares mean percentage change in weight was −20.2% with tirzepatide against −13.7% with semaglutide (P<0.001), and change in waist circumference was −18.4 cm against −13.0 cm (P<0.001). Participants on tirzepatide were more likely to reach reductions of at least 10%, 15%, 20% and 25%. Adverse events in both groups were most commonly gastrointestinal, mostly mild to moderate, occurring primarily during escalation [9].

The trial was open-label, which matters more for an endpoint influenced by behaviour than for a laboratory value. It compared maximum tolerated amounts rather than fixed matched amounts, and it enrolled a population without diabetes.

SYNERGY-NASH: biopsy-confirmed steatohepatitis

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Population, design and endpoint. 190 participants with biopsy-confirmed metabolic dysfunction-associated steatohepatitis and stage F2 or F3 fibrosis, randomised to once-weekly subcutaneous tirzepatide 5, 10 or 15 mg or placebo for 52 weeks in a phase 2, multicentre, double-blind, placebo-controlled amount-finding trial. The primary endpoint was resolution of steatohepatitis without worsening of fibrosis at 52 weeks; a key secondary endpoint was improvement of at least one fibrosis stage without worsening of steatohepatitis [6, 15].

Results as reported. Of the 190 randomised, 157 had evaluable week-52 biopsies, with missing values imputed on the assumption that they would follow the placebo pattern. Resolution without worsening of fibrosis occurred in 10% of placebo participants, 44% at 5 mg (difference 34 percentage points; 95% CI 17 to 50), 56% at 10 mg (46 points; 29 to 62) and 62% at 15 mg (53 points; 37 to 69), all P<0.001. Improvement of at least one fibrosis stage without worsening occurred in 30%, 55%, 51% and 51% respectively, with confidence intervals whose lower bounds sat at 1 to 5 percentage points. Gastrointestinal events were the most common adverse events and mostly mild or moderate [6].

Limitations. This is a phase 2 trial of 190 people, in which a sixth of participants had no evaluable endpoint biopsy and the missing data were imputed. The fibrosis secondary endpoint is the clinically consequential one, and its intervals are wide and barely exclude no effect. The publication itself states that larger and longer trials are needed.

SURMOUNT-OSA: the apnoea–hypopnoea index in obesity

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Population, design and endpoint. Two phase 3, double-blind, randomised, controlled trials in adults with moderate-to-severe obstructive sleep apnoea and obesity: trial 1 enrolled participants not receiving positive airway pressure therapy at baseline, trial 2 those who were. Assignment was 1:1 to the maximum tolerated amount of tirzepatide (10 or 15 mg) or placebo for 52 weeks. The primary endpoint was change in the apnoea–hypopnoea index. Mean baseline index was 51.5 events per hour in trial 1 and 49.5 in trial 2; mean body-mass index was 39.1 and 38.7 [7, 16].

Results as reported. In trial 1, mean change in the index at week 52 was −25.3 events per hour with tirzepatide against −5.3 with placebo, a treatment difference of −20.0 (95% CI −25.8 to −14.2; P<0.001). In trial 2 the change was −29.3 against −5.5, a difference of −23.8 (−29.6 to −17.9; P<0.001). Prespecified key secondary endpoints — percentage change in the index and in body weight, hypoxic burden, patient-reported impairment and disturbance, high-sensitivity C-reactive protein and systolic blood pressure — all showed significant improvement against placebo. Adverse events were most frequently gastrointestinal and mostly mild to moderate [7].

Limitations. The apnoea–hypopnoea index is a physiological measure, not a clinical outcome; the trials did not count cardiovascular events, accidents or deaths. Both ran 52 weeks. Positive airway pressure therapy was the stratifying variable rather than a comparator, so these trials say nothing about tirzepatide relative to established therapy.

SUMMIT: heart failure with preserved ejection fraction

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Population, design and endpoints. 731 patients with heart failure, an ejection fraction of at least 50% and a body-mass index of at least 30, randomly assigned 1:1 to tirzepatide up to 15 mg once weekly or placebo for at least 52 weeks, in an international double-blind placebo-controlled trial. The two primary endpoints were a composite of adjudicated cardiovascular death or a worsening heart-failure event, and change to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score. Median follow-up was 104 weeks [8, 19].

Results as reported. The composite occurred in 36 of 364 patients (9.9%) on tirzepatide and 56 of 367 (15.3%) on placebo, a hazard ratio of 0.62 (95% CI 0.41 to 0.95; P=0.026). Worsening heart-failure events occurred in 8.0% against 14.2% (hazard ratio 0.54; 0.34 to 0.85). Adjudicated cardiovascular death occurred in 8 patients (2.2%) against 5 (1.4%), a hazard ratio of 1.58 with a confidence interval from 0.52 to 4.83. The questionnaire score changed by 19.5 points against 12.7, a between-group difference of 6.9 (3.3 to 10.6; P<0.001). Adverse events leading to discontinuation, mainly gastrointestinal, occurred in 6.3% against 1.4% [8].

Limitations. The composite was driven by worsening heart-failure events; the cardiovascular death component went numerically in the other direction on 13 events in total and is uninformative at that count. With 731 patients and 92 primary events the trial is small for an outcome trial, and it enrolled a specific phenotype — preserved ejection fraction with obesity — that does not generalise to heart failure at large.

SURPASS-CVOT: cardiovascular outcomes against an active comparator

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Population, design and endpoint. 13,299 patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomised 1:1 to weekly subcutaneous tirzepatide up to 15 mg or dulaglutide 1.5 mg in a double-blind, active-comparator-controlled noninferiority trial; 134 were excluded afterwards, leaving 6,586 and 6,579 in the modified intention-to-treat population. Mean age was 64.1 years, 29.0% were women, mean body-mass index 32.6, mean glycated haemoglobin 8.4% and mean diabetes duration 14.7 years. The primary endpoint was a composite of cardiovascular death, myocardial infarction or stroke, with a noninferiority margin of 1.05 on the upper limit of the 95.3% confidence interval [10, 18].

Results as reported. A primary endpoint event occurred in 801 patients (12.2%) on tirzepatide and 862 (13.1%) on dulaglutide: hazard ratio 0.92, 95.3% CI 0.83 to 1.01, P=0.003 for noninferiority and P=0.09 for superiority. Adverse-event incidence appeared similar between groups, with more gastrointestinal events on tirzepatide [10].

Limitations. This is the trial that anchors the whole programme in clinical outcomes, and its result is noninferiority, not superiority. The comparator, dulaglutide 1.5 mg, is an agent already shown to reduce cardiovascular events, so the trial establishes that tirzepatide is not worse than an effective comparator rather than that it is better than no treatment. The population is secondary-prevention type 2 diabetes with long-standing disease, and the finding does not transfer to obesity without diabetes.

What the evidence base does not establish

Superiority on hard outcomes was not demonstrated. SURPASS-CVOT met its noninferiority margin and missed superiority at P=0.09 [10]. SUMMIT showed a composite benefit in a specific heart-failure phenotype on 92 events [8]. Between them these are the only two published trials in this programme whose primary endpoint counts clinical events; every other trial above reports a laboratory, imaging, physiological or anthropometric measure.

The head-to-head comparisons were open-label. Both SURPASS-2 and SURMOUNT-5 compared tirzepatide with semaglutide without masking [3, 9]. That design choice is defensible for a laboratory primary endpoint and less comfortable for a body-composition endpoint that participant behaviour can influence.

No trial has compared tirzepatide with a triple receptor agonist. The comparison between the dual and triple branches of this family has never been randomised, and indirect comparison across separate placebo-controlled trials rests on assumptions that head-to-head randomisation does not require.

Durations are bounded. Fixed-duration trials stop at 72 weeks [4, 5, 9]; SUMMIT followed patients for a median of 104 weeks [8]. What happens over five years, and what happens after discontinuation, is not described by the trials above.

Hepatic evidence is phase 2. SYNERGY-NASH is a 190-participant amount-finding trial with imputed missing biopsies and a fibrosis endpoint whose intervals barely exclude no effect [6]. It is a reason to run a phase 3 trial, not a substitute for one.

Populations are specific. Each trial enrolled against narrow criteria — treatment-naive diabetes, obesity with diabetes excluded, biopsy-proven fibrosis, preserved ejection fraction, established atherosclerotic disease. A result in one of those populations is a result in that population.

All of the research described in this article is research into a pharmaceutical product, conducted by its sponsor under registered protocols, using material manufactured to a regulatory standard and administered under clinical supervision in defined populations. None of it is research into, or evidence about, research-grade material supplied for laboratory use.

Frequently Asked Questions

How many people have been studied in tirzepatide clinical trials?
The published trials described here alone account for more than 20,000 randomised participants, the largest being SURPASS-CVOT with 13,299 randomised [10], followed by SURMOUNT-1 with 2,539 [4] and SURPASS-2 with 1,879 [3]. The full development programme is larger than the trials summarised here.
Has tirzepatide been compared head-to-head with semaglutide?
Twice, in open-label trials. SURPASS-2 compared three tirzepatide amounts with semaglutide 1 mg in 1,879 adults with type 2 diabetes over 40 weeks [3]. SURMOUNT-5 compared the maximum tolerated tirzepatide amount with the maximum tolerated semaglutide amount in 751 adults with obesity and without diabetes over 72 weeks [9]. Both were open-label rather than double-blind.
Has tirzepatide been tested in a cardiovascular outcome trial?
Yes. SURPASS-CVOT randomised 13,299 patients with type 2 diabetes and atherosclerotic cardiovascular disease to tirzepatide or dulaglutide 1.5 mg. The primary endpoint was a composite of cardiovascular death, myocardial infarction or stroke; the hazard ratio was 0.92 (95.3% CI 0.83 to 1.01), meeting noninferiority (P=0.003) but not superiority (P=0.09) [10]. SUMMIT separately reported a composite of cardiovascular death or worsening heart-failure events in 731 patients with heart failure with preserved ejection fraction and obesity [8].
What is the longest tirzepatide trial published?
By treatment duration, 72 weeks in SURMOUNT-1, SURMOUNT-2 and SURMOUNT-5 [4, 5, 9]. By follow-up, SUMMIT reported a median follow-up of 104 weeks [8], and SURPASS-CVOT was an event-driven outcome trial that ran substantially longer than the fixed-duration trials [10].
What adverse events are reported in tirzepatide trials?
Gastrointestinal events — nausea, diarrhoea and vomiting — are the most frequently reported in every published trial, mostly mild to moderate, and concentrated during the escalation period [4, 3]. Discontinuation attributed to adverse events was 4.3% to 7.1% across tirzepatide groups against 2.6% for placebo in SURMOUNT-1 [4], and 6.3% against 1.4% in SUMMIT [8]. SURPASS-CVOT reported a similar overall adverse-event incidence between groups with more gastrointestinal events on tirzepatide [10].
Has tirzepatide been studied in liver disease?
In SYNERGY-NASH, a phase 2 trial of 190 participants with biopsy-confirmed metabolic dysfunction-associated steatohepatitis and stage F2 or F3 fibrosis over 52 weeks. The primary endpoint was resolution of steatohepatitis without worsening of fibrosis, reached by 44%, 56% and 62% of the three tirzepatide groups against 10% of placebo [6]. The authors state that larger and longer trials are needed.
What does the tirzepatide evidence base still not establish?
Superiority over an active comparator on hard cardiovascular outcomes was not demonstrated: SURPASS-CVOT met noninferiority against dulaglutide but not superiority [10]. No published trial has compared tirzepatide with a triple receptor agonist. Fixed-duration trials stop at 72 weeks, so what happens beyond two years, or after discontinuation, is not described in the trials summarised here [4, 9].

References

  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 doi:10.1016/j.molmet.2018.09.009
  2. 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 doi:10.1016/S0140-6736(21)01324-6
  3. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes The New England Journal of Medicine; 2021. PMID 34170647 doi:10.1056/NEJMoa2107519
  4. Tirzepatide Once Weekly for the Treatment of Obesity The New England Journal of Medicine; 2022. PMID 35658024 doi:10.1056/NEJMoa2206038
  5. 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 Lancet; 2023. PMID 37385275 doi:10.1016/S0140-6736(23)01200-X
  6. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis The New England Journal of Medicine; 2024. PMID 38856224 doi:10.1056/NEJMoa2401943
  7. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity The New England Journal of Medicine; 2024. PMID 38912654 doi:10.1056/NEJMoa2404881
  8. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity The New England Journal of Medicine; 2025. PMID 39555826 doi:10.1056/NEJMoa2410027
  9. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity The New England Journal of Medicine; 2025. PMID 40353578 doi:10.1056/NEJMoa2416394
  10. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes The New England Journal of Medicine; 2025. PMID 41406444 doi:10.1056/NEJMoa2505928
  11. A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone. NCT03954834
  12. A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes. NCT03987919
  13. A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight. NCT04184622
  14. A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Who Have Obesity or Are Overweight. NCT04657003
  15. A Study of Tirzepatide (LY3298176) in Participants With Nonalcoholic Steatohepatitis (NASH). NCT04166773
  16. Obstructive Sleep Apnea Master Protocol GPIF: A Study of Tirzepatide (LY3298176) in Participants With Obstructive Sleep Apnea. NCT05412004
  17. A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight With Weight Related Comorbidities. NCT05822830
  18. A Study of Tirzepatide (LY3298176) Compared With Dulaglutide on Major Cardiovascular Events in Participants With Type 2 Diabetes. NCT04255433
  19. A Study of Tirzepatide (LY3298176) in Participants With Heart Failure With Preserved Ejection Fraction (HFpEF) and Obesity: The SUMMIT Trial. NCT04847557

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