Peptide fact-sheet · English

Tirzepatide

Dual GIP and GLP-1 receptor agonist

First dual GIP/GLP-1 receptor agonist with superior weight loss vs semaglutide in the SURMOUNT-5 head-to-head.

Translated and adapted from the canonical Portuguese version: /peptideos/tirzepatida.

Quick answer

Tirzepatide is the first synthetic dual GIP and GLP-1 receptor agonist to reach regulatory approval. It is marketed as Mounjaro for type 2 diabetes (FDA 2022) and Zepbound for chronic weight management (FDA 2023). The pivotal type 2 diabetes trial SURPASS-2 (Frías 2021, NEJM, PMID 34170647, n=1,879, 40 weeks) demonstrated superiority over semaglutide 1 mg, with HbA1c reductions up to -2.30% at the 15 mg dose. The obesity-without-diabetes trial SURMOUNT-1 (Jastreboff 2022, NEJM, PMID 35658024, n=2,539, 72 weeks) reported mean weight loss of -20.9% at 15 mg versus -3.1% with placebo. The head-to-head SURMOUNT-5 trial (Aronne 2025, NEJM, PMID 40353578, n=751, 72 weeks) compared the maximum tolerated doses and reported tirzepatide -20.2% vs semaglutide -13.7%. In 2024, the FDA extended the Zepbound label to include moderate-to-severe obstructive sleep apnea in adults with obesity, based on the SURMOUNT-OSA program. Subcutaneous half-life is approximately 5 days. Gastrointestinal events are the principal adverse events; in SURMOUNT-5, discontinuation for gastrointestinal events was 2.7% with tirzepatide vs 5.6% with semaglutide.

What it is

Tirzepatide (LY3298176) is a synthetic 39-amino-acid peptide developed by Eli Lilly. The backbone is derived from the native GIP (glucose-dependent insulinotropic polypeptide) sequence, with modifications that confer balanced agonism at both the GIP and GLP-1 receptors. A C20 fatty diacid side chain at lysine 20 binds albumin in circulation, extending the half-life to approximately 5 days and supporting once-weekly subcutaneous dosing.

Two registered products are marketed internationally:

Mounjaro — type 2 diabetes, weekly doses 2.5/5/7.5/10/12.5/15 mg. FDA approval May 2022; EMA approval September 2022.
Zepbound — chronic weight management (BMI ≥30, or ≥27 with at least one weight-related comorbidity), same dose range. FDA approval November 2023; EMA approval (as Mounjaro for the same indication in some markets) followed in 2023-2024. Label extension for moderate-to-severe obstructive sleep apnea in adults with obesity approved by FDA in December 2024 following the SURMOUNT-OSA program.

Tirzepatide is the first molecule in clinical practice to combine GIP and GLP-1 receptor agonism in a single peptide, a strategy designed to add the incretin and adipose-tissue actions of GIP to the established GLP-1 effects on insulin secretion, gastric emptying, and central appetite regulation.

Mechanism of action

Tirzepatide acts at two class B G-protein-coupled receptors:

GLP-1 receptor (GLP-1R) — glucose-dependent insulin secretion, glucagon suppression in the postprandial state, delayed gastric emptying, central appetite regulation. The same set of actions seen with selective GLP-1 receptor agonists (semaglutide, liraglutide).
GIP receptor (GIPR) — amplification of glucose-dependent insulin secretion in hyperglycemia, modulation of adipose tissue insulin sensitivity, and a gastrointestinal-event profile that, in clinical trials, has been more favorable than GLP-1 monotherapy at comparable weight-loss magnitudes.

The therapeutic hypothesis behind dual agonism is that GIP signaling complements GLP-1 in pancreatic and adipose tissue without adding to the central nausea pathway, allowing higher net efficacy with a tolerability profile similar to selective GLP-1 receptor agonists. SURMOUNT-5 — the first large head-to-head against semaglutide — supports this hypothesis: greater weight loss and lower gastrointestinal-related discontinuation.

The structural backbone derived from GIP, with substitutions enabling GLP-1R agonism, distinguishes tirzepatide from the strategy of co-administering two molecules. It is a single peptide with balanced affinity for the two receptors.

What the trials show

SURPASS-2 — type 2 diabetes head-to-head with semaglutide (Frías 2021, NEJM, PMID 34170647, NCT03987919). Randomized open-label trial, 40 weeks, n=1,879 adults with type 2 diabetes inadequately controlled on metformin. Tirzepatide 5/10/15 mg weekly vs semaglutide 1 mg weekly. HbA1c reductions: -2.01%, -2.24%, -2.30% (tirzepatide doses) vs -1.86% (semaglutide). Weight reductions: -7.6 kg, -9.3 kg, -11.2 kg vs -5.7 kg. All three tirzepatide doses superior for HbA1c and weight. The trial established the molecule as a first-in-class dual agonist with superior glycemic control vs the leading GLP-1 receptor agonist.

SURMOUNT-1 — obesity without diabetes (Jastreboff 2022, NEJM, PMID 35658024, NCT04184622). Randomized double-blind placebo-controlled trial, 72 weeks, n=2,539 adults with BMI ≥30 or ≥27 with at least one weight-related comorbidity, without type 2 diabetes. Weight changes: -15.0% (5 mg), -19.5% (10 mg), -20.9% (15 mg) vs -3.1% placebo. 91% of participants on 15 mg achieved ≥5% weight loss; 56% achieved ≥20%. The regulatory basis for Zepbound.

SURMOUNT-5 — head-to-head with semaglutide in obesity without diabetes (Aronne 2025, NEJM, PMID 40353578, NCT05822830). Open-label randomized phase 3b trial, 72 weeks, n=751. Maximum tolerated dose tirzepatide (10 or 15 mg) vs maximum tolerated dose semaglutide (1.7 or 2.4 mg). Weight changes: -20.2% (tirzepatide) vs -13.7% (semaglutide), p<0.001. Mean waist-circumference reduction: -18.4 cm vs -13.0 cm. ≥25% weight loss: 32% vs 16%. Gastrointestinal-related discontinuation: 2.7% vs 5.6%. The trial defines the current hierarchy between the two molecules in obesity without diabetes.

SURMOUNT-OSA — obstructive sleep apnea in adults with obesity (Malhotra 2024, NEJM, PMID 38912654). Two phase 3 trials, n=469 combined, 52 weeks. Tirzepatide reduced the apnea-hypopnea index by approximately 25-30 events/hour, with consistent improvements in weight, blood pressure, and inflammatory markers. The regulatory basis for the 2024 FDA OSA label extension.

The SURPASS-CVOT cardiovascular outcomes trial (NCT04255433) reported topline results in 2025 demonstrating non-inferiority versus dulaglutide on MACE; full peer-reviewed publication is the next step for the cardiovascular indication.

Pharmacokinetics

Subcutaneous half-life: approximately 5 days, supporting once-weekly dosing with steady-state achieved in 4 weeks.
Elimination: proteolytic degradation followed by renal and fecal excretion of fragments.
Dosing schedule: escalation 2.5 → 5 → 7.5 → 10 → 12.5 → 15 mg weekly with 4-week intervals between increases. The slow escalation is central to mitigating gastrointestinal adverse events.
No clinically meaningful effect of renal or hepatic impairment on exposure has been reported in dedicated studies.

Safety and adverse events

The adverse-event profile is dominated by gastrointestinal effects, qualitatively similar to selective GLP-1 receptor agonists. In SURMOUNT-1, nausea occurred in 24-33% of tirzepatide participants vs 9% with placebo; diarrhea in 19-23% vs 7%; vomiting in 8-12% vs 1%. Most events were mild to moderate, dose-dependent, and concentrated during titration.

Boxed warning (FDA label): risk of thyroid C-cell tumors based on rodent carcinogenicity studies — a class effect for incretin-based therapies. Personal or family history of medullary thyroid carcinoma or MEN-2 is a contraindication.

Other labeled risks include acute pancreatitis (uncommon), acute gallbladder disease (cholelithiasis observed at higher rates in weight-management trials), acute kidney injury (typically in the setting of severe vomiting or diarrhea), diabetic retinopathy complications in pre-existing retinopathy with rapid HbA1c reduction, and hypoglycemia in combination with insulin or sulfonylureas. The gastrointestinal discontinuation advantage observed in SURMOUNT-5 versus semaglutide (2.7% vs 5.6%) is a consistent finding across the SURMOUNT program.

Regulatory status (international)

FDA: Mounjaro (T2D, May 2022), Zepbound (chronic weight management, November 2023), Zepbound for moderate-to-severe obstructive sleep apnea in adults with obesity (December 2024).
EMA: Mounjaro (T2D and weight management indications, 2022-2023). OSA indication aligned with FDA review.
INN (WHO): tirzepatide (assigned and indexed).
WADA: not currently listed as a prohibited substance in the 2026 Prohibited List. Athletes should verify with their national anti-doping organization.

What we still don't know

Cardiovascular mortality and MACE reduction in obesity without diabetes — SURPASS-CVOT addresses T2D; the equivalent of SELECT for tirzepatide has not been published in peer-reviewed form as of mid-2026.
Long-term durability beyond 72 weeks, including weight regain trajectories after discontinuation.
Comparative effectiveness versus retatrutide (no head-to-head trial published in peer-reviewed literature).
Effects on lean mass, bone density, and physical function during sustained weight loss.
Long-term safety in adolescents (SURMOUNT-ADOLESCENTS program ongoing).

Why it matters

Tirzepatide is the first molecule to demonstrate, in a head-to-head randomized trial, superior weight loss versus semaglutide in obesity without diabetes (SURMOUNT-5). The dual GIP/GLP-1 mechanism is the structural template that informed the design of triple agonists now in late-stage development (retatrutide). The 2024 OSA label extension was the first regulatory recognition that GIP/GLP-1 receptor agonism translates into measurable benefit for an obesity-related comorbidity beyond glycemic and weight endpoints. The SURPASS-CVOT cardiovascular trial in type 2 diabetes is the next major data milestone shaping how tirzepatide is positioned relative to semaglutide and emerging triple agonists.