Dual GIP / GLP-1 Receptor Agonist (Incretin Co-Agonist)

Tirzepatide

Also Known As: LY3298176, Mounjaro, Zepbound

Tirzepatide is a synthetic 39-amino-acid peptide built on the human GIP backbone that simultaneously activates the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R). Two α-aminoisobutyric-acid substitutions (Aib₂ and Aib₁₃) block DPP-4 cleavage, and a C20 fatty di-acid is conjugated to lysine 20 via a γGlu-AEEA-AEEA linker to enable albumin binding and a half-life of approximately five days. Tirzepatide is approved by the FDA and the EMA for type 2 diabetes (Mounjaro), for chronic weight management (Zepbound), and for moderate-to-severe obstructive sleep apnea in adults with obesity (Zepbound).

Identity & Chemistry

Skeletal chemical structure of tirzepatide (LY3298176), a 39-residue peptide with α-aminoisobutyric-acid substitutions at positions 2 and 13 and a C20 fatty-diacid side chain conjugated to lysine 20 via a γ-glutamate–AEEA–AEEA linker.
Image credit: Michael D. Turnbull, via Wikimedia Commons · CC BY-SA 4.0
Amino Acid Sequence
Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-I-A-Q-K(γGlu-AEEA-AEEA-C20 diacid)-A-F-V-Q-W-L-I-A-G-G-P-S-S-G-A-P-P-P-S-NH₂
Molecular Formula
C₂₂₅H₃₄₈N₄₈O₆₈
Molecular Weight
4813.53 Da
CAS Number
2023788-19-2
PubChem CID
156588324
DrugBank ID
DB15171
IUPAC Name
L-Tyrosyl-2-methylalanyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-isoleucyl-2-methylalanyl-L-leucyl-L-α-aspartyl-L-lysyl-L-isoleucyl-L-alanyl-L-glutaminyl-N⁶-[(22S)-22,42-dicarboxy-1,10,19,24-tetraoxo-3,6,12,15-tetraoxa-9,18,23-triazadotetracont-1-yl]-L-lysyl-L-alanyl-L-phenylalanyl-L-valyl-L-glutaminyl-L-tryptophyl-L-leucyl-L-isoleucyl-L-alanyl-glycyl-glycyl-L-prolyl-L-seryl-L-seryl-glycyl-L-alanyl-L-prolyl-L-prolyl-L-prolyl-L-serinamide
Solubility
Soluble in water; research-grade material is typically reconstituted in bacteriostatic water for injection, sterile water, or 0.9% NaCl. Insoluble in most organic solvents. Subcutaneous bioavailability in clinical PK studies is approximately 80%.
Storage
Lyophilized peptide: store at −20 °C, protected from light. Reconstituted solutions: 2–8 °C, protected from light, with limited working stability per the certificate of analysis. Commercial Mounjaro/Zepbound pens are stored under refrigeration per FDA prescribing information.

Mechanism of Action

Tirzepatide is a once-weekly synthetic 39-amino-acid peptide that simultaneously activates GIPR and GLP-1R, with binding affinity intentionally biased toward GIPR (Kᵢ ≈ 0.135 nM at GIPR vs ≈ 4.23 nM at GLP-1R).

Tirzepatide was engineered from the native GIP backbone by Coskun et al. (2018), with two α-aminoisobutyric-acid (Aib) substitutions at positions 2 and 13 introduced to block DPP-4-mediated proteolysis and stabilise the active conformation. A C20 fatty di-acid (1,20-eicosanedioic acid) is conjugated to the side-chain ε-amine of lysine 20 through a γGlu-AEEA-AEEA linker; this acyl chain binds serum albumin, extending plasma half-life to approximately five days and enabling once-weekly subcutaneous dosing. Dual GIPR + GLP-1R agonism produces glucose-dependent stimulation of insulin secretion and suppression of inappropriate glucagon release, slowed gastric emptying that blunts post-prandial glucose excursions, and central anorexigenic signalling that reduces caloric intake and body weight. Receptor pharmacology is intentionally imbalanced (greater GIPR than GLP-1R activity), and at GLP-1R the molecule is biased toward cAMP generation over β-arrestin recruitment — a profile hypothesised to reduce receptor desensitisation while preserving downstream metabolic effects.

Molecular Targets

  • Glucose-dependent insulinotropic polypeptide receptor (GIPR) — full agonist; affinity comparable to native GIP
  • Glucagon-like peptide-1 receptor (GLP-1R) — partial / signal-biased agonist, ~5-fold weaker than native GLP-1, biased toward Gαs / cAMP signalling over β-arrestin recruitment
  • Human serum albumin — non-covalent binding via the C20 fatty di-acid side chain

Signaling Pathways

  • Gαs → adenylyl cyclase → cAMP → PKA / Epac in pancreatic β-cells → glucose-dependent insulin secretion
  • Glucose-dependent suppression of glucagon secretion from pancreatic α-cells
  • Slowed gastric emptying and blunted post-prandial glucose excursions
  • Central effects on hypothalamic appetite circuits → increased satiety and reduced caloric intake

Research Applications

Tirzepatide has been evaluated in a comprehensive Phase III programme in type 2 diabetes (SURPASS), obesity (SURMOUNT), heart failure with preserved ejection fraction (SUMMIT), obstructive sleep apnea (SURMOUNT-OSA), and MASH (SYNERGY-NASH).

Type 2 diabetes (SURPASS-1, monotherapy vs placebo, 40 weeks)

Phase III

Studies report mean HbA1c reductions of −1.87% / −1.89% / −2.07% with tirzepatide 5 / 10 / 15 mg vs +0.04% with placebo.

— Rosenstock et al., Lancet 2021;398(10295):143–155

Type 2 diabetes (SURPASS-2, vs semaglutide 1 mg, 40 weeks)

Phase III

Tirzepatide was superior to semaglutide on HbA1c reduction (estimated treatment difference up to −0.45%) and on body weight (1.9–5.5 kg additional reduction).

— Frías et al., NEJM 2021;385(6):503–515

Obesity (SURMOUNT-1, 72 weeks, BMI ≥30 or ≥27 with comorbidity, no T2D)

Phase III

Studies report mean body-weight change of −15.0% (5 mg), −19.5% (10 mg), and −20.9% (15 mg) with tirzepatide vs −3.1% with placebo.

— Jastreboff et al., NEJM 2022;387(3):205–216

MASH with F2/F3 fibrosis (SYNERGY-NASH, Phase II, 52 weeks)

Phase II

Studies report MASH resolution without worsening of fibrosis in 51.8% (5 mg), 62.8% (10 mg), and 73.3% (15 mg) of tirzepatide-treated participants vs 13.2% on placebo.

— Loomba et al., NEJM 2024;391(4):299–310

Obstructive sleep apnea + obesity (SURMOUNT-OSA, 52 weeks)

Phase III

Studies report change in apnea-hypopnoea index (AHI) of −25.3 / −29.3 events·h⁻¹ with tirzepatide vs −5.3 / −5.5 with placebo (treatment differences of −20.0 and −23.8 events·h⁻¹).

— Malhotra et al., NEJM 2024;391(13):1193–1205

HFpEF + obesity (SUMMIT, median follow-up 104 weeks)

Phase III

Studies report a composite of CV death or worsening heart-failure event in 9.9% on tirzepatide vs 15.3% on placebo (HR 0.62; 95% CI 0.41–0.95; P=0.026).

— Packer et al., NEJM 2024;391(22):2087–2099

Cardiovascular outcomes (SURPASS-CVOT, T2D + ASCVD, median 4-year follow-up)

Phase III

Studies report primary 3-point MACE of 12.2% on tirzepatide vs 13.1% on dulaglutide (non-inferior, P=0.003); expanded MACE-4 reduced with tirzepatide (HR 0.88; 95% CI 0.80–0.96).

— Nicholls et al., NEJM 2025;393:2409–2420

Clinical Status

Regulatory Status
Approved. FDA: Mounjaro (type 2 diabetes, May 2022); Zepbound (chronic weight management, November 2023; moderate-to-severe obstructive sleep apnea in adults with obesity, December 2024). EMA: Mounjaro (type 2 diabetes, September 2022). MHRA (UK): weight management (November 2023). Health Canada (November 2022) and TGA Australia (December 2022) for type 2 diabetes.
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Highest Trial Phase
Approved (Phase IV / post-marketing); Phase III ongoing in cardiovascular outcomes (SURMOUNT-MMO)
Sponsor
Eli Lilly and Company

Key Clinical Trials

  • SURPASS-1: tirzepatide monotherapy vs placebo in type 2 diabetes
    Phase 3
    NCT03954834
  • SURPASS-2: tirzepatide vs semaglutide 1 mg in type 2 diabetes
    Phase 3
    NCT03987919
  • SURPASS-3: tirzepatide vs insulin degludec, add-on to metformin ± SGLT2i
    Phase 3
    NCT03882970
  • SURPASS-5: tirzepatide added to insulin glargine in type 2 diabetes
    Phase 3
    NCT04039503
  • SURPASS-CVOT: tirzepatide vs dulaglutide on MACE in T2D with established ASCVD
    Phase 3
    NCT04255433
  • SURMOUNT-1: tirzepatide for chronic weight management in obesity (no T2D)
    Phase 3
    NCT04184622
  • SURMOUNT-2: tirzepatide for weight management in obesity + type 2 diabetes
    Phase 3
    NCT04657003
  • SUMMIT: tirzepatide in heart failure with preserved ejection fraction and obesity
    Phase 3
    NCT04847557
  • SURMOUNT-OSA: tirzepatide in moderate-to-severe obstructive sleep apnea + obesity
    Phase 3
    NCT05412004
  • SYNERGY-NASH: tirzepatide in metabolic dysfunction-associated steatohepatitis (F2/F3 fibrosis)
    Phase 2
    NCT04166773

Safety Profile

Observed in research settings

Across the SURPASS, SURMOUNT, SUMMIT, SURMOUNT-OSA, and SYNERGY-NASH programmes the adverse-event profile observed in research settings was dominated by mild-to-moderate gastrointestinal events that were typically dose-dependent and most pronounced during dose escalation. Serious events were uncommon but included pancreatitis, gallbladder disease, and hypersensitivity reactions.

Adverse Events Reported in Studies

  • Nausea (up to ~31% on the 15 mg dose, pooled SURPASS data)
  • Diarrhoea (up to ~23%)
  • Vomiting (up to ~13%)
  • Constipation (up to ~17%)
  • Decreased appetite (up to ~11%)
  • Abdominal pain / dyspepsia / eructation (several percent)
  • Injection-site reactions (several percent)
  • Hypoglycaemia (mostly when combined with insulin or sulfonylureas)

Serious Adverse Events

  • Thyroid C-cell tumours — FDA boxed warning based on rat studies; human relevance unknown. Contraindicated in personal/family history of MTC or MEN-2
  • Acute pancreatitis (including haemorrhagic / necrotising) — reported in clinical trials and post-marketing
  • Gallbladder disease (cholelithiasis, cholecystitis) — observed at higher rates than placebo
  • Hypersensitivity reactions including anaphylaxis and angioedema
  • Diabetic-retinopathy complications in patients with pre-existing retinopathy
  • Acute kidney injury secondary to dehydration from severe GI symptoms

References

  1. Coskun T, Sloop KW, Loghin C, et al. 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. Mol Metab 2018;18:3–14. 2018 .

    DOI: 10.1016/j.molmet.2018.09.009 PMID: 30473097 View Source

  2. Rosenstock J, Wysham C, Frías JP, et al. 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;398(10295):143–155. 2021 .

    DOI: 10.1016/S0140-6736(21)01324-6 PMID: 34186022 View Source

  3. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2). N Engl J Med 2021;385(6):503–515. 2021 .

    DOI: 10.1056/NEJMoa2107519 PMID: 34170647 View Source

  4. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). N Engl J Med 2022;387(3):205–216. 2022 .

    DOI: 10.1056/NEJMoa2206038 PMID: 35658024 View Source

  5. Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis (SYNERGY-NASH). N Engl J Med 2024;391(4):299–310. 2024 .

    DOI: 10.1056/NEJMoa2401943 PMID: 38856224 View Source

  6. Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity (SURMOUNT-OSA). N Engl J Med 2024;391(13):1193–1205. 2024 .

    DOI: 10.1056/NEJMoa2404881 PMID: 38912654 View Source

  7. Packer M, Zile MR, Kramer CM, et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity (SUMMIT). N Engl J Med 2024;391(22):2087–2099. 2024 .

    DOI: 10.1056/NEJMoa2410027 PMID: 39555826 View Source

  8. Nicholls SJ, Pavo I, Bhatt DL, et al. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes (SURPASS-CVOT). N Engl J Med 2025;393:2409–2420. 2025 .

    DOI: 10.1056/NEJMoa2505928 PMID: 41406444 View Source

  9. U.S. Food and Drug Administration Mounjaro (tirzepatide) Highlights of Prescribing Information (2025 revision). FDA Drug Label. 2025 .

    View Source

Frequently Asked Questions

What is tirzepatide?
Tirzepatide is a once-weekly synthetic 39-amino-acid peptide developed by Eli Lilly and Company (laboratory code LY3298176; brand names Mounjaro for type 2 diabetes and Zepbound for chronic weight management and obstructive sleep apnea). It is the first approved dual agonist of the GIP and GLP-1 incretin receptors.
How does tirzepatide differ from semaglutide?
Semaglutide is a selective GLP-1 receptor agonist, whereas tirzepatide is a dual GIP + GLP-1 receptor agonist with binding affinity biased toward GIPR. In the head-to-head SURPASS-2 trial in type 2 diabetes, tirzepatide produced greater HbA1c reductions and 1.9–5.5 kg additional body-weight loss versus semaglutide 1 mg over 40 weeks.
Is tirzepatide approved by regulatory agencies?
Yes. The U.S. FDA approved tirzepatide for type 2 diabetes (Mounjaro, May 2022), for chronic weight management in obesity/overweight with comorbidity (Zepbound, November 2023), and for moderate-to-severe obstructive sleep apnea in adults with obesity (Zepbound, December 2024). The European Medicines Agency authorised Mounjaro for type 2 diabetes in September 2022.
What is the molecular structure of tirzepatide?
Tirzepatide is a single-chain 39-residue peptide with molecular formula C₂₂₅H₃₄₈N₄₈O₆₈ and molecular weight ~4813.5 Da, derived from the human GIP sequence. It contains α-aminoisobutyric-acid residues at positions 2 and 13 (which block DPP-4 cleavage), a C-terminal amide, and a 1,20-eicosanedioic-acid (C20 fatty di-acid) attached through a γGlu-AEEA-AEEA linker to the side chain of lysine 20 to enable albumin binding and a ~5-day half-life.
What weight reduction has been reported in clinical trials?
In the 72-week Phase III SURMOUNT-1 study in adults with obesity (without diabetes), mean body-weight change was −15.0% (5 mg), −19.5% (10 mg), and −20.9% (15 mg) with tirzepatide versus −3.1% with placebo. Subsequent SURMOUNT-2/3/4 studies confirmed substantial weight reduction in adjacent populations including adults with type 2 diabetes and after a lifestyle lead-in.
What are the main reported adverse events?
The most frequently reported adverse events are gastrointestinal — nausea, diarrhoea, vomiting, constipation, decreased appetite, and abdominal discomfort — most pronounced during dose escalation and at the 15 mg dose. The U.S. label carries a boxed warning regarding thyroid C-cell tumours observed in rats, and lists acute pancreatitis, gallbladder disease, hypersensitivity reactions, acute kidney injury secondary to dehydration, and possible diabetic-retinopathy complications.

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