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Tirzepatide

Also known as: Mounjaro, Zepbound, LY-3298176

FDA Approved

Molecular Formula

C225 H348 N48 O68

Molecular Weight

4,813.53 Da

Half-Life

~5–6 days (~120–144 hours)

Sequence

YXEGTFTSDYSIXLDKIAQKAFVQWLIAGGPSSGAPPPS (X = α-aminoisobutyric acid [Aib]; K20 modified with 1,20-eicosanedioic acid diacid via linker; C-terminus: L-serinamide)

Clinical Applications & Evidence

Mechanism of Action

Tirzepatide acts as a unimolecular dual agonist at GIP and GLP-1 receptors. It stimulates glucose-dependent insulin secretion, suppresses postprandial glucagon secretion, enhances insulin sensitivity, and signals central satiety in brain regions governing food intake. It transiently delays gastric emptying, an effect most pronounced after initial administration that diminishes over time. Structural modification with a C20 fatty diacid moiety at Lys-20 enables high-affinity albumin binding, extending elimination half-life to 5–6 days.

Investigated Uses

  • Type 2 Diabetes Mellitus (FDA-approved as Mounjaro for adults and pediatric patients aged 10+)
  • Chronic weight management (FDA-approved as Zepbound for adults with obesity or overweight with comorbidities)
  • Obstructive Sleep Apnea (FDA-approved as Zepbound for moderate-to-severe OSA in adults with obesity)
  • Obesity-related HFpEF (Investigational — Phase 3 SUMMIT trial showed significant reduction in composite heart failure events)
  • MASH with F2–F3 fibrosis (Investigational — Phase 2 SYNERGY-NASH trial showed MASH resolution without worsening fibrosis)
Extensive Clinical Data

Regulatory & Safety Status

FDA Status

FDA Approved

WADA / Athletic Status

Not Explicitly Prohibited

Known Side Effects

Boxed Warning: Thyroid C-cell tumor risk in rodent studies; human relevance unestablishedGastrointestinal events (nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, belching)Acute pancreatitis, acute gallbladder disease, and acute kidney injury secondary to volume depletionHypoglycemia risk when coadministered with insulin secretagogues or exogenous insulinPeri-procedural pulmonary aspiration risk during general anesthesia or deep sedation

Contraindications

  • Personal or family history of medullary thyroid carcinoma (MTC) or MEN2 syndrome
  • Known serious hypersensitivity to tirzepatide or product excipients
  • Pregnancy and lactation (Zepbound should be discontinued when pregnancy is recognized)
  • Severe gastroparesis or severe active gastrointestinal disease (Precautionary exclusion)

Drug Interactions

  • Insulin secretagogues and exogenous insulin (Increased hypoglycemia risk; dose reduction may be required)
  • Oral hormonal contraceptives (Delayed gastric emptying may decrease oral contraceptive exposure; switch to non-oral method or add barrier contraception for 4 weeks after initiation and after each dose escalation)
  • Oral medications with narrow therapeutic index (Altered absorption rate due to delayed gastric emptying)

Citations & Clinical Trials

New England Journal of Medicine Tirzepatide for Obesity-Related HFpEF — Phase 3 SUMMIT Trial (NEJM 2024) New England Journal of Medicine Tirzepatide for MASH with Liver Fibrosis — Phase 2 SYNERGY-NASH Trial (NEJM 2024) FDA FDA Approves Zepbound for Obstructive Sleep Apnea in Adults with Obesity FDA Mounjaro (tirzepatide) Prescribing Information (FDA 2026) FDA FDA Concerns Regarding Unapproved GLP-1/GIP Products and Compounding Status USADA USADA Athlete Guidance on GLP-1 Agonists and WADA Status (2026)