Tirzepatide
Tirzepatide is a once-weekly peptide that activates both the GIP and GLP-1 receptors. It is FDA-approved for type 2 diabetes (Mounjaro) and chronic weight management (Zepbound).
Overview
Tirzepatide is a synthetic peptide developed by Eli Lilly that acts on two incretin hormone receptors: the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. It was the first dual GIP/GLP-1 receptor agonist to reach the market and is often described as a "twincretin". Its sequence is based on GIP, with modifications that add GLP-1 receptor activity and a fatty acid side chain for albumin binding.
Tirzepatide is FDA-approved as Mounjaro for type 2 diabetes and as Zepbound for chronic weight management. Its approvals were supported by the SURPASS phase 3 program in type 2 diabetes and the SURMOUNT program in obesity. It is an important reference compound for multi-receptor incretin pharmacology and a forerunner of triple agonists such as retatrutide. Both products are given by subcutaneous injection.
Compare: Semaglutide vs Tirzepatide vs Retatrutide.
Structure
Tirzepatide is a 39-residue linear peptide whose backbone is derived from human GIP, with substitutions that confer GLP-1 receptor activity. It contains two α-aminoisobutyric acid (Aib) residues, including one at position 2 that protects against dipeptidyl peptidase-4 cleavage. A lysine side chain is attached, via a hydrophilic linker and γ-glutamic acid spacer, to a C20 fatty diacid that promotes reversible albumin binding. The C-terminus is amidated.
Mechanism
Tirzepatide is an agonist at both the GIP receptor and the GLP-1 receptor. Its pharmacology is described as imbalanced, with greater relative potency at the GIP receptor than at the GLP-1 receptor compared with the native hormones. At the GLP-1 receptor it has been reported to favor cyclic AMP signaling over beta-arrestin recruitment, which may influence receptor internalization.
Both receptors enhance glucose-dependent insulin secretion. GLP-1 receptor activation also suppresses glucagon, slows gastric emptying and reduces appetite through brain pathways. How GIP receptor agonism contributes to weight loss is still debated, as GIP receptor antagonism has also been explored for obesity. Albumin binding gives tirzepatide a half-life supporting once-weekly dosing.
Research
Type 2 diabetes: SURPASS
The SURPASS phase 3 program evaluated tirzepatide in adults with type 2 diabetes, comparing it with placebo, insulin regimens and semaglutide 1 mg. Across trials it improved glycemic control measured by HbA1c and reduced body weight, meeting primary endpoints. In SURPASS-2, tirzepatide was compared head-to-head with semaglutide 1 mg and showed greater HbA1c reduction. These trials supported approval of Mounjaro.
Obesity: SURMOUNT
The SURMOUNT program studied tirzepatide in adults with obesity or overweight with weight-related conditions. SURMOUNT-1, published in 2022, found substantially greater weight reduction than placebo over 72 weeks, meeting its co-primary endpoints. Other SURMOUNT trials examined people with type 2 diabetes, the effect of intensive lifestyle intervention and weight maintenance after treatment withdrawal. These results supported approval of Zepbound. Head-to-head and outcome trials continue to be reported.
Additional areas of study
Tirzepatide has been investigated in obstructive sleep apnea, heart failure with preserved ejection fraction, metabolic dysfunction-associated steatohepatitis and cardiovascular outcomes, among other areas. Results and regulatory decisions differ by indication, and approved uses are defined by the current labeling. Readers should consult individual trial publications and prescribing information rather than generalizing across trials. Some of these indications have been added to labeling while others remain under study.
Regulatory status
Tirzepatide is FDA-approved as Mounjaro for type 2 diabetes and as Zepbound for chronic weight management, both from Eli Lilly. It is also approved in other countries. Compounding of tirzepatide has been shaped by FDA drug shortage determinations, which change over time; check current FDA guidance. For its status in sport, check the current WADA Prohibited List.
Status changes often. See the regulatory tracker for dated updates.
Quality and identity testing
A COA should confirm identity by mass spectrometry, with the observed mass matching the expected mass for the acylated peptide shown on this page, and report purity by reverse-phase HPLC. Key impurities include peptide lacking the fatty diacid side chain, incompletely assembled linkers, deletion sequences from the 39-residue synthesis and racemized residues. The salt form should be stated, as it may differ from the approved drug substance. Aggregation and oxidation should be monitored, and endotoxin and net peptide content reported.
For a walkthrough of each section of a certificate, see how to read a COA.
Storage and stability
Research material should be stored lyophilized at -20 °C, sealed and protected from light and moisture. As an amphiphilic acylated peptide, tirzepatide can self-associate in solution, so avoid vigorous agitation and inappropriate buffers. Approved drug products are stored according to their labeling, typically refrigerated. Avoid repeated freeze-thaw cycles for laboratory solutions and allow vials to warm to room temperature before opening.
Download the Tirzepatide data sheet (PDF): sequence, masses, expected MS ions and handling on one printable page.
Latest research
The newest PubMed-indexed papers that mention Tirzepatide in their title or abstract, retrieved through Europe PMC and refreshed automatically. Inclusion is not an endorsement of a paper's findings.
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Frequently asked questions
Is tirzepatide FDA approved?
Yes. Tirzepatide is FDA-approved as Mounjaro for type 2 diabetes and as Zepbound for chronic weight management. Both are once-weekly injectable products made by Eli Lilly. Each product has its own labeled indications, which should be checked in current prescribing information. It is also approved in many countries outside the US.
What is the difference between Mounjaro and Zepbound?
Both contain tirzepatide. Mounjaro is approved for type 2 diabetes, and Zepbound is approved for chronic weight management and other indications listed in its labeling. The active ingredient is the same; the products differ in approved uses and labeling. Different dose strengths and labeling apply to each brand.
How does tirzepatide differ from retatrutide?
Tirzepatide activates two receptors, GIP and GLP-1. Retatrutide activates three: GIP, GLP-1 and glucagon. Both are Eli Lilly peptides with fatty acid side chains for once-weekly dosing. Tirzepatide is FDA-approved, while retatrutide remains investigational. The two compounds have separate clinical development programs.
Related compounds
- Semaglutide
Semaglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist. It is FDA-approved for type 2 diabetes (Ozempic, Rybelsus) and chronic weight management (Wegovy).
- Retatrutide
Retatrutide is an investigational once-weekly peptide that activates the GIP, GLP-1 and glucagon receptors. It is not FDA-approved; Eli Lilly plans a BLA submission in Q1 2027 after phase 3 results.
- Cagrilintide
Cagrilintide is an investigational long-acting acylated analogue of amylin, a pancreatic hormone involved in satiety. It has been studied alone and in combination with semaglutide (CagriSema) for weight management.
- AOD-9604
AOD-9604 is a synthetic peptide based on the C-terminal region of human growth hormone, with an added N-terminal tyrosine. It was studied as an anti-obesity agent, but clinical development was discontinued.
References
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022. Find on PubMed
- PubMed: all indexed literature on Tirzepatide
- ClinicalTrials.gov: registered studies mentioning Tirzepatide
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