The history of tirzepatide: from the lab to sport

Tirzepatide became the first registered drug to simultaneously activate the receptors of two gut hormones — GIP and GLP-1. In just a few years it traveled from the laboratory code LY3298176 to one of the most discussed drugs of the decade, and later to gym locker rooms as well. The editors have traced this history: from a scientific idea to clinical trials, approval and unofficial use in sport.

Background: incretins and the "forgotten" hormone GIP

The history of tirzepatide begins long before its synthesis — with the discovery of the incretin effect. As early as the middle of the 20th century, physiologists noticed that glucose taken orally causes a much greater release of insulin than the same amount of glucose given intravenously. The explanation was found in the gut: in response to food, its cells release incretin hormones that "prompt" the pancreas that it is time to produce insulin.

The first incretin identified was glucose-dependent insulinotropic polypeptide — GIP. A little later, in the 1980s, glucagon-like peptide-1 (GLP-1) was described. It was GLP-1 that quickly became the favorite of pharmacologists: it not only stimulated insulin secretion but also suppressed glucagon, slowed gastric emptying and reduced appetite.

GIP, meanwhile, ended up on the sidelines. In people with type 2 diabetes its insulinotropic action turned out to be weakened, and some data even suggested that GIP might promote fat accumulation. For that reason, for many years the development of drugs based on GIP was considered unpromising, and all attention went to GLP-1 receptor agonists — exenatide, liraglutide, later semaglutide.

The turn came in the 2010s, when several research groups showed that against a background of improved glucose control, sensitivity to GIP is partly restored, and simultaneous stimulation of both receptors can give a stronger metabolic effect than each hormone separately. Thus arose the concept of "dual agonists", which in popular texts is sometimes called "twincretins".

The idea was simple only on paper. It was necessary to create a single molecule that activates two different receptors in a balanced way, is stable in the blood and is suitable for convenient administration. Several companies worked on this, but the first to reach registration was the Eli Lilly project.

The birth of the LY3298176 molecule

In 2018 a group of Eli Lilly researchers led by T. Coskun published in the journal Molecular Metabolism a description of the compound LY3298176 — the future tirzepatide. The article traced the path "from discovery to clinical proof of concept": from the design of the peptide to the first data in humans.

Tirzepatide is a linear peptide of 39 amino acids, built on the basis of the GIP sequence. A fatty-acid chain (a C20 diacid) is attached to it via a spacer. This "tail" allows the molecule to bind to blood albumin, which protects it from rapid breakdown and elimination by the kidneys. As a result the half-life is about five days, and the drug can be given subcutaneously once a week.

A fundamental feature of the molecule is its "imbalance" in favor of GIP: according to the developers, its activity toward the GIP receptor is close to that of the natural hormone, whereas toward the GLP-1 receptor it is noticeably weaker than native GLP-1. It is precisely this ratio, the authors believe, that made it possible to obtain a pronounced effect on glucose and body weight.

That same year, 2018, the journal Lancet published the results of a randomized phase 2 trial (Frias et al.), in which tirzepatide was compared with placebo and dulaglutide in patients with type 2 diabetes. The reduction in glycated hemoglobin and body weight at the higher doses exceeded that of the comparator drug, but at the same time gastrointestinal side effects occurred more often. This determined the further strategy — gradual dose escalation.

The SURPASS and SURMOUNT programs

After the encouraging phase 2, Eli Lilly launched a large-scale phase 3 research program called SURPASS. In it tirzepatide was studied in patients with type 2 diabetes at various stages of treatment: as monotherapy, in combination with metformin, with insulin, in people with high cardiovascular risk.

The most prominent was the SURPASS-2 trial (Frías et al., NEJM, 2021), in which tirzepatide at doses of 5, 10 and 15 mg was compared directly with semaglutide 1 mg. All three doses of tirzepatide lowered glycated hemoglobin and body weight more strongly than the comparator drug. For incretin pharmacology this was an important signal: dual agonism really did give an additional effect.

In parallel the SURMOUNT program was launched — now for people with obesity or overweight without diabetes. In the SURMOUNT-1 trial (Jastreboff et al., NEJM, 2022) over 72 weeks the average reduction in body weight was about 15%, 19.5% and 21% at doses of 5, 10 and 15 mg respectively, versus about 3% in the placebo group. Such figures were previously associated mainly with bariatric surgery.

At the same time the trials clearly outlined the safety profile. The most common side effects were nausea, diarrhea, vomiting and constipation, mainly during the dose-escalation period. Some participants discontinued treatment because of gastrointestinal symptoms. These data later formed the basis of the drug's prescribing information.

Approval and new indications

In May 2022 the FDA approved tirzepatide under the trade name Mounjaro for the treatment of type 2 diabetes in adults. That same year the drug received approval in the European Union. It became the first approved agonist of two incretin receptors at once.

In November 2023 the FDA registered the same molecule under the name Zepbound for long-term weight management in adults with obesity or overweight in the presence of comorbid conditions. In 2024 the list of indications was expanded to moderate and severe obstructive sleep apnea in people with obesity — based on the results of the SURMOUNT-OSA trial (Malhotra et al., NEJM, 2024).

The rapid demand caused a shortage of the drug in a number of countries. In the USA, during the period of the official shortage, compounding pharmacies made their own versions of tirzepatide, and on the gray market vials labeled "for research only" appeared. Regulators repeatedly warned about the risks of such products: incorrect content of the active substance, impurities, dosing errors and counterfeits.

The drug's prescribing information contains a number of serious warnings: the risk of pancreatitis, hypoglycemia in combination with insulin or sulfonylurea drugs, acute kidney injury against a background of dehydration, and gallbladder disease. There is also a boxed warning about C-cell thyroid tumors found in rodents, and a contraindication for people with medullary thyroid cancer in their personal or family history.

How tirzepatide got into sport

The sporting community's interest in tirzepatide arose almost immediately after the publication of the SURMOUNT-1 data. In bodybuilding and bikini fitness it began to be discussed as a tool for "cutting", and in weight-class sports as a way to control appetite before the weigh-in. For many amateurs it became the "next step" after semaglutide.

However, the clinical trials were conducted in people with obesity or diabetes, not in athletes. An important detail: in the SURMOUNT program part of the lost mass came from lean mass, not just fat. For an athlete whose goal is to preserve muscle and strength, such a trade-off may be undesirable. There is practically no controlled data on the effect of tirzepatide on athletic performance.

As for antidoping status: as of the latest editions of the WADA Prohibited List, GLP-1 and GIP receptor agonists are not included in the list of prohibited substances. However, this status may change, so athletes should check the current version of the list and the rules of their federation each year.

The main risks of "sporting" use are related not to pharmacology as such, but to the context:

• drugs from the gray market with no guarantees of composition, sterility and concentration;
• self-administration without examination and medical supervision;
• dehydration against a background of vomiting and diarrhea, especially when "cutting" weight;
• insufficient intake of protein and energy, which aggravates the loss of muscle mass;
• combination with other substances for weight loss, which increases the load on the heart and kidneys.

The editors emphasize: tirzepatide is a prescription drug with clearly defined medical indications. Its "sporting career" is off-label use, for which there is no evidence base either for efficacy or for safety.

Editorial conclusions

Tirzepatide grew out of a scientific idea long considered unpromising: to bring the "forgotten" hormone GIP back into play. Combining two incretin mechanisms in a single molecule gave results that changed ideas about the possibilities of drug treatment of diabetes and obesity.

The path from the 2018 publication to several registered indications took only a few years and was based on large randomized trials. It is precisely this evidence base that distinguishes medical use from the unofficial use in sport, where such data do not exist.

For athletes, tirzepatide remains a drug with a non-obvious balance of benefit and risk: weight loss may be accompanied by loss of muscle, while gray-market products add unpredictability.

We also recommend reading our materials on how tirzepatide differs from semaglutide, on the signs of tirzepatide overdose, and on the tests monitored during therapy with GLP-1 agonists.

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.
2. Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet. 2018;392(10160):2180–2193.
3. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503–515.
4. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205–216.
5. Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N Engl J Med. 2024;391(13):1193–1205.
6. Nauck MA, Meier JJ. Incretin hormones: their role in health and disease. Diabetes Obes Metab. 2018;20(Suppl 1):5–21.
7. Eli Lilly and Company. Mounjaro (tirzepatide) injection: prescribing information. U.S. Food and Drug Administration.
8. World Anti-Doping Agency. The World Anti-Doping Code: International Standard — Prohibited List. Montreal: WADA (актуальна редакція).