What it is
Tirzepatide is a synthetic, fatty acid-modified peptide that activates both the GIP and GLP-1 receptors and is given by once-weekly subcutaneous injection. Eli Lilly developed it under the code LY3298176, and Coskun et al. (2018) reported its discovery, mouse pharmacology and first human studies. It is approved in the US as Mounjaro and Zepbound.
Mechanism of action
Tirzepatide is a single peptide that acts on two incretin receptors: the glucose-dependent insulinotropic polypeptide (GIP) receptor and the GLP-1 receptor. Both native hormones are released from the gut after meals and increase glucose-dependent insulin secretion. GLP-1 receptor activation also lowers glucagon, slows gastric emptying and reduces appetite through receptors in the brain. How much GIP receptor activation adds beyond the GLP-1 component is still debated in the research literature. A fatty acid modification promotes binding to serum albumin, which slows clearance and supports once-weekly dosing. Coskun et al. (2018) characterized its signaling in cell lines expressing the incretin receptors, measured body weight, food intake, insulin secretion and glucose in mice, and ran phase 1 studies in healthy volunteers and a 4-week study in people with type 2 diabetes, with dulaglutide as a positive control. That work is the starting point for the SURPASS and SURMOUNT trial programs.
What it’s most studied for
Tirzepatide is most studied for body weight reduction and glycemic control. The SURPASS program tested it in type 2 diabetes, including a 40-week comparison with semaglutide 1 mg, and the SURMOUNT program tested it in adults with obesity, including a 72-week head-to-head trial against semaglutide at weight-management doses. Researchers have also examined outcomes beyond weight: breathing disturbances during sleep in obstructive sleep apnea (SURMOUNT-OSA) and major cardiovascular events against an active GLP-1 comparator in people with type 2 diabetes and atherosclerotic disease (SURPASS-CVOT). Its dual mechanism makes it a common reference point for triple agonists such as retatrutide.
Notable findings
Each finding carries the species or population it was observed in and the dose that study used. Doses are reported as research context, exactly as published. They are not guidance.
Weight reduction over 72 weeks (SURMOUNT-1)
Jastreboff et al. (2022) randomized 2,539 adults with obesity or overweight and without diabetes 1:1:1:1 to three tirzepatide doses or placebo, with lifestyle intervention. Mean weight change at 72 weeks was −15.0% (5 mg), −19.5% (10 mg) and −20.9% (15 mg) versus −3.1% with placebo. Discontinuation for adverse events was 4.3%, 7.1% and 6.2% across the tirzepatide doses versus 2.6% on placebo.
- Dose studied
- Tirzepatide 5 mg, 10 mg or 15 mg once weekly, subcutaneous injection, adults, 72 weeks
[2] Jastreboff AM et al. · 2022 · PMID 35658024 ↗
Head-to-head versus semaglutide in obesity (SURMOUNT-5)
Aronne et al. (2025) randomized 751 adults with obesity and without diabetes, at 32 sites in the US and Puerto Rico, to the maximum tolerated dose of tirzepatide or semaglutide. At 72 weeks, mean weight change was −20.2% with tirzepatide versus −13.7% with semaglutide, and waist circumference fell 18.4 cm versus 13.0 cm. Gastrointestinal adverse events led to discontinuation in 2.7% of the tirzepatide group and 5.6% of the semaglutide group.
- Dose studied
- Tirzepatide 10 mg or 15 mg once weekly versus semaglutide 1.7 mg or 2.4 mg once weekly (maximum tolerated dose), subcutaneous injection, adults, 72 weeks
[4] Aronne LJ et al. · 2025 · PMID 40353578 ↗
Glycemic control versus semaglutide 1 mg (SURPASS-2)
Frías et al. (2021) randomized 1,879 adults with type 2 diabetes taking metformin 1:1:1:1 to one of three tirzepatide doses or semaglutide 1 mg for 40 weeks. HbA1c fell by 2.01, 2.24 and 2.30 percentage points with tirzepatide 5, 10 and 15 mg versus 1.86 with semaglutide, meeting the criteria for noninferiority and superiority at every dose. Weight reductions were also larger with tirzepatide, and gastrointestinal events, mostly mild to moderate, were the most common adverse events.
- Dose studied
- Tirzepatide 5 mg, 10 mg or 15 mg once weekly versus semaglutide 1 mg once weekly, subcutaneous injection, adults with type 2 diabetes, 40 weeks
[3] Frías JP et al. · 2021 · PMID 34170647 ↗
Obstructive sleep apnea severity (SURMOUNT-OSA)
Malhotra et al. (2024) ran two 52-week trials in adults with moderate-to-severe obstructive sleep apnea and obesity, one in people not using positive airway pressure (PAP) therapy and one in people using it. In the first trial, from a mean baseline apnea-hypopnea index (AHI) of 51.5 events per hour, AHI fell by 25.3 events per hour with tirzepatide and 5.3 with placebo; the estimated treatment difference was 20.0 events per hour in the first trial and 23.8 in the second. Commentators noted that AHI change has not been validated as a surrogate for clinical outcomes.
- Dose studied
- Tirzepatide 10 mg or 15 mg once weekly (maximum tolerated dose), subcutaneous injection, adults, 52 weeks
[5] Malhotra A et al. · 2024 · PMID 38912654 (NCT05412004) ↗
Cardiovascular outcomes versus dulaglutide (SURPASS-CVOT)
Nicholls et al. (2025) randomized people with type 2 diabetes and atherosclerotic cardiovascular disease 1:1 to tirzepatide or dulaglutide, with a median follow-up of about 4 years. The composite of cardiovascular death, myocardial infarction or stroke occurred in 12.2% of the tirzepatide group and 13.1% of the dulaglutide group (hazard ratio 0.92, 95.3% CI 0.83 to 1.01). Tirzepatide met the noninferiority criterion but did not show superiority, and commentators pointed out that the comparator dose of dulaglutide was below its maximum.
- Dose studied
- Tirzepatide up to 15 mg once weekly versus dulaglutide 1.5 mg once weekly, subcutaneous injection, adults with type 2 diabetes, median follow-up about 4 years
[6] Nicholls SJ et al. · 2025 · PMID 41406444 ↗
Study quality
The evidence for tirzepatide is strong: several large randomized phase 3 trials in humans, two head-to-head comparisons with semaglutide, a cardiovascular outcomes trial against an active comparator, and FDA approval for type 2 diabetes, chronic weight management and obstructive sleep apnea with obesity. Trials ran 40 to 72 weeks for metabolic endpoints and about 4 years for cardiovascular events. The main caveats are that the manufacturer, Eli Lilly, funded the trials summarized here, and that SURPASS-CVOT compared tirzepatide with another active drug rather than placebo, so it shows noninferiority to dulaglutide rather than an effect against no treatment. SURPASS-2 was open-label. Gastrointestinal adverse events (nausea, diarrhea, vomiting) were the most frequent safety finding across the program, mostly mild to moderate; discontinuation for adverse events in SURMOUNT-1 ranged from 4.3% to 7.1% across doses versus 2.6% on placebo.
References
- 1LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Molecular Metabolism. PMID 30473097
- 2Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine. PMID 35658024
- 3Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. New England Journal of Medicine. PMID 34170647
- 4Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. New England Journal of Medicine. PMID 40353578
- 5Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. New England Journal of Medicine. PMID 38912654 (NCT05412004)
- 6Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. New England Journal of Medicine. PMID 41406444
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