Retatrutide vs tirzepatide: what the trials show and what they don't

Tirzepatide (Mounjaro, Zepbound) is an approved weekly injection that activates two gut-hormone receptors, GIP and GLP-1. Retatrutide is an experimental Eli Lilly drug that activates those two plus the glucagon receptor, and it is not approved anywhere. Its trials report larger average weight loss than tirzepatide's did, but no head-to-head results have been reported yet, and numbers from separate trials cannot be compared directly.^{1,2,3,9,12,17,13}

At a glance

The weight figures in this table come from different trials run at different times in different people. They are not directly comparable and do not show that one drug is better than the other.^12,17

How they work

Tirzepatide activates the receptors for GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide), two hormones made in the gut. It increases insulin release and lowers glucagon only when blood sugar is high, and both receptors are found in brain areas that regulate appetite.^1,2,3

Retatrutide is also a single molecule given as a weekly injection, but it adds a third target, the glucagon receptor. In Lilly's early studies in obese mice, glucagon receptor activation increased energy expenditure (calories burned), adding to the reduced food intake driven by the GIP and GLP-1 actions. That finding comes from mice.^10,11,18

Regulatory status

• Tirzepatide is approved in the US as Mounjaro (type 2 diabetes, and lowering heart-event risk in high-risk adults with type 2 diabetes) and Zepbound (weight management, and obstructive sleep apnea with obesity), and in the EU as Mounjaro (type 2 diabetes and weight management).
• Retatrutide is not approved by any regulator. Lilly calls it an investigational molecule that cannot legally be sold or marketed for human use, and plans to apply for US approval in the first quarter of 2027, after completing its manufacturing (chemistry, manufacturing and controls) data package.
• Outside trials, Lilly lists a pre-approval expanded access program under which a treating doctor can request retatrutide for an individual adult with severe obesity and serious complications who has not responded to the best approved treatment and cannot join a trial.
• The FDA says retatrutide cannot be used in compounding under federal law and has not been found safe and effective for any condition. The UK MHRA says it is not authorized in the UK, so anyone selling it there is doing so illegally.^{1,2,3,18,15,4,5}

The best available results for each

Tirzepatide, SURMOUNT-1 (New England Journal of Medicine, 2022): 2,539 adults with obesity, or overweight with a weight-related complication, and without diabetes received one of three doses or placebo for 72 weeks. Average weight change was -15.0%, -19.5% and -20.9% across the doses versus -3.1% with placebo, regardless of whether people stopped treatment (the treatment-regimen estimand).¹²

Retatrutide, phase 2 (New England Journal of Medicine, 2023): in 338 adults with obesity or overweight, the highest dose tested produced an average weight change of -24.2% at 48 weeks versus -2.1% with placebo.⁹

Retatrutide, TRIUMPH-1 (phase 3, reported by Lilly in May 2026): 2,339 adults with obesity or overweight and without diabetes were treated for 80 weeks. Lilly's headline figures of -19.0%, -25.9% and -28.3% across three doses versus -2.2% with placebo use an efficacy estimand, which estimates the effect had everyone stayed on treatment. Counting everyone regardless of adherence (the treatment-regimen estimand), the figures were -17.6%, -23.7% and -25.0% versus -3.9%.¹⁷

TRIUMPH-1 is one of four phase 3 TRIUMPH trials, which together enrolled more than 5,800 people and also test effects on sleep apnea and knee osteoarthritis. The TRIUMPH figures in this article come from Lilly's press releases; Lilly says detailed results will be published in peer-reviewed journals.^11,17,18

Why cross-trial comparisons are unreliable

• Different analyses: Lilly's 28.3% uses the efficacy estimand, while SURMOUNT-1's 20.9% includes people regardless of whether they stopped treatment. Setting one against the other mixes methods.
• Different lengths: 80 weeks in TRIUMPH-1 versus 72 weeks in SURMOUNT-1.
• Different people: TRIUMPH-1 participants started at an average BMI of 40.0 (in the efficacy analysis), SURMOUNT-1 participants at 38.0.
• Results shift with the population even for the same drug: retatrutide's top-dose weight loss was 20.8% in people with type 2 diabetes (TRIUMPH-2) and 22.6% in people with severe obesity and heart disease (TRIUMPH-3), versus 28.3% in TRIUMPH-1, all by the same efficacy estimand.^12,17,18

Only a randomized head-to-head trial can settle the question. One is under way: TRIUMPH-5, a double-blind phase 3 trial in about 800 adults with obesity, compares retatrutide with tirzepatide on weight change at 80 weeks, with primary completion estimated for November 2026. No results have been reported.¹³

Safety signals

Both drugs mainly cause digestive side effects. In TRIUMPH-1, at the highest retatrutide dose, nausea affected 42.4% versus 14.8% on placebo and vomiting 25.3% versus 4.8%, and 11.3% stopped because of side effects versus 4.9%. In SURMOUNT-1, 4.3% to 7.1% on tirzepatide stopped because of side effects versus 2.6% on placebo.^17,12

Retatrutide trials also report other signals. Altered skin sensation (dysesthesia) affected 12.5% on the highest dose versus 0.9% on placebo in TRIUMPH-1, and 20.9% versus 0.7% in TRIUMPH-4; urinary tract infections affected 8.4% versus 5.3% in TRIUMPH-1. Lilly says these events were generally mild to moderate and most resolved. In TRIUMPH-4, 18.2% on the highest dose stopped because of side effects versus 4.0% on placebo, which Lilly says included stopping for perceived excessive weight loss. The phase 2 trial found dose-dependent heart rate increases that peaked at 24 weeks and then declined.^17,19,9

Heart outcomes for retatrutide are unknown. In TRIUMPH-3 (1,949 adults with severe obesity and cardiovascular disease), major heart events were fewer than expected: 27 heart attacks, strokes or cardiovascular deaths on retatrutide versus 23 on placebo (hazard ratio 1.12, 95% confidence interval 0.64 to 1.96), a range too wide to show either benefit or harm. A heart and kidney outcomes trial of about 10,000 people is running, with results estimated in 2029. Tirzepatide has completed a heart outcomes trial in type 2 diabetes (SURPASS-CVOT), in which it was non-inferior to dulaglutide, another GLP-1 drug, though superiority was not established.^18,14,2

Tirzepatide's label carries a boxed warning because it caused thyroid C-cell tumors in rats (human relevance unknown), and warns of pancreatitis, gallbladder disease, kidney injury from fluid loss and low blood sugar, among other risks. Retatrutide has no approved label.¹

The risks of "research" retatrutide sold online

Because retatrutide cannot legally be sold for human use, products sold online under that name have, as the UK regulator puts it, not been tested for safety, quality or effectiveness. The FDA says it has warned companies that illegally sold unapproved drugs containing retatrutide and other GLP-1 drugs falsely labeled "for research purposes" or "not for human consumption", sold directly to consumers for human use with dosing instructions. It urges consumers not to buy them, as they are of unknown quality and may be harmful.^18,5,4

In the UK, the MHRA seized more than 2,000 unlicensed retatrutide and tirzepatide pens in October 2025 at what it called the first illicit weight-loss medicine production facility found in the country, and in May 2026 reported its largest-ever seizure of unlicensed weight-loss medicines, including retatrutide. It warns there is no guarantee such products even contain retatrutide.^6,7,5

Health Canada lists retatrutide among unauthorized injectable peptides it has seized. It warns that such products may contain too much, too little or none of the active ingredient, or contaminants such as heavy metals, particles or microbes, and that "For Research Use Only" labels do not make them legal.⁸

Independent testing is consistent with these warnings. A 2026 analysis of three products sold as retatrutide in Australia found that all contained retatrutide, but the measured amount ranged from about half to almost double the labeled content. Sterility and endotoxin (bacterial toxin) contamination were not tested, and three samples may not reflect the wider market.¹⁶