Three generations of the same idea. Semaglutide acts on one gut-hormone receptor, tirzepatide on two, and retatrutide on three. Each step has produced larger average weight loss in trials. The most important difference right now is not the percentage, though: semaglutide and tirzepatide are FDA-approved and available today; retatrutide is still investigational.

Key facts

• Semaglutide (Wegovy, Ozempic): GLP-1 only. About 15% average weight loss in its main obesity trial (STEP-1). Approved, injectable and oral.
• Tirzepatide (Zepbound, Mounjaro): GLP-1 + GIP. About 20.9% at the top dose in SURMOUNT-1. Approved, injectable.
• Retatrutide (Lilly, investigational): GLP-1 + GIP + glucagon. 25.0% at the top dose in TRIUMPH-1 (NEJM, all participants). FDA submission planned for Q1 2027.
• In the one head-to-head trial so far (SURMOUNT-5), tirzepatide beat semaglutide: 20.2% vs 13.7% at 72 weeks.
• Retatrutide has not been tested head-to-head against either one yet.

Side by side

An honest warning about comparing these numbers

All three numbers above count everyone who started the trial, which is the fairest like-for-like basis. These figures still come from different trials, run in different years, with different lengths (68, 72 and 80 weeks) and different populations. Longer trials tend to show bigger numbers. So the table shows a clear direction, but it is not a fair race. The only clean comparison is a head-to-head trial, and so far that exists only for tirzepatide vs semaglutide.

Side effects

All three share the same main pattern: nausea, diarrhea, constipation and vomiting, usually worst while the dose is being increased and easing over time. Retatrutide adds one signal the others have not shown in the same way: dysesthesia, an unusual skin sensation, more common at higher doses (roughly 5% to 12.5% vs under 1% on placebo in TRIUMPH-1). Its long-term safety record is also, naturally, much shorter than semaglutide’s.

Why the third receptor matters

The step from semaglutide to tirzepatide added GIP, and average weight loss rose by roughly a third in the main trials. Retatrutide adds glucagon, a hormone that increases energy use and helps the liver burn fat. That is the most likely reason its numbers climb again. It is also why researchers are watching liver fat and heart rate closely in the retatrutide program: a new mechanism deserves its own long-term data, and the TRIUMPH studies are designed to collect it.

For people living with obesity, the encouraging part is the direction of travel. Each generation has given clinicians a stronger tool, and competition between them is already pushing prices and access in a better direction.

Which one makes sense?

If you are looking for treatment now, the real choice is between semaglutide and tirzepatide, and a licensed provider can help you weigh results, tolerance, format (oral vs injection) and cost. You can check the current FDA status of each on our legal status tracker. Our deeper semaglutide vs tirzepatide comparison and the guide to GLP-1 telehealth costs in 2026 cover that decision.

Retatrutide is good news for the field, and it may become an option in late 2027 or 2028. See When will retatrutide be available? and the full TRIUMPH-2 results.

Sources

• Jastreboff et al. Retatrutide, a triple hormone receptor agonist, for treatment of obesity (TRIUMPH-1). N Engl J Med, Sept 29, 2026
• TCTMD: TRIUMPH-1 retatrutide results
• Pharmacy Times: TRIUMPH-2 results
• Wilding JPH et al. Once-weekly semaglutide in adults with overweight or obesity (STEP-1). N Engl J Med, 2021.
• Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med, 2022.
• Aronne LJ et al. Tirzepatide as compared with semaglutide for the treatment of obesity (SURMOUNT-5). N Engl J Med, 2025.

Educational content only, not medical advice. Retatrutide is an investigational medicine and is not FDA-approved.

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