Semaglutide vs. tirzepatide vs. retatrutide: what the data says

Semaglutide acts on one receptor, GLP-1. Tirzepatide acts on two, GLP-1 and GIP. Retatrutide acts on three, adding the glucagon receptor. In the pivotal obesity trials, each extra receptor has come with more weight loss. That sentence is true and also easy to overstate, because only one of the comparisons below was run head to head, and the trials differ in length, population and how they counted people who stopped the drug.

The pivotal trials, side by side

Each row is a separate trial in adults with obesity or overweight and without diabetes. Numbers are mean change in body weight at the end of the trial, at the top dose.

Two cautions on reading that table. First, across-trial comparisons are weak evidence. STEP 1 ran 68 weeks, TRIUMPH-1 ran 80, and the placebo groups lost different amounts. Second, the estimand matters. The STEP 1, SURMOUNT-1 and TRIUMPH-1 figures above count everyone who was randomised, whether or not they stayed on the drug. That is the conservative way to report a trial and the way the table keeps the drugs comparable.

Why retatrutide has two numbers

When Lilly announced TRIUMPH-1 in May 2026, the headline was 28.3 percent weight loss on 12 mg. When the full paper appeared in the New England Journal of Medicine on 29 September 2026, the primary figure was 25.0 percent, against 3.9 percent on placebo. Both are correct. The 28.3 percent is the efficacy estimand, which estimates what would have happened had everyone stayed on treatment. The 25.0 percent is the treatment-regimen estimand, which counts everyone randomised, including people who stopped. Neither is a misprint and neither is spin, but only the second is comparable with the STEP 1 and SURMOUNT-1 numbers in the table. The retatrutide trials page has every phase 2 and phase 3 result, labelled by estimand.

The one real head-to-head

SURMOUNT-5 is the only trial that randomised people to tirzepatide or semaglutide and followed both groups the same way. In 751 adults with obesity and no diabetes, tirzepatide at the highest tolerated dose (10 or 15 mg) produced 20.2 percent weight loss at 72 weeks against 13.7 percent on semaglutide (1.7 or 2.4 mg). Lilly sponsored it and it was open label, so both groups knew which drug they were on, but the primary endpoint was set in advance and weight is hard to fool. It is the strongest single piece of evidence that dual agonism beats single agonism for weight. The semaglutide vs tirzepatide study page goes through it in detail.

There is no head-to-head trial of retatrutide against tirzepatide. Until there is, the gap between them is an estimate across trials, not a measured difference.

How they work, briefly

• Semaglutide mimics GLP-1, a gut peptide released after meals. It slows the stomach, reduces appetite through receptors in the brain, and increases insulin release when glucose is high. Approved as Ozempic for type 2 diabetes and Wegovy for weight management, including an oral Wegovy tablet. See semaglutide.
• Tirzepatide adds GIP, a second incretin. Why GIP agonism adds weight loss is still debated, since GIP on its own was long thought to favour fat storage. The trial results are not in doubt. Approved as Mounjaro and Zepbound. See tirzepatide.
• Retatrutide adds the glucagon receptor, which raises energy expenditure and acts on the liver. In a phase 2a substudy it cut liver fat by a relative 82.4 percent at 24 weeks on 12 mg. It is not approved anywhere. See retatrutide.

Side effects

All three share the same main side effect profile: nausea, diarrhoea, vomiting and constipation, concentrated in the weeks after each dose increase. The trial rates for the top doses:

The retatrutide column mixes two trials because that is what has been published; it should be read as indicative, not as a like-for-like comparison. Retatrutide also showed effects the older drugs do not: in TRIUMPH-2, low blood pressure in 6 percent on 12 mg against under 1 percent on placebo, and dysaesthesia, an abnormal skin sensation, in 7 percent against 1 percent. Heart rate rises on all three. The side effects page covers the label warnings shared by the class.

What is approved, and what is not

Semaglutide and tirzepatide are FDA-approved, with labels, dose ladders, warnings and years of post-marketing data. Retatrutide is investigational. As of October 2026 it is not approved by the FDA or any other regulator; Lilly has said it plans to submit to the FDA in the first quarter of 2027. Product sold as retatrutide outside a clinical trial is not the trial drug, and nothing in the trial data describes what is in such a vial. The compounded glossary entry and the compounded GLP-1 page explain where the approved and compounded supply sits today.

What the data does not answer yet

No cardiovascular outcomes result exists for retatrutide; semaglutide has one, the SELECT trial. No trial has gone past about two years for retatrutide. Nobody knows yet whether the extra weight loss comes with proportionally more lean mass loss, though the muscle loss page covers what is known for the approved drugs. And every one of these drugs loses much of its effect when stopped; see stopping a GLP-1.

Keeping your own record

Whichever drug your prescriber chooses, the useful record is the same: dose and date, weight, side effects by day after the shot, and labs, on one timeline. In Peptide AI that lives in the dose log and bloodwork tracking, and the library carries the trial summaries for each compound. The full trial list is on GLP-1 clinical trials.