Retatrutide vs tirzepatide vs semaglutide: trial results

What it is

Semaglutide, tirzepatide and retatrutide are weekly injections from the same family. They imitate gut hormones that the body releases after a meal. Each one switches on a different number of hormone receptors, the docking points on cells that these hormones use. A molecule that switches a receptor on is called an agonist.

• Semaglutide (Novo Nordisk) is a GLP-1 receptor agonist: one receptor.
• Tirzepatide (Eli Lilly) is a GIP and GLP-1 receptor agonist: two receptors.
• Retatrutide (Eli Lilly) is a GIP, GLP-1 and glucagon receptor agonist: three receptors (Coskun 2022).

GLP-1 and GIP are linked to appetite and insulin release. Glucagon is linked to energy use and to how the liver handles fat. Adding the glucagon receptor is the idea behind retatrutide, and the reason it is sometimes nicknamed "GLP-3" (what that nickname means).

What the studies looked at

The fairest way to compare is to look at the main trial of each compound in adults with obesity and without diabetes. All of them were randomised, double-blind and placebo-controlled: participants were assigned by chance to the drug or to a placebo, an injection with no active ingredient, and nobody knew who received which.

• STEP 1, semaglutide 2.4 mg: 1,961 adults, 68 weeks (Wilding 2021).
• SURMOUNT-1, tirzepatide 5, 10 or 15 mg: 2,539 adults, 72 weeks (Jastreboff 2022).
• Phase 2, retatrutide 1 to 12 mg: 338 adults, 48 weeks (Jastreboff 2023).
• TRIUMPH-1, retatrutide 4, 9 or 12 mg: 2,339 adults, 80 weeks (Jastreboff 2026).
• SURMOUNT-5, tirzepatide against semaglutide: 751 adults, 72 weeks, the only head-to-head trial of the three (Aronne 2025).

What the studies say

Weight change at the highest dose tested, against placebo:

Compound	Trial	Length	Weight change	Placebo
Semaglutide 2.4 mg	STEP 1	68 weeks	−14.9 %	−2.4 %
Tirzepatide 15 mg	SURMOUNT-1	72 weeks	−20.9 %	−3.1 %
Retatrutide 12 mg	Phase 2	48 weeks	−24.2 %	−2.1 %
Retatrutide 12 mg	TRIUMPH-1	80 weeks	−25.0 %	−3.9 %

Sources: Wilding 2021, Jastreboff 2022, Jastreboff 2023, Jastreboff 2026.

The one direct comparison. In SURMOUNT-5 the mean weight change at 72 weeks was −20.2 % with tirzepatide and −13.7 % with semaglutide, and waist circumference fell by 18.4 cm against 13.0 cm (Aronne 2025).

Speed. In the retatrutide phase 2 trial the 12 mg group was already at −17.5 % at 24 weeks, against −1.6 % on placebo, and the curve had not flattened at 48 weeks (Jastreboff 2023).

What the researchers flagged

• Side effects are the same family for all three. Digestive events, mainly nausea and diarrhoea, were the most common, mostly mild to moderate and concentrated while the dose was being increased (Wilding 2021, Jastreboff 2022, Aronne 2025). Retatrutide trials also reported a rise in heart rate that peaked at 24 weeks and skin sensations called dysesthesia (details).
• Stopping for adverse events. 4.5 % stopped semaglutide for digestive events against 0.8 % on placebo in STEP 1. Between 4.3 % and 7.1 % stopped tirzepatide against 2.6 % in SURMOUNT-1. Between 6 % and 16 % stopped retatrutide in its phase 2 trial (Wilding 2021, Jastreboff 2022, Jastreboff 2023).
• The figures are not directly comparable. The trials enrolled different people, at different times, for different lengths, and some report results for everyone randomised while company announcements often report only those who stayed on treatment. Only a head-to-head trial answers "which is stronger", and none has compared retatrutide with tirzepatide or semaglutide yet.
• Status. Semaglutide and tirzepatide are approved medicines. Retatrutide is still investigational; Lilly planned a first US application for early 2027 (Lilly, July 2026).