Retatrutide, Tirzepatide and Semaglutide: What the Trials Measured

Weight-loss figures for three incretin-based drugs look easy to compare. They are not. Here is what each key trial measured and why the numbers do not line up.

By Peptidelogy Editorial Team, published September 25, 2026. 7 min read.

Medically reviewed by

Valeria Marulanda, FNP-BC

Board-Certified Family Nurse Practitioner

Valeria Marulanda is a board-certified Family Nurse Practitioner (FNP-BC) with a Bachelor of Science in Nursing from Florida Atlantic University and a Master of Science in Nursing from St. Thomas University. Since 2018, she has specialized in medical aesthetics, focusing on face and body treatments. Valeria loves longevity, science-driven skin treatments, and regenerating the human body from the inside out.

NPI 1841152584 Editorial policy

Key points

Semaglutide (STEP 1) reduced weight by 14.9% against 2.4% on placebo at 68 weeks. Tirzepatide (SURMOUNT-1) reduced it by 15.0% to 20.9% against 3.1% at 72 weeks. Retatrutide (phase 2) reduced it by up to 24.2% against 2.1% at 48 weeks.
Those are three separate trials with different lengths, populations, phases and dose ranges. Lining the numbers up is not a head-to-head comparison.
The only direct comparison of two of these drugs here is SURPASS-2, in type 2 diabetes over 40 weeks, where tirzepatide outperformed semaglutide on HbA1c and weight.
The retatrutide figures come from a phase 2 trial of 338 adults. Phase 2 looks for signals and doses. It does not settle long-term benefit or risk.

Three drugs, three mechanisms

Semaglutide activates the GLP-1 receptor. Tirzepatide activates both the GIP and GLP-1 receptors. Retatrutide is an investigational agonist of three receptors: GIP, GLP-1 and glucagon.

More receptors is not automatically better or worse. It changes what the drug does, and it changes what the trials have to check for.

What each trial reported

Each result below is the mean change in body weight versus placebo in the trial named. The numbers are reported as the trial authors published them.

STEP 1, semaglutide plus lifestyle intervention, 68 weeks: -14.9% against -2.4% on placebo, an estimated difference of 12.4 percentage points (95% CI 11.5 to 13.4). Weight loss of 5% or more occurred in 86.4% against 31.5%, 10% or more in 69.1% against 12.0%, and 15% or more in 50.5% against 4.9%. Stopping treatment because of gastrointestinal events happened in 4.5% against 0.8%.
SURMOUNT-1, tirzepatide, 72 weeks: across the three dose groups, -15.0%, -19.5% and -20.9%, against -3.1% on placebo. A weight reduction of 20% or more occurred in 50% and 57% of the two higher dose groups against 3% on placebo. Adverse events led to stopping in 4.3%, 7.1% and 6.2% of the dose groups against 2.6% on placebo.
Retatrutide phase 2, 48 weeks, 338 adults: across dose groups, -8.7%, -17.1%, -22.8% and -24.2% at the highest dose, against -2.1% on placebo. In the highest dose group, 100%, 93% and 83% lost at least 5%, 10% and 15% of body weight, against 27%, 9% and 2% on placebo.

Why you cannot rank them from these numbers

The trials ran for 68, 72 and 48 weeks. Weight loss changes over time, so a figure at week 48 is not the same measurement as one at week 72.

The populations differ. In SURMOUNT-1, the mean baseline body weight was 104.8 kg and the mean BMI was 38.0. STEP 1 and the retatrutide trial enrolled their own groups under their own criteria. Baseline weight and health status change what a percentage loss means.

The phases differ too. STEP 1 and SURMOUNT-1 were large trials designed to test an established dose. The retatrutide trial was phase 2, built to explore dose and safety signals in a smaller group.

Even the placebo groups moved differently, from -2.1% to -3.1%. That is a reminder that each trial has its own conditions, not that any one drug is better.

The one direct comparison: SURPASS-2

SURPASS-2 compared tirzepatide with semaglutide head to head in people with type 2 diabetes over 40 weeks. HbA1c fell by 2.01, 2.24 and 2.30 percentage points across the three tirzepatide dose groups and by 1.86 with semaglutide. Tirzepatide at all doses was noninferior and superior to semaglutide.

Weight reductions were also larger with tirzepatide, by 1.9 kg, 3.6 kg and 5.5 kg across the dose groups (p<0.001 for each). Nausea occurred in 17% to 22% on tirzepatide and 18% on semaglutide. Serious adverse events were reported in 5% to 7% of tirzepatide patients and 3% of semaglutide patients.

This is the type of evidence that supports a comparison. It is still a trial in type 2 diabetes, so it does not directly answer the question for weight management in people without diabetes.

Safety patterns worth knowing

Gastrointestinal effects were the most common adverse events in every trial, mostly mild to moderate. In SURMOUNT-1 they occurred mainly during dose escalation, and in the retatrutide trial they were dose-related.

The retatrutide trial also reported dose-dependent increases in heart rate that peaked at 24 weeks and declined afterwards. That is a signal a phase 2 trial can flag but not resolve.

None of this is medical advice. Decisions about any of these drugs belong with a clinician who knows the patient.

What phase 2 means for retatrutide

The retatrutide paper was published in 2023 as a phase 2 trial, and the drug was investigational. Later trials and regulatory decisions may have changed that picture, so check the current status with your regulator before relying on any figure here.

References

Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine. 2021;384(11):989-1002. PubMed 33567185
Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine. 2022;387(3):205-216. PubMed 35658024
Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity - a phase 2 trial. New England Journal of Medicine. 2023;389(6):514-526. PubMed 37366315
Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. New England Journal of Medicine. 2021;385(6):503-515. PubMed 34170647

Figures in this article come from the abstracts and records of the papers above.

This article is for informational and educational purposes only and is not medical advice. It reports what published studies measured and does not recommend acquiring, administering or using any substance. Speak to a qualified clinician about health decisions.