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Research guide

Retatrutide vs Tirzepatide vs Semaglutide: what the research shows

Evidence checked 16 October 2026

One, two or three receptor targets: that is the starting point for understanding these three peptides. Semaglutide acts at GLP-1 receptors, tirzepatide at GIP and GLP-1 receptors, and retatrutide at GIP, GLP-1 and glucagon receptors. (TGA receptor-class guide) (Retatrutide phase 2, NEJM (2023))

The interesting question is how those different designs are being tested. This guide separates the molecular idea, the published clinical studies and the regulatory status, rather than turning three research programmes into a “strongest to weakest” ranking.

The comparison in a minute

At a glance

Triple receptor agonist

Retatrutide

Receptor targets
GIP, GLP-1 and glucagon
Representative evidence
Phase 2 research followed by published phase 3 TRIUMPH-1 and TRIUMPH-2 trials in 2026.
Status to distinguish
Investigational. The TGA identifies retatrutide as an unapproved therapeutic good.

(Retatrutide phase 2, NEJM (2023)) (TRIUMPH-1, NEJM (2026)) (TRIUMPH-2, The Lancet (2026)) (TGA prescription-medicine and retatrutide guidance)

Dual receptor agonist

Tirzepatide

Receptor targets
GIP and GLP-1
Representative evidence
The SURMOUNT research programme includes placebo-controlled studies and a direct comparison with semaglutide.
Status to distinguish
Mounjaro is a prescription medicine in Australia, with approved diabetes and chronic weight-management indications.

(TGA receptor-class guide) (SURMOUNT-1, NEJM (2022)) (SURMOUNT-5, NEJM (2025))

GLP-1 receptor agonist

Semaglutide

Receptor targets
GLP-1
Representative evidence
The STEP research programme includes the large, placebo-controlled STEP-1 study.
Status to distinguish
Ozempic and Wegovy contain semaglutide, but have different approved indications.

(TGA receptor-class guide) (STEP-1, NEJM (2021))

What “single”, “dual” and “triple” actually mean

GLP-1 is short for glucagon-like peptide-1; GIP stands for glucose-dependent insulinotropic polypeptide. (TGA receptor-class guide)A receptor agonist is a substance that activates a receptor. Semaglutide is a GLP-1 receptor agonist, while tirzepatide activates both the GIP and GLP-1 receptors. (TGA receptor-class guide)Retatrutide is a single molecule designed to activate those two receptor types plus the glucagon receptor. (Lilly development update, September 2026)

Receptor count is a useful map of the designs, not a clinical scorecard. To understand what a design does in people, look at the population, comparator, endpoints and safety findings of its trials. The published studies below show why those details matter.

The studies behind the names

Read these as a timeline of different experiments, not as interchangeable rows in a results league table. Each snapshot identifies the study design and funding so you can follow the original paper.

  1. 2021

    STEP-1: semaglutide

    1,961 adults without diabetes; 68 weeks; a double-blind, randomised comparison with placebo. Both groups also received lifestyle intervention. Funded by Novo Nordisk. (STEP-1, NEJM (2021))

  2. 2022

    SURMOUNT-1: tirzepatide

    2,539 adults without diabetes; 72 weeks; a phase 3, double-blind, randomised comparison with placebo. Funded by Eli Lilly. (SURMOUNT-1, NEJM (2022))

  3. 2023

    Retatrutide phase 2

    338 adults; 48 weeks; a double-blind, randomised comparison with placebo. The primary endpoint was body-weight change at week 24. Funded by Eli Lilly. (Retatrutide phase 2, NEJM (2023))

  4. 2025

    SURMOUNT-5: tirzepatide vs semaglutide

    751 adults with obesity and without type 2 diabetes; 72 weeks; a randomised, open-label head-to-head comparison. Retatrutide was not part of this trial. Funded by Eli Lilly. (SURMOUNT-5, NEJM (2025))

  5. 2026

    TRIUMPH-1: retatrutide

    2,339 adults with obesity without diabetes; 80 weeks; a phase 3, double-blind, randomised comparison with placebo. It also assessed knee-osteoarthritis pain and sleep-apnoea outcomes in relevant subgroups. Funded by Eli Lilly. (TRIUMPH-1, NEJM (2026))

  6. 2026

    TRIUMPH-2: retatrutide

    1,152 adults with obesity or overweight and type 2 diabetes; a phase 3, double-blind, randomised comparison with placebo. The primary endpoint was assessed at week 80. Funded by Eli Lilly. (TRIUMPH-2, The Lancet (2026))

Why a head-to-head trial is different

SURMOUNT-5 compared tirzepatide and semaglutide in a randomised, open-label study of 751 adults without type 2 diabetes over 72 weeks. (SURMOUNT-5, NEJM (2025))Its conclusion favoured tirzepatide for body-weight and waist-circumference reduction in that study population, under its protocol. (SURMOUNT-5, NEJM (2025))

That is not a three-way comparison. Retatrutide was not included in SURMOUNT-5, and TRIUMPH-2 studied people with type 2 diabetes, whereas SURMOUNT-5 excluded that population. (SURMOUNT-5, NEJM (2025)) (TRIUMPH-2, The Lancet (2026))Putting headlines from those separate studies side by side would leave out important differences in who was studied and how.

Where the research stands

Phase 3 publication and marketing approval are different milestones. Retatrutide remains investigational in Lilly's September 2026 update, and the TGA identifies it as an unapproved therapeutic good. (Lilly development update, September 2026) (TGA prescription-medicine and retatrutide guidance)

Australian brand names also need care. Ozempic and Wegovy both contain semaglutide, but the TGA distinguishes their diabetes and chronic weight-management indications; Mounjaro contains tirzepatide and has approvals for both. (TGA receptor-class guide)The ingredient name alone does not describe the full approved product or its conditions of use.

Safety findings belong alongside efficacy findings. Gastrointestinal adverse events were common across the cited trials, and the retatrutide phase 2 paper also reported increases in heart rate. (STEP-1, NEJM (2021)) (SURMOUNT-1, NEJM (2022)) (Retatrutide phase 2, NEJM (2023))The TGA has also added precautions about delayed gastric emptying and aspiration during general anaesthesia or deep sedation to approved GLP-1 and dual GIP/GLP-1 medicines. (TGA receptor-class guide)

A useful way to read the next headline

Start with five questions: Which molecule? Which population? Compared with what? Measured when? Reported where? They keep a compelling new research result attached to the experiment that produced it.

This guide explains published research; it is not a product recommendation, prescribing guide or statement of regulatory clearance. It provides no dosing, switching, stacking or personal-use instructions. Clinical trial findings do not establish the identity, quality or suitability of a separately supplied research-labelled product.