Retatrutide vs Tirzepatide vs Semaglutide: How the Trial Data Compare

LynxLab · 24 October 2026 · 8 min read

One, two or three receptors: what GIP, GLP-1 and glucagon agonism means, and how the STEP, SURMOUNT and TRIUMPH trial results for the three drugs line up.

Photo: Julia Taubitz, Unsplash

Semaglutide, tirzepatide and retatrutide are three generations of the same idea: a synthetic peptide, injected once a week, that copies the gut hormones released after a meal. Semaglutide acts on one receptor, tirzepatide on two, and retatrutide on three.

The headline trial figures run roughly 15%, 21% and 28% average weight loss. Those numbers come from different trials with different lengths, populations and statistical methods, so they are a starting point rather than a verdict. This post sets out what each receptor does, what each registration trial found, and where the comparison breaks down. The product page for retatrutide covers the molecule itself.

One, two or three receptors: what the names mean

Semaglutide, sold by Novo Nordisk as Wegovy and Ozempic, is a GLP-1 receptor agonist. It is a modified copy of glucagon-like peptide-1 with a fatty acid chain attached so that it lasts a week rather than minutes.

Tirzepatide, sold by Eli Lilly as Mounjaro in the UK and Zepbound in the US, is a dual agonist. It activates the GLP-1 receptor and the receptor for glucose-dependent insulinotropic polypeptide, or GIP (MHRA, 2023).

Retatrutide, Lilly's code LY3437943, adds a third target: the glucagon receptor. The phase 2 paper describes it as a single peptide joined to a fatty diacid, with activity at all three receptors. Compared with the natural hormones it is weaker at the glucagon and GLP-1 receptors (0.3 and 0.4 times) and about 8.9 times more potent at the GIP receptor (Jastreboff et al., NEJM 2023).

What each hormone does

GLP-1 is released from the gut after eating. It slows stomach emptying, increases insulin release when glucose is high, and signals fullness to the brain. Every drug in this class relies on it, and it is also the source of the nausea that most participants report during dose escalation.

GIP is the other main incretin hormone. On its own it has little effect on weight, but in combination with GLP-1 agonism it appears to improve tolerability and add to weight loss. Tirzepatide's advantage over semaglutide in head-to-head testing is generally attributed to this second receptor.

Glucagon is the odd one out. It is the hormone that raises blood glucose between meals, so adding it to a diabetes drug sounds counter-intuitive. The stated rationale is that glucagon receptor agonism raises energy expenditure and drives fat oxidation in the liver, while the GLP-1 and GIP components keep glucose in check. Research groups buying retatrutide for research are often studying exactly this balance.

Semaglutide: the STEP 1 trial, 2021

STEP 1, led by John Wilding of the University of Liverpool, was published in the New England Journal of Medicine on 10 February 2021. It enrolled 1,961 adults with a BMI of 30 or above (or 27 with a weight-related condition), without diabetes, and gave them 2.4mg semaglutide weekly or placebo for 68 weeks.

Mean weight change was 14.9% with semaglutide against 2.4% with placebo, a difference of 12.4 percentage points. Half the semaglutide group (50.5%) lost 15% or more, against 4.9% on placebo (Wilding et al., NEJM 2021). Nausea and diarrhoea were the most common side effects and 4.5% stopped because of gastrointestinal events.

Tirzepatide: SURMOUNT-1 in 2022 and SURMOUNT-5 in 2025

SURMOUNT-1, led by Ania Jastreboff of Yale, was published in the New England Journal of Medicine on 4 June 2022. It randomised 2,539 adults without diabetes to 5mg, 10mg or 15mg tirzepatide or placebo for 72 weeks.

Weight fell by 15.0%, 19.5% and 20.9% on the three doses against 3.1% on placebo. On 15mg, 57% of participants lost 20% or more of their body weight, against 3% on placebo (Jastreboff et al., NEJM 2022). Discontinuation for adverse events was 6.2% on the top dose.

SURMOUNT-5 is the only direct head-to-head trial among the three drugs. Louis Aronne of Weill Cornell led it, and it appeared in the New England Journal of Medicine in May 2025. A total of 751 adults with obesity and no diabetes received the maximum tolerated dose of tirzepatide (10mg or 15mg) or semaglutide (1.7mg or 2.4mg) for 72 weeks.

Tirzepatide produced 20.2% weight loss against 13.7% for semaglutide, and waist circumference fell 18.4cm against 13.0cm (Aronne et al., NEJM 2025). The trial was open-label, so participants knew which drug they were on.

Retatrutide: phase 2 in 2023 and TRIUMPH in 2025 and 2026

The retatrutide phase 2 trial, also led by Jastreboff, enrolled 338 adults and ran for 48 weeks. The 12mg group lost 24.2% of body weight against 2.1% on placebo (NEJM 2023). At that point the comparison with tirzepatide was already striking: a shorter trial, a smaller group, and a larger number.

The phase 3 TRIUMPH-1 trial randomised 2,339 adults without diabetes to 4mg, 9mg, 12mg or placebo for 80 weeks. The published intention-to-treat results were 17.6%, 23.7% and 25.0% weight loss against 3.9% on placebo (Jastreboff et al., NEJM 2026). Lilly's efficacy estimand, which counts only people who stayed on treatment, gave 28.3% on 12mg (Lilly press release, May 2026).

A full account of every retatrutide readout, including the diabetes and cardiovascular trials, is in the retatrutide trial results from phase 2 to TRIUMPH. LynxLab stocks retatrutide in the UK for research use in 10mg (£59.99), 20mg (£99.99) and 30mg (£134.99) vials, tested to 99% purity, with the lab report for each batch on the product page.

Why the three-way comparison has limits

Only SURMOUNT-5 compared two of these drugs directly, and it did not include retatrutide. Everything else is a cross-trial comparison, and the trials differ in ways that move the numbers.

Duration: STEP 1 ran 68 weeks, SURMOUNT-1 72 weeks, TRIUMPH-1 80 weeks. Weight loss on all three drugs continues past a year.
Baseline weight: TRIUMPH-1 participants averaged 112.7kg and a BMI of 40; SURMOUNT-1 averaged 104.8kg and a BMI of 38. Different starting points make percentage figures less comparable.
Statistics: Lilly's retatrutide press releases lead with the efficacy estimand, while the STEP and SURMOUNT headline figures are treatment-regimen (intention-to-treat). Like with like, TRIUMPH-1 is 25.0%, not 28.3%.
Diabetes: in TRIUMPH-2, people with type 2 diabetes lost 18.8% on 12mg (intention-to-treat), well below the figure in people without diabetes.

Even on the conservative reading, retatrutide's 25.0% against tirzepatide's 20.9% and semaglutide's 14.9% is a consistent ordering. What the data cannot yet say is how much of that gap is the glucagon receptor and how much is dose, duration and population. Anyone who plans to buy retatrutide for comparative receptor work should hold those confounders in mind.

Side effects and the glucagon question

All three drugs share the same gastrointestinal profile: nausea, diarrhoea, constipation and vomiting, concentrated during dose escalation. The rates climb with the dose. In TRIUMPH-4, nausea reached 43.2% on 12mg retatrutide against 10.7% on placebo (Lilly press release, December 2025).

Two signals appear with retatrutide that are not prominent in the semaglutide or tirzepatide trials. The first is dysesthesia, an altered skin sensation, reported by 20.9% of the 12mg group in TRIUMPH-4 and 7% in TRIUMPH-2 against under 1% on placebo. The second is a dose-dependent rise in heart rate, which the phase 2 paper said peaked at 24 weeks and then declined.

Both have been discussed as possible consequences of glucagon receptor activity, though neither mechanism is settled. Hypotension was also more common than placebo in TRIUMPH-2 (Bellido et al., The Lancet 2026). Discontinuation for adverse events on the top retatrutide dose ranged from 7.7% to 18.2% across the TRIUMPH trials, compared with 6.2% on 15mg tirzepatide in SURMOUNT-1.

Where each drug stands with UK regulators

Semaglutide and tirzepatide are both licensed in the UK. The MHRA authorised Mounjaro for weight management on 8 November 2023, and NICE recommended it for NHS use in England in guidance TA1026, published on 23 December 2024 (NICE, 2024). Semaglutide (Wegovy) is likewise licensed by the MHRA for weight management.

Retatrutide has no marketing authorisation anywhere. Lilly said in July 2026 that it planned to file with the US FDA in the first quarter of 2027, and the MHRA stated on 15 October 2026 that retatrutide has not been authorised for use in the UK. The UK timeline is covered in retatrutide's UK status and the MHRA position.

For laboratories, that difference matters in a practical way. Semaglutide and tirzepatide are supplied as licensed medicines with a published summary of product characteristics; retatrutide 20mg and other research vials have no such reference, which is why a batch-specific certificate of analysis is the only purity evidence available.

Frequently asked questions

Is retatrutide stronger than tirzepatide?

In their main obesity trials, retatrutide produced 25.0% average weight loss at 80 weeks (TRIUMPH-1, intention-to-treat) and tirzepatide 20.9% at 72 weeks (SURMOUNT-1). No trial has compared the two directly, and the TRIUMPH-1 participants were heavier and treated for longer, so the gap is indicative rather than proven.

What is the difference between a GLP-1 agonist and a triple agonist?

A GLP-1 agonist such as semaglutide activates one receptor, the GLP-1 receptor, which slows digestion and reduces appetite. A triple agonist such as retatrutide also activates the GIP receptor and the glucagon receptor, which is thought to add energy expenditure and liver fat oxidation. Tirzepatide sits between the two as a GLP-1 and GIP dual agonist.

Does retatrutide have more side effects than semaglutide?

The core gastrointestinal effects are the same class effect. Retatrutide trials also reported dysesthesia (tingling or altered skin sensation) in up to 20.9% of participants on the top dose, and a temporary rise in heart rate, neither of which is a prominent feature of semaglutide trials. Discontinuation rates on the top retatrutide dose were higher than in STEP 1.

Which of the three is approved in the UK?

Semaglutide (Wegovy) and tirzepatide (Mounjaro) are licensed by the MHRA for weight management, and tirzepatide is recommended by NICE for defined groups of patients in TA1026. Retatrutide is not licensed in the UK or anywhere else as of October 2026.

Sources

Research use only

Retatrutide from LynxLab

10mg, 20mg, 30mg vials from £59.99. ≥99% purity, lab report on the page. Same-day dispatch, UK stock.

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