Retatrutide vs Tirzepatide: Comparative Research Review – Literature Review

Research Use Only. This article is a literature summary for laboratory research use only. Nothing on this page is medical advice or an instruction for human or animal use.

Abstract

This review summarises peer-reviewed literature on Retatrutide vs Tirzepatide, with a focus on pharmacology and the published clinical literature. It describes receptor pharmacology, preclinical findings and outcomes reported in published randomised controlled trials, and notes limitations of the current evidence. It does not provide dosing, administration or preparation information.

Background

Retatrutide (LY3437943) is an investigational single-peptide agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon receptors, developed by Eli Lilly and Company. It is not authorised as a medicine by the MHRA, EMA or FDA and remains under clinical investigation.^[1,2]

Tirzepatide (LY3298176) is a 39-amino-acid synthetic peptide with agonist activity at the GIP and GLP-1 receptors. It is an authorised prescription-only medicine in the UK for specific indications under medical supervision; material supplied for laboratory research is not a medicinal product and is not for human or veterinary use.^[3]

Mechanism of action

In preclinical characterisation, retatrutide showed agonism at human GIP and GLP-1 receptors with comparatively greater relative potency at GIPR, and additional glucagon-receptor (GCGR) agonism. Glucagon-receptor engagement is hypothesised to contribute increased energy expenditure and hepatic lipid oxidation, complementing incretin-mediated effects on insulin secretion and central appetite signalling observed in rodent models.^[1,4]

Tirzepatide is an imbalanced dual agonist: in vitro it shows affinity for the GIP receptor comparable to native GIP and weaker GLP-1 receptor affinity than native GLP-1. Preclinical work described glucose-dependent insulin secretion, effects on food intake and improvements in insulin sensitivity in rodent models.^[3,4]

Summary of published research

Retatrutide – Published clinical trial outcomes: body weight

In a 48-week phase 2 randomised, placebo-controlled trial in adults with obesity, retatrutide produced dose-dependent reductions in body weight from baseline, with a mean change of up to −24.2% in the highest-dose group compared with −2.1% with placebo.^[5,6]

A phase 3 trial (TRIUMPH-2) in adults with obesity and type 2 diabetes has since been reported in The Lancet; readers should consult the primary publication for endpoints and results.^[5,6]

Tirzepatide – Published clinical trial outcomes: body weight

In SURMOUNT-1 (72 weeks, adults with obesity or overweight without diabetes), mean percentage change in body weight was −15.0%, −19.5% and −20.9% across the three tirzepatide maintenance-dose arms, versus −3.1% with placebo.^[7,8]

In SURMOUNT-5, an open-label head-to-head trial in adults with obesity without diabetes, tirzepatide produced a greater mean reduction in body weight at week 72 than semaglutide (−20.2% vs −13.7%).^[7,8]

Retatrutide – Published clinical trial outcomes: glycaemic endpoints

A 36-week phase 2 trial in people with type 2 diabetes reported dose-dependent reductions in HbA1c and body weight compared with placebo and with dulaglutide. An earlier phase 1b study characterised pharmacokinetics, pharmacodynamics and tolerability.^[9,2]

Tirzepatide – Published clinical trial outcomes: glycaemic endpoints

In SURPASS-2 (40 weeks, type 2 diabetes on metformin), tirzepatide was noninferior and superior to semaglutide 1 mg for change in HbA1c from baseline (−2.01 to −2.30 percentage points vs −1.86).^[10]

Retatrutide – Published research: hepatic fat

A substudy of the phase 2 obesity trial measured liver fat by MRI-PDFF in participants with metabolic dysfunction-associated steatotic liver disease (MASLD) and reported substantial, dose-dependent relative reductions in liver fat at 24 and 48 weeks, with many participants reaching normal liver-fat levels.^[11]

Tirzepatide – Published research: MASH

In the phase 2 SYNERGY-NASH trial in biopsy-confirmed MASH with stage F2–F3 fibrosis, a higher proportion of participants receiving tirzepatide met the primary endpoint of MASH resolution without worsening of fibrosis at 52 weeks (44–62% vs 10% placebo).^[12]

Tirzepatide – Published research: heart failure

In SUMMIT, adults with heart failure with preserved ejection fraction and obesity receiving tirzepatide had a lower risk of the composite of cardiovascular death or worsening heart-failure events than placebo (hazard ratio 0.62) over a median of 104 weeks, alongside improvements in health-status scores.^[13]

Retatrutide – Reported adverse events in trials

Across phase 2 studies the most commonly reported adverse events were gastrointestinal (nausea, vomiting, diarrhoea, constipation), mostly mild to moderate and more frequent during dose escalation. Dose-dependent increases in heart rate were reported. Long-term safety data from phase 3 programmes are still emerging.^[5,9]

Tirzepatide – Reported adverse events in trials

In the SURMOUNT and SURPASS programmes, the most frequently reported adverse events were gastrointestinal (nausea, diarrhoea, constipation, vomiting), typically mild to moderate and occurring mainly during dose escalation. Discontinuation due to adverse events was more frequent than with placebo.^[7,10]

Limitations of the evidence

Most clinical data come from industry-sponsored trials of defined pharmaceutical formulations under medical supervision; results cannot be extrapolated to research-grade material, which is not manufactured to medicinal GMP standards. Trial populations, durations and comparators differ, so cross-trial comparisons should be interpreted cautiously. Longer-term safety data for newer agents remain limited.

Conclusion

The published literature characterises these peptides as potent incretin-pathway receptor agonists with substantial bodies of preclinical and clinical-trial data. For laboratory work, researchers should rely on primary publications and verified analytical documentation for any material used.

References

1. Coskun T et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab. 2022; 34(9):1234-1247.e9. doi:10.1016/j.cmet.2022.07.013 PMID: 35985340.
2. Urva S et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. Lancet. 2022; 400(10366):1869-1881. doi:10.1016/S0140-6736(22)02033-5 PMID: 36354040.
3. Coskun T et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018; 18:3-14. doi:10.1016/j.molmet.2018.09.009 PMID: 30473097.
4. Drucker DJ et al. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018; 27(4):740-756. doi:10.1016/j.cmet.2018.03.001 PMID: 29617641.
5. Jastreboff AM et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial. N Engl J Med. 2023; 389(6):514-526. doi:10.1056/NEJMoa2301972 PMID: 37366315.
6. Bellido V et al. Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial. Lancet. 2026; 408(10563):1455-1472. doi:10.1016/S0140-6736(26)01861-1 PMID: 42810372.
7. Jastreboff AM et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022; 387(3):205-216. doi:10.1056/NEJMoa2206038 PMID: 35658024.
8. Aronne LJ et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med. 2025; 393(1):26-36. doi:10.1056/NEJMoa2416394 PMID: 40353578.
9. Rosenstock J et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023; 402(10401):529-544. doi:10.1016/S0140-6736(23)01053-X PMID: 37385280.
10. Frías JP et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021; 385(6):503-515. doi:10.1056/NEJMoa2107519 PMID: 34170647.
11. Sanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024; 30(7):2037-2048. doi:10.1038/s41591-024-03018-2 PMID: 38858523.
12. Loomba R et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. N Engl J Med. 2024; 391(4):299-310. doi:10.1056/NEJMoa2401943 PMID: 38856224.
13. Packer M et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2025; 392(5):427-437. doi:10.1056/NEJMoa2410027 PMID: 39555826.

Disclaimer: This article is for laboratory research use only. Not for human or veterinary use, not for consumption, and not intended to diagnose, treat, cure or prevent any disease. This page is an educational literature summary and is not medical advice.