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Retatrutide vs tirzepatide

B Retatrutide Agonist at GIP, GLP-1 and glucagon receptors (triple agonist) Investigational — not FDA-approved A Tirzepatide Dual agonist at GIP and GLP-1 receptors FDA-approved — Mounjaro (2022), Zepbound (2023)

Residue Editorial Team · updated

In brief

Tirzepatide activates GIP and GLP-1 receptors and is FDA-approved1FDAMOUNJARO, MOUNJARO KWIKPEN prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-08-27.,2FDAZEPBOUND, ZEPBOUND KWIKPEN prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-08-28.; retatrutide adds the glucagon receptor and is still investigational. In separate placebo-controlled trials, retatrutide produced −23.7% to −25.0% at 80 weeks3PubMedRetatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity. Jastreboff AM et al. N Engl J Med. 2026. and tirzepatide −15.0% to −20.9% at 72 weeks4PubMedTirzepatide Once Weekly for the Treatment of Obesity. Jastreboff AM et al. N Engl J Med. 2022.. No trial cited here compares them directly.

How do Retatrutide and Tirzepatide compare at a glance?

Table 1. Retatrutide and Tirzepatide on the dimensions that matter most; every entry is cited.
DimensionRetatrutideTirzepatide
ReceptorsGIP, GLP-1 and glucagon3GIP and GLP-11
FDA statusInvestigational; no Drugs@FDA applicationApproved: Mounjaro, Zepbound5FDADrugs@FDA: MOUNJARO, MOUNJARO KWIKPEN, MOUNJARO (AUTOINJECTOR) (NDA215866). ELI LILLY AND CO; original approval 2022-05-13; Prescription.,6FDADrugs@FDA: ZEPBOUND, ZEPBOUND KWIKPEN, ZEPBOUND (AUTOINJECTOR) (NDA217806). ELI LILLY AND CO; original approval 2023-11-08; Prescription.
Pivotal obesity trialTRIUMPH-1: −17.6% to −25.0% vs −3.9%, 80 wk3SURMOUNT-1: −15.0% to −20.9% vs −3.1%, 72 wk4
Obesity with type 2 diabetesTRIUMPH-2: −11.9% to −18.8% vs −5.1%, 80 wk7PubMedRetatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial. Bellido V et al. Lancet. 2026.SURPASS-2: weight −1.9 to −5.5 kg more than semaglutide 1 mg8PubMedTirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. Frías JP et al. N Engl J Med. 2021.
Liver fat−81% to −82% at 24 wk (MRI sub-study)9PubMedTriple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Sanyal AJ et al. Nat Med. 2024.Not a labeled use
Common adverse eventsGastrointestinal, dose-related; heart rate rise10PubMedTriple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. Jastreboff AM et al. N Engl J Med. 2023.Nausea 12–24%, diarrhea 12–22% across SURPASS11PubMedGastrointestinal adverse events and weight reduction in people with type 2 diabetes treated with tirzepatide in the SURPASS clinical trials. Patel H et al. Diabetes Obes Metab. 2024.
Evidence gradeBA

Written by Residue Editorial Team

Reviewed by Residue Editorial Team · source-by-source check,

First published

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Registry data · How we grade · Markdown + sources

Figure 1. Size of the research record, from PubMed and ClinicalTrials.gov at the data edition. Bars are scaled to the larger value in each row; volume is not quality.
PubMed records 207 2,640
Trial publications 11 147
Registered studies 34 300
Phase 3 studies 14 57

Retatrutide Tirzepatide

How do they work differently?

Tirzepatide is a single peptide with agonist activity at the GIP and GLP-1 receptors, as stated in both its labels1,2. Retatrutide (LY3437943) extends the idea to a third receptor, glucagon10. In retatrutide's MRI sub-study, liver fat fell by 81–82% at the 8 and 12 mg doses, and 79–86% of participants reached normal liver fat below 5%9.

How much weight was lost in their own trials?

Retatrutide. In the 48-week phase 2 trial of 338 adults with obesity, weight changed by −24.2% at 12 mg and −22.8% at 8 mg versus −2.1% on placebo10. In phase 3 TRIUMPH-1 (2,339 adults with obesity, no diabetes), 80-week weight change was −17.6%, −23.7% and −25.0% at 4, 9 and 12 mg versus −3.9%3. TRIUMPH-2, in 1,152 adults with obesity and type 2 diabetes, found −11.9%, −16.8% and −18.8% versus −5.1%7.

Tirzepatide. SURMOUNT-1 found −15.0%, −19.5% and −20.9% at 5, 10 and 15 mg versus −3.1% at 72 weeks, with 57% of the 15 mg group losing 20% or more4. In the only head-to-head obesity trial against semaglutide, tirzepatide reached −20.2% versus −13.7%12PubMedTirzepatide as Compared with Semaglutide for the Treatment of Obesity. Aronne LJ et al. N Engl J Med. 2025..

Cross-trial comparison is unreliable: the trials ran for different lengths, used different escalation schedules and enrolled different people. Our methodology does not grade one drug against another on cross-trial numbers.

How do their safety records compare?

Gastrointestinal adverse events dominate both programs. Across SURPASS-1 to -5, tirzepatide produced nausea in 12–24%, diarrhea in 12–22% and vomiting in 2–13%, mostly transient and mild to moderate11. Retatrutide's adverse events were mostly gastrointestinal and dose-related, and heart rate rose in a dose-dependent way, peaking at 24 weeks10; in TRIUMPH-2, hypotension and dysesthesia were also more frequent than with placebo7.

Are they FDA-approved?

Tirzepatide is approved for type 2 diabetes, chronic weight management and obstructive sleep apnea with obesity1,2. Retatrutide had no Drugs@FDA application at our fetch and remains investigational.

Can you take retatrutide and tirzepatide together?

No published trial among the sources we cite tested them together. Retatrutide remains investigational; tirzepatide is labeled for use as a single agent5,2.

Two identical glass beakers, one holding pale amber liquid and one clear, standing either side of a brass balance

Why do they get these evidence grades?

B Retatrutide
Randomized phase 2 and phase 3 trials are published in NEJM and The Lancet; no FDA-approved application exists, so the grade stays at B. Grade B: Randomized human trials.
A Tirzepatide
FDA-approved for type 2 diabetes (Mounjaro) and for chronic weight management and obstructive sleep apnea with obesity (Zepbound). Grade A: Approved / regulatory-grade.

Questions readers ask

Is retatrutide better than tirzepatide?

There is no head-to-head result among the trials we cite. Placebo-adjusted weight loss was larger in retatrutide's TRIUMPH-13 than in tirzepatide's SURMOUNT-14, but the trials differed in duration (80 vs 72 weeks), population and dose schedules.

Is retatrutide FDA-approved?

No. Drugs@FDA listed no retatrutide application at our fetch; tirzepatide is approved as Mounjaro and Zepbound5,6.

What does the glucagon receptor add?

Retatrutide is designed to activate glucagon receptors as well as GIP and GLP-1. In trials it reduced liver fat by more than 80% at the higher doses9; it also raised heart rate in a dose-dependent way, peaking at 24 weeks10.

Do they have the same side effects?

Both are mostly gastrointestinal10,11. In TRIUMPH-2, hypotension and dysesthesia were also more frequent with retatrutide than placebo7.

Can you take retatrutide and tirzepatide together?

No published trial among the sources we cite tested them together. Retatrutide is still investigational; tirzepatide is labeled for use as a single agent5,2.

Is retatrutide better than tirzepatide for weight loss?

There is no head-to-head result among the trials we cite. Placebo-controlled weight loss was larger in retatrutide TRIUMPH-1 (−23.7% to −25.0% at 80 weeks)3 than in tirzepatide SURMOUNT-1 (−15.0% to −20.9% at 72 weeks)4, but populations and schedules differed.

References

Every source below was retrieved from its official API or page and cached on the data-edition date. Numbers match the margin notes.

  1. 1 FDA MOUNJARO, MOUNJARO KWIKPEN prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-08-27.
  2. 2 FDA ZEPBOUND, ZEPBOUND KWIKPEN prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-08-28.
  3. 3 PubMed Jastreboff AM, Kaplan LM, Davies MJ, et al. Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity. N Engl J Med 2026. PMID 42814954; doi:10.1056/NEJMoa2604169.
  4. 4 PubMed Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med 2022. PMID 35658024; doi:10.1056/NEJMoa2206038.
  5. 5 FDA Drugs@FDA: MOUNJARO, MOUNJARO KWIKPEN, MOUNJARO (AUTOINJECTOR) (NDA215866). ELI LILLY AND CO; original approval 2022-05-13; Prescription.
  6. 6 FDA Drugs@FDA: ZEPBOUND, ZEPBOUND KWIKPEN, ZEPBOUND (AUTOINJECTOR) (NDA217806). ELI LILLY AND CO; original approval 2023-11-08; Prescription.
  7. 7 PubMed Bellido V, le Roux CW, Ekinci EI, 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. PMID 42810372; doi:10.1016/S0140-6736(26)01861-1.
  8. 8 PubMed Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med 2021. PMID 34170647; doi:10.1056/NEJMoa2107519.
  9. 9 PubMed Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med 2024. PMID 38858523; doi:10.1038/s41591-024-03018-2.
  10. 10 PubMed Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med 2023. PMID 37366315; doi:10.1056/NEJMoa2301972.
  11. 11 PubMed Patel H, Khunti K, Rodbard HW, et al. Gastrointestinal adverse events and weight reduction in people with type 2 diabetes treated with tirzepatide in the SURPASS clinical trials. Diabetes Obes Metab 2024. PMID 37853960; doi:10.1111/dom.15333.
  12. 12 PubMed Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med 2025. PMID 40353578; doi:10.1056/NEJMoa2416394.