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Retatrutide vs semaglutide

B Retatrutide Agonist at GIP, GLP-1 and glucagon receptors (triple agonist) Investigational — not FDA-approved A Semaglutide GLP-1 receptor agonist (fatty-acid–modified GLP-1 analog) FDA-approved — Ozempic (2017), Rybelsus (2019), Wegovy (2021)

Residue Editorial Team · updated

In brief

Semaglutide is an FDA-approved GLP-1 receptor agonist with a cardiovascular-outcomes trial behind it1FDAWEGOVY prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2024-04-23.,2PubMedSemaglutide and Cardiovascular Outcomes in Obesity without Diabetes. Lincoff AM et al. N Engl J Med. 2023.; retatrutide is an investigational GIP, GLP-1 and glucagon receptor agonist. In their separate obesity 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 semaglutide 2.4 mg −14.9% at 68 weeks4PubMedOnce-Weekly Semaglutide in Adults with Overweight or Obesity. Wilding JPH et al. N Engl J Med. 2021.. No trial cited here compares them directly.

How do Retatrutide and Semaglutide compare at a glance?

Table 1. Retatrutide and Semaglutide on the dimensions that matter most; every entry is cited.
DimensionRetatrutideSemaglutide
ReceptorsGIP, GLP-1 and glucagon3GLP-15FDAOZEMPIC prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-07-30.
FDA statusInvestigationalApproved: Ozempic, Wegovy, Rybelsus6FDADrugs@FDA: OZEMPIC (NDA209637). NOVO; original approval 2017-12-05; Prescription, Discontinued.,7FDADrugs@FDA: WEGOVY, WEGOVY HD, WEGOVY FLEXTOUCH (NDA215256). NOVO; original approval 2021-06-04; Prescription.
Pivotal obesity trialTRIUMPH-1: −17.6% to −25.0% vs −3.9%, 80 wk3STEP 1: −14.9% vs −2.4%, 68 wk4
Cardiovascular outcomes trialNone publishedSELECT: MACE 6.5% vs 8.0%2
Half-lifeWeekly dosing in trials8PubMedTriple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. Jastreboff AM et al. N Engl J Med. 2023.About 7 days9PubMedPharmacokinetics and Clinical Implications of Semaglutide: A New Glucagon-Like Peptide (GLP)-1 Receptor Agonist. Hall S et al. Clin Pharmacokinet. 2018.
Oral formNoYes (type 2 diabetes)10FDAOZEMPIC, RYBELSUS prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-01-30.
Evidence gradeBA

Written by Residue Editorial Team

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

First published

Last updated

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 5,706
Trial publications 11 341
Registered studies 34 785
Phase 3 studies 14 184

Retatrutide Semaglutide

How do they work differently?

Semaglutide is a fatty-acid-modified GLP-1 analog acting on the GLP-1 receptor11PubMedAbsorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species. Jensen L et al. Eur J Pharm Sci. 2017.,5. Retatrutide adds agonism at GIP and glucagon receptors8. The glucagon component is associated in trials with large liver-fat reductions — 81–82% at the higher doses over 24 weeks12PubMedTriple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Sanyal AJ et al. Nat Med. 2024. — and with a dose-dependent heart-rate rise8.

How do weight and metabolic outcomes compare?

Semaglutide 2.4 mg reduced weight by 14.9% versus 2.4% with placebo at 68 weeks in STEP 1 and by 15.2% versus 2.6% at 104 weeks in STEP 54,13PubMedTwo-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Garvey WT et al. Nat Med. 2022.. Retatrutide reduced weight by 17.6%, 23.7% and 25.0% versus 3.9% at 80 weeks in TRIUMPH-13, and by 11.9–18.8% versus 5.1% in people with type 2 diabetes in TRIUMPH-214PubMedRetatrutide 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..

These are separate trials, so the gap between them is not a measured treatment difference. The direct comparison that exists for semaglutide is against tirzepatide (see semaglutide vs tirzepatide).

What outcomes beyond weight have been measured?

Semaglutide's SELECT trial reduced the composite of cardiovascular death, heart attack or stroke from 8.0% to 6.5% in people with cardiovascular disease and obesity but no diabetes2, and Ozempic is labeled for kidney outcomes in type 2 diabetes with chronic kidney disease5. Retatrutide's TRIUMPH-1 reported improvements in knee-osteoarthritis pain and sleep-apnea measures in nested sub-studies3; no cardiovascular-outcomes result is published.

How do their safety records compare?

Both are mainly gastrointestinal in their adverse-event profiles4,8. Semaglutide discontinuation for adverse events was 16.6% versus 8.2% on placebo over SELECT's mean 39.8 months2. Retatrutide's trials additionally reported heart-rate increases8 and, in TRIUMPH-2, more hypotension and dysesthesia than placebo14.

Are they FDA-approved?

Semaglutide is FDA-approved6,7,15FDADrugs@FDA: OZEMPIC, RYBELSUS (NDA213051). NOVO; original approval 2019-09-20; Prescription.. Retatrutide is investigational, with no Drugs@FDA application at our fetch.

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 Semaglutide
FDA-approved as injection and tablet for type 2 diabetes, weight management and cardiovascular risk reduction; supported by large outcomes trials. Grade A: Approved / regulatory-grade.

Questions readers ask

Does retatrutide cause more weight loss than semaglutide?

Its own trials show larger placebo-adjusted reductions (TRIUMPH-1, −25.0% at 12 mg)3 than semaglutide's STEP 1 (−14.9%)4, but the trials were separate and of different lengths; no head-to-head result is cited here.

Which has more evidence?

Semaglutide, by a wide margin: it is approved in injectable and oral forms, has a 17,604-person cardiovascular outcomes trial2 and two-year weight data13. Retatrutide has phase 2 and phase 3 trial reports8,3.

Can retatrutide be prescribed?

Not as an approved drug: Drugs@FDA listed no retatrutide application at our fetch. Semaglutide's approved labels define its uses5,1.

Can you take retatrutide and semaglutide together?

No published trial among the sources we cite tested that combination. Retatrutide is investigational; semaglutide labels describe monotherapy5,1.

What are the side effects of retatrutide vs semaglutide?

Both programs report mostly gastrointestinal events. Retatrutide phase 2 and TRIUMPH reports also note dose-dependent heart-rate increases8; semaglutide's SELECT and STEP programs characterize GI events and gallbladder disorders under the approved labels2,1.

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 WEGOVY prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2024-04-23.
  2. 2 PubMed Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med 2023. PMID 37952131; doi:10.1056/NEJMoa2307563.
  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 Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med 2021. PMID 33567185; doi:10.1056/NEJMoa2032183.
  5. 5 FDA OZEMPIC prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-07-30.
  6. 6 FDA Drugs@FDA: OZEMPIC (NDA209637). NOVO; original approval 2017-12-05; Prescription, Discontinued.
  7. 7 FDA Drugs@FDA: WEGOVY, WEGOVY HD, WEGOVY FLEXTOUCH (NDA215256). NOVO; original approval 2021-06-04; Prescription.
  8. 8 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.
  9. 9 PubMed Hall S, Isaacs D, Clements JN. Pharmacokinetics and Clinical Implications of Semaglutide: A New Glucagon-Like Peptide (GLP)-1 Receptor Agonist. Clin Pharmacokinet 2018. PMID 29915923; doi:10.1007/s40262-018-0668-z.
  10. 10 FDA OZEMPIC, RYBELSUS prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-01-30.
  11. 11 PubMed Jensen L, Helleberg H, Roffel A, et al. Absorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species. Eur J Pharm Sci 2017. PMID 28323117; doi:10.1016/j.ejps.2017.03.020.
  12. 12 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.
  13. 13 PubMed Garvey WT, Batterham RL, Bhatta M, et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med 2022. PMID 36216945; doi:10.1038/s41591-022-02026-4.
  14. 14 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.
  15. 15 FDA Drugs@FDA: OZEMPIC, RYBELSUS (NDA213051). NOVO; original approval 2019-09-20; Prescription.