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Retatrutide vs Semaglutide — Trial Data

Retatrutide is a GIP/GLP-1/glucagon triple receptor agonist; semaglutide is a GLP-1 receptor agonist. This page reports each compound's pivotal trial, retatrutide's topline Phase 3 data labelled as such, and adverse-event data from the same sources.

RetatrutideSemaglutide
MechanismGIP + GLP-1 + glucagon receptor agonistGLP-1 receptor agonist
Brand namesNone — investigationalOzempic (type 2 diabetes), Wegovy (chronic weight management), Rybelsus (oral)
FDA statusNot approvedApproved (Ozempic 2017, Wegovy 2021, Rybelsus 2019)
Pivotal trial result−24.2% at 12mg/48wk vs −2.1% placebo (Phase 2, Jastreboff et al. 2023, PMID 37366315)−14.9% at 2.4mg/68wk vs −2.4% placebo (STEP 1, Wilding et al. 2021, PMID 33567185)
Phase 3 / post-approval statusTRIUMPH-4 topline: 28.7% at 12mg/68wk (Lilly release, Dec 11, 2025 — not yet peer-reviewed)Approved; SELECT cardiovascular-outcomes trial vs placebo reported HR 0.80, P<0.001, PMID 37952131
Trial dosing1, 4, 8, or 12 mg subcutaneous once weekly (Phase 2)2.4 mg subcutaneous once weekly (STEP 1)
On this page
  1. 1.Mechanism
  2. 2.Pivotal Trials
  3. 3.Retatrutide Phase 3 (Topline, Not Yet Peer-Reviewed)
  4. 4.Adverse Events
  5. 5.Approval Status
  6. 6.Dosing
  7. 7.Evidence Level
  8. 8.Reading These Figures
  9. 9.FAQ
  10. 10.References
  11. 11.Related comparisons

Mechanism

Semaglutide activates the GLP-1 receptor alone. Retatrutide adds two further targets, the GIP and glucagon receptors; glucagon receptor activity is reported to increase energy expenditure through a mechanism distinct from GLP-1-driven appetite suppression (Jastreboff et al. 2023, PMID 37366315).

Pivotal Trials

STEP 1 (Wilding et al. 2021, NEJM, PMID 33567185, NCT03548935): a double-blind, randomized, placebo-controlled trial of 1,961 adults with overweight or obesity, randomized to subcutaneous semaglutide (2.4 mg) or placebo once weekly for 68 weeks. At 68 weeks, mean weight change was −14.9% with semaglutide versus −2.4% with placebo.

Retatrutide Phase 2 (Jastreboff et al. 2023, NEJM, PMID 37366315, NCT04881760): a double-blind, randomized, placebo-controlled trial of 338 adults with obesity, randomized to subcutaneous retatrutide (1, 4, 8, or 12 mg) or placebo once weekly for 48 weeks. At 48 weeks, mean weight change was −8.7% (1mg), −17.1% (4mg), −22.8% (8mg), and −24.2% (12mg), versus −2.1% with placebo.

Retatrutide Phase 3 (Topline, Not Yet Peer-Reviewed)

TRIUMPH-4 (Eli Lilly investor press release, December 11, 2025 — not yet peer-reviewed): 28.7% average weight loss reported at the 12 mg dose over 68 weeks in adults with obesity and knee osteoarthritis. No dated primary source for a specific TRIUMPH-4 dysesthesia percentage, liver-fat-reduction figure, or heart-rate change was located; those figures are not reproduced here.

Adverse Events

  • Retatrutide Phase 2: gastrointestinal events were dose-related, mostly mild to moderate, partially mitigated with a lower starting dose. Dose-dependent heart-rate increases peaked at 24 weeks and declined thereafter (PMID 37366315).
  • STEP 1 (semaglutide): nausea and diarrhea were most common, typically transient and mild-to-moderate. Discontinuation due to gastrointestinal events occurred in 4.5% of the semaglutide group versus 0.8% with placebo (PMID 33567185).
  • SELECT (semaglutide vs placebo, cardiovascular outcomes): adverse events leading to permanent discontinuation occurred in 16.6% of the semaglutide group versus 8.2% with placebo (PMID 37952131).

Approval Status

Retatrutide is investigational, with no FDA approval and no approved brand name. Semaglutide is FDA-approved as Ozempic (NDA 209637, type 2 diabetes), Wegovy (NDA 215256, chronic weight management), and Rybelsus (NDA 213051, oral tablet).

Dosing

In the trials above, retatrutide was dosed at 1, 4, 8, or 12 mg subcutaneously once weekly over 48 weeks; semaglutide was dosed at 2.4 mg subcutaneously once weekly over 68 weeks in STEP 1. Dosing guides for each compound: retatrutide, semaglutide.

Evidence Level

Both compounds: Human RCT. Retatrutide's Phase 2 trial and three Phase 3 trials (TRIUMPH-1, TRIUMPH-2, TRANSCEND-T2D-1) are published; TRIUMPH-4 is so far a topline company release. Semaglutide's evidence includes both its pivotal obesity trial (STEP 1) and post-approval cardiovascular-outcomes data (SELECT, PMID 37952131).

STEP 1 and the retatrutide Phase 2 trial enrolled different populations, at different doses, over different durations (68 weeks versus 48 weeks). Their reported figures are cross-trial comparisons, not a head-to-head result. No trial randomizing participants to retatrutide versus semaglutide directly has been identified.

FAQ

What did the retatrutide Phase 2 trial report?

Jastreboff et al. 2023 (NEJM, PMID 37366315, NCT04881760) randomized 338 adults with obesity to subcutaneous retatrutide (1, 4, 8, or 12 mg) or placebo once weekly for 48 weeks. At 48 weeks, mean weight change was −24.2% with the 12 mg dose versus −2.1% with placebo. Gastrointestinal adverse events were dose-related and mostly mild to moderate; dose-dependent heart-rate increases peaked at 24 weeks and declined thereafter. No specific heart-rate figure in beats per minute was reported in the trial's abstract.

What did STEP 1 report for semaglutide?

Wilding et al. 2021 (NEJM, PMID 33567185, NCT03548935) randomized 1,961 adults with overweight or obesity to subcutaneous semaglutide (2.4 mg once weekly) or placebo for 68 weeks. At week 68, mean weight change was −14.9% with semaglutide versus −2.4% with placebo. Weight reductions of 5% or more were reported in 86.4% of the semaglutide group versus 31.5% with placebo. Nausea and diarrhea were the most common adverse events, typically transient and mild-to-moderate; discontinuation due to gastrointestinal events occurred in 4.5% of the semaglutide group versus 0.8% with placebo.

Is the retatrutide Phase 3 TRIUMPH-4 data published?

No. TRIUMPH-4's 28.7% weight-loss figure comes from an Eli Lilly investor press release dated December 11, 2025, not a peer-reviewed publication. It is reported here as a topline company release. No dated primary source for a specific TRIUMPH-4 dysesthesia percentage, liver-fat-reduction figure, or heart-rate change was located; those figures are not reproduced on this page.

Has retatrutide been tested against semaglutide directly?

Not that has been identified. No trial randomizing participants to retatrutide versus semaglutide head-to-head has been located. (Semaglutide has been tested head-to-head against tirzepatide, a different compound, in SURMOUNT-5 — see Semaglutide vs Tirzepatide.) The figures on this page come from two separate trials in different populations, not a shared comparison.

References

  1. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. https://pubmed.ncbi.nlm.nih.gov/33567185/
  2. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. https://pubmed.ncbi.nlm.nih.gov/37366315/
  3. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. https://pubmed.ncbi.nlm.nih.gov/37952131/
  4. Eli Lilly. Lilly's triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial (TRIUMPH-4). December 11, 2025. Topline results, not yet peer-reviewed. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average
  5. FDA drugsfda: Ozempic (NDA 209637), Wegovy (NDA 215256), Rybelsus (NDA 213051).
Retatrutide ProfileSemaglutide Profile

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