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Semaglutide vs Tirzepatide vs Retatrutide — Trial Data

Three incretin-based drugs, three receptor targets. This page reports the pivotal trial behind each compound, the one trial that tested two of them directly against each other (SURMOUNT-5), the cardiovascular-outcomes trials, and adverse-event data — each figure attributed to the study that reported it.

On this page
  1. 1.Mechanism
  2. 2.Pivotal Trials
  3. 3.Head-to-Head: SURMOUNT-5
  4. 4.Cardiovascular Outcomes
  5. 5.Adverse Events
  6. 6.Retatrutide Phase 3 (Topline, Not Yet Peer-Reviewed)
  7. 7.Approval Status and Brands
  8. 8.Other Agents in Trials
  9. 9.Evidence Level
  10. 10.Reading Cross-Trial Comparisons
  11. 11.FAQ
  12. 12.References

Mechanism

Semaglutide is a GLP-1 receptor agonist. GLP-1 receptor activation reduces appetite, slows gastric emptying, and stimulates glucose-dependent insulin release.

Tirzepatide is a dual GIP/GLP-1 receptor agonist, combining GLP-1 receptor activity with GIP receptor activation, reported to improve insulin sensitivity and modulate fat storage.

Retatrutide is a triple GIP/GLP-1/glucagon receptor agonist. Glucagon receptor activity, absent from the other two, is reported to increase energy expenditure via a distinct mechanism from GLP-1-driven appetite suppression (Jastreboff et al. 2023, PMID 37366315).

Pivotal Trials

Each compound's approval or primary evidence rests on a separate, differently-designed trial in a different population. The figures below are as each trial reported them, not a shared comparison.

STEP 1SURMOUNT-1Retatrutide Phase 2
CompoundSemaglutideTirzepatideRetatrutide
CitationWilding et al. 2021, NEJMJastreboff et al. 2022, NEJMJastreboff et al. 2023, NEJM
IdentifierPMID 33567185, NCT03548935PMID 35658024, NCT04184622PMID 37366315, NCT04881760
DesignDouble-blind, randomized, placebo-controlledPhase 3, double-blind, randomized, placebo-controlledPhase 2, double-blind, randomized, placebo-controlled
Population1,961 adults with overweight/obesity (BMI ≥30, or ≥27 with a weight-related condition), no diabetes2,539 adults with obesity (BMI ≥30, or ≥27 with a weight-related complication), no diabetes338 adults with obesity (BMI ≥30, or 27–<30 with a weight-related condition)
Dose(s)2.4 mg subcutaneous once weekly5, 10, or 15 mg subcutaneous once weekly (20-week dose escalation)1, 4, 8, or 12 mg subcutaneous once weekly (48 weeks)
Duration68 weeks72 weeks48 weeks (primary endpoint at 24 weeks)
Primary endpoint result−14.9% body weight vs −2.4% placebo (P<0.001)−15.0% (5mg), −19.5% (10mg), −20.9% (15mg) vs −3.1% placebo, all P<0.001−7.2% (1mg) to −17.5% (12mg) at 24wk vs −1.6% placebo; −24.2% (12mg) at 48wk vs −2.1% placebo

STEP 1 also reported weight reductions of 5% or more in 86.4% of the semaglutide group versus 31.5% with placebo. SURMOUNT-1 reported weight reductions of 5% or more in 85%, 89%, and 91% of the 5mg, 10mg, and 15mg tirzepatide groups respectively, versus 35% with placebo. The retatrutide Phase 2 trial reported weight reductions of 15% or more in 60% (4mg), 75% (8mg), and 83% (12mg) of participants at 48 weeks, versus 2% with placebo.

Head-to-Head: SURMOUNT-5

Aronne et al. 2025 (NEJM, PMID 40353578, NCT05822830) is the one trial in this comparison that tested tirzepatide and semaglutide directly against each other in the same population. It was a phase 3b, open-label (not double-blind), active-comparator, controlled trial. 751 adults with obesity but without type 2 diabetes were randomly assigned 1:1 to the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg), subcutaneously once weekly, for 72 weeks.

The primary endpoint was percent weight change from baseline to week 72. Result: −20.2% (95% CI −21.4 to −19.1) with tirzepatide versus −13.7% (95% CI −14.9 to −12.6) with semaglutide (P<0.001). Waist circumference change was −18.4 cm versus −13.0 cm (P<0.001). Participants receiving tirzepatide were more likely than those receiving semaglutide to reach weight reductions of 10%, 15%, 20%, and 25% or more.

Cardiovascular Outcomes

SELECT tested semaglutide against placebo. SURPASS-CVOT tested tirzepatide against dulaglutide — an active GLP-1 comparator with its own established cardiovascular benefit, not a placebo. No cardiovascular-outcomes trial of retatrutide has completed and reported.

SELECT (Semaglutide)SURPASS-CVOT (Tirzepatide)
CompoundSemaglutideTirzepatide
ComparatorPlaceboDulaglutide (an active GLP-1 comparator with its own established cardiovascular benefit — not placebo)
CitationLincoff et al. 2023, NEJMNEJM, 2025
IdentifierPMID 37952131, NCT03574597PMID 41406444, DOI 10.1056/NEJMoa2505928, NCT04255433
DesignMulticenter, double-blind, randomized, placebo-controlled, event-driven superiority trialActive-comparator-controlled, double-blind, noninferiority trial
Population17,604 adults ≥45 with established cardiovascular disease and BMI ≥27, without diabetes13,165 adults (modified intention-to-treat) with type 2 diabetes and atherosclerotic cardiovascular disease
Primary endpointComposite of cardiovascular death, nonfatal MI, or nonfatal strokeComposite of cardiovascular death, MI, or stroke, tested for noninferiority (margin 1.05)
Result6.5% (semaglutide) vs 8.0% (placebo); HR 0.80 (95% CI 0.72–0.90), P<0.001 for superiority12.2% (tirzepatide) vs 13.1% (dulaglutide); HR 0.92 (95.3% CI 0.83–1.01); P=0.003 for noninferiority, P=0.09 for superiority (not met)

SURPASS-CVOT's result is a noninferiority finding, not a superiority finding: the trial met its noninferiority margin (P=0.003) but did not reach statistical significance for superiority over dulaglutide (P=0.09). SELECT's result is a superiority finding against placebo.

Adverse Events

STEP 1 (semaglutide): 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.

SURMOUNT-1 (tirzepatide): gastrointestinal events were most common, primarily during dose escalation. Discontinuation due to adverse events occurred in 4.3%, 7.1%, and 6.2% of the 5mg, 10mg, and 15mg groups respectively, versus 2.6% with placebo.

Retatrutide Phase 2: gastrointestinal events were dose-related, mostly mild to moderate, and partially mitigated by a lower starting dose. Dose-dependent heart-rate increases peaked at 24 weeks and declined thereafter.

SELECT (semaglutide vs placebo): adverse events leading to permanent discontinuation occurred in 16.6% of the semaglutide group versus 8.2% with placebo.

SURPASS-CVOT (tirzepatide vs dulaglutide): overall adverse-event incidence was similar between groups; more gastrointestinal adverse events were reported with tirzepatide than with dulaglutide.

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

Retatrutide's Phase 3 TRIUMPH-program results reported to date are topline figures from Eli Lilly's own dated investor press releases, not a peer-reviewed publication. They are reported here as such, not as published trial results.

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.

TRANSCEND-T2D-1 (Bajaj et al., Lancet 2026, PMID 42250575; double-blind phase 3, n=537): HbA1c changes of −1.69%, −1.86% and −1.94% at 4, 9 and 12 mg vs −0.81% on placebo, and weight changes of −11.5%, −13.9% and −15.3% vs −2.6%, over 40 weeks.

Approval Status and Brands

Semaglutide is FDA-approved as Ozempic (NDA 209637, injection, type 2 diabetes), Wegovy (NDA 215256, injection, chronic weight management), and Rybelsus (NDA 213051, oral tablet). Tirzepatide is FDA-approved as Mounjaro (NDA 215866, type 2 diabetes) and Zepbound (NDA 217806, chronic weight management). Retatrutide is investigational, with no FDA approval and no approved brand name.

Other Agents in Trials

Other incretin-class agents in active human trials include cagrilintide and its fixed-dose combination with semaglutide, CagriSema; mazdutide, approved in China but not the US; and survodutide, investigational.

Evidence Level

SemaglutideTirzepatideRetatrutide
LevelHuman RCTHuman RCTHuman RCT
BasisSTEP 1 (obesity), SELECT (cardiovascular outcomes)SURMOUNT-1 (obesity), SURPASS-CVOT (cardiovascular outcomes)Phase 2 obesity trial; published Phase 3 trials TRIUMPH-1, TRIUMPH-2 and TRANSCEND-T2D-1 (2026); TRIUMPH-4 topline company release

STEP 1, SURMOUNT-1, and the retatrutide Phase 2 trial enrolled different populations, over different durations, at different doses. Their reported weight-loss figures are cross-trial comparisons, not head-to-head results, and should be read as such. SURMOUNT-5 is the exception: it directly randomized participants to tirzepatide or semaglutide within a single trial, and its result is a genuine head-to-head comparison.

FAQ

What did the SURMOUNT-5 head-to-head trial find?

Aronne et al. 2025 (NEJM, PMID 40353578, NCT05822830) randomized 751 adults with obesity but without type 2 diabetes, 1:1, to the maximum tolerated dose of tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg) subcutaneously once weekly for 72 weeks in an open-label, phase 3b, active-comparator trial (not double-blind). At week 72, mean weight change was −20.2% with tirzepatide versus −13.7% with semaglutide (P<0.001); waist circumference change was −18.4 cm versus −13.0 cm. This is the one trial in this comparison that tested these two compounds directly against each other in the same population.

Is retatrutide FDA-approved?

No. Retatrutide is investigational. Its Phase 2 obesity trial (Jastreboff et al. 2023, PMID 37366315) is peer-reviewed and published; its Phase 3 TRIUMPH-program results reported so far (TRIUMPH-4, TRANSCEND-T2D-1) are topline figures from Eli Lilly's own dated investor press releases, not yet published in a peer-reviewed journal.

Was SURPASS-CVOT placebo-controlled?

No. SURPASS-CVOT compared tirzepatide against dulaglutide, an active GLP-1 receptor agonist with its own established cardiovascular benefit — not a placebo. The trial was designed and reported as a noninferiority comparison against that active comparator (PMID 41406444).

Can the STEP 1, SURMOUNT-1, and retatrutide Phase 2 percentages be compared directly?

Not as a head-to-head result. STEP 1, SURMOUNT-1, and the retatrutide Phase 2 trial enrolled different populations over different durations at different doses, so their reported weight-loss percentages are cross-trial comparisons, not results from a shared trial. SURMOUNT-5 is the one trial in this set that tested two of these compounds against each other directly.

What brands are semaglutide and tirzepatide sold under?

Semaglutide is FDA-approved as Ozempic (NDA 209637, injection), Wegovy (NDA 215256, injection), and Rybelsus (NDA 213051, tablet). Tirzepatide is FDA-approved as Mounjaro (NDA 215866) and Zepbound (NDA 217806). Retatrutide has no approved brand name.

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, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216. https://pubmed.ncbi.nlm.nih.gov/35658024/
  3. 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/
  4. Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med. 2025;393(1):26-36. https://pubmed.ncbi.nlm.nih.gov/40353578/
  5. 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/
  6. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes (SURPASS-CVOT). N Engl J Med. 2025;PMID 41406444. DOI 10.1056/NEJMoa2505928. https://pubmed.ncbi.nlm.nih.gov/41406444/
  7. 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
  8. Bajaj HS, Welch M, Shah P, et al. Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial. Lancet. 2026;407:2402-2413. PMID 42250575. https://pubmed.ncbi.nlm.nih.gov/42250575/
  9. FDA drugsfda: Ozempic (NDA 209637), Wegovy (NDA 215256), Rybelsus (NDA 213051), Mounjaro (NDA 215866), Zepbound (NDA 217806).
Semaglutide ProfileSemaglutide Dosing GuideTirzepatide ProfileTirzepatide Dosing GuideRetatrutide ProfileRetatrutide Dosing GuideRetatrutide vs TirzepatideRetatrutide vs SemaglutideSemaglutide vs Tirzepatide

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