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Semaglutide vs Tirzepatide — Trial Data

Semaglutide activates one receptor target (GLP-1); tirzepatide activates two (GIP and GLP-1). This page reports each compound's pivotal trial, the SURMOUNT-5 trial that tested them directly against each other, the cardiovascular-outcomes trials, and adverse-event data — each figure attributed to the study that reported it.

SemaglutideTirzepatide
MechanismGLP-1 receptor agonistGIP + GLP-1 receptor agonist
Brand namesOzempic (type 2 diabetes), Wegovy (chronic weight management), Rybelsus (oral)Mounjaro (type 2 diabetes), Zepbound (chronic weight management)
FDA statusApproved (Ozempic 2017, Wegovy 2021, Rybelsus 2019)Approved (Mounjaro 2022, Zepbound 2023)
Pivotal trial result−14.9% at 2.4mg/68wk vs −2.4% placebo (STEP 1, Wilding et al. 2021, PMID 33567185)−20.9% at 15mg/72wk vs −3.1% placebo (SURMOUNT-1, Jastreboff et al. 2022, PMID 35658024)
Head-to-head result−13.7% at 72wk (SURMOUNT-5, Aronne et al. 2025, PMID 40353578)−20.2% at 72wk (SURMOUNT-5, same trial, P<0.001 vs semaglutide)
Cardiovascular-outcomes trialSELECT vs placebo: HR 0.80, P<0.001 (PMID 37952131)SURPASS-CVOT vs dulaglutide (active comparator): HR 0.92, P=0.003 for noninferiority, P=0.09 for superiority (not met) (PMID 41406444)
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.Approval Status
  7. 7.Evidence Level
  8. 8.Reading These Figures
  9. 9.FAQ
  10. 10.References
  11. 11.Related comparisons

Mechanism

GLP-1 (glucagon-like peptide-1) is a gut hormone that slows gastric emptying, stimulates glucose-dependent insulin release, and acts on the hypothalamus to reduce appetite. Semaglutide activates the GLP-1 receptor alone.

Tirzepatide adds GIP (glucose-dependent insulinotropic polypeptide) receptor activation on top of GLP-1, reported to further improve insulin sensitivity.

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; weight reductions of 5% or more were reported in 86.4% of the semaglutide group versus 31.5% with placebo.

SURMOUNT-1 (Jastreboff et al. 2022, NEJM, PMID 35658024, NCT04184622): a Phase 3, double-blind, randomized, placebo-controlled trial of 2,539 adults with obesity, randomized to subcutaneous tirzepatide (5, 10, or 15 mg) or placebo once weekly for 72 weeks, including a 20-week dose-escalation period. At week 72, mean weight change was −15.0% (5mg), −19.5% (10mg), and −20.9% (15mg), versus −3.1% with placebo.

Head-to-Head: SURMOUNT-5

Aronne et al. 2025 (NEJM, PMID 40353578, NCT05822830) is the trial 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).

Cardiovascular Outcomes

SELECT (Lincoff et al. 2023, NEJM, PMID 37952131, NCT03574597) randomized 17,604 adults with established cardiovascular disease and BMI ≥27, without diabetes, to semaglutide or placebo. Result: 6.5% (semaglutide) versus 8.0% (placebo) for the composite cardiovascular endpoint; HR 0.80 (95% CI 0.72–0.90), P<0.001 for superiority. SURPASS-CVOT (NEJM 2025, PMID 41406444, DOI 10.1056/NEJMoa2505928, NCT04255433) compared tirzepatide against dulaglutide — an active GLP-1 comparator with its own established cardiovascular benefit, not a placebo — in 13,165 adults with type 2 diabetes and atherosclerotic cardiovascular disease. Result: 12.2% (tirzepatide) versus 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). SELECT's result is a superiority finding against placebo; SURPASS-CVOT's is a noninferiority finding against an active comparator, not a superiority finding.

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.

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.

Approval Status

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).

Evidence Level

Both compounds: Human RCT. Semaglutide's evidence base includes STEP 1 (obesity) and SELECT (cardiovascular outcomes vs placebo). Tirzepatide's includes SURMOUNT-1 (obesity) and SURPASS-CVOT (cardiovascular outcomes vs an active comparator). SURMOUNT-5 is the direct head-to-head trial between the two compounds.

STEP 1 and SURMOUNT-1 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 — though open-label, not double-blind.

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 trial that tested these two compounds directly against each other in the same population.

What did STEP 1 and SURMOUNT-1 report independently?

STEP 1 (Wilding et al. 2021, PMID 33567185) randomized 1,961 adults to semaglutide 2.4 mg or placebo for 68 weeks: −14.9% weight change versus −2.4% placebo. SURMOUNT-1 (Jastreboff et al. 2022, PMID 35658024) randomized 2,539 adults to tirzepatide 5, 10, or 15 mg or placebo for 72 weeks: up to −20.9% weight change at 15mg versus −3.1% placebo. These are each compound's own placebo-controlled pivotal trial, not a comparison to each other.

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, meeting its noninferiority margin (P=0.003) but not reaching statistical significance for superiority (P=0.09) (PMID 41406444).

Can the STEP 1 and SURMOUNT-1 percentages be compared directly?

Not as a head-to-head result. STEP 1 and SURMOUNT-1 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 trial that tested semaglutide and tirzepatide against each other directly.

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. 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/
  4. 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/
  5. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes (SURPASS-CVOT). N Engl J Med. 2025;393(24):2409-2420. DOI 10.1056/NEJMoa2505928. https://pubmed.ncbi.nlm.nih.gov/41406444/
  6. FDA drugsfda: Ozempic (NDA 209637), Wegovy (NDA 215256), Rybelsus (NDA 213051), Mounjaro (NDA 215866), Zepbound (NDA 217806).
Semaglutide ProfileSemaglutide Dosing GuideTirzepatide ProfileTirzepatide Dosing Guide

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