Evidence-led comparison
Semaglutide vs tirzepatide vs retatrutide
Evidence-led, non-promotional comparison of semaglutide, tirzepatide and retatrutide across mechanism, evidence maturity, regulatory status, trial phase, weight-management evidence, diabetes evidence, cardiovascular evidence and safety profile. With explicit notes on what cross-trial comparisons cannot conclude.
This page compares semaglutide, tirzepatide and retatrutide across mechanism, regulatory status, evidence maturity and trial outcomes for researchers and clinicians evaluating the published literature. Tirzepatide and retatrutide show greater mean body-weight reduction in studied populations than semaglutide in available trials; cardiovascular outcome evidence is most mature for semaglutide via SELECT. Cross-trial comparison has limits — see the linked research-methods primer.
| Aspect | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Mechanism | GLP-1 mono-agonist | Dual GLP-1 / GIP agonist | Triple GLP-1 / GIP / glucagon agonist |
| UK regulatory status | MHRA-licensed prescription-only medicine (Wegovy / Ozempic / Rybelsus depending on indication and route). | MHRA-licensed prescription-only medicine (Mounjaro for T2D and obesity). | Investigational; not licensed for human therapeutic use in the UK. |
| Highest published trial phase at the time of review | Outcome trial evidence (SELECT, FLOW). | Outcome trial evidence (SURPASS-CVOT, SUMMIT). | Phase 2 (NEJM 2023); TRIUMPH phase 3 programme ongoing or with topline-only data. |
| Weight-management evidence | STEP programme (phase 3); STEP 5 two-year data. | SURMOUNT 1-5 (phase 3); SURMOUNT-5 head-to-head vs semaglutide 2.4 mg. | Phase 2 obesity trial reported one of the largest mean body-weight reductions for a phase 2 obesity study at the time of publication; phase 3 confirmation pending. |
| Diabetes evidence | SUSTAIN programme; FLOW for T2D+CKD; widespread NHS T2D pathway use. | SURPASS programme; SURPASS-CVOT in T2D+ASCVD. | Investigational; T2D phase 2 data and ongoing phase 3. |
| Cardiovascular evidence | SELECT (MACE reduction in adults with overweight/obesity and pre-existing CVD without diabetes); SUSTAIN-6 in T2D. | SURPASS-CVOT: non-inferiority vs dulaglutide in T2D+ASCVD; SUMMIT: benefit in HFpEF+obesity. Superiority for MACE vs placebo not directly established in obesity at the time of review. | No cardiovascular outcome trial complete at the time of review. |
| Safety profile (broad strokes) | GI events dominant; gallbladder events more frequent than placebo; well-characterised long-term safety in the licensed indications. | GI events dominant; gallbladder events reported; SURPASS-CVOT did not surface novel CV safety signals in the primary publication. | Class-consistent GI events in phase 2; long-term safety still to be established. |
| Head-to-head data | SURMOUNT-5 (vs tirzepatide). | SURMOUNT-5 (vs semaglutide); SURPASS-2 (vs semaglutide 1 mg for T2D). | No completed head-to-head trial vs tirzepatide or semaglutide at the time of review. |
How to use this comparison
Tirzepatide's head-to-head data versus semaglutide (SURMOUNT-5, SURPASS-2) is the strongest direct comparison available. Retatrutide's phase 2 weight numbers should not be quoted in the same breath as semaglutide's or tirzepatide's phase 3 / outcome-trial numbers — the evidence stage is different. For the broader reading-trials guidance see the compare-trials-without-overclaiming primer.
- It does not name a "best" molecule. The right molecule depends on indication, comorbidities, evidence stage and individual clinical assessment.
- Cross-trial comparison without head-to-head data has limits; assumptions matter.
- Phase 2 magnitude is not phase 3 confirmation.
- Cardiovascular outcome evidence for one molecule does not transfer to another.
- Greater weight reduction in a single trial does not establish greater long-term outcome benefit.
Related trials
Related UK regulatory topics
Sources are tagged by class. Regulatory documents, peer-reviewed publications and trial registry records are preferred. Manufacturer disclosures and conference material are accepted where peer-reviewed publication is not yet available; preprints are flagged.
- Regulatory document (MHRA/EMA/FDA)MHRA — Medicines and Healthcare products Regulatory Agency
UK regulatory authority for prescription medicine classification
- Regulatory document (MHRA/EMA/FDA)European Medicines Agency — EPARs
EPARs and product information for approved GLP-1/GIP medicines
- Editorial synthesisSite editorial synthesis — Metabolic Peptides
Editorial comparison of GLP-1 class medicines on this site