Sample: evidence-base review · Stage 0
Satiety-hormone drugs: the evidence base
A sample of our deliverable — an evidence-base review within a niche study. Not medical advice; prescribing decisions rest with the treating physician. We show source discipline: identifiers (NCT, PMID) are given for verification.
Framing
This is an educational review within a niche study, not individual patient guidance. It passed an independent source check — 204 identifier-backed statements, 196 confirmed, zero fabricated references.
Head-to-head data — the most reliable
There is essentially one head-to-head: SURMOUNT-5 (NCT05822830, PMID 40353578), 751 patients, 72 weeks — tirzepatide −20.2% body weight, semaglutide −13.7%, a 6.5 pp difference. Key caveat: the trial was open-label, so 6.5 pp is better read as an upper bound than a point estimate; superiority itself is robust. On glycaemia — SURPASS-2 (NCT03987919, PMID 34170647): HbA1c −2.30% vs −1.86% (semaglutide 1 mg); an objective lab measure, so confidence is higher.
Why the newer drugs can't be ranked on one scale
The percentages below come from different trials (phases, duration, populations, placebo response). Subtracting and comparing these numbers against each other is invalid — the confidence intervals overlap.
| Drug (dose) | Weight loss | Placebo | Duration | N | Phase |
|---|---|---|---|---|---|
| Retatrutide 12 mg | −24.2% | −2.1% | 48 wk | 338 | 2 |
| Tirzepatide 15 mg | −20.9% | −3.1% | 72 wk | 2539 | 3 (SURMOUNT-1) |
| CagriSema 2.4/2.4 | −20.4% | −3.0% | 68 wk | 3417 | 3 (REDEFINE 1) |
| Semaglutide 2.4 mg | −14.9% | −2.4% | 68 wk | 1961 | 3 (STEP 1) |
| Survodutide 4.8 mg | −14.9% | −2.8% | 46 wk | 387 | 2 |
| Orforglipron 36 mg | −11.2% | −2.1% | 72 wk | 3127 | 3 (ATTAIN-1) |
Cardiovascular outcomes — the key gap
For semaglutide it's proven: SELECT (NCT03574597, PMID 37952131) in 17,604 patients showed a 20% reduction in major cardiovascular events (hazard ratio 0.80; CI 0.72–0.90) — hence the cardioprotective indication. Tirzepatide's outcomes trial is ongoing; retatrutide, orforglipron, survodutide and CagriSema have no outcomes data.
Strength of evidence (GRADE)
| Statement | Strength | Basis |
|---|---|---|
| Tirzepatide > semaglutide on HbA1c | high | direct RCT, objective measure |
| Tirzepatide > semaglutide on weight (fact) | high | direct RCT, consistent direction |
| …the exact 6.5 pp figure | moderate | open-label design inflates the estimate |
| Semaglutide reduces major CV events | high | double-blind outcomes trial SELECT |
| Retatrutide ≥ tirzepatide | low | phase 2 only, extrapolation, no outcomes |
Safety and regulatory warnings
The whole class carries a black-box warning for medullary thyroid cancer risk (shown in rodents); hence a contraindication with a personal/family history of that cancer (MTC) or MEN2 syndrome. Warnings also include: pancreatitis; gallbladder disease; acute kidney injury on dehydration; worsening diabetic retinopathy (semaglutide); hypoglycaemia with insulin or sulfonylureas.
- Under pharmacovigilance but without proven causation, two signals are discussed — NAION (a rare optic-nerve neuropathy) and suicidal ideation.
- Important source caveat: comparing brands by the absolute count of spontaneous reports (the FAERS database) is invalid — there is no denominator, i.e. the number of patients actually treated.
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An educational review, not individual patient guidance. Decisions on prescribing, dosing and discontinuation rest with the treating physician given the full clinical picture. NCT/PMID identifiers are provided to verify primary sources.