Semaglutide
Semaglutide is a once-weekly subcutaneous GLP-1 receptor agonist developed by Novo Nordisk (brand names Ozempic for T2D, Wegovy for obesity). It was the leading GLP-1 receptor agonist by market share and clinical evidence at the time tirzepatide was developed, and served as the active comparator in SURPASS-2. In that head-to-head trial, all three tirzepatide doses (5, 10, 15 mg) were superior to semaglutide 1 mg on HbA1c reduction and weight loss at 40 weeks. The comparator dose of 1 mg was the only approved T2D dose at the time; the higher 2 mg T2D dose was approved later and was not used in SURPASS-2, a limitation noted by independent reviewers.
Ontology Semaglutide [compared_against] Tirzepatide Semaglutide [comparator_in] SURPASS-2 Semaglutide [relates] Type 2 Diabetes Semaglutide [relates] GLP-1 Receptor Agonism
Head-to-Head: SURMOUNT-5 (Obesity without T2D, 72 weeks)
SURMOUNT-5 (PMID 40353578, NEJM 2025, n=751): The first published head-to-head RCT of tirzepatide vs semaglutide, in adults with obesity without T2D. At 72 weeks: tirzepatide −20.2% body weight vs semaglutide −13.7% (absolute difference −6.5 percentage points; P<0.001). Tirzepatide was significantly superior. GI-related discontinuation was also lower with tirzepatide (2.7% vs 5.6% semaglutide). All GI adverse events (nausea, vomiting, diarrhoea) were numerically comparable.
Vault caveat — T2D applicability: SURMOUNT-5 enrolled obesity without T2D, so results are not directly transferable to T2D patients. The superior weight loss advantage may be attenuated in T2D populations (where metabolic resistance to weight loss is greater). For T2D specifically, SURPASS-2 remains the primary head-to-head evidence (semaglutide 1mg; tirzepatide still superior). No published head-to-head trial exists comparing tirzepatide to semaglutide 2mg (T2D dose) or semaglutide 2.4mg Wegovy in T2D patients.
Ontology Semaglutide [compared_against] Tirzepatide Semaglutide [comparator_in] SURMOUNT-5 Semaglutide [relates] Weight Loss in T2D
Comparison Against Tirzepatide (SURPASS-2, 40 weeks, both on metformin)
- HbA1c: −1.86% (semaglutide 1mg) vs −2.01%/−2.24%/−2.30% (tirzepatide 5/10/15mg) — tirzepatide superior at all doses
- Weight: Tirzepatide 1.9–5.5 kg greater weight reduction
- Insulin use: Both agents avoid insulin initiation in this population
- Kidney outcomes: No direct comparison in tirzepatide trials; CREDENCE/FLOW trials exist for semaglutide separately
- Cardiovascular outcomes: SUSTAIN-6 showed semaglutide reduces MACE in T2D; SURPASS-4 showed tirzepatide did not increase MACE vs glargine (different comparators; no direct CV outcome head-to-head)
- Side effects: Comparable GI profile; similar nausea/vomiting/diarrhoea rates
- Cost/access: Broadly similar accessibility in most markets; both require weekly injection
- Evidence quality: Both have Phase 3 RCT evidence; semaglutide has dedicated cardiovascular outcomes trial (SUSTAIN-6); tirzepatide does not (SURPASS-4 not powered for CV primary)
Connections
- Tirzepatide — compared_against, [2021], source: SURPASS-2
- SURPASS-2 — comparator_in, [2021], source: PMID 34170647
- GLP-1 Receptor Agonism — mechanism_of_action