Semaglutide vs tirzepatide
Semaglutide and tirzepatide are both once-weekly injectable peptides carrying FDA labels for chronic weight management, and they differ in receptor targets: semaglutide acts at the GLP-1 receptor, while tirzepatide acts at both the GIP and GLP-1 receptors. 1,2 Unusually for two drugs in a class, a randomized head-to-head trial in adults with obesity (SURMOUNT-5) has been published, so this page can draw on direct comparative data as well as on each drug's label. 3
Side by side
| Field | Semaglutide | Tirzepatide |
|---|---|---|
| Class | GLP-1 receptor agonist 1 | GIP receptor and GLP-1 receptor agonist 2 |
| Mechanism / receptors | Selectively binds and activates the GLP-1 receptor; the label describes the molecule as a GLP-1 analogue with 94% sequence homology to human GLP-1. 1 | Binds and activates both the GIP and GLP-1 receptors; the label notes that animal studies show distribution to and activation of neurons in brain regions involved in appetite regulation. 2 |
| Origin | Modified GLP-1 analogue with a C18 fatty di-acid that promotes albumin binding; the peptide backbone is produced by yeast fermentation. 1 | Based on the GIP sequence, with Aib residues at positions 2 and 13 and a C20 fatty diacid attached through a linker. 2 |
| Half-life | Approximately 1 week (per label). 1 | Approximately 5 days (per label). 2 |
| Highest trial phase | Approved; phase 3 programs including STEP 1 and the head-to-head SURMOUNT-5 3,4 | Approved; phase 3 programs including SURMOUNT-1 and SURMOUNT-5 3,5 |
| FDA status | Label (Wegovy) lists reduction of major adverse cardiovascular events in adults with established CV disease and obesity or overweight, chronic weight management, and noncirrhotic MASH with moderate to advanced fibrosis (accelerated approval). 1 | Label (Zepbound) lists chronic weight management in adults with obesity or overweight with a weight-related comorbidity, and moderate to severe obstructive sleep apnea in adults with obesity. 2 |
| Published outcomes (weight) | STEP 1 (adults with obesity, no diabetes, 68 weeks): mean change -14.9% vs -2.4% with placebo. 4 | SURMOUNT-1 (adults with obesity, no diabetes, 72 weeks): mean change -15.0%, -19.5% and -20.9% across three dose arms vs -3.1% with placebo. 5 |
| Head-to-head (SURMOUNT-5) | Mean change at week 72: -13.7% (95% CI -14.9 to -12.6). 3 | Mean change at week 72: -20.2% (95% CI -21.4 to -19.1); P<0.001 for the between-group difference. 3 |
| Safety signals | Boxed warning for risk of thyroid C-cell tumors (observed in rodents; human relevance not determined); label warnings include acute pancreatitis and acute gallbladder disease. 1 | Boxed warning for risk of thyroid C-cell tumors (observed in rats; human relevance not determined). 2 |
| Evidence level | Regulatory and randomized phase 3 human evidence 1,4 | Regulatory and randomized phase 3 human evidence 2,5 |
Semaglutide: what the data says
In STEP 1, a double-blind trial of 1,961 adults with obesity or overweight and without diabetes, participants were randomized 2:1 to once-weekly semaglutide 2.4 mg or placebo for 68 weeks. 4 The mean change in body weight was -14.9% with semaglutide and -2.4% with placebo, and 69.1% of the semaglutide group versus 12.0% of the placebo group reached a weight reduction of at least 10%. 4 Nausea and diarrhea were the most common adverse events, and gastrointestinal events led to discontinuation in 4.5% of the semaglutide group versus 0.8% of the placebo group. 4
The Wegovy label's pooled adverse-reaction table for adults with obesity or overweight reports nausea in 44% of semaglutide-treated participants versus 16% with placebo, diarrhea in 30% versus 16%, and vomiting in 24% versus 6%. 1 The label also describes a 68-week, placebo-controlled trial in 201 adolescents aged 12 years and older that underlies its pediatric weight-management indication. 1
Tirzepatide: what the data says
In SURMOUNT-1, a double-blind phase 3 trial of 2,539 adults with obesity or overweight and without diabetes, participants received once-weekly tirzepatide 5, 10 or 15 mg or placebo for 72 weeks, including a 20-week dose-escalation period. 5 Mean weight change at week 72 was -15.0%, -19.5% and -20.9% in the three tirzepatide arms and -3.1% with placebo. 5 Adverse events were most often gastrointestinal, mostly mild to moderate, and clustered in the dose-escalation period. 5
The Zepbound label's pooled table for two weight-reduction trials reports nausea in 25%, 29% and 28% of participants in the 5 mg, 10 mg and 15 mg arms versus 8% with placebo, and vomiting in 8%, 11% and 13% versus 2%. 2 The label states that rates observed in one drug's trials cannot be directly compared with rates from another drug's trials. 1
Key research differences
- Receptor targets differ: semaglutide is described on its label as a selective GLP-1 receptor agonist, whereas tirzepatide is described as an agonist of both the GIP and GLP-1 receptors. 1,2
- In SURMOUNT-5 (751 adults with obesity and without type 2 diabetes, 72 weeks, open-label), mean weight change was -20.2% with tirzepatide and -13.7% with semaglutide, and mean waist circumference change was -18.4 cm versus -13.0 cm. 3
- SURMOUNT-5 randomized participants to the maximum tolerated dose in each arm (tirzepatide 10 mg or 15 mg; semaglutide 1.7 mg or 2.4 mg), so the dose range compared is the one the investigators specified rather than a single fixed dose. 3
- Registry-posted adverse-event counts from SURMOUNT-5 were similar for nausea (163 of 374 with tirzepatide, 167 of 376 with semaglutide) and differed for vomiting (56 vs 80) and injection-site reactions (32 vs 1). 6
- Labeled indications differ: the semaglutide label includes cardiovascular-event risk reduction and MASH, while the tirzepatide label includes obstructive sleep apnea. 1,2
- Reported half-lives differ, with approximately 1 week stated on the semaglutide label and approximately 5 days on the tirzepatide label. 1,2
Where the evidence is limited
SURMOUNT-5 was open-label, which can influence how outcomes are reported, and it enrolled adults with obesity but without type 2 diabetes, so its findings do not directly describe other populations. 3 Registry-posted adverse-event tables list events at a 5% frequency threshold and cannot by themselves establish which drug caused a given event. 6 Long-term cardiovascular and mortality comparisons between the two drugs are not covered by the sources reviewed here. 1,2
Frequently asked questions
Has tirzepatide been compared directly with semaglutide in obesity?
Do both drugs carry a boxed warning?
How do the two molecules differ in receptor activity?
Can adverse-event percentages from the two labels be compared directly?
References
- WEGOVY (semaglutide) injection, prescribing information FDA label (DailyMed). 2026
- ZEPBOUND (tirzepatide) injection, prescribing information FDA label (DailyMed). 2026
- Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5) N Engl J Med. 2025
- Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1) N Engl J Med. 2021
- Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1) N Engl J Med. 2022
- SURMOUNT-5 registry record with posted adverse-event results (NCT05822830) ClinicalTrials.gov. 2025
For research use only. Not for human or veterinary use. Not a drug, food, or dietary supplement. This page compares published research and is not medical advice or a recommendation.