# Semaglutide vs tirzepatide - Canonical: https://residue.info/vs/semaglutide-vs-tirzepatide/ - Compounds: Semaglutide (https://residue.info/c/semaglutide/), Tirzepatide (https://residue.info/c/tirzepatide/) - Updated: 2026-10-19 · Reviewed by: Residue Editorial Team In both head-to-head randomized trials, tirzepatide came out ahead on the primary endpoint. In SURMOUNT-5 (NEJM 2025; 751 adults with obesity), tirzepatide produced 20.2% versus 13.7% weight loss with semaglutide at 72 weeks [1]. In SURPASS-2 (type 2 diabetes), every tirzepatide dose lowered HbA1c more than semaglutide 1 mg [2]. Semaglutide has a cardiovascular-outcomes trial in people without diabetes [3]. ## Side by side | | Semaglutide | Tirzepatide | |---|---|---| | Mechanism | GLP-1 receptor agonist [4] | GIP and GLP-1 receptor agonist [5] | | Brands (FDA) | Ozempic, Rybelsus, Wegovy [6][7] | Mounjaro, Zepbound [8][9] | | Half-life | About 7 days [10] | About 5 days [11] | | Route | Weekly injection or daily tablet [12] | Weekly subcutaneous injection [8] | | Weight, head-to-head (72 wk) | −13.7% [1] | −20.2% [1] | | HbA1c, head-to-head (40 wk) | −1.86 points (1 mg) [2] | −2.01 to −2.30 points [2] | | Placebo-controlled weight trial | STEP 1: −14.9% vs −2.4% at 68 wk [13] | SURMOUNT-1: −15.0% to −20.9% vs −3.1% at 72 wk [14] | | Cardiovascular outcomes | SELECT: MACE HR 0.80 in people without diabetes [3] | Label indication for MACE reduction in type 2 diabetes at high risk [5] | | Other approved uses | Kidney outcomes in T2D with CKD [4] | Obstructive sleep apnea with obesity [15] | | Evidence grade | A | A | ## What is the short answer? Semaglutide and tirzepatide are both once-weekly injectable peptides built on the incretin system — the gut hormones that amplify insulin release after a meal. Semaglutide acts on one receptor, GLP-1 [4]. Tirzepatide acts on two, GIP and GLP-1 [5]. That pharmacological difference is the main reason the two programs were compared head-to-head, and in both direct trials so far tirzepatide produced larger reductions on the primary endpoint [1][2]. That is not the whole picture. Semaglutide has the larger and longer outcomes record — notably SELECT, a 17,604-person trial in people without diabetes [3] — and an oral form [12]. The two drugs also have somewhat different sets of approved indications. This page sets out what each trial actually measured, with numbers taken from the published abstracts and FDA labels cited alongside. ## What did SURMOUNT-5 find in obesity? SURMOUNT-5 was a phase 3b, open-label trial in adults with obesity but without type 2 diabetes. Participants were randomized 1:1 to the maximum tolerated dose of tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg), each injected once weekly for 72 weeks. The primary endpoint was percentage change in body weight [1]. Among the 751 people randomized, the least-squares mean change in weight was −20.2% (95% CI −21.4 to −19.1) with tirzepatide and −13.7% (95% CI −14.9 to −12.6) with semaglutide (P<0.001). Waist circumference fell 18.4 cm versus 13.0 cm. Participants on tirzepatide were more likely to reach every key threshold — at least 10%, 15%, 20% and 25% weight reduction. The most common adverse events in both groups were gastrointestinal, mostly mild to moderate and concentrated in the dose-escalation period [1]. Two design features matter when reading the result. The trial was open-label, so participants and investigators knew which drug was given. And it was funded by Eli Lilly, tirzepatide's developer [1]. Neither invalidates the finding, but both are standard caveats our [methodology](https://residue.info/methodology/) asks readers to weigh. ## What did SURPASS-2 find in type 2 diabetes? SURPASS-2 was an open-label, 40-week phase 3 trial that randomized 1,879 people with type 2 diabetes 1:1:1:1 to tirzepatide 5, 10 or 15 mg or semaglutide 1 mg. At baseline, mean HbA1c was 8.28%, mean age 56.6 years and mean weight 93.7 kg [2]. HbA1c fell by 2.01, 2.24 and 2.30 percentage points with the three tirzepatide doses and by 1.86 with semaglutide. The estimated differences versus semaglutide were −0.15, −0.39 and −0.45 points, and all tirzepatide doses were both non-inferior and superior. Weight fell more with tirzepatide, by an estimated 1.9, 3.6 and 5.5 kg relative to semaglutide [2]. The semaglutide dose matters here: 1 mg was the comparator, which is below the 2.4 mg dose used in the semaglutide obesity program [13]. SURPASS-2 therefore compares tirzepatide with a diabetes dose of semaglutide, not with Wegovy. ## How do their placebo-controlled trials compare? Each drug also has its own large placebo-controlled weight trial. These are not a direct comparison — populations, durations and doses differ — but they show the scale of effect each produced against placebo. **Semaglutide, STEP 1.** In 1,961 adults with obesity, or overweight with a comorbidity, and no diabetes, 2.4 mg weekly reduced weight by 14.9% versus 2.4% with placebo at 68 weeks; 50.5% lost at least 15% [13]. STEP 5 showed the difference persisting at two years (−15.2% versus −2.6%) [16]. **Tirzepatide, SURMOUNT-1.** In adults with obesity and no diabetes, 72-week weight change was −15.0%, −19.5% and −20.9% at 5, 10 and 15 mg, versus −3.1% with placebo; 57% of the 15 mg group lost 20% or more [14]. In the participants with prediabetes followed for three years, 1.3% developed type 2 diabetes on tirzepatide versus 13.3% on placebo [17]. ## What about cardiovascular and other outcomes? This is where semaglutide's record is deeper. SELECT enrolled 17,604 adults aged 45 or older with established cardiovascular disease and a BMI of 27 or more but no diabetes. Over a mean 39.8 months, the composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred in 6.5% on semaglutide 2.4 mg and 8.0% on placebo (hazard ratio 0.80) [3]. That trial underpins Wegovy's cardiovascular indication [18]. Tirzepatide's labeling also now includes cardiovascular risk reduction, but in a different population: Mounjaro is indicated to reduce major adverse cardiovascular events in adults with type 2 diabetes at high risk [5]. Zepbound carries an indication semaglutide's labels do not — moderate-to-severe obstructive sleep apnea in adults with obesity [15], based on trials in which the apnea–hypopnea index fell by 25.3–29.3 events per hour [19]. Ozempic, in turn, is indicated to reduce kidney-disease progression and cardiovascular death in type 2 diabetes with chronic kidney disease [4]. ## How do their safety records compare? Both drugs share the gastrointestinal profile typical of incretin-based therapy. In SURPASS-2, where the drugs were given side by side, nausea occurred in 17–22% on tirzepatide and 18% on semaglutide, diarrhea in 13–16% and 12%, and vomiting in 6–10% and 8%. Serious adverse events were reported in 5–7% of tirzepatide participants and 3% of semaglutide participants. Hypoglycemia below 54 mg/dL was uncommon in both: 0.2–1.7% versus 0.4% [2]. In their placebo-controlled programs, discontinuation for adverse events was 4.3–7.1% on tirzepatide versus 2.6% on placebo in SURMOUNT-1 [14], and 16.6% on semaglutide versus 8.2% on placebo in the much longer SELECT trial [3]. These figures come from different populations and follow-up durations and should not be compared directly. The full warnings for each product are in its prescribing information [18][15]. ## How long does each last in the body? Semaglutide's half-life is about seven days, so steady state takes four to five weeks [10]. Tirzepatide's is about five days in a population model pooled from 19 studies [11]. Both half-lives support once-weekly injection. Semaglutide is also absorbed from a tablet, though oral exposure is sensitive to food, water volume and dosing conditions [20]. ## What happens after stopping? Weight returns in both programs when treatment ends. One year after stopping semaglutide, STEP 1 extension participants had regained 11.6 of the 17.3 percentage points they had lost [21]. In SURMOUNT-4, people switched from tirzepatide to placebo after a 36-week lead-in regained 14.0%, while those who continued lost a further 5.5% [22]. ## Are they FDA-approved? Both molecules are FDA-approved. Semaglutide is marketed as Ozempic and Wegovy injections and Rybelsus and Ozempic tablets [6][7][23]; tirzepatide as Mounjaro and Zepbound [8][9]. FDA's April 2026 statement says neither is on the drug-shortage list or the 503B bulks list, which restricts compounding [24]. ## What can this comparison not tell you? These trials describe average results in defined populations under trial conditions. They do not tell any individual which medicine to use; that is a decision for a licensed clinician. Residue publishes this summary for research and educational purposes and lists no products or prices. ## Can you take semaglutide and tirzepatide together? No published trial among the sources we cite tested them as a combination. Both act on the GLP-1 receptor — tirzepatide also on GIP — and each approved product label is written for monotherapy [4][5]. SURMOUNT-5 and SURPASS-2 compared them head-to-head as alternatives, not as a stack [1][2]. ## Frequently asked questions **Is tirzepatide stronger than semaglutide for weight loss?** In the only head-to-head obesity trial, SURMOUNT-5, tirzepatide at the maximum tolerated dose (10 or 15 mg) reduced weight by 20.2% versus 13.7% with semaglutide (1.7 or 2.4 mg) at 72 weeks, and more participants reached 10%, 15%, 20% and 25% reductions [1]. **Which has more side effects, semaglutide or tirzepatide?** In SURPASS-2, gastrointestinal event rates were similar: nausea 17–22% with tirzepatide and 18% with semaglutide; diarrhea 13–16% and 12%; vomiting 6–10% and 8%. Serious adverse events were reported in 5–7% versus 3% [2]. In SURMOUNT-5, gastrointestinal events were the most common in both groups and mostly mild to moderate [1]. **Which has proven cardiovascular benefit?** Semaglutide's SELECT trial showed a 20% relative reduction in major cardiovascular events in people with cardiovascular disease and overweight or obesity but no diabetes [3]. Mounjaro's label includes reducing major cardiovascular events in adults with type 2 diabetes at high risk [5]. **What is the difference between Ozempic and Mounjaro?** Ozempic contains semaglutide, a GLP-1 receptor agonist [4]; Mounjaro contains tirzepatide, a GIP and GLP-1 receptor agonist [5]. Both are labeled for type 2 diabetes. Their weight-management counterparts are Wegovy and Zepbound [18][15]. **Do people regain weight after stopping either drug?** Yes, in both programs. After stopping semaglutide, STEP 1 participants regained about two-thirds of the lost weight within a year [21]. In SURMOUNT-4, switching from tirzepatide to placebo led to a 14.0% regain [22]. **Is there a tablet form?** For semaglutide, yes: Rybelsus and Ozempic tablets are approved for type 2 diabetes [12]. The tirzepatide products in Drugs@FDA are injections [8][9]. **Can you take semaglutide and tirzepatide together?** No published trial among the sources we cite tested them as a combination. Both act on the GLP-1 receptor (tirzepatide also on GIP), and each product label is written for monotherapy [4][5]. SURMOUNT-5 and SURPASS-2 compared them head-to-head as alternatives, not as a stack [1][2]. ## Sources [1] Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. Aronne LJ et al. N Engl J Med. 2025. https://pubmed.ncbi.nlm.nih.gov/40353578/ [2] Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. Frías JP et al. N Engl J Med. 2021. https://pubmed.ncbi.nlm.nih.gov/34170647/ [3] Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. Lincoff AM et al. N Engl J Med. 2023. https://pubmed.ncbi.nlm.nih.gov/37952131/ [4] OZEMPIC prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-07-30. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=42bdd912-2393-44c4-b7e0-47672ca28991 [5] MOUNJARO, MOUNJARO KWIKPEN prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-08-27. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0 [6] Drugs@FDA: OZEMPIC (NDA209637). NOVO; original approval 2017-12-05; Prescription, Discontinued. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=209637 [7] Drugs@FDA: WEGOVY, WEGOVY HD, WEGOVY FLEXTOUCH (NDA215256). NOVO; original approval 2021-06-04; Prescription. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=215256 [8] Drugs@FDA: MOUNJARO, MOUNJARO KWIKPEN, MOUNJARO (AUTOINJECTOR) (NDA215866). ELI LILLY AND CO; original approval 2022-05-13; Prescription. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=215866 [9] Drugs@FDA: ZEPBOUND, ZEPBOUND KWIKPEN, ZEPBOUND (AUTOINJECTOR) (NDA217806). ELI LILLY AND CO; original approval 2023-11-08; Prescription. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=217806 [10] Pharmacokinetics and Clinical Implications of Semaglutide: A New Glucagon-Like Peptide (GLP)-1 Receptor Agonist. Hall S et al. Clin Pharmacokinet. 2018. https://pubmed.ncbi.nlm.nih.gov/29915923/ [11] Population pharmacokinetics of the GIP/GLP receptor agonist tirzepatide. Schneck K & Urva S CPT Pharmacometrics Syst Pharmacol. 2024. https://pubmed.ncbi.nlm.nih.gov/38356317/ [12] OZEMPIC, RYBELSUS prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-01-30. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=27f15fac-7d98-4114-a2ec-92494a91da98 [13] Once-Weekly Semaglutide in Adults with Overweight or Obesity. Wilding JPH et al. N Engl J Med. 2021. https://pubmed.ncbi.nlm.nih.gov/33567185/ [14] Tirzepatide Once Weekly for the Treatment of Obesity. Jastreboff AM et al. N Engl J Med. 2022. https://pubmed.ncbi.nlm.nih.gov/35658024/ [15] ZEPBOUND, ZEPBOUND KWIKPEN prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-08-28. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=487cd7e7-434c-4925-99fa-aa80b1cc776b [16] Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Garvey WT et al. Nat Med. 2022. https://pubmed.ncbi.nlm.nih.gov/36216945/ [17] Tirzepatide for Obesity Treatment and Diabetes Prevention. Jastreboff AM et al. N Engl J Med. 2025. https://pubmed.ncbi.nlm.nih.gov/39536238/ [18] WEGOVY prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2024-04-23. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f5e548d0-cc79-4c34-a3f5-e20a5b8b6564 [19] Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. Malhotra A et al. N Engl J Med. 2024. https://pubmed.ncbi.nlm.nih.gov/38912654/ [20] Clinical Pharmacokinetics of Semaglutide: A Systematic Review. Yang XD & Yang YY Drug Des Devel Ther. 2024. https://pubmed.ncbi.nlm.nih.gov/38952487/ [21] Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Wilding JPH et al. Diabetes Obes Metab. 2022. https://pubmed.ncbi.nlm.nih.gov/35441470/ [22] Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. Aronne LJ et al. JAMA. 2024. https://pubmed.ncbi.nlm.nih.gov/38078870/ [23] Drugs@FDA: OZEMPIC, RYBELSUS (NDA213051). NOVO; original approval 2019-09-20; Prescription. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=213051 [24] FDA clarifies policies for compounders as national GLP-1 supply begins to stabilize. U.S. FDA, content current as of 04/01/2026. https://www.fda.gov/drugs/drug-alerts-and-statements/fda-clarifies-policies-compounders-national-glp-1-supply-begins-stabilize --- From Residue. Research and education only; not medical advice. Quote with attribution and a link to the canonical page.