Semaglutide vs tirzepatide

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-14. Tirzepatide acts on two, GIP and GLP-15. 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 endpoint1,2.

That is not the whole picture. Semaglutide has the larger and longer outcomes record — notably SELECT, a 17,604-person trial in people without diabetes3 — and an oral form12. 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 weight1.

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 period1.

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 developer1. Neither invalidates the finding, but both are standard caveats our 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 kg2.

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 semaglutide2.

The semaglutide dose matters here: 1 mg was the comparator, which is below the 2.4 mg dose used in the semaglutide obesity program13. 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%)1616PubMedTwo-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Garvey WT et al. Nat Med. 2022..

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 more14. In the participants with prediabetes followed for three years, 1.3% developed type 2 diabetes on tirzepatide versus 13.3% on placebo1717PubMedTirzepatide for Obesity Treatment and Diabetes Prevention. Jastreboff AM et al. N Engl J Med. 2025..

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 indication1818FDAWEGOVY prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2024-04-23..

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 risk5. Zepbound carries an indication semaglutide's labels do not — moderate-to-severe obstructive sleep apnea in adults with obesity15, based on trials in which the apnea–hypopnea index fell by 25.3–29.3 events per hour1919PubMedTirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. Malhotra A et al. N Engl J Med. 2024.. Ozempic, in turn, is indicated to reduce kidney-disease progression and cardiovascular death in type 2 diabetes with chronic kidney disease4.

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-114, and 16.6% on semaglutide versus 8.2% on placebo in the much longer SELECT trial3. 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 information18,15.

How long does each last in the body?

Semaglutide's half-life is about seven days, so steady state takes four to five weeks10. Tirzepatide's is about five days in a population model pooled from 19 studies11. 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 conditions2020PubMedClinical Pharmacokinetics of Semaglutide: A Systematic Review. Yang XD & Yang YY Drug Des Devel Ther. 2024..

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 lost2121PubMedWeight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Wilding JPH et al. Diabetes Obes Metab. 2022.. 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%2222PubMedContinued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. Aronne LJ et al. JAMA. 2024..

Are they FDA-approved?

Both molecules are FDA-approved. Semaglutide is marketed as Ozempic and Wegovy injections and Rybelsus and Ozempic tablets6,7,2323FDADrugs@FDA: OZEMPIC, RYBELSUS (NDA213051). NOVO; original approval 2019-09-20; Prescription.; tirzepatide as Mounjaro and Zepbound8,9. FDA's April 2026 statement says neither is on the drug-shortage list or the 503B bulks list, which restricts compounding2424FDAFDA clarifies policies for compounders as national GLP-1 supply begins to stabilize. U.S. FDA, content current as of 04/01/2026..

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 monotherapy4,5. SURMOUNT-5 and SURPASS-2 compared them head-to-head as alternatives, not as a stack1,2.