Semaglutide vs tirzepatide: what the trials show

Semaglutide and tirzepatide are both FDA-approved medicines given as once-weekly injections (semaglutide also comes as a daily tablet), but they work differently: semaglutide activates the GLP-1 receptor, while tirzepatide activates both the GIP and GLP-1 receptors. In SURMOUNT-5, the head-to-head trial in adults with obesity and no diabetes, average weight loss over 72 weeks was 20.2% with tirzepatide and 13.7% with semaglutide. Which medicine fits you is your prescriber’s call, based on your health, your other conditions and each drug’s approved uses.

If you inject from a vial, the tirzepatide units calculator and the semaglutide units calculator turn the dose your prescriber gave you into syringe units. Units depend on the mg/mL printed on your own vial or pen, so a number of units for one medicine never carries over to the other.

How they work

Semaglutide is a modified version (analogue) of the gut hormone GLP-1, with “94% sequence homology to human GLP-1,” that “selectively binds to and activates the GLP-1 receptor” (Wegovy label). GLP-1 helps regulate appetite and how much you eat.

Tirzepatide is a single molecule that “selectively binds to and activates both the GIP and GLP-1 receptors.” GIP is a second gut hormone, and the label says nonclinical studies “suggest the addition of GIP may further contribute to the regulation of food intake” (Zepbound label).

Both raise insulin release and lower glucagon in a glucose-dependent way, more when blood sugar is high (Mounjaro label, Ozempic label). Both bind to albumin in the blood, which prolongs their half-life: about 1 week for semaglutide and about 5 to 6 days for tirzepatide (Ozempic label, Mounjaro label, Zepbound label).

Brands and approved uses

Novo Nordisk makes every approved semaglutide product, and Eli Lilly makes both tirzepatide products. This is what the current FDA labels approve, checked on October 16, 2026:

Sources: the Ozempic, Wegovy, Rybelsus and Ozempic tablets, Mounjaro and Zepbound labels.

They aren’t meant to be combined. Zepbound’s label says use “with any GLP-1 receptor agonist is not recommended” (Zepbound label), and Wegovy’s says the same about other semaglutide products and any other GLP-1 receptor agonist (Wegovy label).

How often, and how they’re supplied

• Tirzepatide is injected under the skin once a week. Mounjaro and Zepbound come in the same presentations: single-dose pens, single-dose vials, and multi-dose vials and KwikPens that each hold 4 doses (Mounjaro label, Zepbound label).
• Semaglutide injections are also once a week. Ozempic comes in multi-dose pens and single-dose prefilled syringes; Wegovy in single-dose pens and syringes and a 4-dose FlexTouch pen (Ozempic label, Wegovy label).
• Semaglutide tablets are taken once a day, in the morning on an empty stomach with up to 4 ounces of water, and the label says to wait at least 30 minutes before food, drinks or other pills. Rybelsus and Ozempic tablets “are not substitutable on a mg-to-mg basis” (tablet label).

The injection labels start low and raise the dose in steps at least 4 weeks apart. Follow your prescriber: they set your schedule. The missed-dose rules differ by brand; see what to do if you miss a GLP-1 dose.

SURMOUNT-5: the head-to-head trial

SURMOUNT-5 randomly assigned 751 adults to tirzepatide or semaglutide injections once a week for 72 weeks (Aronne et al., 2025). Everyone had a BMI of 30 or more, or 27 or more with high blood pressure, high cholesterol, sleep apnea or heart disease, and none had diabetes (ClinicalTrials.gov). Each person’s dose was raised to the highest one they tolerated within the trial’s range.

What the trial found at week 72:

• Weight: an average change of −20.2% with tirzepatide and −13.7% with semaglutide (Aronne et al., 2025).
• Waist: −18.4 cm and −13.0 cm (Aronne et al., 2025).
• Losing at least 20% of body weight: 55.0% and 31.1% of people with week-72 data (318 in each group) (ClinicalTrials.gov).
• Losing at least 25%: 36.5% and 18.6% of the same people (ClinicalTrials.gov).
• Side effects: mostly digestive, mostly mild to moderate, and mainly while doses were being increased (Aronne et al., 2025).

The authors concluded that tirzepatide was “superior to treatment with semaglutide with respect to reduction in body weight and waist circumference at week 72” (Aronne et al., 2025).

What SURMOUNT-5 doesn’t tell you

• It was open-label. Participants and investigators knew who got which drug (Aronne et al., 2025).
• Eli Lilly funded it, and several authors work for Lilly (Aronne et al., 2025).
• Nobody in it had diabetes, so it doesn’t directly apply to type 2 diabetes. That comparison is SURPASS-2, below.
• It measured weight and waist size, not heart attacks, strokes or kidney outcomes.
• It tested semaglutide up to 2.4 mg. The current Wegovy label also includes a 7.2 mg dose for weight reduction in adults, which the trial didn’t test (Wegovy label).
• The numbers are averages over 72 weeks. About 15% of each group (113 people in all) left the study early (ClinicalTrials.gov).
• It doesn’t cover compounded versions. Compounded drugs “are not FDA-approved,” and the FDA “does not verify the safety, effectiveness or quality” of them before they’re marketed (FDA). See compounded semaglutide or tirzepatide.

In type 2 diabetes: SURPASS-2

SURPASS-2 compared three tirzepatide doses with one semaglutide dose (1 mg) in 1,879 adults with type 2 diabetes for 40 weeks (Frías et al., 2021). HbA1c fell by 2.01 to 2.30 percentage points with tirzepatide and 1.86 with semaglutide, and weight loss was 1.9 to 5.5 kg greater with tirzepatide. It was also open-label and Lilly-funded, and it didn’t test the 2 mg semaglutide dose now on the Ozempic label (Ozempic label).

Why separate trials can’t be lined up

You’ll often see numbers from two different trials set side by side. STEP 1 found −14.9% with semaglutide vs −2.4% on placebo at 68 weeks (Wilding et al., 2021); SURMOUNT-1 found −15.0% to −20.9% with tirzepatide vs −3.1% on placebo at 72 weeks (Jastreboff et al., 2022). Different lengths, participants and placebo groups make that gap an unfair comparison, which is why SURMOUNT-5 matters.

The same goes for the heart approvals. Mounjaro’s rests on SURPASS-CVOT, which compared tirzepatide with another GLP-1 medicine, dulaglutide, in type 2 diabetes (Nicholls et al., 2025). Wegovy’s rests on SELECT, which compared semaglutide with placebo in people without diabetes (Lincoff et al., 2023). Neither compared the two drugs.

Side effects

Both medicines carry the same boxed warning: they caused thyroid C-cell tumors in rodents, and it’s unknown whether they do in people. The labels say neither may be used by anyone with a personal or family history of medullary thyroid carcinoma or with MEN 2. The most common side effects on every label are digestive: nausea, diarrhea, vomiting, constipation and stomach pain. Zepbound’s list also includes injection-site reactions and hair loss (Zepbound label); Wegovy’s includes unusual skin sensations (dysesthesia), headache and hair loss (Wegovy label).

In SURMOUNT-5, the registry reports these counts among people who got at least one dose (374 on tirzepatide, 376 on semaglutide) (ClinicalTrials.gov):

• Nausea: 44% and 44%.
• Constipation: 27% and 28%.
• Diarrhea: 24% and 23%.
• Vomiting: 15% and 21%.
• Acid reflux: 6% and 11%.
• Hair loss: 8% and 6%.
• Injection-site reactions: 9% and 0.3%.
• Serious adverse events: 4.8% and 3.5%. No one died in either group.

The registry lists these without statistical tests, so small gaps may be chance.

Questions people ask