Semaglutide vs Tirzepatide: What the Trials Found

What is the difference between semaglutide and tirzepatide?

Semaglutide is an analog of one gut hormone, glucagon-like peptide-1, and acts on the GLP-1 receptor alone. Tirzepatide is built on the sequence of a second gut hormone, glucose-dependent insulinotropic polypeptide, and activates both the GIP and GLP-1 receptors. That receptor difference is the whole pharmacological distinction; the rest of the engineering is similar. Both are once-weekly injections in which an aminoisobutyric acid substitution blocks DPP-4, the enzyme that clears the natural hormones, and a fatty diacid side chain binds albumin to stretch the half-life to about a week for semaglutide and 5 to 6 days for tirzepatide.

Semaglutide is sold as Ozempic and Rybelsus for type 2 diabetes and as Wegovy injection and Wegovy tablets for weight management. Tirzepatide is sold as Mounjaro for type 2 diabetes and as Zepbound for weight management and obstructive sleep apnea. The chemistry cards, label schedules and every trial cited here are on the semaglutide and tirzepatide compound pages.

Semaglutide

GLP-1 receptor agonist

31 residues, 4,114 g/mol, C18 fatty diacid on lysine 20, half-life about 1 week.

Tirzepatide

GIP and GLP-1 receptor agonist

39 residues, 4,813 g/mol, C20 fatty diacid on lysine 20, half-life 5 to 6 days.

Shared design

Aib at position 2

Blocks DPP-4 cleavage; the albumin-binding chain does the rest.

Shared warning

Thyroid C-cell tumors

Boxed warning on every label of both drugs, from rodent findings.

What did the STEP and SURMOUNT trials find?

The two phase 3 obesity programs were run separately, in different populations, over different lengths, so their headline figures are not a direct comparison. In STEP 1, 1,961 adults without diabetes on semaglutide 2.4 mg lost a mean 14.9% of body weight at 68 weeks against 2.4% on placebo, and 86.4% lost at least 5%. In SURMOUNT-1, 2,539 adults without diabetes lost 15.0%, 19.5% and 20.9% on tirzepatide 5, 10 and 15 mg at 72 weeks against 3.1% on placebo, and just over half of the two higher-dose groups lost a fifth of their body weight. Both drugs do less in people with type 2 diabetes: SURMOUNT-2 reported 12.8% and 14.7% on 10 and 15 mg.

Semaglutide's ceiling has since moved. The STEP UP trial of 7.2 mg weekly reported 18.7% at 72 weeks under the treatment policy estimand against 15.6% for 2.4 mg, with gastrointestinal events in 70.8% of the high-dose group and altered skin sensation in 22.9%. The 7.2 mg dose is now on the Wegovy label, but it is not the dose that was compared with tirzepatide head to head.

What did the head-to-head SURMOUNT-5 trial show?

SURMOUNT-5 randomized 751 adults with obesity, or overweight plus a weight-related condition, without diabetes, to the maximum tolerated dose of tirzepatide, 10 or 15 mg, or of semaglutide, 1.7 or 2.4 mg, for 72 weeks. Weight fell 20.2% on tirzepatide and 13.7% on semaglutide. Waist circumference fell 18.4 cm against 13.0 cm, and more tirzepatide participants reached every threshold from 10% to 25% weight loss. The trial was open label, which matters for a self-reported outcome less than for a scale reading, and gastrointestinal effects clustered during escalation in both arms. The comparator was the 2.4 mg Wegovy dose, so the result says nothing about 7.2 mg.

What did SURPASS-2 show in type 2 diabetes?

SURPASS-2 enrolled 1,879 adults with type 2 diabetes on metformin, with a mean HbA1c of 8.28%, and compared tirzepatide 5, 10 and 15 mg with semaglutide 1 mg over 40 weeks. HbA1c fell 2.01, 2.24 and 2.30 percentage points on the three tirzepatide doses against 1.86 on semaglutide, and weight fell 1.9, 3.6 and 5.5 kg more. Blood glucose below 54 mg/dL occurred in 0.2% to 1.7% of tirzepatide participants. Two cautions apply. The semaglutide arm used 1 mg, half the 2 mg Ozempic maximum, and gastrointestinal events were similar in kind and frequency across the two drugs, so the comparison is about effect size, not tolerability.

How do the approved escalation schedules compare?

Both labels escalate every four weeks and both say why: to limit nausea, vomiting, diarrhea and constipation while blood levels settle. The Wegovy label runs 0.25, 0.5, 1 and 1.7 mg for four weeks each to a 2.4 mg maintenance dose, with 7.2 mg available to adults who have tolerated 2.4 mg for at least four weeks and need further weight reduction. Ozempic uses the same opening steps and stops at 2 mg. The Zepbound and Mounjaro labels start at 2.5 mg for four weeks, then rise in 2.5 mg steps no sooner than every four weeks to a 15 mg maximum, with 5, 10 and 15 mg named as maintenance doses; 2.5 mg is an initiation dose only. Neither label describes a cycle, a break or a taper.

What happens when treatment stops?

Both programs ran a withdrawal study and both found the same thing. In the STEP 1 extension, participants who had lost 17.3% by week 68 regained 11.6 percentage points of it in the year after stopping, and cardiometabolic measures drifted back with the weight. In SURMOUNT-4, people switched to placebo after 36 weeks of tirzepatide regained 14.0% over the next 52 weeks while those who continued lost a further 5.5%. The labels describe open-ended treatment for this reason. Over longer exposure the cost shows up as discontinuation: in the SELECT cardiovascular trial, 17,604 adults on semaglutide 2.4 mg for a mean of 34 months saw a 20% relative reduction in major cardiovascular events, and 16.6% stopped permanently for adverse events against 8.2% on placebo.

What safety warnings do the two drugs share?

Every label for both drugs opens with the same boxed warning. In rodents, each causes dose-dependent and duration-dependent thyroid C-cell tumors at clinically relevant exposures; whether either does so in humans is unknown, and both are contraindicated in people with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2. Gastrointestinal effects are the most common adverse events for both, concentrated during escalation. The tirzepatide labels add acute gallbladder disease in 0.6% of treated adults against none on placebo, and note that about half of patients develop anti-tirzepatide antibodies, in whom injection site reactions and hypersensitivity were more common.

Why do gray-market vials cause so much confusion?

The approved pens remove arithmetic: a Zepbound pen delivers its dose in a fixed 0.5 mL and a Wegovy pen is prefilled with one dose. Compounded and gray-market vials do not. Semaglutide vials circulate at 2.5 and 5 mg/mL and tirzepatide vials at anything from 5 to 20 mg/mL, so the same milligram dose corresponds to a different number of syringe units depending on the vial. On July 26, 2024 the FDA reported adverse events, some requiring hospitalization, from people who drew 5 to 20 times their intended dose of compounded semaglutide from multi-dose vials, and from prescribers who miscalculated the conversion from milligrams to units or milliliters by 5 to 10 times. The agency later declared the semaglutide shortage resolved and narrowed the conditions under which copies may be compounded.

1. 1
   Find the concentration

   It is printed on the vial or set by the water added: 5 mg in 2 mL is 2.5 mg/mL.

2. 2
   Divide the dose by it

   0.25 mg ÷ 2.5 mg/mL = 0.1 mL. The same 0.25 mg at 5 mg/mL is 0.05 mL.

3. 3
   Convert to U-100 units

   mL × 100: 0.1 mL is 10 units, 0.05 mL is 5 units. A tirzepatide 2.5 mg dose is 25 units at 10 mg/mL and 12.5 units at 20 mg/mL.

4. 4
   Reverse check

   Units ÷ 100 × concentration must give the dose back; the FDA reports show what happens when it is skipped.

The calculator performs that division and the reverse check, and the reconstitution guide covers the water volume step. What no calculation can do is confirm that an unlabeled vial contains the concentration claimed, which is the problem the FDA alert describes.

What this comparison does not establish

The trials show that tirzepatide produced larger mean weight and HbA1c reductions than the semaglutide doses it was compared against. They do not show which drug is right for a given person, how either performs at semaglutide 7.2 mg, how tirzepatide compares on cardiovascular outcomes, or what any gray-market vial contains. Retatrutide, which adds a third receptor, is covered in the retatrutide guide, and the wider class in the metabolic research guide. The full label and trial tables, each row linked to its source, are on the semaglutide and tirzepatide compound pages.