Tirzepatide vs semaglutide: one receptor or two

Tirzepatide and semaglutide are the two best-known incretin peptides. Both are long-acting and given once a week in trials. The main difference is how many receptors each one targets. This comparison sets out how they differ, and what the published trials measured.

Tirzepatide vs semaglutide at a glance

• Semaglutide: a 31-amino-acid analogue of GLP-1, about 4,114 daltons. It acts on one receptor, the GLP-1 receptor.
• Tirzepatide: a 39-amino-acid peptide, about 4,814 daltons. It acts on two receptors, the GIP receptor and the GLP-1 receptor.
• Both carry a fatty acid side chain that binds albumin in the blood. This gives each a half-life of about five to seven days.

Structure

Semaglutide is built on the sequence of human GLP-1. Two changes protect it from the enzyme that breaks down natural GLP-1. A C18 fatty acid chain lets it bind albumin.

Tirzepatide is built on the sequence of GIP, with changes that let it activate the GLP-1 receptor too. It carries a C20 fatty acid chain for the same albumin binding. Our post What is tirzepatide? covers its structure in more detail.

What the trials measured

Both peptides went through large placebo-controlled trials in adults with obesity and without type 2 diabetes.

• STEP 1 (semaglutide): body weight changed by -14.9% over 68 weeks, against -2.4% with placebo (N Engl J Med, 2021).
• SURMOUNT-1 (tirzepatide): body weight changed by -15.0% to -20.9% over 72 weeks, depending on the dose arm, against -3.1% with placebo (N Engl J Med, 2022).

Those trials had different designs, so their numbers can't be compared directly. SURMOUNT-5 compared the two in one trial. It randomised 751 adults with obesity and without diabetes to the highest tolerated weekly dose of either peptide for 72 weeks. Body weight changed by -20.2% with tirzepatide and -13.7% with semaglutide. Waist size changed by -18.4 cm and -13.0 cm. In both groups, the most common side effects were gastrointestinal. The trial was open-label and funded by the maker of tirzepatide (N Engl J Med, 2025).

These are results from clinical trials of approved medicines, under medical supervision. They say nothing about research-grade material.

Where the research goes next

Retatrutide adds a third target, the glucagon receptor. Our post Retatrutide vs tirzepatide compares the two. For the longer story, see the history of incretin peptide research.

Questions people ask

Is tirzepatide the same as semaglutide?

No. They are different peptides. Semaglutide acts on the GLP-1 receptor only. Tirzepatide acts on the GIP and GLP-1 receptors.

Which one lowered weight more in trials?

In SURMOUNT-5, the only head-to-head trial so far, the tirzepatide group lost more weight on average over 72 weeks. That trial was open-label and funded by the maker of tirzepatide.

Does Peptune sell semaglutide?

No. Peptune supplies tirzepatide and retatrutide for laboratory research.

Ordering in Canada

Peptune supplies tirzepatide and retatrutide as research vials. Orders ship across Canada by tracked mail, free on orders of $150 or more.

For laboratory research use only. Nothing in this article is medical advice or a suggestion to use any compound on people or animals.