Journal

Tirzepatide vs Semaglutide: What the Head-to-Head Trial Shows

Explain population, doses and limitations

Why a head-to-head trial matters

Until 2025 the comparison between these two drugs was made by putting separate placebo-controlled trials side by side. That is a weak method. Trials differ in eligibility criteria, in background lifestyle support, in geography, in how missing data is handled, and in the estimand used to report the result. Two trials can produce different numbers for reasons that have nothing to do with the drugs.

SURMOUNT-5 removed that problem by randomising the same population to both.

What was done

A phase 3b, open-label, active-controlled trial at 32 sites across the United States and Puerto Rico, running from April 2023 to November 2024. It enrolled 751 adults with obesity — BMI 30 or above, or 27 or above with at least one obesity-related complication — and without type 2 diabetes, randomised 1:1.

Both arms were titrated to maximum tolerated dose: tirzepatide 10 mg or 15 mg, semaglutide 1.7 mg or 2.4 mg, both once weekly by subcutaneous injection for 72 weeks. The primary endpoint was percentage change in body weight at week 72.

What was found

Least-squares mean weight change was −20.2% with tirzepatide and −13.7% with semaglutide. In absolute terms, −22.8 kg against −15.0 kg, a difference of roughly 7.8 kg. Waist circumference fell 18.4 cm against 13.0 cm. More participants on tirzepatide reached each weight-reduction threshold from 10% upward.

On safety, adverse events were mostly gastrointestinal and mild to moderate in both arms. Serious adverse events occurred in 4.8% of the tirzepatide group and 3.5% of the semaglutide group. Six participants in each group discontinued because of adverse events.

How to read this without over-reading it

Open-label is a real limitation. Neither participants nor investigators were blinded. For a subjective outcome that would be disqualifying; for body weight measured on a scale it matters less, but it is not nothing, because unblinding can influence adherence and dropout.

Maximum tolerated dose is not fixed dose. The design compares two titration strategies rather than two specific doses, which is arguably more clinically realistic and also makes the comparison less clean.

The sponsor makes one of the drugs. Eli Lilly funded the trial comparing its product against a competitor's. That does not make the result wrong — it is published, registered and peer-reviewed — but it belongs in any honest summary.

It excludes people with type 2 diabetes, in whom weight outcomes for both drugs are typically smaller.

What it does not establish

It does not establish what will happen to you. A 20.2% group mean contains people who lost far more and people who lost far less, and the trial population may not resemble you.

It does not establish anything about compounded preparations. Both arms used approved products at studied doses. A compounded preparation at a different concentration or route has not been through this trial or any other, and citing SURMOUNT-5 to sell a compounded product is a category error, however common it has become.

It does not establish long-term outcomes. Seventy-two weeks is long for an obesity trial and short for a chronic condition.

Sources

• Aronne LJ et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med 2025;393(1):26–36. DOI 10.1056/NEJMoa2416394. ClinicalTrials.gov NCT05822830.

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