Tirzepatide vs Semaglutide: The Head-to-Head Trial

Medically reviewed by Lauren Orta, FNP-C

In the first head-to-head trial, tirzepatide beat semaglutide for weight loss: 20.2% vs 13.7% of body weight at 72 weeks. Waists shrank 18.4 cm vs 13.0 cm.

TL;DR

• SURMOUNT-5 put the two biggest weight-loss shots against each other in 751 adults with obesity and no diabetes.
• Tirzepatide: 20.2% average weight loss. Semaglutide: 13.7%. That gap was statistically clear (P<0.001).
• Tirzepatide also took about 5 more centimeters (roughly 2 inches) off the waist.
• Side effects were mostly stomach-related for both, and mostly during the dose ramp-up.

What the study did

SURMOUNT-5 was a phase 3b, open-label randomized trial published in the New England Journal of Medicine in 2025 (PubMed 40353578; DOI 10.1056/NEJMoa2416394). It enrolled 751 adults with obesity who did not have type 2 diabetes.

Half got tirzepatide at their maximum tolerated dose (10 or 15 mg weekly). Half got semaglutide at its maximum tolerated dose (1.7 or 2.4 mg weekly). Both were weekly injections for 72 weeks. The main outcome was percent change in body weight. Waist size and the share of people hitting 10%, 15%, 20% and 25% loss were key secondary outcomes.

What it found

• Weight: −20.2% with tirzepatide (95% CI −21.4 to −19.1) vs −13.7% with semaglutide (95% CI −14.9 to −12.6), P<0.001.
• Waist: −18.4 cm with tirzepatide vs −13.0 cm with semaglutide, P<0.001.
• Bigger milestones: people on tirzepatide were more likely to lose at least 10%, 15%, 20% and 25% of their body weight.
• Side effects: mostly gastrointestinal in both groups, mostly mild to moderate, and mostly during dose escalation.

What it means for you

Both drugs work. Tirzepatide worked better here. It acts on two gut-hormone receptors (GLP-1 and GIP) instead of one, which is the leading explanation for the gap. For a guy carrying weight around the middle, the waist number matters as much as the scale: belly fat tracks with blood sugar, blood pressure and, in men, lower testosterone (see weight and testosterone and low T and weight gain).

Other tirzepatide data point the same way. In a 3-year SURMOUNT-1 analysis of adults with prediabetes, 1.3% on tirzepatide developed type 2 diabetes versus 13.3% on placebo (Jastreboff et al., NEJM 2025).

The medication is a tool, not the whole plan. Protein, lifting and sleep decide how much of the loss is fat instead of muscle. Start with how GLP-1 medications work and sustainable weight-loss habits.

The fine print

• The trial used brand-name, FDA-approved tirzepatide and semaglutide. The tirzepatide AZTRT dispenses is a compounded preparation. It is not FDA-approved, and these trial results can't be assumed to carry over to it one-for-one.
• Open-label: patients and doctors knew which drug was used.
• Adults with obesity and no diabetes. People with type 2 diabetes weren't studied here.
• 72 weeks is about 1.4 years. It doesn't tell you what happens after stopping. Other trials show weight tends to return when the drug stops.
• Funded by Eli Lilly, which makes tirzepatide. Several authors are Lilly employees.

FAQ

Is tirzepatide better than semaglutide for weight loss?

In SURMOUNT-5, the first head-to-head trial, tirzepatide produced 20.2% average weight loss vs 13.7% for semaglutide over 72 weeks in adults with obesity and no diabetes.

How much did waist size change?

Waist circumference dropped 18.4 cm on tirzepatide and 13.0 cm on semaglutide, a difference of about 2 inches.

What were the side effects?

Mostly nausea and other stomach effects in both groups, usually mild to moderate and mostly during the dose ramp-up.

Is AZTRT's tirzepatide the same as the one in the trial?

No. AZTRT dispenses a compounded tirzepatide preparation, which is not FDA-approved. The trial tested the brand-name product.

Next step

Thinking about tirzepatide? Get the facts on how we prescribe it in Arizona. See AZTRT tirzepatide, or book a free consult. AZTRT serves men in Arizona through licensed telehealth providers.

Sources

1. Aronne LJ et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5). N Engl J Med. 2025;393(1):26-36. PubMed · DOI
2. Jastreboff AM et al. Tirzepatide for Obesity Treatment and Diabetes Prevention. N Engl J Med. 2025. PubMed · DOI

This article is for education, not medical advice. Treatment decisions are made with a licensed provider after an evaluation and labs. Results vary.