Semaglutide vs tirzepatide

These are the two molecules behind the four brand names people actually search for. Semaglutide is in Ozempic and Wegovy. Tirzepatide is in Mounjaro and Zepbound. In each pair, one product is approved for type 2 diabetes and the other for chronic weight management.

How they differ

Semaglutide is a GLP-1 receptor agonist. It mimics a gut hormone released after eating, which signals fullness, slows stomach emptying and affects appetite.

Tirzepatide does that and one more thing. It acts on the GIP receptor as well, a second gut hormone pathway. That dual action is the leading explanation for why it tends to produce larger results.

Neither is a stimulant, and neither works by speeding up metabolism.

The head to head

Most drug comparisons rely on stitching together separate trials, which is unreliable because trial populations and designs differ. Here there is something better.

In 2025 the New England Journal of Medicine published a trial comparing tirzepatide with semaglutide directly for the treatment of obesity. Tirzepatide produced greater weight loss.

That is the single most reliable comparison available, and it points one way.

The numbers from the separate trials

A 2025 meta-analysis of GLP-1 medicines for weight management gives the wider picture:

Different trials, different durations, so treat this as a rough ordering rather than a precise ranking. The head to head is the stronger evidence.

For context on what semaglutide achieves on its own: in its main obesity trial, semaglutide 2.4 mg produced 14.9 percent average weight loss against 2.4 percent on placebo, with 86.4 percent reaching at least 5 percent loss, 69.1 percent reaching 10 percent, and 50.5 percent reaching 15 percent.

Where semaglutide leads

Cardiovascular outcomes. In the SELECT trial, semaglutide 2.4 mg reduced a combined endpoint of cardiovascular death, non-fatal heart attack and non-fatal stroke, hazard ratio 0.80 (95 percent confidence interval 0.72 to 0.90), with 6.5 percent of the semaglutide group having an event against 8.0 percent on placebo over a mean of just under 40 months.

A meta-analysis of GLP-1 agonists also found reductions in all-cause mortality, relative risk 0.83 (0.72 to 0.94), and myocardial infarction, relative risk 0.73 (0.62 to 0.87), with no significant difference in cardiovascular mortality specifically.

Tirzepatide's weight loss results are larger. Semaglutide's outcome evidence is longer established. Those are two different questions.

Side effects

Similar across the class and dominated by the gut. Across trials, gastrointestinal events were reported by 47 to 84 percent of participants on a GLP-1 medicine against 13 to 63 percent on placebo. Nausea, vomiting, diarrhoea and constipation, mostly during dose escalation, decreasing over time.

Overall adverse events ran 80 to 97 percent on the medicines against 63 to 100 percent on placebo, which tells you that "had a side effect" is close to universal in both arms and not a useful number on its own.

Serious adverse events were rare, 0 to 10 percent against 0 to 12 percent on placebo, and in one meta-analysis there was no difference between GLP-1 agonists and placebo.

Both molecules carry a boxed warning for thyroid C-cell tumours.

Body composition, honestly

Weight loss on these medicines is not all fat. In a body composition analysis of liraglutide at 20 weeks, body fat fell 15.4 percent while lean tissue fell 2.0 percent. So lean mass does decrease, considerably less than fat mass in that study.

The practical implication that shows up repeatedly in the literature is resistance training and adequate protein during weight loss. That is a conversation for a clinician who knows your situation.

Stopping

The same for both. A meta-analysis of 11 studies covering 12,539 people found that after stopping a high dose GLP-1 medicine, 50 to 65 percent of the lost weight returned within twelve months, most of it in the first three to six months.

What this adds up to

If the question is purely how much weight, the evidence favours tirzepatide, and the head to head trial is the reason that is a statement rather than an impression.

If the question includes cardiovascular risk, semaglutide has the outcome trial.

If the question is which one you should take, that depends on your history and your coverage, and it is a clinical decision.

What to ask

• Which molecule am I being prescribed, and in which brand and indication?
• Does my situation include cardiovascular risk that should influence the choice?
• What is the titration schedule and how long until I reach the target dose?
• What is the plan for maintaining muscle during weight loss?
• What happens if I stop?

Sources

• Tirzepatide as compared with semaglutide for the treatment of obesity. New England Journal of Medicine, 2025. doi:10.1056/NEJMoa2416394
• Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine, 2022. doi:10.1056/nejmoa2206038
• Once-weekly semaglutide in adults with overweight or obesity (STEP 1). New England Journal of Medicine, 2021
• Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). New England Journal of Medicine, 2023
• Efficacy and safety of GLP-1 receptor agonists for weight management, systematic review and meta-analysis, 2025
• Effect of GLP-1 receptor agonists and co-agonists on body composition, systematic review and network meta-analysis. Metabolism, 2024. doi:10.1016/j.metabol.2024.156113
• Weight regain after discontinuation of high dose GLP-1 receptor agonists, meta-analysis of 11 studies, 2026

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Keep reading

The brand level comparison of the two weight management products, at /guides/wegovy-vs-zepbound.

The new oral option and how it compares, at /guides/orforglipron.