Tirzepatide acts on GLP-1 and GIP receptors. This article covers the weight trials, the head-to-head trial against semaglutide, the sleep apnea trials, what happens when treatment is stopped, and how the dose is built up.
Weight: SURMOUNT-1
SURMOUNT-1 randomized 2,539 adults with obesity, or overweight with a weight-related condition, and no diabetes, to 5, 10 or 15 mg weekly or placebo for 72 weeks, including a 20-week dose escalation. The mean change was -15.0% at 5 mg, -19.5% at 10 mg and -20.9% at 15 mg, against -3.1% on placebo (intention to treat; SURMOUNT-1, NEJM 2022). At 15 mg, 57% of participants lost at least 20% of their weight, against 3% on placebo.
Against semaglutide: SURMOUNT-5
SURMOUNT-5 gave 751 adults without diabetes the maximum tolerated dose of tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg) weekly for 72 weeks. The mean change was -20.2% with tirzepatide and -13.7% with semaglutide (SURMOUNT-5, NEJM 2025). The trial was open label, so participants and staff knew which drug they were taking.
Sleep apnea: SURMOUNT-OSA
Two trials enrolled adults with obesity and moderate to severe obstructive sleep apnea: trial 1 in people not using positive airway pressure (PAP), and trial 2 in people already using it. Over 52 weeks, the mean change in apnea-hypopnea events per hour was -25.3 with tirzepatide and -5.3 with placebo in trial 1, and -29.3 and -5.5 in trial 2 (SURMOUNT-OSA, NEJM 2024).
What happens when it stops: SURMOUNT-4
SURMOUNT-4 first gave 36 weeks of open-label tirzepatide at the maximum tolerated dose, then randomized 670 people to continue it or switch to placebo for 52 weeks. From week 36 to week 88 the mean change was -5.5% with continued tirzepatide and +14.0% with placebo. Of those who continued, 89.5% kept at least 80% of their lead-in weight loss, against 16.6% on placebo (SURMOUNT-4, JAMA 2024).
The dose ladder
The label starts at 2.5 mg once weekly for four weeks, then moves to 5 mg after four weeks. Later increases are in 2.5 mg steps, each after at least four weeks on the current dose. The maximum recommended dose for all indications is 15 mg once weekly (Zepbound prescribing information, DailyMed).
Side effects
- Most adverse events in SURMOUNT-1 were gastrointestinal, mild to moderate, and occurred mostly during dose escalation.
- Adverse events caused stopping in 4.3%, 7.1% and 6.2% of participants on 5, 10 and 15 mg, against 2.6% on placebo (SURMOUNT-1, NEJM 2022).
- In SURMOUNT-4, gastrointestinal events were more common with tirzepatide than with placebo (SURMOUNT-4, JAMA 2024).
What this does not say
- The figures are for the injected product at the studied doses. They are averages, not predictions. Compounded tirzepatide and the sublingual form were not studied in these trials.
- SURMOUNT-5 was open label and sponsored by the manufacturer; an independent check is needed before reading it as proof of superiority.
- The weight trials ran 72 weeks and the sleep apnea trials 52 weeks. Long-term outcomes such as heart events are not in these sources.
How we use this
Our physicians start tirzepatide on the labeled ladder and adjust it to you. Because SURMOUNT-4 shows regain after stopping, we talk about what happens after the goal is reached before you start, not after.
If you want to compare it with semaglutide, bring the head-to-head trial to your consultation and ask which fits your history.
Explore weight loss treatmentsSources
- 1.Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med 2022. NEJM
- 2.Aronne LJ et al. Tirzepatide as compared with semaglutide for the treatment of obesity (SURMOUNT-5). N Engl J Med 2025. NEJM
- 3.Tirzepatide for the treatment of obstructive sleep apnea and obesity (SURMOUNT-OSA). N Engl J Med 2024. NEJM
- 4.Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity (SURMOUNT-4). JAMA 2024. JAMA
- 5.Zepbound (tirzepatide) injection, prescribing information, dosage and administration. DailyMed