Semaglutide vs tirzepatide vs retatrutide
How the three weekly weight-loss injections differ: how they work, what the trials showed, side effects and approval status.
Semaglutide, tirzepatide and retatrutide are weekly injections that copy gut hormones involved in appetite and blood sugar. They are often compared because each new one activates more hormone receptors than the last. This guide puts what is known side by side; it is not a recommendation for any of them.
How they work
- Semaglutide activates the GLP-1 receptor: it releases insulin when blood sugar is high, lowers glucagon, slows down the stomach and acts on the brain’s appetite centers.
- Tirzepatide activates two receptors, GIP and GLP-1: it lowers appetite, slows down the stomach and improves the body’s response to insulin.
- Retatrutide activates three: GLP-1 and GIP, plus glucagon, which raises energy use and fat burning in the liver.
What the trials showed
- Semaglutide: in the STEP trials, people lost about 15% of their weight in 68 weeks. The SELECT trial showed 20% fewer heart attacks and strokes in people with obesity.
- Tirzepatide: in SURMOUNT-1, the highest dose led to about 20% weight loss in 72 weeks, and in a head-to-head trial it caused more weight loss than semaglutide.
- Retatrutide: in a phase 2 trial, the highest dose led to about 24% weight loss in 48 weeks. Phase 3 trials are still running.
Approval status
Semaglutide is approved for type 2 diabetes (Ozempic), long-term weight management (Wegovy) and lowering cardiovascular risk. Tirzepatide is approved for type 2 diabetes (Mounjaro), weight management (Zepbound) and obstructive sleep apnea in people with obesity. Retatrutide is not approved anywhere: anything sold outside clinical trials is unregulated.
How they are dosed
All three are injected once a week and started at a low dose that goes up every 4 weeks, so the stomach can adapt. Semaglutide’s label starts at 0.25 mg and steps up to 2.4 mg; tirzepatide’s starts at 2.5 mg and goes up in 2.5 mg steps. Their half-lives are long: about 1 week for semaglutide, about 5 days for tirzepatide and about 6 days for retatrutide, which is why one injection a week is enough.
Side effects and cautions
- Nausea, vomiting, diarrhea and constipation are common with all three, especially when the dose goes up.
- Pancreatitis and gallbladder problems are possible.
- None of them is for people with a personal or family history of medullary thyroid cancer or MEN2.
- Tirzepatide can make hormonal birth control less reliable. Retatrutide also raises the heart rate.
- Some muscle is lost along with fat, and weight usually returns after stopping.
Which one?
The right choice depends on your health, your goals and what is approved where you live, and it is a decision to make with a doctor. Each compound page in uPrime lists who it makes sense for, who should avoid it, the research protocol and the calculator for its vial.
Educational reference only. It is not medical advice and does not recommend any compound or dose. Talk to a doctor before using any of these compounds.
Last reviewed: 2026-10-26
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