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Tirzepatide vs semaglutide vs retatrutide: what the trials show

Protocol Unlocked editorial team · November 15, 2026 · 4 min read

Semaglutide, tirzepatide and retatrutide are all once-weekly injections that cause large weight loss. They work in related but different ways, and their trial results differ too. Here is what the published trials actually found, with sources at the end.

How they work

  • Semaglutide (Wegovy, Ozempic) acts on one hormone receptor: GLP-1. It increases fullness, slows the stomach and helps the body release insulin when blood sugar is high.
  • Tirzepatide (Zepbound, Mounjaro) acts on GIP and GLP-1. GIP seems to improve how the body handles fat and how well GLP-1 effects are tolerated.
  • Retatrutide acts on GIP, GLP-1 and glucagon. The glucagon part adds energy use and liver-fat loss on top of the appetite effects.

Weight loss in the main trials

DrugTrialLengthPeopleAverage weight loss
Semaglutide 2.4 mgSTEP 168 weeksObesity, no diabetes14.9% (placebo 2.4%)
Tirzepatide 5 / 10 / 15 mgSURMOUNT-172 weeksObesity, no diabetes15.0% / 19.5% / 20.9% (placebo 3.1%)
Retatrutide 12 mgPhase 248 weeksObesity, no diabetes24.2% (placebo 2.1%)
Retatrutide 4 / 9 / 12 mgTRIUMPH-2 (phase 3)80 weeksObesity with type 2 diabetes11.9% / 16.8% / 18.8% (placebo 5.1%)

Two cautions when reading this table:

  • Different trials aren't a fair race. They enrolled different people for different lengths of time. People with type 2 diabetes usually lose less weight on these drugs, which is part of why TRIUMPH-2's numbers are lower than the retatrutide phase 2 result.
  • Phase 2 trials are small. The 24.2% figure comes from a mid-stage trial. Phase 3 results for people without diabetes are the ones to watch.

The head-to-head trial

Only one large trial has put two of these against each other directly. In SURMOUNT-5, 751 adults with obesity but without diabetes took the highest dose they could tolerate of either tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg) for 72 weeks.

  • Weight loss: 20.2% with tirzepatide vs 13.7% with semaglutide.
  • Waist: down 18.4 cm vs 13.0 cm.
  • Side effects in both groups were mostly stomach-related, mild to moderate, and happened mainly while the dose was being stepped up.

The trial was open-label (everyone knew which drug they were on) and funded by Lilly, which makes tirzepatide.

Beyond the scale

  • Heart outcomes: in the SELECT trial of 17,604 adults with obesity and heart disease, semaglutide cut major cardiac events by 20%.
  • Stopping: in the STEP 1 extension, people regained about two-thirds of the weight they had lost within a year of stopping semaglutide. Plan for what happens after.
  • Muscle: fast weight loss takes some muscle with it. Keeping protein high and lifting weights helps, and tracking fat-free mass shows whether it's working.

Side effects they share

All three cause the classic GLP-1 side effects, most often while the dose is going up:

  • nausea, especially after a dose step
  • constipation or diarrhea
  • reflux and burping
  • lower appetite and thirst, which can lead to dehydration

Retatrutide adds a few of its own in trials: a faster resting heart rate, skin tingling or burning (dysesthesia, 4–7% vs 1% on placebo in TRIUMPH-2), and low blood pressure or dizziness on standing, mostly at 9–12 mg.

All of them carry the class warnings: not for anyone with a personal or family history of medullary thyroid cancer or MEN2, and severe belly pain needs urgent care (pancreatitis and gallbladder problems are uncommon but reported).

Where each one stands

  • Semaglutide: FDA-approved as Wegovy (injection and, since December 2025, a daily 25 mg tablet) for weight, and as Ozempic and Rybelsus for type 2 diabetes.
  • Tirzepatide: FDA-approved as Zepbound for weight and sleep apnea, and as Mounjaro for type 2 diabetes.
  • Retatrutide: investigational and not approved. Anything sold as retatrutide today is a research chemical with no quality control.

The short version

On average, tirzepatide produced more weight loss than semaglutide, including in the one direct comparison. Retatrutide has shown the largest numbers so far but is still in trials. All three share the same side effects and the same tendency for weight to come back after stopping.

For each drug's full summary, storage and interactions, see our library pages on semaglutide, tirzepatide and retatrutide.

Sources

General information, not medical advice. Doses mentioned are what drug labels or trials used, not recommendations. Talk to a clinician before starting or changing anything.