Tirzepatide vs Retatrutide vs Semaglutide

A plain English comparison of the three most talked about GLP-1 class peptides: how they work, what the clinical trials actually showed, how they are dosed, and how to pick one. Educational reference only, not medical advice.

At a glance

Class
Semaglutide: GLP-1 receptor agonist
Tirzepatide: Dual GLP-1 and GIP receptor agonist
Retatrutide: Triple GLP-1, GIP, and glucagon receptor agonist
Mechanism
Semaglutide: Slows gastric emptying, boosts insulin, curbs appetite via GLP-1 pathway.
Tirzepatide: GLP-1 appetite and insulin effects plus GIP, which improves insulin sensitivity and fat handling.
Retatrutide: Adds glucagon agonism on top of GLP-1 and GIP, increasing energy expenditure and lipolysis.
Headline trial weight loss
Semaglutide: About 15 percent average at 68 weeks (STEP 1, 2.4 mg weekly).
Tirzepatide: About 20 to 22 percent at 72 weeks (SURMOUNT-1, 15 mg weekly).
Retatrutide: About 24 percent at 48 weeks (Phase 2, 12 mg weekly).
Typical dose cadence
Semaglutide: Once weekly, titrate 0.25 to 2.4 mg over 16 to 20 weeks.
Tirzepatide: Once weekly, titrate 2.5 to 15 mg over 20 weeks.
Retatrutide: Once weekly, titrate 2 to 12 mg (research protocols vary).
Half life
Semaglutide: About 7 days
Tirzepatide: About 5 days
Retatrutide: About 6 days
Common side effects
Semaglutide: Nausea, constipation, fatigue, reflux; usually worst during titration.
Tirzepatide: Nausea, diarrhea, decreased appetite; often milder than semaglutide at matched loss.
Retatrutide: Nausea, elevated heart rate, transient blood sugar swings from glucagon activity.
Best fit
Semaglutide: First GLP-1 users who want the most published data and steady appetite control.
Tirzepatide: Users who plateaued on semaglutide or want stronger effect with fewer GI issues.
Retatrutide: Higher BMI users chasing maximum loss and willing to titrate slowly.

Mechanism, in one paragraph each

Semaglutide mimics the gut hormone GLP-1. It slows how fast food leaves the stomach, blunts hunger signals in the brain, and helps the pancreas release insulin only when glucose is high. Effect on weight is driven mostly by lower calorie intake.

Tirzepatide hits GLP-1 and adds GIP receptor activity. GIP improves how fat cells store and release energy and appears to soften some GI side effects. In head to head data it produces roughly 5 to 7 percentage points more weight loss than semaglutide at matched cadence.

Retatrutide is a triple agonist: GLP-1, GIP, and glucagon. The glucagon arm raises energy expenditure and drives lipolysis, which is why Phase 2 subjects lost roughly a quarter of body weight. The tradeoff is a bigger heart rate bump and more careful titration.

Dosing overview

All three are once weekly subcutaneous injections and all three titrate up slowly to limit nausea. Use the calculator to convert mg per week into insulin syringe units for your specific vial and BAC water volume.

  • Semaglutide: 0.25 mg wk 1 to 4, then double every 4 weeks up to 2.4 mg.
  • Tirzepatide: 2.5 mg wk 1 to 4, step to 5, 7.5, 10, 12.5, then 15 mg.
  • Retatrutide: Research protocols typically start 2 mg and step to 4, 8, then 12 mg every 4 weeks.
Open dose calculatorRetatrutide calculator

How to choose

  • New to the class and want the deepest safety data? Start with semaglutide.
  • Plateaued or want more loss with fewer GI issues? Tirzepatide is the usual next step.
  • High BMI and chasing max loss with slower, careful titration? Retatrutide, once you are comfortable managing heart rate and glucose swings.
  • Whatever you pick, titrate slow, hydrate, and pair with protein forward eating and resistance training to protect lean mass.

Related

Educational content only. Not medical advice. Consult a licensed clinician before starting any peptide protocol.

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