The GLP-1 Pioneer (Ozempic/Wegovy)
Semaglutide is a GLP-1 receptor agonist that mimics the natural incretin hormone GLP-1. It slows gastric emptying, suppresses appetite via hypothalamic signaling, and improves insulin sensitivity. The weekly injectable form (Wegovy) achieved 15% average body weight loss in the STEP trials. It's the most clinically validated of the three compounds with the longest safety record.
The Dual GIP/GLP-1 Agonist (Mounjaro/Zepbound)
Tirzepatide is a dual GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 receptor agonist. The addition of GIP agonism significantly amplifies fat cell lipolysis and improves adipose tissue metabolism beyond what GLP-1 alone achieves. The SURMOUNT trials showed 22.5% average body weight loss at 72 weeks — substantially better than semaglutide.
Retatrutide is the most powerful of the three for pure weight loss (24.2% in Phase 2 trials), but it's not yet FDA-approved. Tirzepatide is the current clinical gold standard with 22.5% weight loss and FDA approval. Semaglutide is the safest bet for first-timers with the longest safety record. For maximum fat loss right now: Tirzepatide. For the bleeding edge: Retatrutide (compounded). For the most accessible option: Semaglutide.
Do NOT combine GLP-1 agonists. They work through overlapping mechanisms and combining them increases side effects (nausea, vomiting, pancreatitis risk) without proportional benefit. Choose one and optimize the dose.
[1] Wilding JPH et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity. NEJM. PMID: 33567185
[2] Jastreboff AM et al. (2022). Tirzepatide Once Weekly for the Treatment of Obesity. NEJM. PMID: 35658024
[3] Jastreboff AM et al. (2023). Triple–Hormone-Receptor Agonist Retatrutide for Obesity. NEJM. PMID: 37354011
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