Obesity involves chronic positive energy balance driven by dysregulated appetite signaling, impaired satiety hormones, reduced metabolic rate, and neurobiological changes that defend excess fat stores. Modern peptide research — particularly the GLP-1 and multi-agonist classes — represents the most significant advance in obesity pharmacology in decades, achieving weight loss previously only attainable through surgery.
1. Semaglutide — GLP-1 / Hypothalamic Appetite Suppression
Semaglutide activates hypothalamic GLP-1 receptors to powerfully suppress appetite and increase satiety. The STEP clinical trials demonstrated 15–17% average body weight reduction — unprecedented for a pharmaceutical agent. Beyond weight loss, semaglutide reduces cardiovascular events and improves all metabolic obesity comorbidities.
Dosing Protocol: 0.25 mg SubQ once weekly. Titrate by 0.25 mg every 4 weeks to 2.4 mg/week (obesity dose). Titration minimizes GI side effects.
2. Tirzepatide — Dual GIP/GLP-1 / Superior Weight Loss
Tirzepatide combines GLP-1 and GIP receptor activation for superior weight loss to semaglutide alone — SURMOUNT trials showed 20–22% body weight reduction. The GIP component enhances fat cell lipolysis directly, adds CNS satiety signaling through separate receptor pathways, and reduces the GI side effects common with GLP-1 agonists alone.
Dosing Protocol: 2.5 mg SubQ once weekly. Titrate by 2.5 mg every 4 weeks to 10–15 mg/week. Most research participants reach 10 mg as an effective dose.
3. Retatrutide — Triple Agonist / Maximum Efficacy
Retatrutide (GLP-1/GIP/Glucagon triple agonist) has produced the most dramatic weight loss of any peptide studied — up to 24% body weight reduction in Phase 2 trials. The added glucagon receptor activation increases energy expenditure and further enhances lipolysis, pushing weight loss beyond what dual agonists achieve.
Dosing Protocol: 1–12 mg SubQ once weekly based on phase 2 trial protocols. Still in clinical development; 4–8 mg demonstrated robust efficacy with manageable tolerability.
4. AOD-9604 — Selective Visceral Fat / Maintenance
AOD-9604 is valuable as an adjunct to GLP-1 therapy and for maintaining fat loss after primary weight loss goals are achieved. It directly targets adipocyte lipolysis via beta-3 adrenergic receptor activation — providing fat burning independent of caloric restriction and complementing the appetite suppression of GLP-1 agonists.
Dosing Protocol: 300–500 mcg SubQ daily, fasted or pre-workout. Best used as an adjunct or maintenance protocol.
Semaglutide and Tirzepatide provide the powerful central appetite suppression and metabolic improvement that drives meaningful weight loss. Retatrutide adds glucagon-driven energy expenditure for patients needing maximum efficacy. AOD-9604 targets peripheral fat cell lipolysis for a complementary mechanism — particularly useful for stubborn body fat that persists after GLP-1-driven weight loss reaches a plateau.
Research Use Only. All information on this page is for educational purposes only and is not medical advice. PepSherpa does not sell peptides. Consult a licensed healthcare provider before making any health decisions. Many of the studies cited are preclinical (animal/in-vitro).