Pep IQ
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Each GLP-1 agonist has its own preclinical evidence base. The class mechanism — agonism of the GLP-1 receptor in pancreatic β-cells, hypothalamic appetite circuits, and gut motility neurons — is well-characterised across decades of research. Individual compounds (semaglutide, tirzepatide, liraglutide, retatrutide, amycretin, cagrisema) differ in receptor selectivity (some are dual or triple agonists), half-life, and dose-response profile.
Community use varies dramatically by specific compound. The shared principle across the class is titrate UP slowly for GI tolerance, not for efficacy — the goal is the minimum effective dose, not the maximum. Higher doses do not equal better results; they equal more nausea, vomiting, and discontinuation. Most users land at a dose well below the trial maximum and stay there long-term. This is chronic medication, not a cycled peptide — stopping typically causes weight regain.
Class evidence is enormous. Semaglutide STEP trials (NEJM 2021), tirzepatide SURMOUNT trials (NEJM 2022), liraglutide SCALE trials, retatrutide Phase 2 (NEJM 2023), amycretin Phase 1b/2a (Lancet 2025), cagrisema Phase 3 REDEFINE (NEJM 2025). The GLP-1 class has more high-quality obesity and diabetes trial evidence than any other peptide category.
Several class members are FDA/EMA/MHRA approved for diabetes and obesity (semaglutide, tirzepatide, liraglutide). Others are investigational (retatrutide, amycretin, cagrisema — all advancing but not yet approved). Compounded versions and research-peptide sourcing exist for off-label cosmetic weight loss; quality and authenticity vary widely.
The GLP-1 class is the most clinically validated weight-loss and diabetes peptide category in existence. Pep IQ has individual entry pages for each major compound — see those for specific protocols, dosing, evidence, and Pep IQ's stance on each. Class principles: titrate up for tolerance, find minimum effective dose, expect weight regain on discontinuation, plan for long-term use rather than cycles. Compounded sourcing carries quality risks — pharmacy-grade is preferable where accessible.
The story of GLP-1 begins with an observation in the 1970s: oral glucose produced more insulin secretion than intravenous glucose delivered directly into the bloodstream — even when blood sugar levels were identical. This "incretin effect" pointed to gut-derived signals that amplified insulin release after eating. GLP-1 (glucagon-like peptide-1) was identified in the 1980s as a key incretin hormone — a 30 amino acid peptide secreted by L-cells in the gut after meals.
The next leap came in an unlikely place. Exendin-4, found in the saliva of the Gila monster lizard, turned out to be structurally similar to GLP-1 but resistant to rapid degradation. This became exenatide — the first GLP-1 receptor agonist, approved for type 2 diabetes in 2005. Liraglutide followed, and then the transformative moment: semaglutide, which with once-weekly dosing at 2.4mg produced 15% average body weight reduction in the STEP trials — results no anti-obesity medication had ever achieved before.
What began as diabetes treatment has become a fundamental shift in how medicine approaches obesity. Tirzepatide — a dual GIP/GLP-1 agonist — pushed further, with over 20% average weight loss in trials. The category is now expanding into liver disease, heart failure, kidney disease, neurodegeneration, and addiction — making GLP-1 potentially the most therapeutically versatile drug class discovered in decades.
GLP-1 agonists work through a receptor expressed in multiple organ systems simultaneously — which is why their effects extend so far beyond simple blood sugar control.
The muscle loss concern deserves honest treatment. GLP-1 agonists cause significant weight loss, but a meaningful proportion of that weight loss comes from muscle mass, not just fat. In the SURMOUNT-1 tirzepatide trial, roughly 25-40% of weight lost was lean mass in some analyses — consistent with any major calorie-restriction-induced weight loss. This has prompted growing interest in combining GLP-1 agonists with resistance training and adequate protein intake to preserve muscle during the weight loss process.
GLP-1 agonists represent the highest level of evidence of any compound covered in these pages — multiple Phase 3 RCTs, regulatory approval in multiple jurisdictions, post-marketing surveillance data on millions of patients, and ongoing expansion into new indications.