glp-1 launch History of glucagon-like peptide-1 receptor agonists Inside the Race to Launch

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doi: 10.1056/NEJMoa1607141 9 GoldneyJSargeantJADaviesMJ

metabolite Ac-LKKTE identified as potentially more active than parent compound Paradoxical finding: Both peptides show biological effects persisting hours to days after administration despite rapid plasma clearance Possible explanations: Tissue retention, active metabolites, or persistent signaling cascade activation Excretion Pathways Limited data exists on excretion for both peptides[22]: Likely renal elimination of peptide fragments Hepatic metabolism may contribute to clearance No accumulation detected in chronic dosing studies (animal models) Combined excretion kinetics have not been characterized in any species The disconnect between short plasma half-lives and prolonged biological effects represents a key area requiring mechanistic clarification for both individual peptides and their combination

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[1] [2] However, individual patient experiences vary, and several indirect mechanisms might potentially contribute to oral symptoms in those taking semaglutide