Abstract 13440: Effect of Pemvidutide (ALT-801), a Novel GLP-1/Glucagon Dual Receptor Agonist, on Pathogenic Lipid Mediators

Abstract

Introduction: GLP-1 based agents are receiving intense attention for their potential to decrease CV risk. Pemvidutide is a unique, balanced GLP-1/glucagon dual receptor agonist (RA) combining the anorectic effects of GLP-1 RA with the increased energy expenditure and lipid-lowering effects of glucagon RA. In a 12-week double-blind clinical trial in subjects with overweight/obesity, pemvidutide reduced body weight by 10.3% and significantly decreased total cholesterol (-28%), LDL-C (-26%), and triglycerides (-38%). Here we leveraged lipidomics to investigate the effects of pemvidutide on other lipid mediators implicated in atherosclerosis and metabolic syndrome (MetS). Methods: Plasma lipidomic mass spectrometry was performed on baseline and Day 84 samples from 34 subjects receiving 1.2 mg, 1.8 mg, or 2.4 mg pemvidutide, or placebo, subcutaneously weekly. Results: Pemvidutide achieved significant dose-dependent reductions from baseline across multiple bioactive lipid classes (Figure), including pro-atherogenic lysophosphatidylcholines (Lyso-PC, a major oxidized LDL component), and lipotoxic sphingolipids, including sphingomyelins and ceramides, across the 12 weeks of treatment. Significant decreases were also observed in ether-linked alkyl phosphatidylcholine (PC) and phosphatidyl-ethanolamine (PE) glycerophospholipids, and in shorter chain, more saturated glycerolipids associated with insulin resistance were also observed. Conclusions: Pemvidutide induced pronounced, rapid weight loss with substantial decreases in lipotoxic and pro-atherogenic lipid species. These findings support pemvidutide’s potential benefit on obesity-associated CV co-morbidities, including atherosclerosis and MetS.