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

• Published in: Circulation (New York, N.Y.) Vol. 146; no. Suppl_1; p. A13440
• Main Authors: Plutzky, Jorge, Harris, M. Scott S, Alonso, Cristina, Suschak, John, Noor, Mustafa, Ortiz, Pablo, Georges, Bertrand, Rader, Daniel J, Roberts, Scot S, Browne, Sarah K
• Format: Journal Article
• Language: English
• Published: Lippincott Williams & Wilkins 08.11.2022
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.146.suppl_1.13440

IntroductionGLP-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). MethodsPlasma 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. ResultsPemvidutide 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. ConclusionsPemvidutide 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.