title: Perspectives on cardiovascular effects of incretin-based drugs: From bedside to bench, return trip.
abstract: Recently, cardiovascular outcome trials with glucose-lowering drugs used in type 2 diabetes mellitus, namely glucagon-like peptide-1 receptor agonists (GLP-1RA), liraglutide and semaglutide, showed a reduction in cardiovascular events, which had not been observed in trials with other incretin-based drugs, such as lixisenatide or with dipeptidyl peptidase-4 inhibitors (DPP4i). Mechanisms underlying the observed cardiovascular differences between DPP4i and GLP1-RA, and across individual GLP1-RA are poorly understood. This review is aimed at collecting and summarizing available evidence from experimental and mechanistic studies on the action of GLP1-RA and DPP4i on the cardiovascular system, both deriving from clinical and pre-clinical sources. The results of cardiovascular outcome trials are interpreted on the basis of the experimental preclinical data available, paying particular attention to the heart failure results, and suggesting some novel intriguing hypotheses to explain some of the unexpected findings of cardioprotection of incretin-based drugs. In particular, we discuss the possible contribution to the incretin cardiovascular effects of a direct cardiac action of GLP-1 metabolites through GLP-1 receptor-independent pathways, and of DPP4 substrates other than GLP-1.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, Endocrinology Unit, University of Florence, Florence, Italy. Electronic address: michaela.luconi@unifi.it.
authors.forename: Michaela
authors.initials: M
authors.lastname: Luconi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, Endocrinology Unit, University of Florence, Florence, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Cantini
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain; IRCCS MultiMedica, Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ceriello
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, Endocrinology Unit, University of Florence, Florence, Italy; Diabetes Agency, Careggi Hospital, Florence, Italy. Electronic address: edoardo.mannucci@unifi.it.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Mannucci
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000453:epidemiology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004763:Glucagon-Like Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D054795:Incretins / Q000494:pharmacology / Q000627:therapeutic use*; D000069450:Liraglutide / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000099194:Semaglutide; D000067757:Glucagon-Like Peptide-1 Receptor
chemical_list: D002316:Cardiotonic Agents; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004763:Glucagon-Like Peptides; D054795:Incretins; D000069450:Liraglutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000099194:Semaglutide; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor
keywords: Cardiovascular outcome trials; Dipeptidyl peptidase-4 inhibitors; Glucagon-like peptide-1 receptor agonists; Heart failure; Inflammatory chemokines; MACE