title: Cardiovascular actions of incretin-based therapies.
abstract: Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors represent 2 distinct classes of incretin-based therapies used for the treatment of type 2 diabetes mellitus. Activation of GLP-1R signaling or inhibition of DPP-4 activity produces a broad range of overlapping and unique cardiovascular actions. Native GLP-1 regulates cardiovascular biology via activation of the classical GLP-1R, or through GLP-1(9-36), a cardioactive metabolite generated by DPP-4-mediated cleavage. In contrast, clinically approved GLP-1R agonists are not cleaved to GLP-1(9-36) and produce the majority of their actions through the classical GLP-1R. The cardiovascular mechanisms engaged by DPP-4 inhibition are more complex, encompassing increased levels of intact GLP-1, reduced levels of GLP-1(9-36), and changes in levels of numerous cardioactive peptides. Herein we review recent experimental and clinical advances that reveal how GLP-1R agonists and DPP-4 inhibitors affect the normal and diabetic heart and coronary vasculature, often independent of changes in blood glucose. Improved understanding of the complex science of incretin-based therapies is required to optimize the selection of these therapeutic agents for the treatment of diabetic patients with cardiovascular disease.
authors.affiliation: From the Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Ussher
authors.affiliation: From the Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, Canada. drucker@lunenfeld.ca.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002319:Cardiovascular System / Q000187:drug effects* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications*; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D054795:Incretins / Q000494:pharmacology* / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D018027:Receptors, Glucagon / Q000819:agonists; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D018027:Receptors, Glucagon; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: diabetes mellitus; dipeptidyl peptidase 4; glucagon-like peptide 1; heart; heart failure; myocardial ischemia