title: The cardiovascular safety trials of DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors.
abstract: In this paper, we review the results of large, double-blind, placebo-controlled randomized trials mandated by the US Food and Drug Administration to examine the cardiovascular safety of newly-approved antihyperglycemic agents in patients with type 2 diabetes. The cardiovascular effects of dipeptidyl peptidase-4 (DPP-4) inhibitors remain controversial: while these drugs did not reduce or increase the risk of primary, pre-specified composite cardiovascular outcomes, one DPP-4 inhibitor (saxagliptin) increased the risk of hospitalization for heart failure in the overall population; another (alogliptin) demonstrated inconsistent effects on heart failure hospitalization across subgroups of patients, and a third (sitagliptin) demonstrated no effect on heart failure. Evidence for cardiovascular benefits of glucagon-like peptide-1 (GLP-1) agonists has been similarly heterogeneous, with liraglutide and semaglutide reducing the risk of composite cardiovascular outcomes, but lixisenatide having no reduction or increase in cardiovascular risk. The effect of GLP-1 agonists on retinopathy remains a potential concern. In the only completed trial to date to assess a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin reduced the risk of composite cardiovascular endpoints, predominantly through its impact on cardiovascular mortality and heart failure hospitalization.
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Secrest
authors.affiliation: Women's College Research Institute, Department of Medicine, Women's College Hospital, Toronto, Ontario, Canada; Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Udell
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada; Division of Clinical Epidemiology, Department of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: kristian.filion@mcgill.ca.
authors.forename: Kristian B
authors.initials: KB
authors.lastname: Filion
mesh_terms: D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000378:metabolism; D006801:Humans; D054795:Incretins / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012307:Risk Factors; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D054795:Incretins; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: Cardiovascular; DPP-4 inhibitors; Diabetes; GLP-1 agonists; Randomized controlled trial; SGLT2 inhibitors