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Inconclusive effects of once‐weekly exenatide on cardiovascular outcomes in type 2 diabetes
Author(s) -
Wong Chih,
Fisher Miles
Publication year - 2017
Publication title -
practical diabetes
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.205
H-Index - 24
eISSN - 2047-2900
pISSN - 2047-2897
DOI - 10.1002/pdi.2140
Subject(s) - medicine , exenatide , lixisenatide , liraglutide , mace , rosiglitazone , dulaglutide , myocardial infarction , type 2 diabetes , semaglutide , diabetes mellitus , clinical trial , intensive care medicine , type 2 diabetes mellitus , heart failure , adverse effect , endocrinology , insulin , conventional pci
302 PRACTICAL DIABETES VOL. 34 NO. 9 COPYRIGHT © 2017 JOHN WILEY & SONS Following the rosiglitazone controversy, where rosiglitazone was associated with an increase in myocardial infarctions in its phase 3 development programme,1 regulatory bodies including the Food and Drug Administration (FDA) and European Medicines Agency (EMA) mandate robust cardiovascular safety for new antidiabetes drugs.2,3 This includes recruiting patients at high cardiovascular risk to the phase 3 programme e.g. older patients, patients with chronic kidney disease and patients with established cardiovascular disease, and blindly adjudicating cardiovascular events in the programme. It also usually includes a dedicated, randomised-controlled cardiovascular outcomes trial (CVOT), which may be completed before or after licensing has been approved. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce glucose concentrations in people with type 2 diabetes mellitus through various mechanisms, with additional favourable effects on weight, blood pressure and the lipid profile. Three cardiovascular outcome trials with GLP-1 RAs have been completed and published (ELIXA with lixisenatide,4 LEADER with liraglutide,5 and SUSTAIN-6 with semaglutide6). All three trials confirmed cardiovascular safety by demonstrating non-inferiority for MACE (major adverse coronary events, i.e. cardiovascular death, non-fatal myocardial infarction, non-fatal stroke). Two of these trials (LEADER and SUSTAIN-6) then demonstrated superiority with reductions in MACE. In addition, the top-line results of the FREEDOM-CVO trial with ITCA 650, an implanted subcutaneous system for the delivery of exenatide, have been reported as showing non-inferiority but not superiority.7 The original twice-daily formulation of exenatide was licensed before these stringent requirements were enforced so no CVOT with twice-daily exenatide is planned. The EXSCEL (Exenatide Study of Cardiovascular Event Lowering) trial was academically led by the Diabetes Trials Unit in Oxford and the Duke Clinical Research Institute and designed to satisfy the FDA criteria and further assess the effect of exenatide once-weekly on cardiovascular outcomes in patients with type 2 diabetes.8