Insights From Cardiovascular Outcome Trials with Novel Antidiabetes Agents: What Have We Learned? An Industry Perspective
- 941 Downloads
Owing to the close association of cardiovascular (CV) disease with type 2 diabetes and the uncertainty surrounding the CV safety of antidiabetes agents, in 2008 the Food and Drug Administration issued guidance for the demonstration of CV safety for new antidiabetes drugs. Recently the results from CV outcomes trials of three dipeptidyl peptidase-4 (DPP-4) inhibitors and a glucagon-like peptide-1 receptor agonist have been reported. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial, the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) trial, and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed the safety of saxagliptin, alogliptin, and sitagliptin, respectively, in patients with type 2 diabetes with CV disease or at high risk for CV disease. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) assessed the safety of lixisenatide in patients with type 2 diabetes and a recent acute coronary syndrome event. The results show that these agents neither increased nor deceased major adverse CV events (CV death, nonfatal myocardial infarction, and nonfatal stroke) compared with placebo. However, the resources needed to conduct these studies may detract from the ability to understand the potential long-term benefit and risk in the majority of patients that are candidates for use of these medications.
KeywordsAlogliptin Antidiabetes drugs Cardiovascular safety DPP-4 inhibitors Saxagliptin Sitagliptin
Medical writing support for the preparation of this manuscript was provided by Richard Edwards, PhD, and Janet Matsuura, PhD, from Complete Healthcare Communications, Inc. (Chadds Ford, PA), with funding from AstraZeneca.
Compliance with Ethics Guidelines
Conflict of Interest
Boaz Hirshberg is an employee of MedImmune, LLC, a wholly owned subsidiary of AstraZeneca.
Arie Katz is an employee of AstraZeneca.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. 2014. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed June 11 2015.
- 7.•Food and Drug Administration. Guidance for industry: diabetes mellitus - evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring, MD: Center for Drug Evaluation and Research. 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed June 11 2015. Document discusses recommendations for assessing cardiovascular risk of new antidiabetes drugs.
- 8.European Medicines Agency. Guidelines on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf. Accessed June 11 2015.
- 15.Johansen OE, Neubacher D, von Eynatten M, Patel S, Woerle HJ. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol. 2012;11:3. doi: 10.1186/1475-2840-11-3.PubMedCentralCrossRefPubMedGoogle Scholar
- 24.Udell JA, Bhatt DL, Braunwald E, Cavender MA, Mosenzon O, Steg PG, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes and moderate or severe renal impairment: observations from the SAVOR-TIMI 53 trial. Diabetes Care. 2015;38(4):696–705. doi: 10.2337/dc14-1850.PubMedGoogle Scholar
- 29.••Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015. Cardiovascular outcomes trial of sitagliptin. Google Scholar
- 30.Evaluation of cardiovascular outcomes in patients with type 2 diabetes after acute coronary syndrome during treatment with ave0010 (lixisenatide) (ELIXA). 2015. https://clinicaltrials.gov/ct2/show/NCT01147250?term=elixa&rank=1. Accessed June 30 2015.
- 31.••No cv benefit with lixisenatide in ELIXA, but results reassure., Medscape. http://www.medscape.com/viewarticle/846074#vp_1. Accessed June 30 2015. Cardiovascular outcomes trial of lixisenatide.
- 33.Udell JA, Cavender MA, Bhatt DL, Chatterjee S, Farkouh ME, Scirica BM. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2015;3(5):356–66.CrossRefPubMedGoogle Scholar
- 36.Fu AZ, Johnston S, Sheehan J, Ghannam A, Tsai K, Cappell K, et al. Risk of hospitilization for heart failure with dipeptidyl petidase-4 inhibitors vs sulfonylureas and with saxaagliptin vs sitagliptin in a US claims database. Diabetes. 2015;64(Suppl 1A):LB42.Google Scholar
- 37.Giorda CB, Picariello R, Tartaglino B, Marafetti L, Di Noi F, Alessiato A, et al. Hospitalisation for heart failure and mortality associated with dipeptidyl peptidase 4 (DPP-4) inhibitor use in an unselected population of subjects with type 2 diabetes: a nested case–control study. BMJ Open. 2015;5(6), e007959.PubMedCentralCrossRefPubMedGoogle Scholar