Recent cardiovascular outcome trials confirm the safety of the dipeptidyl peptidase-4 inhibitors, but new questions emerge
In 2007, a meta-analysis of clinical trial data implicated the blood glucose-lowering drug rosiglitazone as unexpectedly increasing, rather than reducing, cardiovascular risk in patients with type 2 diabetes.1 This report proved controversial, but its major consequence was that the United States Food and Drug Administration (FDA) required the manufacturer of every new blood glucose-lowering therapy to conduct a postmarketing (Phase IV) cardiovascular safety study when there was no convincing evidence of non-inferiority or superiority over conventional agents, such as metformin and sulfonylureas, based on cardiovascular end point data collected in Phase II–III studies.2 In line with this requirement, the manufacturers of most incretin-based therapies, which comprise the glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins), have initiated Phase IV cardiovascular safety studies. The exceptions are the GLP-1 analogue exenatide, which was already registered and marketed in the US at the time the FDA requirement came into effect, and the DPP-4 inhibitor vildagliptin, whose manufacturer elected not to do such a study and therefore not to market the drug in the US.
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- 1. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 2457-2471.
- 2. Center for Drug Evaluation and Research, US Food and Drug Administration. Guidance for industry. Diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring, Md: FDA, 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf (accessed Oct 2013).
- 3. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1317-1326.
- 4. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369: 1327-1335.
- 5. Monami M, Ahren B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013; 15: 112-120.
- 6. Brown A, Reynolds LR, Bruemmer D. Intensive glycemic control and cardiovascular disease: an update. Nat Rev Cardiol 2010; 7: 369-375.
- 7. Marney A, Kunchakarra S, Byrne L, Brown NJ. Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans. Hypertension 2010; 56: 728-733.
- 8. Meléndez GC, Li J, Law BA, et al. Substance P induces adverse myocardial remodelling via a mechanism involving cardiac mast cells. Cardiovasc Res 2011; 92: 420-429.
- 9. European Society of Cardiology. Vildagliptin shows no adverse effect on ejection fraction in diabetic patients with HF [Heart Failure Congress 2013 news]. 27 May 2013. http://www.escardio.org/congresses/hf2013/congress-to-you/Pages/vildagliptin-shows-no-adverse-effect-ejection-fraction-diabetic-patients-with-heart-failure.aspx (accessed Aug 2013).
- 10. Mahaffey KW, Hafley G, Dickerson S, et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J 2013; 166: 240-9.e1.
I am supported by a National Health and Medical Research Council Practitioner Fellowship.
I have served on advisory boards for, and received research funding, speaker fees and travel assistance to attend meetings from, Merck Sharp & Dohme (manufacturer of sitagliptin) and Novartis (manufacturer of vildagliptin). I have also served on advisory boards for, and received speaker fees and travel assistance to attend meetings from, AstraZeneca/Bristol-Myers Squibb (manufacturers of saxagliptin) and Boehringer Ingelheim (manufacturer of linagliptin), and have served on advisory boards for, and received speaker fees from, Takeda (manufacturer of alogliptin).