Letter to the Editor

Abstract

I thank Dr. Snyman for his thoughtful comments and perspective on diabetes as a risk factor for cardiovascular (CV) disease. Diabetes is associated with excessive CV morbidity and mortality (1Lau D.C.W. Shen G.X. Cardiovascular Complications of Diabetes.Can J Diabetes. 2013; 37: 279-281Abstract Full Text Full Text PDF Scopus (3) Google Scholar). The widely cited Finnish cohort study heralded the notion that diabetes can be considered a coronary heart disease risk equivalent (2Haffner S.M. Lehto S. Rönnemaa T. et al.Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.N Engl J Med. 1998; 339: 229-234Crossref PubMed Scopus (5902) Google Scholar). The 7-year risk for myocardial infarction in people with diabetes was found to be almost the same as in nondiabetic subjects having a history of previous myocardial infarction (2Haffner S.M. Lehto S. Rönnemaa T. et al.Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.N Engl J Med. 1998; 339: 229-234Crossref PubMed Scopus (5902) Google Scholar). Several studies have since refuted this tenet. A Scottish cross-sectional and cohort study reported that people with type 2 diabetes were at a lower risk for cardiovascular events than people with established coronary heart disease (3Evans J.M. Wang J. Morris A.D. Comparison of cardiovascular risk between patients with type 2 diabetes and those who had had a myocardial infarction: cross-sectional and cohort studies.Br Med J. 2002; 324: 939-943Crossref PubMed Google Scholar). A systematic review and meta-analysis of 13 studies with 45108 patients followed for a mean of 13.4 years reported significantly lower risk for fatal or nonfatal myocardial infarction, with an overall odds ratio of 0.56 (95% CI 0.53 to 0.60) when compared with nondiabetic individuals with previous myocardial infarction (4Bulugahapitiya U. Siyambalapitiya S. Sithole J. et al.Is diabetes a coronary risk equivalent? systematic review and meta-analysis.Diabetic Med. 2009; 26: 142-148Crossref PubMed Scopus (264) Google Scholar). It is important to note that the landmark Steno-2 study has provided compelling evidence that mortality resulting from CV disease can be drastically reduced in type 2 diabetes by aggressive multifactorial interventions-to-treat so as to target lipid level, blood pressure and glycemic goals (5Gaede P. Lund-Andersen H. Parving H.H. et al.Effect of a multifactorial intervention on mortality in type 2 diabetes.N Engl J Med. 2008; 358: 580-591Crossref PubMed Scopus (2780) Google Scholar). Vascular protection and CV disease-risk reduction have become a major focus in the management of people with diabetes, as emphasized by the evidence-based 2013 Canadian Diabetes Association clinical practice guidelines (6Canadian Diabetes Association Clinical Practice Guidelines Expert CommitteeVascular protection in people with diabetes.Can J Diabetes. 2013; 37: S100-S104Abstract Full Text Full Text PDF Scopus (31) Google Scholar). The alarming concern that glucose-lowering drugs may be associated with increased CV deaths was first raised by Nissen in 2007 (7Nissen S. Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.N Engl J Med. 2007; 356: 2457-2471Crossref PubMed Scopus (4092) Google Scholar), and it has subsequently led the Food and Drug Administration (FDA) to mandate that all novel antihyperglycemic drugs demonstrate no increase in CV safety signals before they are approved. Further, a compulsory requirement of the FDA approval process for all glucose-lowering drugs involves the conduct of long-term CV outcome trials. The first 2 neutral CV outcomes studies, both oral incretins (saxagliptin and alogliptin), have been published (8Scirica B.M. Bhatt D.L. Braunwald E. et al.Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.New Engl J Med. 2013; 369: 1317-1326Crossref PubMed Scopus (2721) Google Scholar, 9White W.B. Cannon C.P. Heller S.R. et al.Alogliptin after acute coronary syndrome in patients with type 2 diabetes.New Engl J Med. 2013; 369: 1327-1335Crossref PubMed Scopus (2037) Google Scholar). Over the next several years, we will learn more about the cardiovascular safety of novel glucose-lowering agents from no fewer than 15 ongoing CV-outcome clinical trials (http://www.ClinicalTrials.gov/). Because diabetes confers excessive CV risk, it could be predicted that few, if any, of the ongoing CV outcome trials involving glucose-lowering agents, will be able to demonstrate superiority during the relatively short study period of 6 to 8 years in people with type 2 diabetes enrolled in these trials, most of whom are already at high CV risk. In any case, prospective clinical trials will provide much more robust and insightful information concerning CV risk in people with diabetes than does a comprehensive retrospective analysis of Canadian CV mortality attributable to diabetes, as suggested by Dr. Snyman.