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Cardiovascular Complications of Diabetes

      This issue of the Canadian Journal of Diabetes is devoted to the cardiovascular complications of diabetes, to coincide with and celebrate Vascular 2013 (Montréal, Québec, October 17 to 20, 2013). Vascular 2013 Summit is a unique one-time scientific conference where the Canadian Diabetes Association and Canadian Society of Endocrinology and Metabolism are joining forces with the Canadian Cardiovascular Congress, Canadian Stroke Congress, Hypertension Canada and the Heart and Stroke Foundation of Canada. All the organizations will host their individual sessions but will come together for a “Vascular Day” to present topics that are of interest to their members.
      Let me start with a brief background overview of cardiovascular disease (CVD) in people with diabetes to provide our readers with a greater appreciation of the various articles published in this issue of the Journal that address diverse aspects of the cardiovascular complications of diabetes.
      People with type 1 and type 2 diabetes are at significantly increased risk of developing atherosclerotic cardiovascular disease. Diabetes is associated with microvascular and macrovascular complications, and is a major and independent risk factor for CVD. The lifetime risk for CVD in people with diabetes is high, about 67% in men and 57% in women at age 50 years (
      • Lloyd-Jones D.M.
      • Leip E.P.
      • Larson M.G.
      • et al.
      Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age.
      ). In a meta-analysis of 37 prospective cohort studies of fatal coronary heart disease among a total of 447 064 people, the rate of fatal coronary heart disease was about 3.5-fold higher in patients with diabetes than in those without (
      • Huxley R.
      • Barzi F.
      • Woodward M.
      Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies.
      ). The relative risk for fatal coronary heart disease associated with diabetes is 50% higher in women than it is in men. This greater excess coronary risk may be explained by more adverse cardiovascular risk profiles among women with diabetes, combined with possible disparities in treatment that favour men (
      • Huxley R.
      • Barzi F.
      • Woodward M.
      Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies.
      ). A more recent meta-analysis of 102 prospective studies in 698 782 people confirms that diabetes, independently from other conventional risk factors, doubles the risk for coronary heart disease and ischemic stroke, and that the risk is higher in women than men (
      The Emerging Risk Factors Collaboration
      Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.
      ). In people with no history of diabetes, every 1 mmol/L higher fasting glucose above 5.6 mmol/L increased the risk of coronary heart disease by about 12%; and impaired fasting glucose (5.6 to 7.0 mmol/L) independently increased the risk of coronary heart disease by 15% in women and 7% in men (
      The Emerging Risk Factors Collaboration
      Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.
      ). Data from the EpiDREAM, an international prospective cohort study, which assessed the relationship between glucose levels and incident cardiovascular events and death, concluded that each 1 mmol/L increase in fasting plasma glucose was associated with a 17% increase in the risk of future cardiovascular events (
      • Anand S.
      • Dagenais G.
      • Mohan V.
      • et al.
      Glucose levels are associated with cardiovascular disease and death in an international cohort of normal glycaemic and dysglycaemic men and women: the EpiDREAM cohort study.
      ). Taken together, current evidence indicates that CVD risk begins in prediabetes and significantly increases in people with diabetes, and especially in women with diabetes.
      Many people with prediabetes and diabetes also have clusters of other CVD risk factors, namely, obesity, dyslipidemia, hypertension, proinflammatory and prothrombotic states. Metabolic syndrome has been proposed as a simple clinical paradigm to identify people who are at increased CVD risk. Along with impaired fasting glucose or impaired glucose tolerance, abdominal obesity, atherogenic dyslipidemia characterized by increased triglyceride and decreased high-density lipoprotein cholesterol levels, and increased systolic or diastolic blood pressure are the five components of the metabolic syndrome. Any 3 of the 5 components fulfills the diagnosis of metabolic syndrome (
      • Lau D.C.W.
      Metabolic syndrome: perception or reality?.
      ). The metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality (
      • Lau D.C.W.
      Metabolic syndrome: perception or reality?.
      ,
      • Mottillo S.
      • Filion K.B.
      • Genest J.
      • et al.
      The metabolic syndrome and cardiovascular risk: A Systematic Review and Meta-Analysis.
      ). A more comprehensive and consolidated approach is the broader concept of global cardiometabolic risk, which includes the subset of people with metabolic syndrome (
      • Leiter L.A.
      • Fitchett D.H.
      • Gilbert R.E.
      • et al.
      Identification and management of cardiometabolic risk in Canada: A position paper by the Cardiometabolic Risk Working Group (Executive Summary).
      ). As a majority of people with prediabetes and diabetes have increased cardiometabolic risk, identification of the latter greatly facilitates the clinical management strategy (
      • Leiter L.A.
      • Fitchett D.H.
      • Gilbert R.E.
      • et al.
      Identification and management of cardiometabolic risk in Canada: A position paper by the Cardiometabolic Risk Working Group (Executive Summary).
      ).
      CVD also accounts for a large proportion of the excess and premature mortality related to diabetes. As many as 60% to 80% of people with type 2 diabetes will develop and eventually die from CVD. Evidence suggests that diabetes is associated with significantly increased all-cause mortality, a 2-fold increase in men and 3-fold increase in women, and life expectancy is reduced by about 12 years (
      • Manuel D.G.
      • Schultz S.E.
      Health-related quality of life and health-adjusted life expectancy of people with diabetes in Ontario, Canada, 1996–1997.
      ,
      • Booth G.L.
      • Kapral M.K.
      • Fung K.
      • et al.
      Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study.
      ). Data from a Canadian population-based retrospective cohort study of all adults with (n=379 003) and (n=9 018 082) without diabetes mellitus indicated that for both men and women, the transition to a high-risk category occurred at a younger age for men and women with diabetes than for those without diabetes. Diabetes confers cardiovascular age of about 15 years in advance of an individual's chronological age (
      • Booth G.L.
      • Kapral M.K.
      • Fung K.
      • et al.
      Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study.
      ). Also, duration of diabetes increases the risk of coronary heart disease death independent of coexisting CVD risk factors. According to data from the Framingham Heart Study, the risk of coronary heart disease was 1.4-fold higher for each 10-year increase in duration of diabetes, after adjustment for age, sex and CVD risk factors (
      • Fox C.S.
      • Sullivan L.
      • D’Agostino R.B.
      • et al.
      The significant effect of diabetes duration on coronary heart disease mortality: The Framingham Heart Study.
      ).
      With the rapidly rising prevalence of diabetes in North America and globally, the health and economic burden of diabetes becomes an important consideration. Diabetes was ranked sixth as the cause of death in the US, seventh for years of life lost and eighth for years lived with disability and disability-adjusted life years (
      • Murray C.J.L.
      • Lopez A.D.
      Measuring the global burden of disease.
      ). One can surmise that the global burden of diabetes will increase much more dramatically over the next 2 decades.
      What are the mechanisms underlying the increased CVD risk and accelerated atherosclerosis in diabetes are the subjects of 3 review papers. Preclinical and clinical studies appear to support an emerging proatherogenic role for insulin resistance, whereas hyperglycemia might exert a synergistic influence. Zeadin et al explore the molecular and cellular mechanisms linking insulin resistance and diabetes to accelerated atherosclerosis (
      • Zeadin M.G.
      • Petlura C.I.
      • Werstuck G.H.
      Molecular mechanisms linking diabetes to the accelerated development of atherosclerosis.
      ). On the other hand, Wang et al draw our attention to a putative role of heparanase in diverse cellular processes involved in diabetes and vascular complications, ranging from the initiation of β-cell failure to promotion of endothelial dysfunction in early atherosclerosis, to cardiac metabolic switching in animal models of diabetic cardiomyopathy (
      • Wang F.
      • Wan A.
      • Rodrigues B.
      The Function of Heparanase in Diabetes and its Complications.
      ). A third paper is focused on the involvement of microRNAs in the pathogenesis of vascular complications of diabetes (
      • Ruiz M.A.
      • Chakrabarti S.
      microRNAs: the underlying mediators of pathogenetic processes in vascular complications of diabetes.
      ). microRNAs are a group of noncoding RNAs (ribonucleic acids) that are post-transcriptional regulators of gene expression. They not only exert epigenetic influences in diverse biologic processes, but have recently been shown to influence the expression of inflammatory mediators involved in the pathogenesis of diabetic nephropathy, diabetic retinopathy and cardiomyopathy.
      One possible explanation for the onset of CVD risk in people with prediabetes and/or increased cardiometabolic risk is the development of atherogenic diabetic dyslipidemia. The pathophysiology and emerging therapeutic strategies targeting the abnormal lipoprotein metabolic pathways are reviewed by Dominic Ng (
      • Ng D.
      Diabetic dyslipidemia: from evolving pathophysiological insight to emerging therapeutic targets.
      ).
      A second group of 5 papers originate from researchers who were awarded team grants by a joint Canadian-Finnish initiative. The Canadian Institutes for Health Research Institute of Circulatory and Respiratory Health, along with its funding partners (Canadian Diabetes Association, Heart and Stroke Foundation of Canada, Health Canada and Pfizer Canada) and its Finnish counterpart Tekes, the Finnish Funding Agency for Technology and Innovation, developed a new research initiative entitled “Cardiovascular Complications of Diabetes.” The aim of this research funding is to support the creation or development of expert teams comprising investigators undertaking collaborative, team-based research in the area of cardiovascular complications of diabetes. Three teams were successfully awarded a 5-year team grant and highlights of their research programs are presented in this issue.
      The multidisciplinary research team under the leadership of Rob Petrella investigated the benefits and potential pitfalls in exercise prescription in preventing and reducing cardiovascular complications in people with type 1 diabetes (
      • Noble E.
      • Melling J.
      • Shoemaker K.
      • et al.
      Innovation to reduce cardiovascular complications of diabetes at the intersection of discovery, prevention and knowledge exchange.
      ). Their research involved animal as well as human studies, as well as randomized clinical trials to address a number of important research questions related to the cardiovascular responses to exercise and prescription of exercise programs to people with type 1 diabetes. Preliminary findings from their clinical trials suggested that cardiometabolic risk factors, which correlated with changes in heart rate variability, improved with exercise prescription.
      In addition to exercise, specific dietary therapy, as discussed by Matti Uusitupa, may also have an impact in reducing inflammation as well as weight loss, which may become an integral component in the prevention of type 2 diabetes in individuals who are at high risk for the disease (
      • Uusitupa M.
      Diet, inflammation and prediabetes - impact of quality of diet.
      ).
      The second team, led by André Marette, focused their effort on the genetic and clinical determinants of cardiovascular complications of diabetes through a unique multidisciplinary approach (
      • Marette A.
      • Avramoglu R.K.
      • Laplante M.-A.
      • et al.
      The genetic and metabolic determinants of cardiovascular complications in type 2 diabetes: recent insights from animal models and clinical investigations.
      ). They use novel animal models to gain insights into the molecular and cellular mechanisms underlying insulin resistance and the key determinants of the cardiovascular complications of diabetes. They hope to identify novel target genes and molecular mechanisms linking insulin resistance and inflammation to vascular dysfunction and coronary heart disease. The Canadian team also included a clinical trial investigating the long-term effects of lifestyle modification on various CVD markers in subjects with diabetes and atherosclerotic coronary heart disease.
      Richard Gilbert and his team investigated the pathogenetic mechanisms of endothelial cell loss in the diabetic microvascular complications, and the application of novel therapies to repair the dysfunctional endothelial cell loss. In his review, Dr. Gilbert discusses the use of angiogenic bone marrow-derived endothelial progenitor cells to repair endothelial cell loss in animal models of diabetic nephropathy (
      • Gilbert R.
      Augmenting endothelial repair in diabetes: role of bone marrow derived cells.
      ).
      In another review, Kim Connelly and colleagues discuss the potential beneficial cardiovascular effects of incretin mimetics in type 2 diabetes (
      • Advani A.
      • Bugyei-Twum A.
      • Connelly K.
      Cardiovascular effects of incretins in diabetes.
      ). This is a timely and clinically relevant topic, as some of the glucose-lowering agents (namely, thiazolidinediones and sulphonylurea insulin secretagogues) have recently been reported to be associated adverse cardiovascular outcomes. Incretin mimetics, which include the injectable glucagon-like peptide 1 receptor agonists and the oral dipeptidyl peptidase-4 (DPP-4) inhibitors, appear to exert direct and indirect effects on the cardiovascular system (
      • Ussher J.R.
      • Drucker D.J.
      Cardiovascular biology of the incretin system.
      ). Data from preclinical and early phase clinical studies appear to demonstrate that incretin mimetics are associated with cardiovascular benefits through a variety of molecular and cellular mechanisms, which are independent of their glucose-lowering efficacy (
      • Advani A.
      • Bugyei-Twum A.
      • Connelly K.
      Cardiovascular effects of incretins in diabetes.
      ). Two randomized clinical trials on cardiovascular outcomes, each comparing a DPP-4 inhibitor (saxagliptin and alogliptin) with placebo in patients with type 2 diabetes at high risk for cardiovascular complications, will be reported at the European Society of Cardiology this fall. We already know the topline results of one of the 2 trials, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction (SAVOR-TIMI Study), which compared the efficacy and safety of saxagliptin with placebo in approximately 16 500 subjects. While saxagliptin did not show cardiovascular benefits in this large, double-blinded, multicenter trial, we now know it is a safe glucose-lowering agent devoid of harmful effects on the cardiovascular system. Over the next several years, we will learn more about the results of at least 6 additional long-term cardiovascular outcome studies using incretin-based therapies.
      The series of papers published in this special issue provide a glimpse of the diverse research and clinical studies to gain new insights into the pathogenesis and management of the cardiovascular complications of diabetes. Significant gaps still exist in our knowledge translation and implementation of strategies. Reducing the burden of cardiovascular disease in people with diabetes will require ongoing and close collaborations of researchers and practitioners from different sectors and disciplines. Vascular 2013 is a first step towards this important effort. Let's hope that it is the beginning of long-lasting valuable partnerships.
      Finally, I am delighted to share an important and exciting news with our readers. The Journal has just received MEDLINE indexing by the US National Library of Medicine. I would like to take this opportunity to thank the members of the editorial board and the editorial staff for their tireless effort and dedication, the 2 professional sections (Diabetes Educator Section and the Clinical and Scientific Section), senior staff and members of the Board of Directors at the Canadian Diabetes Association for their unwavering support and guidance. We also owe our gratitude to Dr. George Fantus and Dr. Heather Dean, Editor-in-Chief emeriti, who have laid a solid foundation and path for journal indexing. Elsevier, our publisher, under the aegis of Dr. Andrew Miller, has been instrumental in our success. On behalf of the editorial board members and the CDA, we express our sincere thanks and acknowledgement for the enormous partnership and guidance. Most importantly, the contributing authors from across the country and abroad have been tremendous in generously sharing their research and knowledge with our readers by publishing in the Journal. The stars are aligned for the Journal to flourish and we will endeavor to do our best to become a leading diabetes publication that we can take pride in.

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