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Diabetes mellitus (DM) is an important risk factor for cardiovascular disease (CVD), which in turn represents the principal cause of disability and mortality in individuals with DM. The pathophysiological basis of this link is atherosclerosis, which accounts for the majority of CVD and it is accelerated by DM. However, conventional vascular risk factors (e.g., obesity, physical inactivity, hypertension and high cholesterol level) cannot fully explain the excess CVD risk associated with DM, although HbA1c appears to be an important mediator (1).
Furthermore, while myocardial infarction (MI) and stroke are the most commonly investigated complications of DM, the associations of DM with other vascular disorders are for a large part unknown. Two recent large scale studies that thoroughly investigated the relationship between DM and the risk of CVD shed some light on this topic. A meta-analysis of 102 studies from the Emerging Risk Factors Collaboration including data of 698,782 people without initial CVD evaluated the associations between DM and fasting plasma glucose (FPG) concentrations and a wide range of fatal and non-fatal cardiovascular outcomes (2). According to their results, DM accounted for 11% of vascular deaths which corresponds to an estimated 325,000 death/year in high income countries alone. Subjects with DM compared to those without it, had about a two-fold higher risk for (CHD), ischaemic stroke, unclassified stroke, and deaths for other vascular diseases, independently of other risk factors (age, sex, smoking status, BMI, and systolic blood pressure) (2). Interestingly, greater HRs for CHD with DM were found in groups at lower absolute cardiovascular risk, such as younger individuals, women, non-smokers, those with below average BMI and with below average systolic blood pressure. In subjects with DM, FPG concentrations were non-linearly related to risk of CHD or ischaemic stroke (2), but information about haemoglobin A1c (HbA1c), which is known to be more strongly associated with CVD as compared with FPG (3), were not provided. A large prospective cohort using health records from the CALIBER programme implemented the knowledge on the link between DM and CVD evaluating the association between diabetes status and 12 different initial cardiovascular presentations, including angina, MI, peripheral arterial disease, heart failure (HF), abdominal aortic aneurysm (4). The cohort consisted of 1,921,260 individuals, of whom 34,198 (1.8%) had type 2 DM. 113,638 cardiovascular events occurred during a median follow-up time of 5.5 years; among these, peripheral arterial disease was the first presentation in 992 (16.2%) of the 6137 subjects with type 2 DM who had cardiovascular events whereas HF was the first presentation in 866 (14.1%) of them (5). This result is consistent with the previous finding of a high prevalence of HF among diabetic patients (30.6%); interestingly, the proportion of patients with preserved (HFpEF) vs reduced ejection fraction (HFrEF) was considerably higher (24.8% vs 5.8%) (5). This suggests that other pathophysiological mechanisms, in addition to atherosclerosis, affect the myocardium of subjects with DM, such as cardiomyocyte hypertrophy, caused by hyperinsulinemia and endothelial dysfunction caused by hyperglycaemia (6). While hyperglycaemia is one of the principal causes of macrovasculopathy In DM, it also represents the driver of microvascular complications (retinopathy, nephropathy, and neuropathy). In this regard, macro- and microvascular complications can be seen as part of the same spectrum, as the two disorders are strongly interconnected, and thus require a common preventive strategy. Taken together these data not only confirm that DM represents a strong and independent risk factor for CVD, but they also point out that the association is not restricted to CHD or stroke goes but concerns multiple acute and chronic cardiovascular outcomes.
Moreover, DM confers an increased risk of CHD even in those categories such as women and young individuals which are traditionally regarded as low risk groups. These findings have several important implications; the surveillance and prevention of DM complications should be directed towards multiple diseases and multiple subgroups of patients, and DM clinical trials should start considering other CV events, in addition to MI and stroke, as possible outcomes.
Note: The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology
Elisa Dal Canto, Joline WJ Beulens were commenting on these articles:
Emerging Risk Factors Collaboration, Sarwar N, Gao P, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215-22.
Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol. 2015;3(2):105-13
1. Khaw KT, Wareham N, Luben R, Bingham S, Oakes S, Welch A, Day N. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of european prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ. 2001 Jan 6;322(7277):15-8.2. Emerging Risk Factors Collaboration, Sarwar N, Gao P, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215-22.3. Selvin E, Steffes MW, Zhu H, et al. Glycated haemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med. 2010;362(9):800-11. 4. Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol. 2015;3(2):105-13.5. Boonman-de Winter LJ, Rutten FH, Cramer MJ, et al. High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes. Diabetologia. 2012;55(8):2154-62.6. Petar M. Seferović, Walter J. Paulus; Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes, Eur Heart J. 2015;36(27):1718-27.
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