Epidemiology of macrovascular disease
The burden and public health impact of macrovascular disease in patients with diabetes mellitus is increasing with the increasing prevalence of diabetes. It has been proven beyond doubt that the highest rates of diabetes-related morbidity and mortality are attributable to one of the three major macrovascular complications: coronary heart disease (CHD), stroke, and peripheral arterial disease (PAD).
Cardiovascular risks in diabetes, pre-diabetes and the population
Mortality rates in diabetes mellitus are approximately twice as high compared to individuals without diabetes. The increased risk of cardiovascular disease in diabetes is the most important explanation for these high mortality rates.
Diabetic patients without a previous myocardial infarction have about the same risk rate of major cardiovascular events as non-diabetic patients with a previous myocardial infarction (figure 1).
Figure 1. Relative risk of cardiovascular events in those without and with diabetes, with and without a history of previous myocardial infarction (MI). Furthermore, the combination of diabetes and a prior myocardial infarction is associated with a steep increase in CHD mortality risk. Several epidemiologic studies have shown an increased cardiovascular risk in the earliest stages of the disease. Already in subjects with pre-diabetes, such as an impaired fasting glucose (IFG), an increased risk is found. The increased cardiovascular risk in those with impaired glucose tolerance (IGT) is in fact independent of the subsequent development of diabetes (figure 2)
Figure 2. Cumulative hazards for CVD based on the 2-hour glucose results following an Oral Glucose Tolerance Test..
Figure 3. Mortality risk in men related to HbA1c levels. Finally, the EPIC-Norfolk study demonstrated a continuous relationship between glycated haemoglobin (HbA1c) and all cause, cardiovascular, and CHD mortality across the whole study population distribution, with the lowest rates in those with a HbA1c below 5.0% (figure 3).These findings also show that the extent and nature of the increased cardiovascular risk related to hyperglycemia is generally underestimated .
Gender differences in cardiovascualr risk
Gender differences in diabetes mellitus have been observed with increasing evidence showing that the disease affects women and men differently, in particular for CHD and stroke risk. In type 2 diabetes a greater excess coronary risk (relative risk up to 50%) has been found in women compared to men . Furthermore, a greater risk of stroke in diabetic women has been found with a relative risk increase of 27%. The clearly increased frequency of PAD in those with diabetes compared to patients without diabetes is not always disproportionally affecting women. Apart from the under-representation of women in studies and possible disparities in treatment, explanations for a more adverse cardiovascular risk profile in women could be altered estrogen-related protective mechanisms, altered insulin action, low-grade inflammation, and changes in coagulation and fibrinolysis. These latter factors could, individually or combined, result in more pronounced endothelial dysfunction in an early stage of the disease. Still, a substantial proportion of the higher cardiovascular risk in women with diabetes remains unclear.
Risk factors for cardiovascular disease in diabetes
Overlapping in type 1 and type 2 diabetes, important predictors of cardiovascular morbidity and mortality include diabetes duration, glycemic control, hypertension, age, smoking, dyslipidemia, microalbuminuria and a history of CHD.
Microalbuminuria is a strong and independent risk factor for future cardiovascular morbidity and mortality in both people with and people without diabetes. Furthermore, there is an independent and continuous association between the degree of albuminuria in combination with a reduced eGFR and the risk for cardiovascular outcomes in patients with type 2 diabetes (figure 4).
Figure 4. Combined effects of albuminuria and renal function (expressed as eGFR) at baseline on the risk for cardiovascular death.To reduce cardiovascular risk it is important to target the potentially modifiable risk factors in diabetes. Therefore, assessment and reduction of microalbuminuria play an important role in diabetes management.
Reducing cardiovascular risk in diabetes
Two decades ago, the DCCT and The United Kingdom Prospective Diabetes Study [UKPDS] were the pioneering studies demonstrating that intensive blood glucose control results in a remarkable reduction of diabetes-related complications. In type 1 diabetes, the DCCT/EDIC study showed, along with improvements in glycated hemoglobin, a reduced risk for the first occurrence of any cardiovascular outcome by 42% in the intensive treatment group as compared with the conventional treatment group after 11 years of follow up (figure 5) 
Figure 5. Cumulative incidence of the first of any adverse cardiovascular outcomes in patients with type 1 diabetes initially treated with intensive or conventional therapy.. Similar findings were documented for type 2 diabetes in the UKPDS: a clinically relevant post-trial risk reduction of 15% emerged over time for myocardial infarction, whereas differences during the interventional phase of the trial were not significant. In the Danish Steno-2 intervention trial a 'modern' multimodal intensive therapy (i.e. aiming at intensive control of glucose, blood-pressure, dyslipidaemia and smoking cessation) showed an absolute risk reduction of 13% in cardiovascular mortality amongst type 2 diabetes patients with microalbuminuria.
The Framingham Heart Study investigated age- and sex-adjusted incidence rates of cardiovascular disease among subjects with and without diabetes in two different time periods. In line with the known increased risk for those with type 2 diabetes, this study showed an almost three fold higher incidence of cardiovascular disease in the diabetic group compared to the non-diabetic group in both time periods. But in the later period the incidence rate for cardiovascular disease in the diabetic patients decreased markedly by almost 50% compared to the earlier period. The latter result is probably due to improvement of diabetes care over the years. The incidence of cardiovascular disease in participants without diabetes was 35% lower in the later period . In the last two decades, consistent results have been found in the U.S.: mortality rates among men and women with diabetes decreased significantly. This decline reduced the absolute difference between individuals with and without diabetes . Furthermore, a large reduction in the incidence of cardiovascular disease, particularly acute myocardial infarction has been observed as well. Of note, the rate reduction of acute myocardial infarction, stroke, amputation, and end-stage renal disease among the patients with diabetes surpassed the rate reduction in the patients without diabetes . Although it is difficult to compare such findings, the same trends were observed in other countries. However, while improvements in diabetes care, including self-management and intensifying medical treatment, result in improved cardiovascular morbidity and mortality rates, this is offset by the increasing incidence of diabetes mellitus; the societal burden of diabetes-related cardiovascular complications still remains high.
^ Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. 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; 339:229-234
^ DECODE Study Group, the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria Arch Intern Med 2001; 161:397-405
^ 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; 322:15-18
^ Singh A, Donnino R, Weintraub H, Schwartzbard A. Effect of strict glycemic control in patients with diabetes mellitus on frequency of macrovascular events. Am J Cardiol 2013;112:1033-1038
^ Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, Golden SH. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann intern Med 2004;141:421-431
^ Juutilainen A, Kortelainen S, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Gender difference in the impact of type 2 diabetes on coronary heart disease risk. Diabetes Care 2004;27:2898-2904
^ 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. BMJ 2006;332:73-78
^ Peters SA, Huxley RR, Woodward M. Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775385 individuals and 12539 strokes. Lancet 2014;S0140-6736(14)60040-4. doi: 10.1016/S0140-6736(14)60040-4 [Epub ahead of print]
^ Shah B, Rockman CB, Guo Y, Chesner J, Schwartzbard AZ, Weintraub HS, Adelman MA, Riles TS, Berger JS. Diabetes and vascular disease in different arterial territories. Diabetes Care. 2014 doi: 10.2337/dc13-2432 [Epub ahead of print]
^ Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; Diabetes Control and Complications Trial/Epidemiology of Deiabetes interventions and Complications (DCCT/EDIC)Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353:2643-2653
^ Gaede P, Lund-Andersen H; Parving H-H; Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358:580-591
^ Fox CS, Coady S, Sorlie PD, Levy D, Meigs JB, D’Agostino RB Sr, Wilson PW, Savage PJ. Trends in cardiovascular complications of diabetes. JAMA 2004; 292:2495-2499
^ Gregg EW, Cheng YJ, Saydah S, Cowie C, Garfield S, Geiss L, Barker L. Trends in death rates among U.S. adults wit hand without diabetes between 1997 and 2006: findings from the National Health Interview Survey. Diabetes Care 2012; 35:1252-1257
^ Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D; Williams DE, Geiss L. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med 2014; 370:1514-1523