Cardiovascular risk is increased at any stage of diabetic nephropathy, and the majority of patients with such nephropathy will die not of uremia but of macrovascular complications [183,184,188,226]. Prevention of these complications is mandatory, and risk factors for macroangiopathy other than hypertension should also be treated.
Diabetic nephropathy is accompanied by lipid disorders which are believed to contribute essentially to the high cardiovascular risk [227]. Treatment of dyslipoproteinemia is mandatory, as are “stop smoking” programs for smokers.
Platelet aggregation inhibition with aspirin is recommended in diabetic patients with albuminuria [228]. Radiopaque media should only be used after careful hydration of the patient [229].
Patients with endstage renal disease will need renal replacement therapy. Chronic hemodialysis, peritoneal dialysis (intraperitoneal, continual ambulatory), and renal transplantation in combination with pancreas transplantation [230] are presently the methods of choice. The prognosis of patients who have undergone transplantation has recently been improved but still is not as good as in non-diabetic subjects [176,187,230].
Almost 100% of patients with endstage renal disease also have diabetic retinopathy and/or diabetic neuropathy. Monitoring and treatment of these complications is equally important.
Macroangiopathy
The term “macroangiopathy” was introduced by Lundbaek [231] to draw attention to the fact that large-vessel disease in diabetes is not just a matter of atherosclerosis occurring in a diabetic subject, but is a facet of diabetic angiopathy as important as microangiopathy. The major clinical complications of macroangiopathy are coronary artery disease, stroke, and amputation. Only coronary artery disease will be discussed in more detail in this chapter.
Epidemiology
Due to the insidious course of macroangiopathy and the difficulties of early diagnosis, reliable population-based data on its incidence and prevalence are lacking. Some epidemiological data on the clinical manifestations are available [232]. The figures for their incidence and prevalence in diabetes depend on their occurrence in the general population to which they belong and differ considerably between countries [233]. However, clinical, epidemiological [154,234–236], and autopsy studies [237,238] and cause-of-death statistics [29,239] agree that the figures are higher in people with type 1 diabetes/IDDM and type 2 diabetes/ NIDDM than in the general population. After 30 years of IDDM, cardiovascular disease accounts for two-thirds of all deaths [21]. Macroangiopathy develops earlier in life and occurs almost independently of gender [154,240]. The increase in risk is higher in women than in men [236,241,242]. Thrombotic complications of macroangiopathy are the leading cause of death in diabetes [29,243–245].
Coronary artery disease is 3.3 times more frequent in diabetic than in nondiabetic people [246]. Myocardial infarction is 3.7 times more frequent in diabetic men and 5.9 times more frequent in diabetic women [242]. In another study [247] the increase was 6.7 times in type 2 and 12.2 times in type 1 diabetic women. The higher risk of women goes along with more atherogenic lipid profiles (see below). The standardized mortality rate (corrected for age and gender) for any heart disease is 9.1 times higher if diabetes mellitus is diagnosed before the age of 30 and 2.3 times higher if it is diagnosed later [248]. As a rough estimate, in western societies about half of diabetic people die of premature cardiac death. Stroke is about twice as frequent as in the general population, and two out of three amputations are performed in diabetic people.
Pathology
The histology of lesions in the arterial wall of diabetic subjects is similar to what is seen in the general population. However, lesions tend to be located in more distal regions of the vasculature. In diabetic subjects, the established sequence of early events in atherogenesis seems to be the same as in nondiabetic subjects:-adhesion of monocytes to endothelial cells, mediated by VCAM-1-penetration of monocytes into the vessel wall, mediated by MCP-1-activation of monocytes to form macrophages/foam cells/fatty streaks, mediated by MCSF (macrophage colony stimulating factor). The classical risk factors of atherosclerosis are also effective in diabetes mellitus [135,154,249–251], and diabetes enhances the impact of these risk factors. Hyperglycemia contributes to the pathogenesis of macroangiopathy. However, the correlation with the duration of diabetes and HbA1c is weak. There must be additional specific risk factors in diabetic people, which are absent or only weakly expressed in non-diabetic people (Table 1.13).
Activated hemostasis seems to play an important role. It results from increased plasma coagulation and decreased fibrinolysis together with a loss of physiological endothelial platelet resistance, increased thrombogenicity of the subendothelial matrix, and platelet activation [138,