Traditional risk factors for stroke such as arterial hypertension, dyslipi-demia, atrial fibrillation, heart failure, and previous myocardial infarction are more common in people with DM (3, 36). However, the impact of DM on stroke is not just due to the higher prevalence of these risk factors, as the risk of mortality and morbidity remains over twofold increased after correcting for these factors (4, 37). Risk factors for stroke in diabetic patients identified in previous studies are summarized in Table 2. It is informative to distinguish between factors that are non-specific and specific to DM. DM-specific factors, including chronic hyperglycemia, DM duration, DM type and complications, and insulin resistance, may contribute to an elevated stroke risk either by amplification of the harmful effect of other "classical" non-specific risk factors, such as hypertension, or by acting independently.
Risk factors of stroke in patients with diabetes
Age, male sex, arterial hypertension, atrial fibrillation Prior cerebrovascular disorders, arterial hypertension, smoking, elevated cholesterol and triglyceride levels, low HDL cholesterol, hyperglycemia, duration of diabetes Age, arterial hypertension, ischemic change on ECG, microvascular complications, therapeutic regimen Age, arterial hypertension, smoking, baseline glucose levels
Total cholesterol, male gender Systolic blood pressure, duration of disease (only in women with type 2 diabetes), smoking (in men with type 2 diabetes), probable ECG changes (type 1 diabetic men), possible ECG changes (type 2 diabetics) Age, hemoglobin A1C, spot urine albumin-to-creatinine ratio, and history of coronary heart disease Age and history of stroke
Younger age, females, duration of diabetes, smoking, obesity, atrial fibrillation, and hypertension
As hyperglycemia is the typical metabolic abnormality in patients with DM it is important to address the association between the elevated glucose levels and the risk of stroke in diabetic patients. A casual and linear relationship between hyperglycemia and the risk of microvascular complications of DM has been proven by many epidemiological and interventional studies. In contrast, for macrovascular complications the relation with high glucose levels remains controversial. Hyperglycemia was shown to be a significant predictor of the risk of fatal or non-fatal stroke in subjects with DM in a substantial number of studies (11-15, 43, 44). Some studies suggest that this relation may be more evident in type 2 than type 1 DM (32). In a meta-analysis of three studies addressing the relationship between HbA1c levels and the risk of cardiovascular disease in type 2 diabetic patients the pooled relative risk for stroke was 1.17 for each 1-percentage point increase in HbA1c level (45).
The recently published data from the Northern Manhattan Study suggested that inappropriate glycemic control, rather than the presence of DM itself, was associated with an increased risk of stroke. It was shown that diabetic subjects with elevated fasting blood glucose were at increased risk of stroke with the hazard ratio of 2.7, but those with target fasting glucose levels were not (46). In the same study it was revealed that an association between risk of stroke and fasting glycemia exists in African-Americans only while being non-significant in subjects of other ethnic origin (47).
Age seems to modify the role of hyperglycemia as a stroke risk factor. A linear increase in stroke morbidity and mortality for each 1% increment of HbA1c was found in older diabetic patients with onset of disease at an age older than 30 years, while there was no such association in younger subjects (48, 49).
The UKPDS showed that the odds of stroke being fatal was 1.37 per 1% HbA1c (50), but did not confirm the importance of hyperglycemia in stroke incidence (51). The estimated decrease in risk of stroke for a 1% reduction in HbA1c was 4% (p = 0.44) (52).
The controversy on the relation between blood glucose levels and the risk of stroke extends beyond studies in individuals with DM. While several studies report relations between different indices of glucose metabolism and the risk of stroke in non-diabetic individuals (53-55), other studies do not confirm such associations (56-58).
We may conclude that the relationship between hyperglycemia and stroke remains subject of debate. In this respect, the association between hyper-glycemia and cerebrovascular disease is established less strongly than the association between hyperglycemia and coronary heart disease. Nevertheless, better understanding of the impact of hyperglycemia on increased stroke risk is important to establish effective guidelines for stroke prevention. The results of clinical trials addressing the possibility of decreasing the risk of macrovascular complications by achieving normoglycemia could provide the deeper insight into the role of hyperglycemia as the stroke risk factor in diabetic patients (see below).
Other DM-specific stroke risk factors are microvascular complications and diabetic neuropathy. Patients with retinopathy are at increased risk of predominantly lacunar stroke (59, 60) [but see (61)], and post-stroke mortality is increased (62-64). The relation between stroke and retinopathy is more evident in type 2 than type 1 DM (32), but this may be due to the age of the patients who were studied. Proteinuria may also be an independent risk factor for stroke (65, 66), but the relation between the degree of proteinuria (microalbuminuria or macroalbuminuria) and the level of the risk of stroke is not yet clear (32, 66, 67), and some studies failed to reveal a significant association between albuminuria and the risk of stroke or stroke mortality
(38, 68, 69). Diabetic autonomic neuropathy represents another risk factor for stroke (70, 71). The presence of orthostatic drop of blood pressure of 10mmHg, for example, doubled the risk of stroke associated with sympathetic autonomic neuropathy (71).
The presence of the diabetic foot syndrome also increases the risk of stroke (72), although this association may be attributed to the underlying generalized vascular damage or severe neuropathy.
Metabolic Syndrome (MS) as Stroke Risk Factor
The term "metabolic syndrome" (MS) refers to a cluster of risk factors, including hypertension, dyslipidemia, obesity, and abnormalities in glucose metabolism that are closely associated with DM (in particular type 2 DM) and with cardiovascular disease, including stroke. Although the fact that these risk factors often co-occur is not debated, it is yet uncertain if the whole concept of the MS entails more than its individual components. The clustering of risk factors complicates the assessment of the contribution of individual components to the risk of vascular events, as well as assessment of synergistic or interacting effects. In addition, there is no general agreement on the actual definition of the syndrome (NCEP, 2001, 2005; WHO, 1999; IDF, 2005), and it is yet unclear if the presence of the MS has a higher predictive value for cardiovascular disease than widely used prediction scores such as Framingham, PROCAM, and SCORE (73-75). In the context of DM and stroke, the main relevance of the MS is that the majority of individuals with DM2 can be classified as having the MS. Moreover, the MS may precede the actual onset of type 2 DM by many years. Consequently, the MS, or its individual components, could represent key factors in the increased stroke risk in individuals with type 2 DM.
Indeed, the presence of the MS is associated with an approximately two-to threefold increased stroke risk, depending on the population studied and the MS definition used (76-78). In the recently published results of the prospective study of 7,853 subjects the HR for ischemic stroke in men were 1.59, 1.52,1.16, and 1.27, respectively, for the WHO, NCEP, NCEP revised, and IDF definitions of MS, and in women - 2.20, 2.68, 2.31, and 1.91, respectively. None of the definitions of MS predicted hemorrhagic stroke (79). In the Framingham Offspring Study it was found that relative risk of stroke in persons with both DM and MS was 3.3 and was higher than that for either condition alone; 2.1 - for MS alone, 2.5 - for DM alone. The population-attributable risk, owing to its greater prevalence, was greater for the MS alone than for DM alone (19% vs. 7%), particularly in women (27% vs. 5%) (80). In a prospective study of more than 14 thousand patients with pre-existing atherosclerotic vascular disease, subjects with the MS without DM exhibited a 1.5-fold increased odds for ischemic stroke or TIA, whereas those with frank DM had a 2.3-fold increased odds. The relative odds for ischemic stroke or TIA, associated with presence of the MS per se, were 1.4 in men but 2.1 in women (81). However, in a recently published prospective study of 594 diabetic patients followed-up for more than 10 years neither MS nor the combinations of its components predicted the development of ischemic stroke (82). Possibly, the relative impact of MS on increased stroke risk differs in patients with normal or impaired glucose tolerance or overt DM.
Insulin resistance is considered to be the central pathogenetic mechanism of the MS. There are some studies which addressed an association between insulin resistance and the risk of stroke. In the analysis of the data from the Third National Health and Nutrition Survey (1988-1994), it was found that patients with stroke had lower insulin sensitivity as assessed by HOMA index than participants without stroke and HOMA was independently associated with stroke (83). However, in another study, although the HOMA beta-cell index was inversely related to the stroke risk, there was no relation between the HOMA insulin resistance index and stroke risk, suggesting that insulin deficiency is a more important risk factor for stroke than insulin resistance (84). Also, in the landmark UKPDS, insulin sensitivity as measured by HOMA was not associated with subsequent stroke and estimation of insulin sensitivity provided no additional useful information with respect to the risk of the first occurrence of stroke in patients with newly diagnosed type 2 DM (85).
Hyperinsulinemia indicating insulin resistance was found in some groups of patients with stroke although these results were not consistent in different studies (86-88). Prospective studies addressing the role of hyperinsulinemia as a risk factor for stroke did not provide conclusive answers. An association between higher insulin levels and increase in incidence of either thromboembolic or hemorrhagic stroke was revealed in the Honolulu Heart Study (89). There was a J-shaped relationship between non-fasting serum insulin levels and the risk of stroke in non-diabetic men and this risk was higher in the first and fourth or higher quintiles compared to the second quintile (13). However, although hyperinsulinemia was associated with an increased risk for stroke morbidity and mortality in some studies this association became statistically non-significant after adjustment for obesity and other confounding variables (90-92). While the fasting insulin level was found to be a significant predictor of stroke in elderly non-diabetic subjects, there was no such an association in diabetic patients (15). In the recently published results of the prospective study of 1,151 elderly men increased fasting intact proinsulin level and decreased insulin sensitivity revealed by clamp predicted subsequent fatal and non-fatal stroke/TIA, independently of DM whereas fasting insulin did not (93). Hyperinsulinemia was not a stroke predictor in the UKPDS (38).
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