Diabetes, the Metabolic Syndrome, and Ischemic Stroke: Epidemiology and possible mechanisms

It has been well documented that diabetes confers a significantly increased risk of stroke, as well as increased mortality following stroke (1–7). Stroke is a preventable disease with high personal and societal cost. While great progress has been made in understanding the link between diabetes and coronary heart disease (CHD), the literature on diabetes and stroke has been less enlightening. CHD is a larger problem that accounts for 40–50% of mortality in diabetes. Because of the overwhelming impact of CHD, the impact of stroke has been relatively underappreciated. Thus, physicians, diabetes educators, and nurses are less equipped to educate patients. We therefore review the relationship between diabetes and stroke.

Given that more than one million people are diagnosed with diabetes yearly, a figure that is expected to rise, the impact of diabetes on the incidence of stroke is of increasing importance. Diabetic patients compose roughly 6.3% of the U.S. population but account for 15–27% of all incident strokes, based on 2002 estimates (4,7–12). This is certainly an underestimation, as most studies classify patients as having diabetes only if diagnosed before stroke. When considering age-adjusted incidence rates, diabetic patients are 2.9 times as likely to have a stroke compared with nondiabetic patients, a disparity that is seen in multiple racial/geographic groups (4,7,9,13–15). This is due specifically to an increase in the rate of ischemic stroke rather than hemorrhagic stroke (7,16–18).

The heaviest burden of stroke for the general population lies with older and minority groups (4,12,19–22). Diabetes appears to amplify these nonmodifiable risks, in part due to the increased prevalence of diabetes in these groups (7,23,24). Diabetes also confers an increased risk for neurovascular disease at younger ages (25). The Greater Cincinnati–Northern Kentucky Stroke Study (GCNKSS) found that the risk for ischemic stroke in white diabetic patients is higher at every age-group compared with nondiabetic patients, with highest relative risk (RR) of 5.3 found in the 45- to 54-year age-group. Among African Americans, the highest risk was even greater (RR 9.9) and was found in the 35- to 44-year age-group. A substantial peak in stroke risk is seen in the 45- to 64-year age-group in whites and in the 35- to 54-year age-group in African Americans (7).

Although stroke is more common among diabetic patients, most studies report a significantly reduced rate of transient ischemic attacks (TIAs) in diabetic patients compared with nondiabetic patients. Diabetic patients are more likely to present with cerebral infarct, indicating that ischemia in diabetic patients is less likely to be reversible (7,26–28). This presents a unique problem for preventing stroke in this population. TIAs can serve as a warning sign, providing a window of opportunity for medical intervention to prevent a completed stroke. The relative lack of warning in diabetic patients requires that physicians, nurses, and educators be aggressive about risk factor intervention, as comprehensive programs to reduce risk can be highly successful (29). For those who do present with a TIA, aggressive treatment is equally important since diabetes has been shown to increase the risk of subsequent completed stroke (30).

Many attempts have been made to discern the underlying mechanisms through which diabetes increases stroke risk. Such studies have largely taken cues from the cardiovascular literature in which diabetes and the associated components of the metabolic syndrome (i.e., hypertension and hyperlipidemia) have been found to contribute to cardiovascular disease development (31–33). This approach has been informative, yet the relationships between diabetes, the components of the metabolic syndrome, and stroke are clearly unique. Here, we discuss these individual relationships, highlighting the differences between stroke and cardiac risk.

As in any discussion of diabetes and its sequelae, the fundamental question arises as to whether stroke risk is increased due to chronic hyperglycemia. Published studies provide conflicting evidence. Lehto et al. (34) studied 1,059 diabetic patients and correlated their baseline fasting glucose levels, A1C, and duration of diabetes with stroke over 7 years of follow-up. All three factors contributed significantly to increased risk of stroke, while fasting hyperglycemia (>13.4 mmol/l) remained significant after accounting for other cardiovascular risk factors (odds ratio [OR] 2.6 [95% CI 1.5–3.8] compared with normoglycemia) (34). The Honolulu Heart Program reported similar results in nondiabetic patients when comparing the extremes (80th and 20th percentiles) of serum glucose levels (RR for thromboembolic stroke 1.4 [95% CI 1.1–1.8]) (16). A Finnish cohort study measured A1C and fasting glucose in diabetic and nondiabetic patients. In both groups, they found a significant association between each measure of glucose control and stroke risk using multivariate analysis (35). More recent data from the Atherosclerosis Risk in Communities (ARIC) Study reiterated this relationship, finding an increased RR of stroke with increasing levels of A1C in both diabetic and nondiabetic patients (36). In contrast, the European Prospective Investigation Into Cancer (EPIC)-Norfolk Study did not find a significant relationship between A1C and stroke risk until a threshold level was reached (37).

The only clinical trial to date that has directly evaluated the effect of tight glucose control on stroke is the UK Prevention in Diabetes Study (UKPDS). Type 2 diabetic patients in the intensive treatment group (average A1C 7.0%) had no significant reduction in stroke incidence (P = 0.52) compared with those receiving traditional medical therapy (average A1C 7.9%), indicating that tight glucose control is not sufficient to prevent excess strokes (38,39), though the study may not have been sufficiently powered to detect a stroke-specific relationship and/or the intensive control may not have been “intensive enough” to substantially impact stroke incidence.

To summarize, there is no clear relationship between hyperglycemia and stroke incidence. Rather, it is apparent that diabetic patients have an increased risk of stroke regardless of their level of metabolic control.

Without substantive evidence that intensive glucose control reduces stroke risk, the focus has shifted to insulin resistance and its associated metabolic syndrome. Type 2 diabetes, characterized by an inability to produce enough insulin to overcome insulin resistance, frequently coexists with a constellation of cardiovascular risk factors including hypertension, obesity, and hyperlipidemia. Together, these have been termed the metabolic syndrome (also known as syndrome X or insulin-resistance syndrome). The role that these factors have played individually, as well as together, in the development of cardiovascular disease (40) has made them the target of studies regarding stroke as well.

Insulin resistance, as measured by basal hyperinsulinemia (or impaired glucose tolerance, which is equated to a state of insulin resistance) has been associated with coronary artery disease (CAD) and subsequent cardiovascular events (41–44). Several studies have evaluated whether an analogous relationship exists between insulin resistance and stroke. In a retrospective study, impaired glucose tolerance was not associated with stroke (45). A prospective study of Japanese men found no relationship between insulin resistance and stroke incidence (46). In contrast, the ARIC Study found an increase in RR for ischemic stroke of 1.19 for every 50 pmol/l increase in basal insulin among nondiabetic patients, supporting a role for insulin resistance (2). This was similar to results from the elderly patient population of the Finnish cohort study that included both diabetic patients and nondiabetic patients (35). As with studies of insulin resistance and cardiovascular disease, the association of insulin resistance with stroke is attenuated by the adjustment for other cardiovascular risk factors (2,35,43,44). However, data from the Third National Health and Nutrition Survey (NHANES III) revealed a small, but significant, independent association between insulin resistance and stroke when other risk factors such as hypertension and level of glycemic control were taken into account (OR 1.06) (47). To summarize, a significant association between insulin resistance and stroke risk has been found, but the magnitude of this association is less than the association seen with cardiovascular disease.

Among the components of the metabolic syndrome, hypertension is the single most important risk factor for the development of stroke. In this respect, stroke varies significantly from cardiac disease, where hypertension is a lesser risk factor.

Evidence suggests that some of the increased risk of stroke among diabetic patients is attributable to the increased prevalence of hypertension. The GCNKSS found that the prevalence of hypertension was 79% among diabetic patients and 57% among nondiabetic patients (P < 0.0001) (7). A significant, though smaller, difference was found in the Copenhagen Stroke Study (48 vs. 30%, respectively, P < 0.0001) (10). Prospectively, follow-up of diabetic patients in the UKPDS found that the occurrence of vascular complications, including stroke, were significantly associated with hypertension (48). The converse relationship has also been seen. Among hypertensive patients, diabetes is a significant predictor of ischemic stroke (OR 3.76 [95% CI 1.67–8.46]) (49). Data from the ARIC Study suggest a similar increased risk among diabetic patients with prehypertension, as compared with nondiabetic patients, although the number of strokes was insufficient to calculate an RR for stroke alone (50). No study has included statistical modeling to specifically address whether hypertension fully accounts for the increased risk of stoke in diabetic patients. It appears that the two are synergistic in increasing stroke risk and account for up to 40% of the population-attributable risk for all ischemic strokes (7). A number of studies have found antihypertensive treatment to reduce the incidence of cardiovascular events, including stroke, in those with diabetes (51–57), but fewer studies have focused on stroke specifically. The Systolic Hypertension in Europe Trial specifically noted a 73% decrease in stroke incidence in diabetic patients treated with antihypertensive medication. Stroke incidence was decreased in nondiabetic patients by 38% (58). Thus, diabetic patients appear to benefit preferentially from antihypertensive treatment.

Hyperlipidemia is one of the most important risk factors for CHD and CAD but a less important risk factor for stroke. As with hypertension, diabetic patients who have suffered a stroke are more likely to have hyperlipidemia than those without diabetes (16 vs. 8%, respectively, P < 0.0001 in the GCNKSS) (7,10). It is currently not clear to what degree the increased prevalence of hyperlipidemia accounts for the increased risk of stroke, especially as the contribution of hyperlipidemia alone to stroke incidence is controversial (59–64). Subset analysis from large placebo-controlled trials, such as the Helsinki Heart Study and Scandinavian Simvastatin Survival Study, which evaluated cholesterol reduction as primary or secondary prevention of cardiovascular disease, indicate that diabetic patients may benefit preferentially from treatment in stroke reduction. Recently reported results from the Heart Protection Study, in contrast, did not support this difference, finding that risk reduction did not vary with diabetic status (65). The Collaborative AtoRvastatin Diabetes Study (CARDS), which expressly evaluated the contribution of hyperlipidemia to stroke risk in the diabetic population without known CAD, was halted early due to a significant 48% reduction in the incidence of stroke among the treatment group (66). CARDS, taken together with the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Study (67), is highly significant in that statin treatment can now be recommended for stroke prevention even in patients who do not have cardiovascular disease, regardless of diabetes status. However, based on the CARDS results, it seems that patients with diabetes may significantly benefit from statins, making it even more important that those with diabetes be considered for statin treatment as part of their stroke prevention regimen.

Obesity contributes to more than 300,000 deaths per year and nearly doubles the risk of death from all causes (68–70). Given its particular association with CAD, hypertension, and diabetes (71), investigators have attempted to discern the contribution that obesity makes to stroke incidence with variable results. Many studies utilize BMI (measured as weight divided by the square of height in meters), which provides a broad though nonspecific estimate of obesity, is easily obtained from patient self-report or medical charts and is commonly used in clinical practice. Both the ARIC and Northern Manhattan Stroke Study failed to find a convincing association between BMI and risk for stroke (2,72). An association has been noted in studies of specific subpopulations, such as middle-aged, Korean, or nonsmoking Japanese men (73–75). The Nurses’ Health Study reported a significant association with BMI, such that subjects with BMI 27–28.9 kg/m² had an RR of 1.8 (95% CI 1.2–2.6), subjects with BMI 29–31.9 kg/m² had an RR of 1.9 (1.3–2.8), and subjects with BMI ≥32 kg/m² had an RR of 2.4 (1.6–3.5) compared with those with BMI <25 kg/m² (76). A less robust, but still significant, association was found in the Women's Health Study (77). The Physician's Health Study found an RR of 1.95 (1.39–2.72) for ischemic stroke for those with BMI >30 kg/m² compared with those with BMI <23 kg/m². The risk increased by 6% for each unit increase in BMI, although it was attenuated when other cardiovascular risk factors were taken into account (78).

While BMI has been commonly used in the literature as an obesity measure, many studies have shown it to poorly reflect the health impact of obesity. Rather, abdominal obesity has been more specifically associated with vascular disease and other health complications (79). Waist-to-hip ratio (WHR), while highly correlated with BMI, better represents abdominal obesity and therefore may provide additional information on stroke risk. Despite the lack of a relationship between stroke and BMI, the Northern Manhattan Stroke Study did find a significant relationship between WHR and risk of stroke. Analysis included 576 ischemic stroke patients and 1,142 age-, sex-, and race/ethnicity-matched control subjects. Compared with the first quartile, the third and fourth quartiles of WHR had an increased risk of stroke (third quartile: OR 2.4 [95% CI 1.5–3.9]; fourth quartile: 3.0 [1.8–4.8]) after adjustment for other risk factors. These findings were consistent across both sexes and all race/ethnic groups, although the effect of WHR was stronger among younger subjects (72). Direct comparison of BMI versus WHR and stroke risk in 28,643 male health care professionals without previous cardiovascular or cerebrovascular disease yielded similar results. RR for the first and fifth quintiles of WHR was 2.33 (95% CI 1.25–4.37), whereas that for the first and fifth quintiles of BMI was 1.29 (0.73–2.27) (80).

Taken together, these studies suggest that obesity—in particular, abdominal obesity—is a significant risk factor for ischemic stroke (81). Regardless, the impact that obesity has on the risk ofdiabetes, CAD, hypertension, and hyperlipidemia will confound studies that address the risk of stroke (71). It has been estimated that the reductions in diabetes, hypertension, and hyperlipidemia associated with a 10% weight loss could lead to reduction of stroke of up to 13 per 1,000 people (82).

The World Health Organization definition of the metabolic syndrome also includes microalbuminuria (30–300 mg/24 h) as a final component. Microalbuminuria is a significant marker of cardiovascular disease and is highly associated with hypertension (83,84). It is encountered in diabetic patients more than twice as often as in nondiabetic patients (84) and may also contribute to the increased risk of stroke. The largest population-based prospective study to evaluate microalbuminuria and stroke risk is the EPIC-Norfolk Study. Among 23,630 individuals aged 40–79 years over 7.2 years of follow-up, microalbuminuria conferred a significantly increased risk of total and ischemic stroke in multivariate modeling (hazard ratio [HR] 1.49 [95% CI 1.13–2.14] and 2.01 [1.29–3.31], respectively) (85). Data from the Heart Outcomes Prevention Evaluation Study implicate microalbuminuria as a factor in stroke incidence among those with diabetes (57). Treatment of nonhypertensive diabetic patients with an ACE inhibitor, a class of medications known to reduce microalbuminuria (86–88), reduced stroke incidence by 32% despite a minimal decrease in blood pressure (57). These data support a role for microalbuminuria in increasing the risk of ischemic stroke, which may not be entirely dependent on its direct relationship with hypertension and other well-known stroke risk factors.

Each of the components of the metabolic syndrome is associated with higher stroke risk to various degrees, as described above. As has been mentioned, analysis of individual factors causes substantial adjustment of observed risk because of the interrelationship of these factors. Therefore, studying the metabolic syndrome as a whole may provide a better estimation of the true risk for ischemic stroke.

The Botnia Study examined risk for cardiovascular events and stroke conferred by the metabolic syndrome in 4,483 subjects. In a multiple logistic regression analysis, the metabolic syndrome was a significant independent risk for stroke (RR 2.3, P < 0.001 compared with those without the metabolic syndrome). None of the individual components of the metabolic syndrome contributed significantly to stroke risk (89). Similar results were obtained from examination of more than 10,000 subjects in the NHANES III. In logistic regression modeling, the metabolic syndrome was associated with increased odds of stroke (OR 2.2 [95% CI 1.5–3.2] compared with those without the metabolic syndrome). After the metabolic syndrome was in the model, each individual component was also tested. Only hypertriglyceridemia entered as an additional factor with independent significance, while hypertension and insulin resistance/diabetes trended toward significance (90). A few studies have evaluated the risk of stroke associated with the metabolic syndrome in the absence of diabetes, revealing similar twofold increases (91,92). In the ARIC Study, both hypertension and low HDL cholesterol independently and significantly increased risk (92).

The data presented above provide evidence that the individual components of the metabolic syndrome significantly contribute to the incidence of ischemic stroke. These components are more prevalent among diabetic patients and may act synergistically to promote increased risk of stroke. In addition, several studies support a significant relationship between the collective metabolic syndrome and ischemic stroke.

The metabolic syndrome and diabetes have their association with insulin resistance in common. At a cellular and molecular level, insulin resistance confers changes that are becoming recognized as increasingly important in the pathophysiology of vascular disease, including stroke.

Both diabetic patients and those with impaired glucose tolerance have decreased endothelium-dependent vasodilation (93–95), due to either decreased nitric oxide (NO) production or impaired NO metabolism (95). Normally, NO exerts a protective effect against platelet aggregation and plays an important role in the response to ischemic challenge (96,97).

Only indirect evidence is available at the present time linking NO dysregulation and stroke. A recent study found a decreased response of cerebrovascular blood flow to NO synthase inhibition in diabetic patients compared with nondiabetic patients, although not enough patients were enrolled to determine significance (98). In addition, parasympathetic neurons that secrete NO into the perivascular space have been documented to degenerate and eventually die in the absence of insulin signaling (99). Numerous studies have found that HMG-CoA reductase inhibitors (statins), which upregulate NO synthesis in addition to their activity in stabilizing atherosclerotic plaques (100), significantly reduce the risk of stroke (56,67,101–104). The dual actions of statins make it difficult to distinguish which action exerts the greatest effect. However, the growing body of evidence indicates that statins exert protective effects against stroke independent of changes in cholesterol levels.

Defects in endothelial function may be further confounded by the hypercoagulable state of diabetic patients. Plasminogen activator inhibitor-1 and antithrombin III, which inhibit fibrinolysis, as well as tissue plasminogen activator antigen, a marker of impaired fibrinolysis, consistently have been found to be elevated in diabetic patients and in those with insulin resistance (105–107). Some studies have further suggested that coagulation factors, such as factor VII, factor VIII, and von Willebrand factor, also rise with degree of insulin resistance (108,109). This upregulation is likely secondary to a chronic inflammatory state induced by diabetes, as several inflammatory markers (e.g., C-reactive protein, lipoprotein-associated phospholipase A2) have been correlated with increased thrombotic factors and stroke incidence (108,110–112). The promotion of thrombus formation likely occurs via platelet hyperreactivity. Studies of platelets from diabetic patients have found increased aggregation in response to ADP (113), a response that may be mediated by the upregulation of GPIIb-IIIa receptors that occurs in diabetic patients (114). Insulin normally acts to inhibit platelet aggregation in response to ADP; however, this action is attenuated in diabetic patients (115). Thromboxane A₂ is also elevated in diabetic patients, possibly contributing to hyperaggregation as well (116).

The relative contribution of these mechanisms to increased ischemic stroke risk in those with diabetes has not been specifically evaluated, although several studies have implicated these pathways in the general population. In both cross-sectional and prospective studies, increased tissue plasminogen activator antigen and plasminogen activator inhibitor-1 levels have been significantly associated with ischemic stroke (117–119). Treatment with aspirin or clopidogrel targets platelet aggregation by inhibiting thromboxane A₂ and ADP, respectively, and are now widely used in the secondary prevention of stroke, as they significantly reduce the risk of recurrent stroke (120–125). Several trials, such as the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA), Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE), and Management of ATherothrombosis with Clopidogrel in High-risk patients (MATCH) studies, evaluated whether diabetic patients derived more or less benefit from antiplatelet therapy in preventing recurrent ischemic events with mixed results. As the reported end point in these studies was a composite of all ischemic events and mortality, the specific impact of antiplatelet therapy in diabetic patients on stroke is unclear (126–128). Further investigation is required to determine the relative importance of these mechanisms in diabetic patients.

Consideration has also been given to the impact of the increased incidence of atherosclerosis among those with diabetes and stroke incidence. Carotid intima-media thickness (CIMT) has been found in a number of studies to be increased with diabetes. The Insulin Resistance Atherosclerosis Study found a significant increase in common carotid thickness in the setting of established diabetes as compared with those with newly diagnosed diabetes (129). Although not to the same degree, impaired glucose tolerance is also associated with increased CIMT (130). Diabetic patients that have suffered a stroke have significantly greater CIMT than both those without stroke and nondiabetic patients (131,132). As hyperglycemia, regardless of diabetes duration, was directly related to CIMT, tight glucose control may yield benefits on carotid disease (129).

Despite the uncertainties of the pathogenesis of stroke in those with diabetes, the impact of hyperglycemia and diabetes on outcomes has been more consistently defined. Hyperglycemia during the poststroke period, regardless of diabetic status, is associated with increased morbidity and mortality. Studies have generally found increased 30-day and 1-year mortality rates among hyperglycemic patients (133–137), although increased mortality was not seen in other studies (7,138). Morbidity, as defined by functional outcome and neurologic recovery, is also worsened in the setting of hyperglycemia and diabetes (134,139–142). This holds true among those with only transient hyperglycemia, although such individuals fare better than those with chronically elevated glucose levels whether diagnosed pre- or poststroke with diabetes (143,144). In imaging studies, the initial infarct size and infarct progression are greater in hyperglycemic patients (142,145–147). One recent study has found a decreased recanalization rate following recombinant tissue plasminogen activator (rt-PA) administration in the presence of hyperglycemia, although this was not seen in the pivotal National Institute of Neurological Diseases and Stroke rt-PA trial (139,148). Normalization of glucose levels was associated with 4.6 timesdecreased risk in mortality in one retrospective study, indicating the potentially large impact that can be made with aggressive medical management in these patients (149).

Diabetes is also one of the most consistent predictors of recurrent stroke or stroke after TIA (150–162). The increased risk of recurrent stroke due to diabetes ranges from 2.1 to 5.6 times that of nondiabetic patients (154,156) and is independent of glucose control during the interstroke period (163). The significance of these findings is underscored by the increased morbidity and mortality associated with recurrent stroke (164).

Diabetes significantly increases the risk of incident stroke and stroke recurrence. The magnitude of this problem will continue to expand as the prevalence of diabetes increases in the U.S., thus presenting numerous challenges for the future. Foremost among these is educating those with diabetes as to their true risk of stroke. A significant barrier appears to be the incongruence between the information the medical community believes it is imparting to patients and the actual level of knowledge demonstrated by patients. Ninety percent of physicians report discussing the risk of cardiovascular disease and the importance of prevention, although only one-half of patients report their physician had discussed risk factor modification (165). Recent data from the REduction of Atherothrombosis for Continued Health (REACH) registry corroborates the continued undertreatment of cardiovascular risk factors (166). Frequent and repeated patient advising regarding cardiovascular and cerebrovascular complications of diabetes and warning signs is necessary to improve utilization of primary and secondary prevention measures.

The potential benefit of aggressive multiple risk-reduction measures in those with diabetes has been highlighted by the Steno-2 Study. Intensive standardized risk factor reduction, including 1) treatment of hyperglycemia, hypertension, dyslipidemia, and microalbuminuria; 2) secondary prevention of cardiovascular disease with aspirin; and 3) behavioral modification, resulted in significant reductions in cardiovascular disease, including stroke (HR 0.47 [95% CI 0.24–0.73]). This effect was larger than that seen in studies that targeted treatment to individual risk factors (29). Although the specific mechanisms that underlie the relationship between diabetes, the metabolic syndrome, and stroke require ongoing investigation to provide new methods for prevention and treatment, these data underscore the strides that can be made with the tools at hand.