Cerebrovascular Disease in Patients with Diabetes

Stroke—in particular the ischemic subtype—is one of the major vascular manifestations of diabetes, together with coronary heart disease (CHD), peripheral arterial occlusive disease, and diabetic retinopathy. The relationship between hyperglycemia and stroke is bidirectional: on the one hand, diabetic patients exhibit more than a twofold risk of ischemic stroke compared with patients without diabetes (see the later discussion of epidemiology of stroke in diabetes), even after statistical correction for other vascular risk factors. On the other hand, acute stroke can generate acute disturbances of glucose metabolism with poststroke hyperglycemia (PSH) (see the later discussion of PSH), which is associated with an approximate twofold risk of a bad outcome. Treatment of hyperglycemia in patients with diabetes combined with multiple vascular risk factor management can substantially decrease the rate of stroke in primary as well as in secondary prevention. However, diabetes-associated end-organ damage to the brain is not only restricted to neuronal damage by strokes, but also involves chronic and insidious damage of the brain resulting in cognitive decline and dementia. Dementia in patients with diabetes not only results from vascular-mediated neuronal damage manifesting as vascular dementia (VD), but also is caused by an enhancement of neurodegenerative changes in the brain manifesting as Alzheimer disease (AD). In addition, between diabetes and dementia, bidirectional relations are likely: on the one hand, people with diabetes have double the risk of developing dementia by mechanisms that are not yet fully understood; and on the other hand, the cognitive and behavioral manifestations of dementia such as lack of physical exercise and interference with therapeutic compliance may lead to disturbances of glucose metabolism resulting in lability of glucose control, including an increased frequency of episodes of severe hypoglycemia.

Epidemiology of Stroke in Diabetes

Epidemiology of Stroke: General Observations and Time Trends

Stroke is the second most frequent cause of death worldwide and the second leading cause of long-term disability in industrialized countries. The incidence of stroke is considerable across the United States and European countries, with the subtypes of ischemic stroke and transient ischemic attack (TIA) being the most common events (80% to 85%). Stroke incidence in European epidemiologic studies ranges from 114 cases/100,000 persons per year in France for first-ever stroke to 350 cases/100,000 persons per year in Germany for all stroke subtypes. Stroke prevalence estimates range from 1.5% in Italy and 3% in the United Kingdom and United States.

The epidemiologic Oxford Vascular Study analyzed the frequency of three types of vascular events (acute coronary, cerebrovascular, and peripheral) in a population of 91,106 inhabitants in Oxfordshire, United Kingdom, from 2002 to 2005. Cerebrovascular events (618 strokes and 300 TIAs), with a proportion of 45%, were more frequent than coronary vascular events, which affected 42% of the cohort (159 ST-segment elevation myocardial infarctions (STEMIs); 316 non–ST-elevation MIs; 218 unstable angina events; 163 sudden cardiac deaths), and peripheral vascular events, with an incidence of 9% (43 aortic; 53 embolic visceral or limb ischemic events; 92 critical limb ischemic events). Sixty-two deaths remained unclassifiable. The relative incidence of cerebrovascular events compared with coronary events was 1.19 (95% confidence interval [CI] 1.06-1.33) overall, and 1.40 (1.23-1.59) for nonfatal events. Event and incidence rates rose steeply with age in all arterial territories, with 735 (80%) cerebrovascular, 623 (73%) coronary, and 147 (78%) peripheral vascular events in 12,886 (14%) individuals aged 65 years or older; and 503 (54%), 402 (47%), and 105 (56%), respectively, in the 5919 (6%) aged 75 years or older ( Fig. 28-1 ). Similar data were shown by French investigators.

Figure 28-1, Age-specific event rates for nonfatal stroke (red line), nonfatal myocardial infarction (blue line), and nonfatal acute peripheral vascular events (green line).

A comparison of incidence rates among different subtypes of stroke shows approximately 80% to 85% for ischemic stroke, 10% to 15% for intracerebral hemorrhage, and 5% for subarachnoid hemorrhage. It is not surprising that all studies have demonstrated that the incidence and prevalence of stroke in general increase with age. However, the stroke subtype involving subarachnoid hemorrhage, because of its distinct cause (ruptured aneurysms), does not follow this pattern. The stroke incidence is higher in men than in women of the same age, based on age-adjusted data. Some studies on time trends of stroke epidemiology have indicated that the incidence and the individual personal risk have decreased during the last 20 years.

Stroke mortality rates have been decreasing consistently over time, with recent reports indicating a 29.2% reduction in stroke mortality between 1999 and 2008 in the United States. A German registry found decreased mortality rates from 52.4 deaths per population of 100,000 in 2000 to 32.3 deaths per 100,000 in 2008 in both men and women combined; a greater rate of decline was observed in women. Such increased survival of stroke patients may be linked to advances in preclinical and hospital treatment in acute stroke and in neurorehabilitation.

In the United Kingdom, an analysis of 32,151 stroke patients within the UK General Practice Research Database revealed that stroke incidence fell significantly by 30% from 1.48/1000 person-years in 1999 to 1.04/1000 person-years in 2008. Fifty-six–day stroke mortality after first stroke was reduced significantly from 21% in 1999 to 12% in 2008. Stroke prevalence, however, increased significantly by 12.5%, from 6.40/1000 in 1999 to 7.20/1000 in 2008. The positive changes in stroke incidence coincided with a marked increase in primary care prescription of primary and secondary cardiovascular preventive medications such as lipid-lowering, antihypertensive, and antithrombotic drugs. Despite these positive findings, the study clearly demonstrated an underuse of oral anticoagulation in patients with atrial fibrillation (AF) at high risk of stroke, and lower use of all preventive treatments in women compared with men.

Diabetes and Other Risk Factors for Stroke

The risk of stroke associated with diabetes has been assessed predominantly in people with type 2 diabetes, because stroke is more common in that population than in the age group typical of persons with type 1 diabetes. Epidemiologic studies identified a twofold to fourfold increase in stroke risk for persons with diabetes. As early as 1988, a population-based study demonstrated diabetes mellitus (DM) as an independent risk factor for stroke; during a follow-up of 3778 persons aged 50 to 79 years over 12 years, diabetes was associated with an increase in risk of 1.8 in men (95% CI 1.0-3.2) and 2.2 in women (95% CI 1.0-4.5). The Nurses' Health Study observed 120,000 women for more than 8 years and found an unadjusted 5.4-fold increase in stroke risk that was associated with diabetes and, after correction for other confounding variables, an adjusted threefold increased stroke risk with diabetes. During the longest observation period of 30 years in the Framingham Heart Study, a 2.5- to 3.6-fold increased risk of stroke in diabetic patients was found. A meta-analysis of 102 prospective studies including 530,083 participants demonstrated a hazard ratio (HR) for ischemic stroke of 2.3 (95% CI 2.0-2.7) for patients with versus without diabetes. A Finnish cohort study with 25,155 men and 26,423 women aged 25 to 74 years showed that diabetes at baseline carried a similar risk for stroke as a prior stroke (PS) at baseline.

The duration of diabetes was independently associated with ischemic stroke risk according to data from the Northern Manhattan Study, adjusting for other risk factors. The observed risk increase associated with diabetes overall was 3% each year, and tripled with diabetes duration of 10 years or longer ( Table 28-1 ).

Table 28-1

Duration of Diabetes and Ischemic Stroke Risk

Data from Banerjee C, Moon YP, Paik MC, et al: Duration of diabetes and risk of ischemic stroke: the Northern Manhattan Study. Stroke 43:1212-1217, 2012.

Diabetes Duration (years)	Adjusted Hazard Ratio (HR)	95% Confidence Interval (CI)
0-5	1.7	1.1-2.7
5-10	1.8	1.1-3.0
> 10	3.2	2.4-4.5

Assuming a population-wide prevalence of diabetes of 10%, these epidemiologic findings indicate a diabetes-attributable risk of stroke of approximately 12%. Hence, one in eight cases of stroke may be attributable to diabetes. Taking into account overall stroke mortality in general and its observed increased risk in diabetes, cerebrovascular disease causes approximately 20% of deaths of diabetic patients.

Comparison of Vascular Risk Factors Between Stroke and Coronary Heart Disease

The case-control study INTERSTROKE —analogous to the INTERHEART study—examined the worldwide burden of stroke and the quantitative impact of known risk factors in different countries, in particular in developing countries. Of all fatal strokes worldwide, 85% occur in countries with low to middle income, and the number of strokes worldwide is massively driven by the increase in stroke incidence in developing and newly industrialized countries. Comparing 3000 stroke patients (78% ischemic stroke, 22% hemorrhagic stroke) and 3000 controls, the study extracted the 10 risk factors listed in decreasing order in Table 28-2 (odds ratios [ORs] and percentage of the population attributable risk [PAR]). For comparison, the corresponding numbers from the INTERHEART study are given in a third column.

Table 28-2

Impact of Ten Vascular Risk Factors on Stroke and Myocardial Infarction: Odds Ratios and Percentage of the Population Attributable Risk (PAR)

Risk Factor/Behavior	Odds Ratio	PAR (%) for Stroke	PAR (%) for Myocardial Infarction
1. Arterial hypertension	2.64	34.6	17.9
2. Waist-to-hip ratio	1.65	26.5	20.1
3. Regular physical activity	0.69	28.5	12.2
4. Smoking	2.09	18.9	35,7
5. Diet risk score	1.35	18.8	13.7
6. Diabetes	1.36	5.0	9.9
7. Alcohol intake	1.51	3.8	6.7
8. Psychosocial factors (stress, depression)	1.3	9.8	32.5
9. Cardiac causes	2.38	6.7	—
10. Ratio of apolipoproteins B to A1	1.89	24.9	49.2

Collectively the listed 10 risk factors account for 90% of all strokes, and the first five risk factors—namely, arterial hypertension, smoking, abdominal adiposity, diet habits, and little physical exercise—explain 80% of all strokes. Hypertension was the most important individual epidemiologic risk factor, which tripled the stroke risk, and therefore has a higher relative importance for the risk of stroke than for the risk of CHD. DM as the sixth strongest by PAR% was placed in the middle field, being surrounded by diabetes-related risk factors such as adiposity, lack of physical exercise, and diet habits.

From the mentioned epidemiologic data, an individual stroke risk calculation can be deduced. Kothari and colleagues developed a mathematical model from the United Kingdom Prospective Diabetes Study (UKPDS) data to calculate an individual's risk of stroke within the following 5 years. In this model, for example, a 67-year-old smoker with arterial hypertension, hypercholesterolemia, and diabetes duration of 12 years has a 10.5% risk of stroke within the next 5 years.

It is not surprising that diabetes not only doubles the risk for a first-ever stroke, but in the same manner doubles the risk for a recurrent stroke after a first event. ^,

Obviously, there has been a decline in cardiovascular death including stroke in individuals with diabetes; a recent report from the U.S. National Institutes of Health compared 3-year death rates between 1997 and 2004 and found a decline in the cardiovascular disease (CVD) death rate of 40%.

Diabetes as a Stroke Risk Factor IN Younger Patients

Type 1 and type 2 diabetes play an important role as stroke risk factors, particularly in younger and middle-aged patients, because in these age groups other competing stroke risk factors are less prevalent and henceforth contribute less attributable risk than at older ages. According to an observational study in the United States of persons aged 18 to 44 years, diabetes raised the relative stroke risk from 6-fold to 23-fold, depending on gender and race or ethnicity. In general, in patients younger than 60 years, the relative risk (RR) of stroke in those with versus without diabetes is approximately double that of individuals older than 70 years. According to calculations from several studies, diabetes leads to an advanced cerebrovascular aging of approximately 10 to 15 years.

Multiplicative Risk Increase by Additional Vascular Risk Factors

Patients with diabetes almost always have additional vascular risk factors such as arterial hypertension, dyslipoproteinemia, obesity, lack of physical exercise, and nonvalvular AF. These comorbidities not only add to the risk of stroke from diabetes, but multiplicatively affect the risk of stroke. Some studies, for example, found that the combination of diabetes and hypertension was associated with a 5-fold to 10-fold increased risk of stroke, suggesting a synergistic impact on stroke risk.

Stroke Risk in Prediabetes- and Diabetes-Associated Metabolic Risk Configurations (Insulin Resistance, Metabolic Syndrome, Adiposity)

Prediabetes (Impaired Fasting Glucose, Impaired Glucose Tolerance, Hemoglobin A1c)

Not only in diabetes per se, but also in prediabetic states, the risk for cerebrovascular disease is increased, although in general more modestly than with fully established diabetes. Prediabetes is defined as the condition in which glycemic variables are higher than normal but lower than the established diabetes thresholds. Prediabetes is a high-risk state for diabetes development: 5% to 10% of people with prediabetes will convert to diabetes each year.

A prospective study found a significant relationship between levels of fasting plasma glucose (FPG) even below the diabetes threshold and the incidence of stroke in 43,933 asymptomatic nondiabetic men with a mean age of 44 years, who were free of known CVD at baseline. A total of 595 stroke events occurred during 702,928 person-years of follow-up. Age-adjusted fatal, nonfatal, and total stroke event rates per 10,000 person-years for normal FPG (80 to 109 mg/dL), impaired fasting glucose (110 to 125 mg/dL), and undiagnosed diabetes (≥ 126 mg/dL) are listed in Table 28-3 . For FPG levels of 110 mg/dL or greater, each 10-unit increment of FPG was associated with a 6% higher risk of total stroke events ( P = .05).

Table 28-3

Stroke Rates per 10,000 Patient-Years in Different Levels of Fasting Plasma Glucose (FPG)

Data from Sui X, Lavie CJ, Hooker SP, et al: A prospective study of fasting plasma glucose and risk of stroke in asymptomatic men, Mayo Clin Proc 86:1042-1049, 2011.

	Normal FPG (80-109 g/dL)	Impaired FPG (110-125 mg/dL)	Undiagnosed diabetes (≥ 126 mg/dL)	Significance
Fatal strokes	2.1	3.4	4.0	P < .002
Nonfatal strokes	10.3	11.8	18.0	P < .008
Total strokes	8.2	9.6	12.4	P < .008

In another study of 14,000 patients with CHD, a J-shaped association was found between fasting glucose and incident stroke. Stroke events after adjustment were increased in patients with fasting glucose levels of 100 to 109 mg/dL (OR 1.3), 110 to 125 mg/dL (OR 1.6), when compared with levels of 90 to 99 mg/dL. However, patients with very low fasting glucose levels (< 80 mg/dL) also exhibited a 1.5-fold increased risk of stroke. The mechanisms underlying this association remain unclear.

In 3127 patients with TIA or minor ischemic stroke in the Dutch TIA Trial, a J-shaped relationship between baseline nonfasting glucose levels and stroke risk was also observed. In patients with impaired glucose tolerance (defined as glucose 7.8 to 11.0 mmol/L), risk of stroke was almost doubled compared with those with normal glucose levels (HR 1.8, 95% CI 1.1-3.0) and almost tripled in diabetic patients (glucose ≥ 11.1 mmol/L; HR 2.8, 95% CI 1.9-4.1). Patients with low glucose levels (< 4.6 mmol/L) had a 50% increased stroke risk (HR 1.5, 95% CI 1.0-2.2) compared with those with normal glucose levels. There was no association between glucose levels and risk of MI or cardiac death. When impaired glucose tolerance was measured by oral glucose tolerance test (OGTT) as in the Japanese Hisayama study, 2-hour values of the OGTT of 11.1 mmol/L were associated with a more-than-doubled risk for stroke (in men, HR 2.71; in women, HR 2.19).

Glycated hemoglobin concentrations are also associated with the risk of stroke even below diabetes thresholds. On analysis of nondiabetic adults participating in the community-based Atherosclerosis Risk in Communities (ARIC) study, HbA1c concentrations—adjusted for potential confounders and for other vascular risk factors—of greater than 6% were associated with two to three times increased risk of stroke. The adjusted HRs for ischemic stroke according to baseline HbA1c are displayed in Figure 28-2 .

Figure 28-2, Adjusted hazard ratios for ischemic stroke according to baseline glycated hemoglobin.

A meta-analysis from 15 prospective cohort studies, which included 760,925 participants, tested the association of stroke risk with prediabetes defined in two ways. Among the eight studies that defined prediabetes as fasting glucose levels ranging from 100 to 125 mg/dL (5.6 to 6.9 mmol/L), which is the current American Diabetes Association (ADA) definition, there was no increase in the risk for stroke after adjustment for established cardiovascular risk factors (1.08; 95% CI 0.94-1.23). In contrast, among the five studies that used the ADA's more stringent 1997 definition of prediabetes (fasting glucose levels ranging from 110 to 125 mg/dL [6.1-6.9 mmol/L]), there was a 21% increased RR after adjustment for established cardiovascular risk factors (1.21; 95% CI 1.02-1.44; P = .03), indicating that the extent of the relationship between prediabetes and risk for stroke is a matter of definition of prediabetes.

For those studies that included data on impaired glucose tolerance or combined impaired glucose tolerance and impaired fasting glucose, there was an increased risk for stroke after adjustment for established cardiovascular risk factors (1.26; 95% CI 1.10-1.43; P < .001).

Metabolic Risk Configurations (Insulin Resistance, Metabolic Syndrome, Adiposity)

Insulin resistance (IR), a state in which cells fail to respond to the normal actions of insulin, has also been found to be associated with an increased risk of stroke. In the Cardiovascular Health Study, individuals without prevalent diabetes or stroke at baseline were followed for 17 years. Higher IR measured with the Gutt index or 2-hour postload glucose levels was associated with a higher stroke incidence. For calculation of the Gutt index (insulin sensitivity index), plasma glucose and insulin concentrations from fasting (0-min) and 120-minute samples from the OGTT are used. The index is defined as follows:

MCR / log MSI

$MCR / log MSI$

The metabolic clearance rate (MCR) is obtained by MCR = m /MPG, where MPG is the mean of the 0- and 120-min glucose values from the OGTT. The mean serum insulin (MSI, mU/L) is the mean insulin concentration obtained from the 0- and 120-min samples of the OGTT.

The glucose uptake rate in peripheral tissues, m (mg/min), is obtained by the following formula:

m = (75, 000 mg + ({Glucose}_{0} - {Glucose}_{120}) \times 0.19 \times BW) / 120 min

$m = (75, 000 mg + ({Glucose}_{0} - {Glucose}_{120}) \times 0.19 \times BW) / 120 min$

where the term (0.19 × BW) denotes glucose space, and BW is body weight (kg).

The RR for the lowest quartile versus the highest quartile of the Gutt index was 1.64 (95% CI 1.24-2.16), adjusted for demographics and prevalent cardiovascular and kidney disease. Similarly, the adjusted risk ratio (RR) for the highest quartile versus the lowest quartile of 2-hour glucose was 1.84 (95% CI 1.39-2.42). In contrast, the adjusted RR for the highest quartile versus the lowest quartile of fasting insulin was not significant (1.10; 95% CI 0.84-1.46).

Higher levels of IR are associated with a 10% to 100% increased risk of stroke, depending on the degree of elevation and on the presence of other associated vascular risk factors. The U.S. National Health and Nutrition Examination Survey (NHANES) revealed the homeostatic model assessment of insulin resistance (HOMA-IR; equation: Fasting glucose [mmol/L] × Fasting insulin [mU/L]/22.5) as a measure for insulin resistance to be independently and significantly associated with stroke risk with an OR of 1.06 (95% CI 1.01-1.12) for each HOMA-IR unit, after adjustment for age, history of MI, the presence of hypertension or claudication, activity level, and HbA1c. It seems clear that IR is a risk factor for stroke, but it remains controversial whether insulin concentrations themselves or markers of glucose tolerance convey the highest risk.

The role, and impact of the metabolic syndrome (MetS), a clustering of disturbed glucose and insulin metabolism, obesity, and abdominal fat distribution, dyslipidemia, and hypertension remain controversial. A Finnish population-based cohort study on stroke risk with an average follow-up of 14.3 years revealed for men a 2.41-fold (95% CI 1.12-5.32) increased risk for ischemic stroke associated with MetS, after adjustment for socioeconomic status, smoking, alcohol, and family history of CHD. After additional adjustments the results remained significant.

In the Northern Manhattan Study, 3298 stroke-free individuals were prospectively followed for 6.4 years with a 44% prevalence of MetS, which was associated with a 50% increase in stroke risk after adjustment for sociodemographic and risk factors. The effect of MetS on stroke risk was greater in women (HR 2.0; 95% CI 1.3-3.1) than in men (HR 1.1; 95% CI 0.6-1.9) and among Hispanics (HR 2.0; 95% CI 1.2-3.4) compared with blacks (HR 1.3; 95% CI 0.7-2.3) and whites (HR 1.28; 95% CI 0.6-2.5).

A contrary result was found in a Greek study with a 10-year follow-up, in which MetS per se at baseline or combinations of its components did not predict the development of ischemic stroke in patients with type 2 diabetes. After statistical calculations, only waist circumference (HR 1.006) and age (HR 1.061) were significant predictors for stroke risk. However, habits of food consumption and the influence of the Mediterranean diet in the Greek population were not considered.

Also, in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, which analyzed the effect of treatment with atorvastatin versus placebo in reducing stroke in patients with a recent stroke or TIA, patients with MetS were not at increased risk for stroke or major cardiovascular events, but more frequently had revascularization procedures (adjusted HR 1.78; 95% CI 1.26-2.5; P = .001).

The difference in the results of epidemiologic studies compared with an intervention study such as SPARCL might be a result of the effect of intensive risk factor management for patients enrolled in clinical drug trials. For example, during the SPARCL trial, blood pressure—as a component of MetS—and other risk factors were carefully controlled, and all persons received appropriate antithrombotic treatment, which is usually not reliably the case for those included in epidemiologic studies.

All together, the available data support the consideration of MetS as an independent risk factor for stroke, depending on the metabolic and vascular risk configuration of the affected person on the whole and depending on the definition of MetS. The fact that the incremental stroke risk associated with MetS appears greater than the sum of its components suggests potential biologic interaction among MetS components, generating a risk that is more than additive. According to the type of study and the definition of MetS, its relation to increased risk of stroke is most commonly statistically significant.

The methodologic problems of such association studies with MetS are also obvious, if one notes the variability of the proportion of patients with diabetes included, which ranged from 0% to 100%: the Northern Manhattan Study had a proportion of 17% with diabetes; in the Finnish study no patients with diabetes were included; and the Greek study analyzed a group with 100% prevalence of diabetes. However, all studies similarly analyzed and reported the “independent” contribution of MetS to the risk of stroke.

Obesity in most studies is associated with an increased risk of stroke, whether measured by body mass index (BMI), waist-to-hip ratio, waist-to-height ratio, or waist circumference. Persons with a BMI of 30 kg/m ² or more have a twofold risk of stroke compared with individuals with a BMI of less than 23 kg/m ² . According to the results of a collaborative analysis of 57 prospective studies with 900,000 individuals, each unit increase in BMI is associated with an increase in the adjusted risk of stroke by approximately 6%. Among adults who are overweight or obese (BMI 25 to 50 kg/m ² ), each 5 kg/m ² increase in BMI is associated with an approximately 40% higher mortality rate from stroke (HR 1.39; 95% CI 1.31-1.48). In the INTERSTROKE study, persons with a waist-to-hip ratio in the highest tertile had a 65% increased risk of stroke (OR 1.65, 99% CI 1.36-1.99) compared with those in the lowest tertile.

However, all measures of adiposity and obesity such as BMI, waist-to-hip ratio, and waist circumference do not consistently improve prediction of stroke risk when added to the most robustly associated stroke risk factors such as arterial hypertension and diabetes. Despite these often discordant observations, excess adiposity remains a major modifiable determinant of these causal risk factors for stroke.

Pathophysiology and Subtypes of Ischemic Stroke in Diabetes

Stroke in diabetes is the clinical culmination of atherosclerotic changes in the extracranial and intracranial large and small arteries associated with hyperglycemia. The proatherogenic effects in diabetes on cerebral blood vessels are not different from effects on coronary arteries and encompass advanced glycation endproducts (AGEs), oxidative stress, endothelial dysfunction, inflammation, and hypercoagulability. In addition, the increased rate of CHD among patients with diabetes causes cardiomyopathy and AF, both of which predispose to cardioembolic stroke. AF is responsible for at least 20% to 30% of ischemic strokes. Recent findings indicate that AF may be relatively common in diabetic patients, with the risk of AF increased by 30% to 40% in individuals with diabetes. The severity of cardioembolic strokes and the resulting disability are greater than with noncardioembolic stroke, and hospital mortality is doubled.

A recent U.S. cohort study comparing 17,372 patients with diabetes with age- and gender-matched patients without type 2 diabetes found a significantly higher prevalence of AF among patients with versus without diabetes (3.6 versus 2.5%). Over a mean follow-up of 7.2 ± 2.8 years, diabetic patients without AF at baseline developed AF at an age- and gender-adjusted rate of 9.1 per 1000 person-years (95% CI 8.6-9.7) compared with a rate of 6.6 (95% CI 6.2-7.1) among nondiabetic patients. After full adjustment for other risk factors, diabetes was associated with a 26% increased risk of AF in women (HR 1.26; 95% CI 1.08-1.46), but diabetes was not a statistically significant factor in men (HR 1.09; 0.96-1.24). Diabetes not only is a risk factor for developing AF, but also increases the risk of its systemic and cerebral embolic complications. Depending on other accompanying risk factors, stroke rates in AF can reach almost 20% per year. Diabetes is one of the risk items counting as one point in the six-point CHADS ₂ score and the nine-point CHA ₂ DS ₂ -VASc score, both of which are used to calculate an individual's stroke risk in AF and to inform clinical decision making with regard to antithrombotic therapies.

Because of its impact on cerebrovascular and cardiac systems, diabetes incrementally increases risk for all three subtypes of ischemic stroke: lacunar, large artery occlusive, and thromboembolic. The distribution of these stroke subtypes among patients with diabetes is similar to that in the general population; however, those with diabetes have a greater burden of small-vessel, or lacunar, infarcts, which sometimes are clinically silent. In addition, the proportion of ischemic strokes with infratentorial localization is relatively increased in patients with diabetes ( Fig. 28-3 ).

Figure 28-3, Diabetes increases the risk for all subtypes of ischemic stroke: A, lacunar; B, hemodynamic by large artery occlusion; and C, cardioembolic.

Primary and Secondary Prevention of Stroke in Diabetes

Glucose Control

In the 1441 patients with type 1 diabetes (aged 13 to 40 years) enrolled in the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) study, intensive glucose management for 6.5 years reduced the risk of cardiovascular composite events (nonfatal MI, stroke, or cardiovascular deaths) significantly by 57% over a mean follow-up period of 17 years, compared with individuals under conventional treatment. However, the absolute numbers of stroke were low, with only one event in the intensive treatment group and five in the conventional treatment group. The target preprandial blood glucose in the intensively treated group was 70 to 120 mg/dL (< 180 mg/dL postprandial); the mean HbA1c values were approximately 2% lower than in the conventional treatment group (7.4% versus 9.1%).

In patients with type 2 diabetes in the UKPDS study, intensive treatment with sulfonylureas or insulin did not significantly reduce cardiovascular outcomes compared with conventional diet therapy. However, in the substudy within the UKPDS in which obese patients received metformin as a first-line treatment, the risk of stroke was reduced by 42% compared with the group receiving conventional treatment (3.3 versus 6.2 events per 1000 patient-years).

Three more recent large long-term trials (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE]; Action to Control Cardiovascular Risk in Diabetes [ACCORD]; Veterans Affairs Diabetes Trial [VADT]) also compared the effects of intensive versus standard treatment in individuals with longstanding type 2 diabetes and a fairly high risk of cardiovascular and cerebrovascular events. In the ADVANCE and the VADT studies, no difference in cardiovascular outcomes—including stroke—could be found between the two glucose-lowering strategies. In the ACCORD study the rates of nonfatal stroke were similar in the intervention and control groups.

No beneficial effects of tight glucose management over a mean period of 5 years could be found in a meta-analysis of 34,533 patients with type 2 diabetes (HR 0.96; 95% CI 0.83-1.1). A similar result was communicated in a Cochrane review summarizing the findings from 29,986 patients with type 2 diabetes from 20 randomized trials. The duration of intervention varied from 3 days to 12.5 years. Targeting intensive glycemic control did not reduce the RR of nonfatal stroke (risk ratio 0.96; 95% CI 0.8-1.2).

Taken together, to date, insufficient data are available to prove that intensive and tight glycemic control per se improves occurrence of stroke—in particular in type 2 diabetes. Treatment of patients with a high risk of stroke must balance the risk of recurrent hypoglycemia against the potential advantages of lower targets of HbA1c.

Management of Diabetes Associated Vascular Risk Factors

In the UKPDS, the variables that predicted the 188 incident strokes in DM included duration of diabetes, age, gender, smoking, systolic blood pressure (SBP), dyslipoproteinemia, and the presence of AF. Modifiable risk factors for stroke accompanying diabetes have been targeted for stroke prevention in several randomized controlled trials.

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