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www.DCMSonline.org Northeast Florida Medicine Spring 2005 17

Diabetes and Stroke

Diabetes Mellitus and Stroke By Nader Antonios, MD and Scott Silliman, MD

There are 18.2 million people in the United States who have diabetes mellitus (DM).1 The prevalence of this medical disorder increases with age. Half of all cases occur in people over the age of 55, and it is estimated

that 18% of the United States population over the age of 60 have DM.1

Patients with DM are more prone to develop vascular diseases, including strokes. In addition to being a deadly disorder in diabetics, stroke is a disabling disorder. Most stroke survivors are left with some physical

and/or cognitive deficits. Stroke is the leading cause of permanent disability in the United States and it is thesecond leading cause of cognitive decline. Thus healthcare providers who care for patients with DM should

be knowledgeable about the interrelationship between DM and stroke, as well as interventions that canminimize their patients’ risk of primary and secondary stroke. In this article we will discuss epidemiologic

relationships between DM and stroke, effects of DM on outcome from stroke, and stroke preventionstrategies for the diabetic patient.

Epidemiology of diabetes mellitus and strokeIn adults with stroke , DM is often present as a co-morbid condition. Prospective, community based

epidemiologic studies conducted in the United States and Europe suggest that approximately one fifth of strokepatients have DM.2,3 An initial diagnosis of DM is often made at the time of acute hospitalization for stroke. For

example, in the Copenhagen Stroke Study, 75% of the diabetics had known DM prior to their stroke, whereasDM was diagnosed in the remaining 25% of patients during hospitalization for their stroke.

A risk factor is an antecedent condition that is considered to be a component of a disease pathway. Risk factorsmay, or may not, be related to the etiology of the disease. Case control studies of stroke patients and prospectiveepidemiologic studies have confirmed an independent effect of diabetes on ischemic stroke in both men and

women, with an increased relative risk in diabetics ranging from 1.8 to nearly 6-fold.4

Since diabetics have an increased susceptibility to developing atherosclerosis, it is very likely that DM is a risk

factor that plays an essential role in producing the vascular pathology underlying ischemic stroke.

Other established independent risk factors for ischemic stroke include cigarette smoking, chronichypertension, hyperlipidemia, and atrial fibrillation. A substantial number of strokes are attributable to theserisk factors. The population-attributable risk is an estimate of the percentage of excess stroke in a populationthat is attributable to a given risk factor. The population-attributable risk takes into account both the

prevalence and potency of a risk factor. In the United States chronic hypertension has the highest population-attributable risk, estimated to be associated with 50 % of all strokes.4 DM is estimated to have a population-

attributable risk of approximately 35%.4 This figure for DM is greater than the estimates of the populationattributable risk for cigarette smoking (12.3%)4 and atrial fibrillation (9.4%).

Intracerebral hemorrhage (ICH) accounts for approximately 15% of strokes in the United States. Most case-

control studies examining the relationship between DM and ICH have not concluded that DM is anindependent risk factor for ICH. A cohort study, however, conducted on over 20,000 middle-aged male

cigarette smokers found that the presence of DM marginally increased the risk of ICH.5 A meta-analysis that

combined this cohort study with 9 case-control studies suggested that DM is a risk factor for ICH (RR=1.30;95% CI, 1.02 to 1.67)6 DM is not, however, as potent a risk factor for ICH as chronic hypertension sinceepidemiologic studies have consistently shown a stronger association between chronic hypertension andICH.

Subarachnoid hemorrhage (SAH) is usually due to rupture of an intracranial aneurysm. SAH accounts for

5% of strokes in the western hemisphere. DM has not been found to be independently associated withaneurysmal SAH in epidemiologic studies.

DM independently associated with some subtypes of ischemic stroke The cerebrovascular system is comprised of large and small caliber arteries. The components of the large

arterial circulation are the extracranial and intracranial segments of the carotid and vertebral arteries, and the



18 Spring 2005 Northeast Florida Medicine www.DCMSonline . org

other arteries that comprise the Circle of Willis (basilar artery, middle cerebral arteries, anterior cerebral

arteries, and the posterior cerebral arteries). Infarction occurring in the distribution of these arteries isusually of thrombo-embolic origin. Small caliber arteries comprise the microcirculation. These arteries are100µm-400µm in diameter and they supply blood to the white matter of the cerebral and cerebellar

hemispheres, the thalami, the basal ganglia, and brainstem parenchyma. Occlusion of a small artery isthought to be produced by degenerative arterial pathology within the vessel wall. These arteriopathies

include microatheromas, lipohyalinosis, and fibrinoid necrosis. A brain infarction produced by anoccluded small artery is commonly called a lacunar infarction. DM has been independently associated with

two forms of large artery disease and with small artery infarctions detected by neuroimaging studies.

Diabetes accelerates the development of carotid artery atherosclerosis. In a population-based cohortstudy of 1192 men and women examined at a 5-year interval, progression of intima-media thickness on

ultrasound studies of the common carotid artery (CCA) and internal carotid artery (ICA) was approxi-mately twice the rate in diabetics compared with non-diabetics. Progression rate in the ICA was greater

in patients with undiagnosed diabetes compared to patients with diagnosed diabetes.7

Intracranial large artery atherosclerotic disease produces stenotic lesions within the arteries that comprise

the Circle of Willis. This arteriopathy is responsible for approximately 10% of all ischemic strokes. DM was found to be an independent risk factor for intracranial large vessel occlusive disease in a hospital-basedstudy of 166 patients with a first ischemic stroke or TIA due to a stenotic intracranial artery.8 In addition,

the diabetic patients were more likely than non-diabetic patients to have had a larger number of diseased vessels than non-diabetics. The greatest extent of intracranial large vessel occlusive disease was seen in

diabetics with high lipoprotein (a) levels, suggesting a synergistic interaction between these two factors.

DM is a well established risk factor for small artery occlusive disease affecting the retina, kidneys, and cranialnerves. The role of DM in cerebral small vessel occlusive disease is less well characterized. Autopsy studies

have yielded conflicting results, some of them suggesting a relationship between diabetes and lacunes,9 andothers no significant relationship.10 No prospective epidemiologic studies have been conducted to examine

whether or not DM is an independent risk factor for stroke due to small vessel occlusion.

Studies that have utilized neuroradiologic imaging suggest that DM is associated with the development

of small vessel occlusions in the brain.

A retrospective analysis of 184 lacunar stroke patients in the Stroke Data Bank of the National Institute

of Neurological and Communicative Disorders and Stroke found that DM was significantly related (OR 2.3; 95% CI, 1.1 to 4.5) to multiple, but not single lacunes, seen on CT scans.11 In the Cardiovascular

Health Study, 3660 participants over the age of 65 underwent brain MRI imaging. Most participants (89%)had no history of stroke; however 841 participants (23%) had lacunar infarcts on their MRI scan. DM wasindependently associated with the presence of an imaged lacunar infarct (OR, 1.33; P<.05).12 A similar

conclusion was found in another study that utilized MRI imaging.13 Mean age of this cohort was 67 years,and all subjects had chronic hypertension but no history of stroke. One or more silent lacunar infarcts

were found in 82% of the diabetics and in 58% of the non-diabetics (p<0.001). DM was an independentdeterminant of the presence of > 1 silent lacunes (OR 2.95; 95% CI, 1.56-5.57).

Diabetes mellitus negatively affects outcome from strokeDM not only significantly increases the risk of stroke, but also is a predictor of reduced survival following

stroke. Higher mortality rates from stroke have been reported in diabetics, compared to non-diabeticsin most3,14-17 but not all studies.18 These studies demonstrate that the higher mortality rate is present

throughout the entire post-stroke time period. Mortality rates are higher in diabetics during acute

hospitalization for stroke,3

one year,17

and one decade15

after the stroke.DM may affect the rate of recovery of neurologic function following a stroke. Lithner et al. reported that

four days after hospital admission, more stroke patients with DM than without DM were still confined tobed.19 In the Copenhagen Stroke Study, patients with DM recovered more slowly than non-diabetic patients;

however the amount of neurological deficit at hospital discharge was equivalent between the two groups.

Intravenous recombinant tissue plasminogen activator (rtPA) has been approved since 1996 as anacute intervention for ischemic stroke, provided that the drug is administered within three hours of

symptom onset.

The most critical complication of rtPA is intracerebral hemorrhage (ICH). In the National Institute of Neurological Disorders and Stroke rtPA Trial, 6.4% of rtPA treated patients had neurological deterioration




due to ICH compared with 0.6% in the placebo treated arm.20 In a multivariate regression analysis of the

NINDS rt-PA Stroke Trial data, Bruno et al found that the odds for neurologic improvement decreased asadmission glucose increased.21 Those with neurologic improvement had a mean glucose of 144 mg/dL, andthose without neurologic improvement had a mean glucose of 160 mg/dL (OR=0.76 per 100 mg/dL increase

in admission glucose, p=.01).

Also, as admission glucose increased, the odds of symptomatic ICH increased. Those with symptomatic

ICH had a mean admission glucose level of 187 mg/dL, and those without had a mean glucose level of 148

mg/dL (OR 1.75 per 100mg/dL increase in admission glucose, 95% CI, p=.02). It is not known whetherlowering blood glucose before administration of IV rt-PA would reduce the risk of ICH in these patients.

A study of 138 rtPA treated patients also suggested that diabetes may be a predictor of ICH in rtPA-treatedpatients.22 In this cohort of patients who were treated within two university hospital systems, DM was

associated with a 25% (8 of 32) symptomatic hemorrhage rate compared with a 5% symptomatic hemorrhagerate (5 of 106) in non-diabetics. DM independently predicted ICH (OR, 6.73; 95% CI 2.20 to 22.4). The

association of elevated admission blood glucose with increased risk of ICH from rtPA does not prove a causeand effect relationship, and until this association is confirmed and clarified, rtPA should not be withheldfrom diabetic patients with ischemic stroke who are candidates to receive this drug.

Impact of acute hyperglycemia on brain infarction Animal models of stroke have generally shown that hyperglycemia negatively impacts stroke outcome. For

example, Pulsinelli et al. compared the effects of glucose infusion with that of saline or mannitol in rats

subjected, post infusion, to 4 vessel occlusion. Glucose injection resulted in severe brain injury, with necrosisof the majority of neocortical neurons and glia, substantial neuronal damage throughout the remainder of

the forebrain, and severe brain edema. Saline or mannitol infusion resulted in only scattered damage, confinedonly to neurons, and no brain edema resulted.23

Likewise, observational studies conducted in people with stroke have suggested that hyperglycemia

negatively impacts outcome and survival from stroke. Patients with hyperglycemia at acute stroke onsethave been shown to have higher mortality and poorer stroke outcome, 24 whether or not the cause of

the hyperglycemia was stress, newly diagnosed diabetes, or known diabetes. In one study, only 43%of patients with blood sugar above 120 mg/dl eventually returned to work, whereas 76% of those withlower blood sugar values did.25 Infarct size may be affected by hyperglycemia. In a study utilizing serial

diffusion-and-perfusion weighted MRI scans, the presence of acute hyperglycemia correlated withgreater infarct size and worse functional outcome.26 The worse outcome was independent of baseline

stroke severity or diabetic status.

The mechanism of the negative impact of acute hyperglycemia on stroke outcome has not been

established. It has been postulated that tissue acidosis, impaired cellular metabolism, decreased cere-brovascular reactivity, increased blood-brain barrier permeability, or increased lactate production in the

brain may play roles in enhancing brain damage during stroke when hyperglycemia is present.22,26

Hypothetically , aggressive control of hyperglycemia should improve outcome from stroke. There haveonly been three studies in humans that have assessed the impact of treating acute hyperglycemia in stroke.

In the Glucose and Insulin in Stroke Trial (GIST-UK)— a randomized trial of 145 patients—glucose,insulin, and potassium were infused in hyperglycemic patients with acute stroke. Outcome was measured

by the European Stroke Scale (ESS), a measure of neurological impairment. The ESS improved betweenadmission and day 6 in the treated patients compared to controls, but the ESS was not significantly

different on day 7 between the two groups.27

In a follow up study of GIST-UK, hyperglycemic post-acute stroke patients were infused with eitherglucose-insulin-potassium (GKI) or saline. The GKI group had much more rapid euglycemia, but resultsof impact on stroke outcome have not yet been reported.28

Bruno et al. infused IV insulin during acute cerebral infarction in 24 diabetics for blood sugar elevations of

170-400mg/dL, in a protocol to keep blood sugar in the 70-130 range within five hours of starting the protocol.Seventeen (70.8%) of the stroke patients remained neurologically stable or improved continuously, four (16.7%)

had initial neurologic deterioration, and then improved, and three (12.5%) died of stroke complications. There was no control group, and the purpose of the study was to assess the feasibility and safety of the IV insulininfusion protocol.29 The protocol appeared feasible, but impact on stroke outcome cannot be determined. Thus

there is currently no positive trial data suggesting that acute correction of hyperglycemia improves outcome fromstroke. More well-designed clinical trials exploring this intervention are needed.




Stroke prevention in diabeticsPrevention of stroke is divided into primary and secondary prevention. Primary prevention refers to

prevention of a first stroke. Secondary prevention refers to prevention of stroke following a TIA or an

initial stroke. The clinician who cares for patients with DM can invoke multiple interventions to preventprimary and secondary strokes in these patients, some of which are outlined below.

Treatment of hyperglycemiaGlycemic control may have a protective effect in primary stroke prevention. The UKPDS-35 study was

a prospective study of 3642 patients with a median follow-up of 10.4 years for all cause mortality. Thestudy investigators found stroke risk was decreased by 12% for every 1% reduction in hemoglobin A1C,

although this was not statistically significant (p=.035).30 In this study, the hemoglobin A1C was reducedfrom a median of 7.9% to 7.0%. It is possible that the impact on stroke risk would have been more

profound if patients with worse initial diabetic control had been treated more aggressively.

In the Veterans Administration feasibility trial, there was no benefit found on stroke incidence withintensive versus conventional insulin treatment in type 2 DM.31 Despite the findings of these two studies,

and the remaining uncertainty as to whether tight diabetic control can significantly reduce risk of a firststroke, tight control has been shown to prevent other vascular complications in the diabetic, and it may

be inferred that stroke risk may be reduced. In addition, improved diabetic control may reduce theprogression of large vessel atherosclerotic disease in the diabetic. The Atherosclerosis Risk in Commu-

nities Study Investigators (ARIC) found that patients with previously undiagnosed DM were found tohave an even greater rate of progression of carotid atherosclerosis than known diabetics, suggesting that

early diagnosis and treatment of DM may help to prevent progression of large vessel disease.32

No clinical trial assessing the utility of aggressive control of hyperglycemia in diabetic stroke patients,

with secondary stroke as an outcome, has been conducted. Thus we do not know whether tight glucosecontrol decreases the risk of recurrent stroke.

Treatment of hypertensionHypertension (HTN) is the leading risk factor for ischemic stroke, and the prevalence of hypertension

is disproportionately higher in diabetics than in non-diabetics. Chronic HTN, defined by serial bloodpressure measurements >130/80 or the use of antihypertensive medications, has been reported to bepresent in 73% of adult type II diabetics according to the American Diabetes Association.33

The presence of chronic HTN clearly increases stroke risk in the diabetic. In the SHEP trial, elderly diabeticshad a > 20% reduction in stroke with control of isolated systolic HTN.34 In the UKPDS 36 trial of type

2 diabetics, every 10mmHg reduction in systolic blood pressure decreased risk of ischemic stroke by 19%.35

The American Diabetes Association recommends a target blood pressure goal of <130/80 if it can be

“safely achieved.” The JNC-7 Guidelines concur with this recommendation, and indicate that BP shouldbe kept consistently <130/80mmHg in the diabetic in order to minimize vascular events.36

Various antihypertensive drugs have been shown to be effective in lowering cardiovascular events in

DM, such as ACE inhibitors, angiotensin receptor blockers (ARBs), beta blockers, diuretics, and calciumchannel blockers.37 The choice of antihypertensive agent depends in part on the comorbidities that the

patient with DM may have, and often more than one agent is required for adequate BP control.

The MICRO-HOPE study was a substudy of 3,577 diabetic patients who were randomized in the HOPE

study. The MICRO-HOPE study showed that the ACE inhibitor ramipril, when added to the current medicalregimen of diabetics with a prior history of cardiovascular events (coronary artery disease, stroke, or peripheral

vascular disease) or at least one other cardiovascular risk factor (total cholesterol >5.2mmol/L, HDL cholesterol< or=0.9mmol/L, hypertension, known microalbuminuria, or current smoking), decreased their risk of strokeby 33%. Combined mortality due to stroke, myocardial infarction, and cardiovascular events was reduced by

25%.38 In addition, there were a reduced number of diabetic complications such as overt nephropathy, needfor dialysis, or need for laser retinal therapy, in patients who took ramipril.

For primary and secondary prevention of stroke in patients with DM, clinicians should adhere to the JNC-7 Guidelines with respect to blood pressure control. An ACE inhibitor should be included in theantihypertensive regimen, if there is no clinical contraindication.




Treatment of hyperlipidemiaDiabetics frequently have hyperlipidemia as a comorbidity. The National Cholesterol Education Program (NCEP) Guidelines39

suggest that all patients with DM have their cholesterol aggressively lowered regardless of whether or not they have had a stroke.

Patients with diabetes—along with patients who have coronary artery disease, symptomatic carotid artery disease, or > 50%asymptomatic carotid stenosis—are classified by the NCEP as high risk for future cardiovascular events. The recommended goal

is to keep their LDL cholesterol < 100mg/dL. In very high-risk patients, for example, a diabetic with cardiovascular disease, the LDLcholesterol goal is < 70mg/dL.

The Collaborative Atorvastatin Diabetes Study (CARDS) demonstrated that risk of a first stroke is reduced in diabetics who takea statin. This multicenter randomized study compared atorvastatin 10 mg/day versus placebo in 2,838 type 2 diabetics with a LDL

cholesterol of < 160 mg/dL, and no history of stroke or cardiovascular disease.40 Cerebrovascular events occurred in 39 (2.8%) patientstaking placebo and 21 (1.5%) taking atorvastatin [hazard ratio 0.52; 95%CI 0.31 to 0.89]. There was a 27% reduction in mortality in the atorvastatin group. The authors concluded that diabetics may be considered for treatment with statins to lower their risk of

first stroke, even if their baseline LDL cholesterol is “normal.”

No prospective, double blind, placebo-controlled trial to confirm whether or not statins reduce the risk of recurrent stroke in

diabetics has been completed. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study is a multicenter,prospective, double blind, trial of 4732 patients with prior TIA or stroke, an LDL cholesterol of 100-180, and no history of coronary artery disease. Subjects have been randomized to placebo versus atorvastatin 80mg per day. The study is expected to be completed

in 2005.41 A subgroup analysis of diabetics enrolled in this trial will provide evidence-based information regarding the efficacy of a statin drug in secondary stroke prevention.

Antithrombotic therapy Aspirin therapy, at a dose of 75-162 mg/day as primary prevention of cardiovascular events, is recommended by the American

Diabetes Association for those with type 1 or type 2 DM who are over 40 or who have additional risk factors, i.e. family history of

cardiovascular disease, chronic hypertension, cigarette smoking, dyslipidemia, or albuminuria.37 Provided that no contraindicationexists, all diabetics with a history of ischemic stroke should be taking an antithrombotic drug to reduce their risk of secondary strokeand cardiovascular events. A meta-analysis of 145 prospective trials of antiplatelet agents used after myocardial infarction, ischemic

stroke, TIA, or positive cardiovascular history was reported by the Anti-Platelet Trialists.42 Diabetics had reduction of recurrentischemic stroke risk of about one quarter, with the use of aspirin at doses of 325 mg or less. This was similar to the benefit seen

for non diabetics. Other antiplatelet options include clopidogrel (Plavix), 75 mg/day, for patients intolerant to aspirin, and Aggrenox. Aggrenox is a combination of extended release dipyridamole 200 mg and aspirin 25 mg, and it is taken twice daily. Warfarin should

be used for primary and secondary stroke prevention in diabetics with atrial fibrillation.

Conclusion

DM is a leading worldwide health concern. Diabetics are prone to complications of vascular disease including stroke. DM is anindependent risk factor for ischemic stroke, and diabetics are at an increased risk for having large and small vessel ischemic strokes.

Diabetic stroke patients have a higher mortality rate than stroke patients without DM. Further clinical research is needed to findtherapies that reduce the stroke mortality rate associated with DM. Clinicians who care for patients with DM have several interventionsthat they can utilize to reduce their patients’ risk of stroke. These interventions include antithrombotic drugs, aggressive lowering

of cholesterol and blood pressure, and use of ACE inhibitors.

Authors

Dr. Antonios is a Post Graduate Associate in Stroke and Cerebrovascular Diseases, Department of Neurology, Shands Jacksonville. Dr. Silliman is AssociateProfessor of Neurology, University of Florida College of Medicine and the director of the Comprehensive Stroke Program at Shands Jacksonville.

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dm and stroke

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