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 the second 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 can minimize 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 prevention strategies for the diabetic patient.

Epidemiology of diabetes mellitus and stroke

In 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 stroke patients 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, whereas DM 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 factors may, or may not, be related to the etiology of the disease. Case control studies of stroke patients and prospective epidemiologic 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, chronic hypertension, hyperlipidemia, and atrial fibrillation. A substantial number of strokes are attributable to these risk factors. The population-attributable risk is an estimate of the percentage of excess stroke in a population that 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 populationattributable risk, estimated to be associated with 50 % of all strokes.4 DM is estimated to have a populationattributable risk of approximately 35%.4 This figure for DM is greater than the estimates of the population attributable 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 casecontrol studies examining the relationship between DM and ICH have not concluded that DM is an independent 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 since epidemiologic studies have consistently shown a stronger association between chronic hypertension and ICH. 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 with aneurysmal 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
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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 is usually of thrombo-embolic origin. Small caliber arteries comprise the microcirculation. These arteries are 100m-400m 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 is thought to be produced by degenerative arterial pathology within the vessel wall. These arteriopathies include microatheromas, lipohyalinosis, and fibrinoid necrosis. A brain infarction produced by an occluded 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 cohort study 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 approximately 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-based study 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 cranial nerves. 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 and others 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 was independently 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 independent determinant of the presence of > 1 silent lacunes (OR 2.95; 95% CI, 1.56-5.57).

Diabetes mellitus negatively affects outcome from stroke

DM 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-diabetics in 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 to bed.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 an acute 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
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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 as admission glucose increased.21 Those with neurologic improvement had a mean glucose of 144 mg/dL, and those 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 whether lowering 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-treated patients.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 hemorrhage rate (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 cause and effect relationship, and until this association is confirmed and clarified, rtPA should not be withheld from 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 necrosis of 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, confined only 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 onset have 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 with lower 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 with greater 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 cerebrovascular 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 have only 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 patientsglucose, 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 between admission 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 either glucose-insulin-potassium (GKI) or saline. The GKI group had much more rapid euglycemia, but results of 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 insulin infusion 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 from stroke. More well-designed clinical trials exploring this intervention are needed.
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Stroke prevention in diabetics

Prevention 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 prevent primary and secondary strokes in these patients, some of which are outlined below.

Treatment of hyperglycemia
Glycemic 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. The study 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 reduced from 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 with intensive 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 first stroke, 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 the progression of large vessel atherosclerotic disease in the diabetic. The Atherosclerosis Risk in Communities Study Investigators (ARIC) found that patients with previously undiagnosed DM were found to have 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 glucose control decreases the risk of recurrent stroke.

Treatment of hypertension
Hypertension (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 blood pressure measurements >130/80 or the use of antihypertensive medications, has been reported to be present 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 diabetics had 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 should be 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 calcium channel 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 medical regimen 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 stroke by 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, need for 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 the antihypertensive regimen, if there is no clinical contraindication.

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Treatment of hyperlipidemia
Diabetics 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 diabetesalong with patients who have coronary artery disease, symptomatic carotid artery disease, or > 50% asymptomatic carotid stenosisare 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 LDL cholesterol goal is < 70mg/dL. The Collaborative Atorvastatin Diabetes Study (CARDS) demonstrated that risk of a first stroke is reduced in diabetics who take a 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%) patients taking 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 contraindication exists, all diabetics with a history of ischemic stroke should be taking an antithrombotic drug to reduce their risk of secondary stroke and 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 recurrent ischemic 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 an independent 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 find therapies that reduce the stroke mortality rate associated with DM. Clinicians who care for patients with DM have several interventions that 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 Associate Professor of Neurology, University of Florida College of Medicine and the director of the Comprehensive Stroke Program at Shands Jacksonville. References 1. 2. 3. 4. 5. 6. 7. Website: www.diabetes.org. Accessed 9/18/04. Kannel WB, McGee DL. Diabetes and Cardiovascular Disease. The Framingham Study: JAMA 1979; 241(19):2035-2038. Jorgensen H, Nakayama H, Raaschou HO, Olsen TS. The Copenhagen Stroke Study. Stroke in patients with diabetes. Stroke 1994; 25:1977-1984. Goldstein LB, Adams R, Becker K, et al., for the Members. AHA Stroke Council. Primary Prevention of Ischemic Stroke. A Statement for Healthcare Professionals from the Stroke Council of the American Heart Association. Circulation 2001; 103:163. Leppala JM, Virtamo J, Fogelholm R, Albanes D, Heinonen OP. Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants. Stroke 1999; 30:2535-2540. Ariesen MJ, Claus, SP, Rinkel GJE, Algra A. Risk factors for intracerebral hemorrhage in the general population. A systemic review. Stroke 2003; 34(8):2060-2065. Wagenknecht LE, Zaccaro D, Espeland MA, et al. Diabetes and progression of carotid atherosclerosis: the insulin resistance atherosclerosis study.Arterioscler Thromb Vasc Biol. 2003; 23(6):917-918.

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Neurology. 2002;59:669-674. 22. Demchuk A, Morgenstern L, Krieger DW, Chi LT. Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke. Stroke. 1999;30:34-39. 23. Pulsinelli WA, Waldman S, Rawlinson D, Plum F. Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat. Neurology. 1982; 32:1239-1246. 24. Kiers L, Davis SM, Larkins R, et al. Stroke topography and outcome in relation to hyperglycaemia and diabetes. J Neurol Neurosurg Psychiatry. 1992; 55:263-270. 25. Pulsinelli WA, Levy DE, Sigsbee B, et al. Increased damage after ischemic stroke in patients with hyperglycemia with or without established diabetes mellitus. Am J Med. 1983; 74:540-544. 26. Parsons MW, Barber PA, Desmond PM, et al. Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Ann Neurol.2002;52:20-28. 27. Scott JF, Robinson GM, French JM, et al. Blood pressure response to glucose potassium insulin therapy in patients with acute stroke with mild to moderate hyperglycaemia. J Neurol Neurosurg Psychiatry. 2001; 70:401-414. 28. Gray CS, Hildreth AJ, Alberti GK, OConnell JE; GIST Collaboration. Stroke 2004; 35:122-126. 29. Bruno A, Saha C, Williams L, Shankar R. IV insulin during acute cerebral infarction in diabetic patients. Neurology. 2004; 62:1441-1442. 30. Stratton IM, Adler AI, Neil HAW, et al., for the UK Prospective Diabetes Study Group. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000; 321:405-412. 31. Abraira C, Colwell J, Nuttall F, et al., for the Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes (VACSDM) Group. Cardiovascular events and correlates in the Veteran Affairs Diabetes Feasibility Trial. Arch Intern Med . 1997; 157:181-188. 32. Folsom AR, Rasmussen ML, Chambless ME, et al. Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Diabetes Care. 1999; 22:471-475. 33. Website: www.diabetes.org/diabetes-statistics/national-diabetes-fact-sheet-jsp. National Diabetes Fact Sheet-American Diabetes Association, accessed 9-21-04. 34. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA . 1996; 276:1886-1892. 35. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000; 321:412-419. 36. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003; 42:1206-1252. 37. American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care 2004; 27(Supplement 1):S15-S35. 38. H-O-P-E Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000; 355:253-259. 39. Grundy SM, Cleeman JI, Merz, CNB, et al. for the Coordinating committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Educational Program Adult Treatment Panel III guidelines. Circulation. 2004; 110:227-239. 40. Colhoun HM, Betteridge DJ, Durrington PN, et al. 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