Diabetes,hyperglycaemia,and acute ischaemic stroke

发布于:2021-10-21 16:10:58

Review

Diabetes, hyperglycaemia, and acute ischaemic stroke
Merel J A Luitse, Geert Jan Biessels, Guy E H M Rutten, L Jaap Kappelle

Diabetes and ischaemic stroke often arise together. People with diabetes have more than double the risk of ischaemic stroke after correction for other risk factors, relative to individuals without diabetes. Multifactorial treatment of risk factors for stroke—in particular, lifestyle factors, hypertension, and dyslipidaemia—will prevent a substantial number of these disabling strokes. Hyperglycaemia occurs in 30–40% of patients with acute ischaemic stroke, also in individuals without a known history of diabetes. Admission hyperglycaemia is associated with poor functional outcome, possibly through aggravation of ischaemic damage by disturbing recanalisation and increasing reperfusion injury. Uncertainty surrounds the question of whether glucose-lowering treatment for early stroke can improve clinical outcome. Achievement of normoglycaemia in the early stage of stroke can be di?cult, and the possibility of hypoglycaemia remains a concern. Phase 3 studies of glucose-lowering therapy in acute ischaemic stroke are underway.

Lancet Neurol 2012; 11: 261–71 Department of Neurology, University Medical Centre (UMC) Utrecht Stroke Centre and Rudolf Magnus Institute of Neuroscience (M J A Luitse MD, G J Biessels MD, Prof L J Kappelle MD), and Julius Centre for Health Sciences and Primary Care (Prof G E H M Rutten MD), UMC Utrecht, Utrecht, Netherlands Correspondence to: Prof L J Kappelle, Department of Neurology, UMC Utrecht G03.232, PO Box 85500, 3508 GA Utrecht, Netherlands l.kappelle@umcutrecht.nl

Introduction
Diabetes and ischaemic stroke are common disorders that often arise together. Worldwide, 347 million people have diabetes,1 and the type 1 and type 2 forms are the most typical (panel 1). Diabetes is a leading cause of renal failure, coronary heart disease, non-traumatic lower limb amputations, and visual impairment (?gure 1). Stroke is the second leading cause of long-term disability in high-income countries and the second leading cause of death worldwide.18 In 2005, 16 million people had a ?rst stroke and 5·7 million died because of the e?ects of stroke.19 The relation between disturbed glucose metabolism and ischaemic stroke is bidirectional. On the one hand, people with diabetes have more than double the risk of ischaemic stroke after correction for other risk factors, compared with people without diabetes.20 On the other hand, acute stroke can give rise to abnormalities in glucose metabolism, which in turn could a?ect outcome.21 Importantly, the relation between disturbed glucose metabolism and cerebrovascular disease is not restricted to acute ischaemic stroke. Diabetes is also associated with more insidious ischaemic damage to the brain, mainly manifesting as small-vessel disease and increased risk of cognitive decline and dementia.22 Moreover, a relation between admission hyperglycaemia and poor outcome has been noted for haemorrhagic stroke, in particular aneurysmal subarachnoid haemorrhage.23 In this Review, we describe the interplay between glucose metabolism and acute ischaemic stroke and focus on clinical implications for prevention and management in the acute stage. We address the epidemiology of the association between diabetes and stroke, highlighting potentially modi?able risk factors and long-term outcome. We review ?ndings from many trials on prevention of stroke in people with diabetes, which suggest that rigorous assessment and treatment of associated risk factors can substantially reduce the risk of stroke in patients with diabetes. We then describe the cause, outcome, and management of hyperglycaemia at the time of an acute ischaemic stroke. Admission hyperglycaemia is a common risk factor for poor outcome after ischaemic stroke. However, much uncertainty surrounds the
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question of whether intensive glucose-lowering treatment after stroke bene?ts clinical outcome.

Diabetes and risk of stroke
Diabetes is an important risk factor for ischaemic stroke. In a meta-analysis of prospective studies (including 530 083 participants), the reported hazard ratio for ischaemic stroke was 2·3 (95% CI 2·0–2·7) in people with versus those without diabetes.20 Assuming a population-wide prevalence of diabetes of around 10%, these ?ndings indicate a diabetes-attributable risk of stroke of around 12% (ie, one in eight or nine cases of stroke is attributable to diabetes). The risk of stroke associated with diabetes is assessed predominantly in people with type 2 diabetes, because in the age group in which most strokes take place, type 2 diabetes is much more common than type 1 diabetes. Studies that allow direct comparison between both types of diabetes show that the relative risk of stroke in people with type 1 diabetes is at least similar or maybe even higher than in individuals with type 2 diabetes.24,25 In patients younger than 60 years, the relative risk of stroke in those with versus those without diabetes is double that of individuals older than 70 years.20 Sex and ethnic origin also modulate the risk of stroke in people with diabetes. The risk is higher in women (hazard ratio 2·8, 95% CI 2·4–3·4) than in men (2·2, 1·8–2·5).20 In US populations, people of African-American origin are over-represented among patients with diabetes who have a stroke.26 Diabetes causes atherosclerotic changes in the heart and the cerebropetal arteries and is associated with di?erent subtypes of ischaemic stroke, including lacunar, large artery occlusive, and thromboembolic strokes.27–29 Moreover, the risk of atrial ?brillation—a major cause of thromboembolic stroke—is increased by 40% in individuals with diabetes.30 Diabetes-associated risk factors for stroke include not only diabetes-speci?c factors (eg, hyperglycaemia) and vascular risk factors (eg, hypertension, dyslipidaemia) but also genetic, demographic, and lifestyle factors. The contribution of these factors, many of which are strongly inter-related, is likely to di?er according to diabetes type and age. Nevertheless, after

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Panel 1: Update on diabetes Type 1 diabetes Type 1 diabetes is a cell-mediated autoimmune disease with destruction of β cells that leads to absolute insulin de?ciency, resulting in hyperglycaemia and lipolysis.2 The disorder accounts for 5–10% of the total diabetes population.3 Onset of type 1 diabetes usually happens before age 30 years. Incidence is 16·4 per 100 000 in men and 8·9 per 100 000 in women.4 All patients need insulin treatment. Type 2 diabetes Type 2 diabetes is characterised by insulin resistance and relative insulin de?ciency and accounts for 90% of patients with diabetes.5 The progression from normal glucose metabolism to type 2 diabetes is gradual and happens over many years. When the pancreas fails (after a compensatory increase in insulin secretion), the patient develops hyperglycaemia. The estimated global prevalence of type 2 diabetes is 3·8%.6 Prevalence does not di?er by sex7 and increases with age, to 20–25% in patients older than 65 years.8 Over past decades, type 2 diabetes has become more prevalent in younger age groups, including adolescents.9 Insulin resistance develops because of environmental factors, particularly obesity and a sedentary lifestyle.10 Moreover, a family history confers a 2·4-times risk of the disorder.5 Treatment is aimed at reduction of insulin resistance and increasing endogenous insulin secretion. In more advanced stages of type 2 diabetes, treatment with exogenous insulin could be necessary. Prediabetic stages People whose glucose levels are raised but are still below the diabetes threshold are at higher risk for progression to type 2 diabetes than are individuals with normal values. Stages of elevated glucose are de?ned as impaired glucose tolerance (ie, 2 h after glucose loading, a glucose concentration of 7·8–11·1 mmol/L) or impaired fasting glucose (ie, a fasting glucose level of 6·1–6·9 mmol/L).11 Both impaired glucose tolerance and impaired fasting glucose are associated with cardiovascular disease.12 These prediabetic disorders sometimes occur with obesity, dyslipidaemia, hypertension, and prothrombotic and proin?ammatory states.9 Vascular complications in diabetes Prolonged hyperglycaemia is associated with microvascular complications, such as retinopathy (?gure 1A and 1B),13 neuropathy, and nephropathy, and with macrovascular complications caused by atherosclerosis (?gure 1C).3 Despite intensive treatment, most patients with type 1 diabetes develop microvascular complications before midlife.14 Type 1 diabetes is also a risk factor for macrovascular complications later in life.15 In patients with type 2 diabetes, microvascular complications develop as exposure to hyperglycaemia increases.16 Macrovascular complications might already start to develop in prediabetic stages.17

Diabetes and long-term outcome after stroke
During the ?rst 3 months after ischaemic stroke, mortality is not increased in patients with diabetes compared with those without.35,36 However, mortality more than 1 year after stroke was slightly increased (hazard ratio 1·2, 95% CI 1·1–1·2); a similar ?nding was reported in patients younger than 50 years.36,37 Furthermore, risk of recurrent stroke is raised (1·8, 1·2–2·8),38 which could be even more striking in patients with diabetes younger than 50 years.37 Finally, diabetes is associated with augmented risk of long-term functional de?cits after stroke (odds ratio 1·5, 95% CI 1·1–1·9),35 including an increased risk of post-stroke dementia (1·5, 1·1–2·3).39

Diabetes and prevention of stroke
Several risk factors for stroke in patients with diabetes are potentially modi?able, in particular lifestyle factors, glucose concentrations, blood pressure, and dyslipidaemia, which have been targeted in several large randomised controlled trials (panel 2). Neurologists typically distinguish between primary prevention (eg, prevention of ?rst stroke) and secondary prevention (eg, prevention after transient ischaemic attack or ischaemic stroke). However, this distinction is not always made in published work on prevention of cardiovascular events in people with diabetes. Lifestyle probably has the largest e?ect on risk of stroke, and smoking, obesity, inactivity, excessive alcohol intake, and unhealthy diets should be strongly discouraged in people with diabetes. Lifestyle modi?cation in this population is associated with a substantial decline in stroke incidence (hazard ratio 0·62, 95% CI 0·39–0·98).42 Moreover, modest weight loss (5–10% of bodyweight) in individuals with type 2 diabetes has been associated with substantial improvement of cardiovascular risk factors and glycaemic control.43,44

Glucose-lowering treatment
Three large long-term trials have compared the e?ects of intensive versus standard glycaemic control in participants at fairly high risk of stroke with longstanding type 2 diabetes. In two of these trials, no di?erence in cardiovascular outcomes was reported with intensive glycaemic control.48,49 In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study,50 the glycaemic control study was terminated after 3·7 years owing to increased mortality in the intensive treatment group (HbA1c <42 mmol/mol [6%]). Participants assigned to the intensive therapy group were subsequently switched to the standard control group (HbA1c 53–64 mmol/mol [7–7·9%]) and were followed up for about 1·2 years. Both before and after the transition, risk for non-fatal stroke was similar (hazard ratio 0·99, 95% CI 0·77–1·1, and 0·87, 0·65–1·2, respectively). At the end of the study, the rate of death from any cause was 19% higher in the intensive treatment group (hazard
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adjustment for the above-mentioned risk factors, diabetes is associated with a doubling in the risk of ischaemic stroke (hazard ratio 2·2, 95% CI 1·9–2·6) compared with those without diabetes.20 The risk of stroke is already raised in prediabetic stages. Insulin resistance is a risk factor for stroke,31 but whether insulin concentrations themselves or markers of glucose tolerance convey the highest risk is debatable.32,33 Therefore, amounts of HbA1c have also been investigated.34 HbA1c concentrations of greater than 42 mmol/mol (6%) increased the risk of stroke between two and three times in adults without diabetes, taking the potential confounding e?ects of other vascular risk factors into account.34
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ratio 1·5 vs 1·3, 95% CI 1·0–1·4). Reasons for the higher mortality in the intensive therapy group in the pretransition period remain unclear.51 In a meta-analysis of 34 533 patients with type 2 diabetes, no bene?cial e?ects of tight glycaemic control versus standard glycaemic control could be seen on stroke rates during a mean treatment period of 5 years (hazard ratio 0·96, 95% CI 0·83–1·1).52 Similar ?ndings were noted in a Cochrane review, in which the e?ects of targeting intensive versus conventional glycaemic control were assessed in 29 986 patients with type 2 diabetes from 20 randomised controlled trials, with a duration of intervention of between 3 days and 12·5 years.53 Targeting intensive glycaemic control did not reduce the risk of cardiovascular mortality (risk ratio 1·1, 95% CI 0·90–1·3) or non-fatal stroke (0·96, 0·80–1·2).53 Heterogeneity between trials did not a?ect the results. Of 837 non-fatal strokes, 423 were reported from one trial.48 In a separate meta-analysis dealing exclusively with glycaemic control in usual care settings, the e?ect estimate on prevention of non-fatal stroke remained non-signi?cant (risk ratio 1·0, 95% CI 0·87–1·2). Risk of severe hypoglycaemia was increased signi?cantly when intensive glycaemic control was targeted (relative risk 2·0, 95% CI 1·4–3·0).53 Findings of the Diabetes Control and Complications Trial (DCCT) showed that 1422 patients with type 1 diabetes who were treated with intensive control of glucose concentration for 6·5 years had a 57% reduced risk of cardiovascular events over a mean follow-up period of 17 years (95% CI 12–79), compared with individuals receiving conventional treatment.54 However, strokes were rare, with only one event in the intensive treatment group and ?ve in the conventional treatment group.54 To date, insu?cient evidence is available to show that stroke prevention will be improved by intensive glucose-lowering treatment, in people with either type 1 or type 2 diabetes. Clinicians should balance risk of (recurrent) hypoglycaemia against the advantages of a lower amount of HbA1c, taking into account patient’s age, duration of diabetes, and comorbidities.

A

C

B

Figure 1: Microvascular and macrovascular complications of diabetes (A) Non-proliferative diabetic retinopathy showing microhaemorrhage and hard exudates (arrows). (B) Proliferative diabetic retinopathy with neovascularisation (arrows). Reproduced from Cheung and colleagues,13 by permission of Elsevier. (C) Large-vessel atherosclerosis.

Panel 2: Stroke prevention in diabetes ? Regulate blood pressure below 130/80 mm Hg; angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers are recommended as ?rst-line treatment40,41 ? Prescribe statins40 ? Discourage smoking, inactivity, excessive alcohol intake, and obesity42–44 ? Prescribe platelet-aggregation inhibitors in patients with clinically manifest vascular disease and sinus rhythm45 ? Apply the CHA2DS2-VAS score and prescribe warfarin in patients with clinically manifest vascular disease and with atrial ?brillation40,46 ? Undertake carotid surgery in patients with symptomatic high-grade carotid stenosis47
CHA2DS2-VAS=congestive heart failure/left-ventricular dysfunction (1 point); hypertension (1); age ≥75 years (2); diabetes mellitus (1); stroke/transient ischaemic attack/thromboembolism (2); vascular disease, ie, previous myocardial infarction/ peripheral artery disease/aortic plaque (1); age 65–74 years (1); female sex (1).

Vascular risk factors
In patients with type 2 diabetes, lowering of blood pressure has a large e?ect on risk of future stroke.55–58 In a metaanalysis of 37 736 patients (13 trials) with type 2 diabetes, impaired fasting glucose or impaired glucose tolerance assessed the e?ects of blood pressure control (≤135 mm Hg vs ≤140 mm Hg).59 More intensive control of blood pressure was associated with a 10% reduction in all-cause mortality (odds ratio 0·90, 95% CI 0·83–0·98) and a 17% reduction in strokes (0·83, 0·73–0·95), compared with standard treatment. This di?erence was mainly driven by trials in which the aim was to achieve systolic pressure of 130–135 mm Hg. Control of blood pressure below 130 mm Hg was associated with a greater reduction in stroke but a 40% increase in serious adverse events, with
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no bene?t for cardiac, renal, and retinal outcomes.59 Most guidelines recommend a blood pressure of less than 130/80 mm Hg for patients with diabetes.40 The choice of antihypertensive drugs is probably less important than the target levels. Currently, angiotensin-converting-enzyme (ACE) inhibitors or angiotensin II receptor blockers are typically recommended as ?rst-line drugs.40,41 In a post-hoc analysis of the Heart Protection Study, a daily dose of 40 mg simvastatin administered to
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5963 patients with type 2 diabetes, of whom half did not have any evidence of arterial occlusive disease, was associated with a 28% (95% CI 8–44) reduction in ischaemic stroke, independent of baseline lipid levels.60 In people with type 2 diabetes with no history of cardiovascular disease, daily use of 10 mg atorvastatin was associated with a 37% (17–52) reduction in cardiovascular events and with a 48% (11–69) reduction in all types of stroke.61 In 9795 patients with type 2 diabetes, of whom 7664 had no history of cardiovascular disease, micronised feno?brate 200 mg once daily versus placebo reduced the risk of cardiovascular events (hazard ratio 0·89, 95% CI 0·80–0·99), including ischaemic stroke (0·91, 0·73–1·1).62 The combination of feno?brate and simvastatin did not reduce the rate of fatal or non-fatal cardiovascular events more than simvastatin alone.63 On the basis of this evidence, statins are recommended for secondary prevention in all individuals with type 2 diabetes—and in most for primary prevention—depending on their 10-year cardiovascular risk.40 Consensus on choice of statin has not been reached. In three trials,64–66 multifactorial prophylactic treatment was assessed in people with type 2 diabetes. Of 160 highrisk individuals with longstanding type 2 diabetes and microalbuminuria who participated in the Steno-2 study,64 a multifactorial approach—including use of statins, ACE inhibitors, angiotensin II receptor blockers, or an antiplatelet drug as appropriate, and modi?cation of lifestyle—was associated with reduction of cardiovascular events by 59% (hazard ratio 0·41, 95% CI 0·25–0·67), compared with conventional treatment. The number of all types of stroke during a mean follow-up period of 8 years was ?ve times higher in the group receiving conventional treatment.64 In 3488 patients participating in the Euro Heart Survey on Diabetes and the Heart,65 intensive treatment of vascular risk factors had an independent protective e?ect on 1-year mortality and cardiovascular events (relative risk 0·61, 95% CI 0·40–0·91, and 0·61, 0·39–0·95, respectively). No e?ect on stroke rate was recorded, but cerebrovascular revascularisation procedures were reduced by half.65 The bene?ts of combined control

of many vascular risk factors immediately after early diagnosis of type 2 diabetes were investigated in 3055 patients with diabetes, in the Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care (ADDITION-Europe).66 During a mean follow-up period of 5·3 years, stroke rates did not di?er between groups. A non-signi?cant reduction of cardiovascular events (hazard ratio 0·83, 95% CI 0·65–1·1) was noted in the intensive treatment group versus the routine care group.66 Intensive monitoring of vascular risk factors is important in the long term, as shown by follow-up of individuals participating in the UK Prospective Diabetes Study (UKPDS).67 Reported di?erences in blood pressure and stroke rate disappeared 2 years after termination of the trial. Training programmes for patients aimed at acquiring the skills for a healthy lifestyle and self-monitoring of blood glucose and blood pressure can be useful.68

Antithrombotic treatment
Findings of a trial in which the e?cacy of aspirin was assessed speci?cally in patients with type 2 diabetes with no history of cardiovascular disease did not show a protective e?ect on atherosclerotic events (hazard ratio 0·80, 95% CI 0·58–1·1).69 This trial was not powered to detect an e?ect on stroke. In a meta-analysis on use of aspirin for primary prevention in patients with diabetes, no bene?ts were recorded with respect to reduction of serious vascular events, including stroke.70 The e?ectiveness of antithrombotic drugs for secondary prevention of stroke has not been studied in a major trial, speci?cally in people with diabetes. In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial,71 in which clopidogrel was compared with aspirin in patients with atherosclerotic disease (including minor disabling ischaemic stroke), the bene?t of clopidogrel for prevention of ischaemic events was higher in individuals with diabetes than in those without (relative risk reduction 12·9%, 95% CI ?3·0 to 26·4).71 However, the conclusions of a meta-analysis of the e?cacy of antithrombotic agents in more than 5000 patients with diabetes showed that these drugs reduced both coronary events and ischaemic stroke to a similar degree as in people without diabetes.45 Although the e?ect of antithrombotic treatment on prevention of future cardiovascular events is relatively low compared with rigorous control of risk factors, this type of drug should be considered in every patient with diabetes who is at risk of future vascular complications. Diabetes not only is a risk factor for atrial ?brillation30 but also increases the risk of embolic complications in individuals with atrial ?brillation, as indicated by the CHA2DS2-VAS score (a measure of the risk of stroke, in which 1 point is assigned to each factor, unless otherwise noted: congestive heart failure or left-ventricular dysfunction; hypertension; age 75 years or older [2 points]; diabetes mellitus; stroke, transient ischaemic
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Panel 3: Di?erential diagnosis of hyperglycaemia in acute ischaemic stroke ? Known pre-existing diabetes ? Newly diagnosed diabetes ? Fasting glucose >6·9 mmol/L or random glucose >11·1 mmol/L, persisting after discharge77 ? HbA1c ≥6·5% at admission indicates pre-existing type 2 diabetes40 ? Stress hyperglycaemia ? Fasting glucose >6·9 mmol/L or random glucose >11·1 mmol/L, reverting to normal range after discharge77

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attack, or thromboembolism [2 points]; vascular disease [previous myocardial infarction, peripheral artery disease, or aortic plaque]; age 65–74 years; and female sex).46 Therefore, patients with diabetes and atrial ?brillation should receive platelet aggregation inhibitors if they have none of the other risk factors included in CHA2DS2-VAS46 and warfarin in all other cases.72 Dabigatran, rivaroxaban, and apixaban are proven to protect patients with atrial ?brillation as well as—or even better than—warfarin, but the de?nite role of these new antithrombotic drugs in patients with a recent transient ischaemic attack or minor ischaemic stroke remains to be established.73

Cerebral infarction

Penumbral tissue Infarct core Blood clot

Normoglycaemic condition

Hyperglycaemic condition

Carotid surgery
Carotid endarterectomy for secondary stroke prevention in patients with high-grade stenosis of the carotid artery is e?ective, but has not been investigated speci?cally in patients with diabetes. Both periprocedural and longterm risks are higher in individuals with diabetes than in those without,74,75 but this increased risk should not be a reason to withhold surgery in this group.
Impaired recanalisation ↑Thrombin-antithrombin complexes ↑Tissue factor pathway leads to ↑coagulation ↑Plasminogen activator inhibitor ↓Recombinant tissue plasminogen activator inhibitor leads to ↑?brinolysis

Hyperglycaemia in acute ischaemic stroke
Hyperglycaemia arises in 30–40% of people with acute ischaemic stroke.76 Most of these individuals do not have a known history of diabetes mellitus.21 In some patients, hyperglycaemia re?ects pre-existing but unrecognised diabetes, but more often it is the result of an acute stress response, typically named stress hyperglycaemia (panel 3). Glucose concentrations are raised in people with stress hyperglycaemia but revert to normal after discharge from hospital.77 Therefore, high levels of glucose on admission do not distinguish between stress hyperglycaemia and diabetes, but under these conditions, raised amounts of HbA1c (≥48 mmol/mol [6·5%]) could help to identify people with previously undiagnosed diabetes.40,77 Stress hyperglycaemia usually resolves spontaneously after dissipation of the acute illness. The stress reaction that results in hyperglycaemia is initiated by activation of the hypothalamic-pituitary-adrenal axis, which leads to raised amounts of glucocorticoids (cortisol) and activation of the sympathetic autonomic nervous system. Increased levels of stress hormones stimulate glucose production by glycogenolysis, gluconeogenesis, proteolysis, and lipolysis. Augmented epinephrine also can result in insulin resistance and hyperinsulinaemia.77,78

Decreased reperfusion ↓Nitric oxide leads to ↑vasodilatation ↑Prostaglandins lead to vasoconstriction

Time

Increased reperfusion injury ↑Oxidative stress leads to tissue damage, oedema, and impaired blood–brain barrier ↑In?ammatory response ↑Cytokines lead to tissue damage Direct tissue injury Mitochondrial dysfunction Anaerobic glycolysis leads to lactic acidosis Haemorrhagic conversion

Figure 2: Potential e?ects of hyperglycaemia over time on pathophysiological processes entailed in development of cerebral infarction Reproduced from Kruyt and colleagues,78 by permission of Nature Publishing Group.

Outcome
Compared with patients with normoglycaemia, the unadjusted relative risk of in-hospital or 30-day mortality after an ischaemic stroke in individuals who are hyperglycaemic at admission is 3·3 (95% CI 2·3–4·7) in those without known diabetes and 2·0 (0·04–90·1) in those with a known history of diabetes.21 This increased risk is independent of other predictors of poor outcome. By
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contrast, for persistent hyperglycaemia, at 24–48 h after stroke the relation with poor outcome is less clear.79 The association between hyperglycaemia and poor outcome after stroke is mainly relevant to patients with largevessel infarction.80 In lacunar stroke, moderate hyperglycaemia has even been associated with good rather than poor outcome.76,81
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A

B

200 150 100 50 0

C

D

20 15 10 5 0

20 15 10 5 0

E

F

Figure 3: Perfusion CT in acute ischaemic stroke Perfusion abnormalities can be identi?ed on the basis of an area with decreased cerebral blood ?ow (B, arrow), increased mean transit time (C, arrow), and decreased cerebral blood volume (D, arrow). With these measures, the infarct core (A, red) and the potentially salvageable ischaemic penumbra (A, green) can be identi?ed. CT angiography (E) shows occlusion of the middle cerebral artery (arrow). Follow-up CT (F) shows the ?nal lesion at 3 months.

Pathophysiology
Both experimental and clinical studies have investigated extensively the potential mechanisms underlying the relation between hyperglycaemia and poor outcome after stroke.78 Results of a meta-analysis of experimental
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studies82 showed that infarcts were larger in animal models of hyperglycaemia, and this e?ect was more striking for streptozotocin than after dextrose infusion (140% larger vs 48% larger). The authors expressed concerns about the validity of experimental observations for the clinical situation,82 because studies either include models with prolonged hyperglycaemia before stroke (streptozotocin) or with very high glucose loads. Although hyperglycaemia—in amounts that can be encountered in patients—has not been proven de?nitively to be a causal factor for impaired outcome after stroke, several mechanisms have been identi?ed through which hyperglycaemia could aggravate cerebral damage in ischaemic stroke, including impaired recanalisation and reperfusion injury (?gure 2).78 Impaired recanalisation has been attributed to disturbances in coagulation and in ?brinolytic pathways.83,84 These pathways have been investigated extensively in people with diabetes, at prediabetic stages, with persistent dysglycaemia, and who are resistant to insulin85 but infrequently in those with acute stroke. Amounts of plasminogen activator inhibitor 1 and tissue-type plasminogen activator antigens, for example, were higher in individuals with glucose intolerance compared with those with normal glucose tolerance.85 Hyperinsulinaemia is associated mainly with impaired ?brinolysis in people with glucose intolerance.86 Moreover, raised levels of fasting insulin are linked to impaired ?brinolysis and hypercoagulability in individuals with normal glucose tolerance.86 Acute and chronically raised glucose concentrations show important similarities in their e?ects on coagulation activation and impaired ?brinolysis.85 In patients with acute stroke, such disturbances could impinge on the e?cacy of ?brinolytic treatment. Indeed, ?ndings of transcranial doppler imaging studies show that hyperglycaemia is associated with persistent arterial occlusion after thrombolytic treatment in individuals with ischaemic stroke.87,88 Both acute and chronic hyperglycaemia are associated with widespread abnormalities in blood vessels that can a?ect blood ?ow and vascular reactivity.89,90 Disturbances in metabolism of endothelium-derived nitric oxide probably have a key role in these vessel abnormalities,91,92 which can become especially detrimental when blood ?ow is acutely compromised—eg, during acute cerebral ischaemia. Even when perfusion is restored, hyperglycaemia could further threaten the tissue, through augmented reperfusion injury.90,93 This process is mediated by increased oxidative stress and in?ammation,94,95 both of which are a?ected by hyperglycaemia. Moreover, admission hyperglycaemia has been linked to increased risk of haemorrhagic complications after thrombolytic treatment.78 In an observational study of a large series of patients with acute ischaemic stroke treated with intravenous thrombolysis, the increased risk of haemorrhage was only raised signi?cantly when admission glucose concentrations were greater than 10 mmol/L.96 In another study, this increased risk
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Review

Phase Bruno et al107 2

Patients Ischaemic stroke <12 h, all with diabetes mellitus; n=46 (31 intervention, 15 controls) All stroke; n=933 (464 intervention, 469 controls) Ischaemic stroke <24 h; n=74 (24 intervention, 50 controls)

Intervention Continuous intravenous insulin infusion for 72 h (target 5–7·2 mmol/L); monitor every 1 h Glucose-insulin-potassium continuous intravenous infusion for 24 h (target capillary 4–7 mmol/L, plasma glucose 4·6–8 mmol/L); monitor every 8 h Intravenous insulin infusion and subcutaneous insulin (target 3·9–11·1 mmol/L, loose control) or continuous intravenous insulin infusion for 5 days (target 3·9–6·1 mmol/L, tight control); monitor every 1–4 h Continuous intravenous insulin infusion for 5 days (target 4·4–6·1 mmol/L); monitor every 1–4 h Continuous intravenous insulin infusion and CTF for 5 days (target 4·4–6·1 mmol/L); monitor every 1–2 h

Outcome Mean glucose di?erence between the two groups European Stroke Scale and modi?ed Rankin scale at 90 days Within-target success at 24 h; hypoglycaemia

Results Signi?cantly lower glucose concentrations in intervention group (p=0·001); 35% hypoglycaemia No signi?cant reduction in mortality at 90 days (glucose-insulin-potassium vs control, odds ratio 1·14, 95% CI 0·86–1·51, p=0·37) Within-target success 90% in loose control group, 44% in tight control group; 4% hypoglycaemia in loose control group, 30% in tight control group, 4% in controls Signi?cantly lower glucose levels in intervention group (p=0·0005); signi?cantly more hypoglycaemia (incidence rate ratio 5·3, 95% CI 1·2–22·4) in intervention group Median time within target, 55% in insulin CTF group, 19% in insulin group, and 58% in controls; 20% hypoglycaemia in insulin CTF group, 31% in insulin group 6·0 vs 6·8 mmol/L (p=0·03); 8% hypoglycaemia in intervention group, 0% in controls Signi?cant improvement in neurological status in intervention group (p=0·05); no reports on hypoglycaemia Two insulin-dosing regimens with a di?erent basal to bolus insulin ratio failed to lower glucose in intermittently fed patients in the ?rst 2–5 days after stroke Signi?cant reduction in mean area under glucose/time curve in intervention group (p=0·04); one event of hypoglycaemia

Gray et al108

3

Johnston et al109

2

Kreisel et al110

2

Ischaemic stroke <24 h; n=40 (20 intervention, 20 controls)

Hypoglycaemia; severe hyperglycaemia

Kruyt et al111

2

Ischaemic stroke <24 h; n=38 (10 insulin CTF, 13 insulin, 15 controls)

Time spent within target range

Staszewksi et al112

2

Ischaemic stroke <12 h; n=50 Continuous intravenous insulin infusion (target Time spent within target range; hypoglycaemia (26 intervention, 24 controls) 4·5–7 mmol/L); monitor every 1 h, every 4 h once stable for 24 h Ischaemic stroke <12 h; n=128 Continuous intravenous infusion 100 mL/h per (61 intervention, 67 controls) 4 h with insulin doses (target <7 mmol/L); monitor every 4 h Ischaemic stroke <24 h; n=49 (13 basal insulin, 10 meal-related insulin, 10 hyperglycaemic control, 16 normoglycaemic control) Ischaemic stroke <24 h; n=25 (13 intervention, 12 controls) Reduction in plasma glucose concentration

Vinychuk et al113

2

Vriesendorp et al114 2

Basal insulin using intravenous insulin, or strict Time spent within target range glucose control with predominantly meal-related insulin using subcutaneous insulin (target 4·4–6·1 mmol/L); monitor every 1–4 h Continuous intravenous insulin infusion for 48 h (target 5–7·9 mmol/L); monitor every 2 h Time spent within target range

Walters et al115

2

CTF=continuous tube feeding.

Table: Overview of phase 2 and 3 glucose-lowering trials in acute ischaemic stroke

was more evident in patients who had persistent hyperglycaemia during the ?rst 48 h after admission compared with those with admission hyperglycaemia only.97 Tight control of blood glucose could be indicated in the hyperacute phase after thrombolysis, but data from randomised trials are needed.96 In patients with large-vessel thromboembolic stroke, hyperglycaemia-related mechanisms are likely to a?ect salvage of the penumbra, the part of the ischaemic area that can still potentially recover if adequate reperfusion is restored within hours after stroke onset (?gure 3). Indeed, ?ndings of MRI studies indicate that reduced penumbral salvage is a key contributor to increased infarct size in patients with hyperglycaemia at admission.98,99 This e?ect on the penumbra might also explain why hyperglycaemia is not associated with worse outcome in lacunar stroke, since a penumbra is usually not present in this stroke subtype. Moreover, lactate produced by astrocytes has been suggested to be an important rescue source of energy for axons in the basal ganglia region.76 Enhanced lactate production due to hyperglycaemia in lacunar stroke might fuel and salvage axons.76
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Management
Amounts of glucose in plasma should be measured on admission in all patients suspected of acute stroke, because they direct diagnosis and treatment. Exclusion of patients with a known history of diabetes from receiving thrombolytic treatment is unnecessary. The odds of improvement after thrombolysis are similar in people with or without a history of diabetes (odds ratio 1·5, 95% CI 1·3–1·6 vs 1·53, 1·4–1·6).100 Severe hyperglycaemia can cause focal neurological de?cits with sudden onset, thus mimicking stroke.101,102 For this reason, patients with glucose concentrations of greater than 22·2 mmol/L have been excluded from trials on intravenous thrombolysis. Therefore, whether intravenous thrombolysis is safe and useful in such patients is unclear. Modern imaging techniques, such as perfusion CT scanning, can help to di?erentiate acute cerebral ischaemia from hyperglycaemia-related focal neurological de?cits (?gure 3). This method might make neurologists less reluctant to withhold intravenous thrombolysis in patients with severe hyperglycaemia, although the risk of haemorrhagic transformation remains a concern.96
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Panel 4: Management of hyperglycaemia in acute ischaemic stroke ? Treat hyperglycaemia (recommended cuto?s 10·0 mmol/L or 11·1 mmol/L)118,119 and consider that: ? bene?t on clinical outcome is not yet established ? phase 2 studies show that glucose regulation is feasible, but ?uctuations in glucose concentrations and risk of hypoglycaemia are a concern111,114 ? Di?erentiate between stress hyperglycaemia and newly diagnosed diabetes (panel 3)77

The observed relation between hyperglycaemia and poor outcome in patients with ischaemic stroke raises the question of whether outcome can be improved by glucose-lowering treatment. Experience in disorders other than stroke suggests that glucose-lowering treatment might be e?ective.103–105 Trial ?ndings suggested that intensive insulin therapy had a bene?cial e?ect on outcome of critically ill patients with hyperglycaemia in the intensive-care unit (ICU) and, subsequently, intensive glucose treatment protocols were implemented on ICUs worldwide. Data from later studies, however, could not con?rm these earlier positive results. A systematic review of 21 trials of intensive insulin therapy in the ICU, perioperative care, myocardial infarction, and stroke or brain injury settings concluded that evidence was inconsistent to show improvement of health outcomes in admitted patients, and such treatment was associated with an increased risk of severe hypoglycaemia.106 Several studies have assessed speci?cally the feasibility and safety of glucose-lowering treatment in patients with acute stroke (table). Although glucose concentrations can be lowered by various insulin treatment regimens, achievement of stable normoglycaemia can be di?cult in the ?rst few days after stroke onset, probably because oral food intake causes ?uctuations in glucose levels.114 A

Search strategy and selection criteria We searched PubMed from 1975 to Dec 15, 2011, with the terms (and synonyms) “stroke”, “cerebral ischaemia”, “cerebral infarction”, “hyperglycaemia”, “diabetes”, “glucose”, and “insulin”, in combination with the key terms “epidemiology”, “risk factors”, “treatment”, “prevention”, and “outcome”. We only searched for papers published in English. We also searched reference lists of reports identi?ed with this strategy for relevant publications. Furthermore, we searched the Stroke Trials Registry, and ClinicalTrials.gov. From the large amount of published work on these topics we selected mainly randomised controlled trials, observational studies, and systematic reviews or meta-analyses published in core clinical journals over the past 5 years. Our ?nal selection was based on originality and relevance to topics covered in this Review.

possible solution was reported in a study that used continuous tube feeding in combination with intravenous insulin administration.111 However, important safety issues remain with respect to glucose-lowering treatment, because even with intensive monitoring, many patients can experience one or more episodes of hypoglycaemia.78,114 To facilitate control of hyperglycaemia and to counter the risk of hypoglycaemia, various computer-guided treatment protocols have been developed.111,116 Introduction of continuous glucose monitoring devices might also help to improve treatment protocols and enhance safety. As yet, no evidence shows that glucose-lowering treatment improves clinical outcome in patients with acute ischaemic stroke. Findings of randomised controlled trials speci?cally targeting individuals with stroke have failed to show bene?cial e?ects. In a metaanalysis of 1296 patients with acute stroke from seven trials, intensively monitored intravenous insulin treatment (aimed at maintenance of glucose concentrations between 4·0 and 7·5 mmol/L) was compared with usual care.117 No di?erence was seen with respect to poor outcome (odds ratio 1·0, 95% CI 0·8–1·3), and the risk of symptomatic hypoglycaemia was signi?cantly higher in the group treated with insulin (25·9, 9·2–72·7).117 It is noteworthy that the results of this meta-analysis mainly came from 926 participants in the UK Glucose Insulin in Stroke Trial (GIST-UK).108 Although this trial was important it did have some limitations. Patients were treated for only 24 h, during which time mean amounts of glucose in plasma were only 0·57 mmol/L lower in the intensively treated group than in the saline-treated group. Moreover, 22% of participants had lacunar stroke. A large randomised controlled trial is planned, in which 1400 patients will be randomly allocated to either standard care (aiming at glucose levels of <10 mmol/L) or intravenous insulin treatment (aiming at glucose concentrations of 4·4–7·2 mmol/L) for 72 h after stroke (ClinicalTrials.gov identi?er NCT01369069). An insulin infusion protocol will be used that has proven safe and feasible in a pilot study.109 Several questions remain regarding management of hyperglycaemia in patients with acute ischaemic stroke. Should we monitor and lower glucose concentrations and, if so, how? How long should we maintain strict glucose management after stroke? Furthermore, should we account for stroke subtype when deciding whether to treat hyperglycaemia? Current American Heart Association and European Stroke Organisation guidelines for management of ischaemic stroke advise that glucose concentrations exceeding 11·1 mmol/L118 or 10·0 mmol/L119 should trigger the administration of insulin (panel 4).

Conclusions
Diabetes is associated with a doubling of the risk of stroke and with poor long-term outcome after ischaemic stroke. Therefore, neurologists should monitor glucose metabolism in all patients with ischaemic stroke. All
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individuals should be classi?ed as either normoglycaemic or with stress hyperglycaemia, and with either newly diagnosed type 2 diabetes or known diabetes. Although the e?ectiveness of glucose-lowering treatment on clinical outcome has yet to be established, protocols are becoming available for patients with ischaemic stroke. The possibility of hypoglycaemia remains a concern. Neurologists and primary-care doctors should collaborate with respect to treatment of vascular risk factors for stroke prevention.
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