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(Stroke. 2001;32:2029.)
© 2001 American Heart Association, Inc.

Original Contributions

Sulfonylurea Drugs Do Not Influence Initial Stroke Severity and In-Hospital Outcome in Stroke Patients With Diabetes

Markus Weih, MD; Nicola Amberger; Susanne Wegener, MD; Ulrich Dirnagl, MD; Thomas Reuter, MD Karl Einhäupl, MD

From the Department of Neurology and Department of Hepatology and Gastroenterology (T.R.), Charite Hospital, Humboldt University Berlin (Germany).

Correspondence to Dr Markus Weih, Neurological Intensive Care Unit, Department of Neurology, Charite Hospital, Humboldt University Berlin, Schumannstrasse 20-21, 10098 Berlin, Germany.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—— Sulfonylurea drugs inhibit ATP-dependent potassium channels and may increase mortality after myocardial infarction. Sulfonylurea drugs also inhibit ischemic preconditioning in experimental models of brain ischemia and in clinical studies in the human heart.

Methods—— In the present study we examined the impact of sulfonylurea drugs on in-hospital mortality and the immediate neurological deficit of diabetic stroke patients. From a larger stroke data bank, we studied 146 diabetic patients with acute hemispheric ischemic stroke. Sixty patients were using sulfonylurea drugs.

Results—— Major baseline characteristics such as age, blood pressure, admission glucose level, HbA_1c, distribution of cardiovascular risk factors, and presumed stroke etiology (Trial of Org 10172 in Acute Stroke Treatment [TOAST] criteria) were not different. Mortality (15% versus 14%; P=0.86) and initial stroke severity (Canadian Neurological Scale score, 7.4 versus 7.5; P=0.79) were not significantly different between patients with and without sulfonylurea drugs. Further end points such as Rankin Scale score, deteriorating stroke, duration of hospital stay, type of infarcts on CT/MRI, requirement of intensive care, and complications were not different. In a stepwise logistic regression model, sulfonylurea drugs were not independent predictors for increased mortality, deteriorating stroke, or stroke severity.

Conclusions—— In the present hospital-based study, sulfonylurea drugs in patients with diabetes and stroke are not associated with increased stroke severity, mortality, or a worse in-hospital outcome.

Key Words: cerebral ischemia • clinical study • hypoxia • preconditioning

	Introduction

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Diabetes mellitus increases the risk for coronary heart disease and ischemic stroke approximately 2- to 3-fold.^1,2 Diabetic or hyperglycemic patients have a worse prognosis and an increased mortality after stroke.^3–6 Experimental models have shown that hyperglycemia increases damage after cerebral ischemia, probably by increasing acidosis-related damage.⁷

Many diabetic patients are treated with oral sulfonylurea drugs, which depolarize pancreatic beta cells by inhibiting ATP-dependent potassium channels (K_ATP). This depolarization leads to calcium influx (similar to glucose binding) and finally to exocytosis of insulin-containing secretory granules. Some studies in the heart found that sulfonylurea drugs increase early and late mortality after myocardial ischemia in non-insulin-dependent patients with diabetes mellitus.^8–10 However, these results have been repeatedly challenged by other authors.^11–13

The ongoing discussion about sulfonylurea drugs has been refocused by recent experimental observations that sulfonylurea drugs impair ischemic preconditioning.¹⁴ K_ATP are activated after brief hypoxic stimuli (which cause rapid ATP hydrolysis), hyperpolarize the cell, and confer resistance or tolerance against a subsequent prolonged hypoxic stress. Ischemic preconditioning can be simulated by agonists of K_ATP and blocked when antagonists such as glibenclamide are applied. Similar effects have been observed in experimental brain ischemia.^15,16 Sulfonylurea binding sites and K_ATP are expressed in the human brain.^17,18 However, whether sulfonylurea drugs in diabetic stroke patients affect immediate stroke severity, clinical course, and in-hospital mortality has not been examined to date. In this retrospective study we compared diabetic stroke patients with or without prior use of sulfonylurea drugs. Our results reveal no influence of common doses of sulfonylurea drugs in the immediate clinical outcome after ischemic stroke.

	Subjects and Methods

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The medical records of 439 consecutive patients with the diagnosis of acute stroke between January 1994 and May 2000 were reviewed. Patients were included if they met the following criteria: (1) acute ischemic deficits attributable to the anterior circulation and (2) diabetes as defined by repeated fasting plasma glucose >140 mg/dL, plasma glucose >200 mg/dL after glucose load or meals, or known or treated diabetes, according to the patient or referring physician. Patients who had no known diabetes and only transient hyperglycemia ("stress" hyperglycemia after stroke) were not included. After admission, hyperglycemia >150 to 160 mg/dL was treated by insulin, according to local stroke management guidelines,¹⁹ irrespective of whether the patient had been treated with insulin before. Oral antidiabetic drugs were continued in 34 of 60 patients (57%). The remaining cases were treated with insulin. All patients received a CT scan, blood pressure and temperature measurement, and ECG immediately after admission and, depending on type and severity of the infarct, a repeated CT or MRI after 1 to 7 days to assess final infarct volume. Doppler/duplex sonography was performed, usually within 24 hours. Blood pressure was maintained within systolic values of 140 to 190 mm Hg by means of colloidal or starch infusion or, if elevated, by calcium antagonists or urapidil. Patients without contraindications received thrombolysis with recombinant tissue plasminogen activator within 3 hours. Heparin was administered intravenously in an unfractionated dose-adjusted manner in cases with presumed high stroke recurrence risk or low-flow conditions (atrial fibrillation, high-grade carotid stenosis, dissection) or with unfractionated heparin according to local stroke treatment guidelines.

Exclusion criteria were hemorrhagic stroke, subarachnoid hemorrhage, transient ischemic attacks (TIAs), and cerebral sinus thrombosis. Stroke etiologies were defined according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST).²⁰

End points were as follows: (1) in-hospital case mortality rate; (2) motor impairment, assessed by the Canadian Neurological Scale (CNS)²¹; (3) length of hospital stay; (4) requirement of intensive care; (5) clinical course within the first 72 hours after admission, derived from the medical record; (6) in-hospital complications (eg, pneumonia, urinary tract infection, recurrent stroke, hemorrhage); and (7) Rankin Scale score at follow-up (3 months after stroke).

Cardiovascular risk factors were as follows: hypertension (blood pressure 140/90 mm Hg,²² known or treated hypertension); peripheral vascular disease (intermittent claudication, ischemic rest pain, stenosis); ischemic heart disease (angina pectoris, previous myocardial infarction, coronary artery stenosis); lipid elevation (cholesterol >220 mg/dL, triglyceride elevation, or any lipid-lowering medication on admission); and atrial fibrillation (arrhythmia with no P wave on ECG, intermittent atrial fibrillation on Holter ECG, or known atrial fibrillation).

After discharge, patients were contacted by mail or telephone after at least 3 months to determine final outcome and were assessed by the Rankin score.²³

After data acquisition, diabetic stroke patients were stratified into 2 groups: a group that used sulfonylurea drugs and a group that did not.

Statistical Analysis
Frequencies and univariate comparisons were analyzed by ² test for dichotomous variables and Wilcoxon U test for numeric variables. A backward stepwise logistic regression was used to correct for possible confounding factors for the end points. The following covariates were entered: sulfonylurea drug use, cardiovascular risk factors (hypertension, coronary artery disease, peripheral vascular disease, smoking, lipid elevation), age, sex, and stroke etiology.

	Results

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Of a total of 439 patients, 146 patients (33%) had diabetes and hemispheric stroke and were eligible for the study. Sixty patients were using sulfonylurea drugs at time of stroke onset as their only hypoglycemic drug.

The control group consisted of the remaining 86 diabetic stroke patients who did not use sulfonylurea drugs. The majority of these patients were treated with insulin, by diet alone, or with other oral glucose-lowering drugs such as acarbose or metformin. The majority of patients in the sulfonylurea group (53/60 [88%]) were treated with glibenclamide; 6 patients were treated with glimepiride and 1 with glibornuride. The mean daily dose of glibenclamide was 5.9±3.8 mg. The overall mortality of all diabetic stroke patients was 15 of 146 (10.3%), which was higher (but not significantly) than that in stroke patients without diabetes (18/293 [6.1%]; P=0.12).

The baseline characteristics of the 2 groups are shown in Table 1. There were no significant differences in the left/right distribution of the infarcts, cardiovascular risk factors (hypertension, ischemic heart disease, lipid elevation, smoking, TIAs), admission blood pressure, admission glucose and HbA_1c, and presumed stroke etiology according to TOAST criteria. There was a nonsignificant sex trend, with fewer women taking sulfonylurea drugs. The duration of diabetes was significantly longer in patients who were not using sulfonylurea drugs. The majority (71%) of patients in this group were using insulin.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Diabetic Stroke Patients With or Without Treatment With Sulfonylurea

The clinical end points are shown in Table 2. Mortality rate and stroke severity (as measured by the validated CNS, in which low numbers indicate severe motor hemiparesis²⁴) were not different between the groups. All deaths were directly stroke related (transtentorial herniation due to edema or secondary hemorrhage). End points of in-hospital outcome were also not significantly different in the univariate analysis. Rankin score at follow-up (0 to 1, independent patients; 2 to 5, patients who have restrictions in lifestyle or are dependent), frequency of intensive care unit treatment, type of infarct on CT or MRI, length of hospital stay, and percentage of patients who could be discharged home did not differ between the groups. There was a nonsignificant trend toward neurological improvement in the sulfonylurea group, and more patients without sulfonylurea drugs had a fixed neurological deficit within the first 3 days.

View this table: [in this window] [in a new window]   Table 2. Stroke Severity, CT/MRI, and In-Hospital Outcome of Diabetic Stroke Patients With or Without Treatment With Sulfonylurea

Next, a multivariate logistic regression analysis was performed to determine independent factors for death and severe stroke. For death, only smoking and the presence of peripheral vascular disease were independent predictors in the logistic regression. For severe stroke (as assessed by a CNS score <7), cardioembolism, lipid elevation, and peripheral vascular disease were independent predictors. Sulfonylurea drugs were not independent predictors for either end point (Table 3). For deteriorating stroke, only coronary artery disease and smoking were independent factors.

View this table: [in this window] [in a new window]   Table 3. Multivariate Analysis: Factors Influencing Death, Deteriorating Stroke, or Severe Stroke

To investigate other forms of preconditioning, we compared diabetic stroke patients with and without prodromal TIAs, as described.²⁵ Twenty-one patients had prodromal TIAs; these patients had fewer neurological deficits (mean CNS score, 8.2±2.3 versus 7.6±2.3; P=0.22) and an improved Rankin score (1.9±1.4 versus 3.2±1.8; P=0.07), but the differences were not significant.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In summary, we found no adverse in-hospital outcome of diabetic stroke patients who used sulfonylurea drugs before stroke. In addition, the in-hospital mortality rate was not increased in patients who used sulfonylurea drugs. This is in contrast to previous studies that showed increased mortality in this patient group.^8,26 However, other observations also showed no increased mortality,¹² and cardiological studies usually are not designed to examine stroke, death after stroke, or stroke severity as primary end point. In the study of Jollis et al,¹² the rate of cerebrovascular disease also was not different: 15% in diabetics treated with sulfonylurea and 20% in patients treated with insulin. The differences might also be due to different classes of sulfonylurea drugs: in earlier studies many patients used tolbutamide,¹⁰ in contrast to glibenclamide or other newer drugs such as glimepiride. One explanation of why some sulfonylurea drugs may have deleterious effects after stroke is that they may depolarize hypoxic neurons and favor neurotoxic cascades such as glutamate release and intracellular calcium increase. Experimental studies have also shown that ischemic tolerance in the brain is impaired by sulfonylurea drugs.^15,16 Additionally, as in the heart, there is now evidence that ischemic tolerance occurs in the human brain.^25,27 However, the relative action of sulfonylurea drugs depends on their ability to cross the blood-brain barrier, the receptor affinity, and spatial expression. Sulfonylureas bind to K_ATP, which is a hetero-octameric complex consisting of 8 subunits. K_ATP and sulfonylurea receptors are expressed in the human brain,^18,28 but whether K_ATP is involved in the regulation of vascular tone in the brain is not known. In humans, glibenclamide modulates peripheral vascular tone²⁹ but does not affect CO₂-induced cerebral vasodilation.³⁰

In addition to pharmacological concerns, methodological errors must be taken into account. Since our study was hospital based and stroke has a high mortality, we cannot rule out that stroke patients with sulfonylurea drugs die before reaching the hospital; this is a general problem of hospital-based studies that might also explain outcome differences after myocardial infarction.³¹

The mean dose of glibenclamide in the present study was lower than in other studies (5.9 versus 7.4 mg in the study of Klamann et al¹³). Therefore, we cannot exclude that a possible deleterious effect was missed because of relative underuse of sulfonylurea drugs or lower dosage in our group.

Another reason that a difference was not detected between the groups may be that the control group was too heterogeneous: these patients were treated with insulin, with diet alone, or with acarbose or metformin. In some patients diabetes was not previously recognized.

Another shortcoming of our retrospective study is that use of sulfonylureas may be underreported or missed in the acute stroke setting. Conversely, we also cannot exclude noncompliance. Both cases might reduce the difference between the groups and finally lead to failure to detect a possible adverse effect of sulfonylurea drugs.

Despite the limitations of our small study, we conclude that sulfonylurea drugs were not associated with increased mortality or adverse clinical outcome in patients with diabetes and ischemic stroke. Despite concerns about sulfonylurea drugs because of increased mortality and impairment of ischemic preconditioning, glibenclamide and derivatives seem to be safe and had no impact on the immediate outcome after stroke in our study population.

Received March 13, 2001; revision received May 18, 2001; accepted June 8, 2001.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Weih, M. Articles by Einhäupl, K. Search for Related Content PubMed PubMed Citation Articles by Weih, M. Articles by Einhäupl, K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Diabetes Stroke Related Collections Other diabetes Receptor pharmacology Acute Cerebral Infarction Risk Factors for Stroke