Neuroprotective effect of sulfonylurea drugs for people with ischemic stroke

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To evaluate the neuroprotective effect of sulfonylurea drugs for people with ischemic stroke.

Background

Description of the condition

Globally, stroke is the second most common cause of death and a major cause of impairment and disability (WHO 2020). Large hemispheric infarction is the most malignant type of supratentorial ischemic stroke, which is caused by occlusion of the internal carotid or middle cerebral artery. Because of the fatal intracranial edema, mortality of large hemispheric infarction fluctuates between 53% to 78% after the strongest medical treatment (Hacke 1996; Hofmeijer 2009; Jüttler 2007; Vahedi 2007; Zhao 2012). Decompressive craniectomy is the only proven method which can decrease mortality by around 17% to 36%, according to randomized controlled trials (RCTs) (Frank 2014; Geurts 2013; Hofmeijer 2009; Jüttler 2007; Vahedi 2007; Zhao 2012). However, the neurological outcomes are not satisfactory, and not all patients can receive surgery (Su 2016). Hypothermia was considered to be a very hopeful method to improve outcomes; preclinical trials demonstrated that hypothermia had the effects of neuroprotection and intracranial pressure reduction (van der Worp 2007). But it causes many complications in patients (Su 2016). Research shows that hypothermia may have no effect on mortality and an unclear effect on neurological outcome for people with ischemic stroke (Den Hertog 2009; Lakhan 2012; Neugebauer 2019).

Recently, studies have suggested that sulfonylurea drugs may have a neuroprotective effect, thereby improving neurological outcome. Research has shown that glibenclamide could reduce mortality and brain edema, and improve neurological outcome in animal models of ischemic stroke (Simard 2006; Simard 2009; Simard 2012a). Some clinical trials have also shown positive outcomes (Huang 2019; Kunte 2007; Kunte 2012; Sheth 2016). Sulfonylureas may be a promising treatment in people with large hemispheric infarction.

Description of the intervention

Sulfonylureas are antidiabetic medications and are widely used in people with type II diabetes who still have a certain insulin secreting function. They can stimulate the secretion of insulin by pancreatic beta‐cells, increase the level of insulin in the portal vein, inhibit hepatic glycogenolysis and gluconeogenesis, and increase insulin sensitivity and glucose utilization in the extrapancreas. Sulfonylureas mainly combine to the sulfonylurea receptor (SUR) of a beta‐cell and act on the adenosine triphosphate‐sensitive potassium channel (KATP) to regulate insulin secretion. Current research on the neuroprotective effects of sulfonylureas is mainly focused on glibenclamide and glimepiride.

Glimepiride has the same basic structure as glibenclamide. Both can induce depolarization of beta‐cells by inhibiting SUR1‐regulated KATP (SUR1‐Kir6.2) channels, and open calcium channels to increase intracellular calcium concentration and to stimulate insulin release through exocytosis. In addition, glibenclamide and glimepiride can also combine specifically to 65 kDa protein in the beta‐cell membrane to directly enhance calcium‐dependent insulin secretion (Kramer 1994). Glimepiride stimulates glucose utilization by increasing the number of glucose transfer molecules in muscle cells and adipocytes, increasing the activity of glycosyl‐phospholipyl‐specific phospholipase C, and decreasing cyclic adenosine monophosphate levels and protein kinase A activity (Müller 1994). Glimepride also has an effect on improving insulin resistance compared to glibenclamide (Emini‐Sadiku 2019).

Glibenclamide and glimepiride have similar efficacy in lowering glucose, but the dose of glimepiride is smaller (Draeger 1996; Korytkowski 2004). Adverse effects include hypoglycemia, diarrhea, nausea, vomiting, headache, stomach ache, rash, etc. Rare and serious adverse effects include liver function disorder and bone marrow suppression. Studies have found that severe hypoglycemia occurred 1.7 to 6.5 times more frequently with glibenclamide than with glimepiride (Holstein 2001; Leonard 2018; Manuel 2009; Xu 2010). Moreover, sulphonylureas may reduce the response to ischemia due to the effect of cardiac potassium channels (SUR2A). Glibenclamide has been associated with increased all‐cause mortality and cardiovascular mortality in type 2 diabetes (Khalangot 2009; Raee 2017; Simpson 2015), while glimepiride had little adverse cardiovascular effects because of the lower binding affinity for cardiac potassium channels (Massi‐Benedetti 2003). A recent study implied that sulfonylureas, especially gliclazide, are associated with reduced out‐of‐hospital cardiac arrest in diabetes (Eroglu 2021).

How the intervention might work

SUR1 is an adenosine triphosphate‐binding cassette which serves as the regulatory subunit of two different ion channels. The KATP channel contains SUR subunits (SUR1, SUR2A or SUR2B) and Kir subunits (Kir 6.1 or Kir 6.2). Different KATPs are composed of different combinations of the subunits, which are present in the pancreas, heart or brain. The octameric KATP channel, which contains four SUR1 subunits and four Kir6.2 subunits, is expressed in the brain (Aittoniemi 2009; Bryan 2007; Burke 2008). Opening of the KATP channel will hyperpolarize the cells (Yamada 2005). SUR1 also co‐associates with the transient receptor potential melastatin 4 (TRPM4) forming the SUR1‐TRPM4 channel, which is also called the SUR1‐regulated nonselective cation Ca‐adenosine triphosphate channel (Woo 2013). Its opening depolarizes the cells. The SUR1‐TRPM4 channel is associated with cytotoxic edema, delayed hemorrhage and death of necrotic cells after injury (Simard 2012b; Simard 2012c). After focal ischemia, SUR1 is transcriptionally upregulated in neurons, astrocytes, oligodendrocytes, and microvascular endothelial cells in animal models (Simard 2006; Simard 2010), and humans (Mehta 2013). The upregulation of SUR1 is parallel to that of TRPM4 (Loh 2014), and is associated with transcriptionally upregulated expression of SUR1–TRPM4 channels after central nervous system injury (Simard 2006).

Sulfonylureas such as glibenclamide are potent pharmacological inhibitors of SUR1. Experimental studies indicate that glibenclamide substantially alleviates edema and tissue necrosis, attenuates the inflammatory response, and prevents delayed capillary fragmentation and hemorrhage; this may be achieved by blocking the SUR1‐TRPM4 channels (Caffes 2015; Sheth 2018; Simard 2006), and the KATP channels (Nisticò 2007; Ortega 2012). Current clinical evidence also suggests that glibenclamide has therapeutic effects in ischemic stroke (Huang 2019; Sheth 2016; Vorasayan 2019). It may have a neuroprotective effect by reducing brain water accumulation, so as to reduce brain swelling. Patients may have a better modified Rankin Scale score and lower mortality risk (Huang 2019). Glibenclamide can reach the acidic ischemic tissues under a lower dose due to its weak acidity (Simard 2006), greatly lowering the risk of hypoglycemia (King 2018).

Why it is important to do this review

Large hemispheric infarction is the most malignant type of supratentorial ischemic stroke and causes high mortality and poor long‐term disability. It causes cerebral edema, which can lead to intracranial hypertension and even herniation. Treatment options for large hemispheric infarction are limited. Osmotherapy is used in standard practice, and decompressive craniectomy is the only proven method that can decrease the mortality risk. However, there are contraindications to surgery, the cost is high, and the neurological outcomes are not satisfactory. Hypothermia shows exciting effects in preclinical trials, but it can cause many complications and unsatisfactory result in patients. Sulfonylureas have been used safely in people with type II diabetes for decades. It is easily obtained, inexpensive, and has few complications. It may now be a very promising drug for the treatment of severe ischemic stroke to improve neurological outcomes. In this review, we will evaluate the neuroprotective effect of sulfonylureas on people with severe ischemic stroke, and clarify the best way to use them. It will provide the most comprehensive evidence for the management of severe ischemic stroke and a new direction for future research.

Objectives

To evaluate the neuroprotective effect of sulfonylurea drugs for people with ischemic stroke.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized controlled trials (RCTs).

Types of participants

We will include people with severe hemispheric ischemic stroke (typically with a National Institute of Health Stroke Scale (NIHSS) score > 7). Ischemic stroke is diagnosed by clinical ischemic insults and confirmed by head computerized tomography or magnetic resonance imaging. There are no limitations for age or gender.

Types of interventions

We will include trials comparing sulfonylurea drugs with placebo/hypothermia/usual care/other. The intervention is any sulfonylurea drug, including glibenclamide, glimepiride, glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, tolbutamide, tolazamide, acetohexamide, carbutamide, and chlorpropamide. Sulphonylurea drugs will be given in addition to usual care. There are no limits on dose or mode of delivery.

Types of outcome measures

Primary outcomes

1. Neurological outcome, measured by NIHSS or equivalent at:

   1. three months;

   2. more than three months.

2. Functional outcome, measured by modified Rankin Scale (mRS) or equivalent at:

   1. three months;

   2. more than three months.

Secondary outcomes

1. Death

2. Quality of life, using any validated instrument

3. Adverse events: all adverse events reported, with hypoglycemia being of main interest

4. Complications: early neurological deterioration, hemorrhagic transformation, secondary infarction, and pneumonia

Search methods for identification of studies

See the 'Specialized register' section on the Cochrane Stroke Group website (apps.ccbs.ed.ac.uk/csrg/entity/searchmethods.pdf). We will search for trials published in all languages and arrange translation of relevant papers published in languages other than English. In addition, we will search the Chinese literature to reduce language bias.

Electronic searches

We will search the Cochrane Stroke Group's Trials Register and the following bibliographic databases and trials registers.

• Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library

• Cochrane Database of Systematic Reviews (CDSR), in the Cochrane Library

• MEDLINE (Ovid; from 1946)

• Embase Medline (Embase; from 1974)

• PubMed

• China Biological Medicine Database (CBM; from 1978) (www.sinomed.ac.cn/index.jsp)

• China National Knowledge Infrastructure (CNKI; from 1979) (oversea.cnki.net/index/)

• Web of Science (from 1985)

The subject search strategies for databases included in this review will be designed by our institution’s Medical Subject Librarian and the Cochrane Stroke Group’s Information Specialist (Appendix 1). We will combine all search strategies deployed with subject strategy adaptations of the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying RCTs in MEDLINE: sensitivity‐maximizing version (2008 revision), as described in boxes 3.c and 3.d in the Technical Supplement to Chapter 4 of The Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2021).

We will search the following ongoing trials registers:

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.ClinicalTrials.gov).

• Chinese Clinical Trial Registry (www.chictr.org.cn/searchproj.aspx).

• International Standard Randomized Controlled Trials Number (ISRCTN) Registry (www.isrctn.com/)

Searching other resources

In an effort to identify further published, unpublished, and ongoing trials, we will check the bibliographies of included studies and any relevant systematic reviews identified, and use Cited Reference Search within Google Scholar (scholar.google.co.uk/). Furthermore, we will also search grey literature sources: British Library EthOS (ethos.bl.uk/Home.do;jsessionid=B7B5592D49E2A382F87F7FC322AA3BCB), and ProQuest Dissertations and Theses (about.proquest.com/en/dissertations/).

Data collection and analysis

Selection of studies

Two review authors (FL and WT) will independently screen titles and abstracts of the references obtained as a result of our searching activities and will exclude obviously irrelevant reports. We will retrieve the full‐text articles for the remaining references and two review authors (FL and WT) will independently screen the full‐text articles and identify studies for inclusion, recording reasons for exclusion of the ineligible studies. We will resolve any disagreements through discussion or, if required, we will consult a third review author (BX). We will collate multiple reports of the same study so that each study, not each reference, is the unit of interest in the review. We will record the selection process and complete a PRISMA flow diagram.

Data extraction and management

Two review authors (FL and WT) will independently extract data from included studies as follows: methods, characteristics of participants, interventions, and primary and secondary outcomes. If the two review authors have any disagreements on data extraction, the full review team will discuss the disagreements and make a final decision. We will contact the original study authors for information when absent in the full text. For dichotomous data, we will extract the number of participants experiencing the event and the total number of participants in each arm of the trial. For continuous data, we will extract the mean value and standard deviation (SD) for the changes in each arm of the trial, along with the total number in each group.

Assessment of risk of bias in included studies

Two review authors (FL and WT) will independently assess risk of bias for each study using the criteria outlined in the Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). We will resolve any disagreements by discussion or by involving another author (BX). We will assess the risk of bias according to the following domains.

• Random sequence generation

• Allocation concealment

• Blinding of participants and personnel

• Blinding of outcome assessment

• Incomplete outcome data

• Selective outcome reporting

• Other bias

We will grade the risk of bias for each domain as high, low or unclear and provide information from the study report together with a justification for our judgment in the risk of bias tables.

Measures of treatment effect

For dichotomous data (e.g. death, pneumonia), we will calculate effect sizes as risk ratios (RRs) with 95% confidence intervals (CIs). For continuous data (e.g. NIHSS), we will convert data into mean differences (MDs) and present these with 95% CIs. In the event of missing summary data, such as missing SDs, we will obtain these, where possible, using calculations provided in Chapter 6: Choosing effect measures and computing estimates of effect in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). We will extract both change scores (i.e. change from baseline) and final values. We will incorporate studies with change from baseline outcomes into a meta‐analysis with studies with final measurement outcomes by using the (unstandardized) mean difference method in RevMan Web (RevMan Web 2022).

Unit of analysis issues

We will assess the level of randomization for all included studies. For studies with nonstandard designs (e.g. multiple‐arm studies), we will manage the data following the advice in the Chapter 6: Choosing effect measures and computing estimates of effect in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022).

Dealing with missing data

We will conduct a complete case analysis as far as possible on an intention‐to‐treat basis for all outcomes, according to the methods described in the Chapter 10: Analysing data and undertaking meta‐analyses in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). In the case of missing data on dropouts, withdrawals, and outcome measures, we will make efforts to contact the original study authors or sponsors to request the required information, where appropriate. When this is not possible, we will consider both best‐case and worst‐case scenarios for dichotomous data (e.g. death), as sensitivity analyses.

Assessment of heterogeneity

We will follow the rough guide to interpretation of heterogeneity suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022, taking the value of I² as one factor to identify and measure heterogeneity, which is:

• 0% to 40% might not be important;

• 30% to 60% may represent moderate heterogeneity;

• 50% to 90% may represent substantial heterogeneity; and

• ≥ 75% considerable heterogeneity.

If there is substantial heterogeneity, we will explore the individual trial characteristics to identify potential sources of heterogeneity by subgroup analysis.

Assessment of reporting biases

We will construct funnel plots for all outcomes to assess the potential existence of small‐study bias and reporting bias, if 10 or more included studies contain data for the outcome. If not, we will assess reporting bias qualitatively.

Data synthesis

Where we consider studies to be sufficiently similar, we will conduct a meta‐analysis by pooling the appropriate data using RevMan Web (RevMan Web 2022). We will use a random‐effects model in the presence of substantial heterogeneity; otherwise, we will use a fixed‐effect model for meta‐analysis.

Subgroup analysis and investigation of heterogeneity

Providing there is a sufficient number of studies (e.g. at least one study in two distinctive subgroups for any of outcome), we will perform subgroup analyses for the primary outcome by:

• oral versus intravenous administration;

• lower dose versus higher dose;

• adults versus children;

• different sulfonylurea drugs;

• different comparators.

We will evaluate differences between subgroups using the test for subgroup differences in RevMan Web (RevMan Web 2022).

Sensitivity analysis

We will conduct sensitivity analyses by excluding studies:

• with inadequate allocation concealment;

• which were unpublished;

• in which loss to follow‐up was not reported or was more than 10%;

• in which the funder played an important role that may affect the primary outcome.

We will perform both best‐case and worst‐case scenarios to explore the impact of incomplete or missing data for dichotomous outcomes. For continuous outcomes, we will assume a fixed difference between the mean values of missing data and the measured outcome data. We will use both fixed‐effect and random‐effects models to investigate the influence of small‐study effect.

Summary of findings and assessment of the certainty of the evidence

We will create a summary of findings table using the following outcomes: neurological outcome (NIHSS) at three months and more than three months, functional outcome (mRS) at three months and more than three months, death, hypoglycemia, early neurological deterioration, and pneumonia (Table 1). We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence as it relates to the studies that contribute data to the meta‐analyses for the prespecified outcomes (Atkins 2004). We will use the methods and recommendations described in Chapter 14: Completing ‘Summary of findings’ tables and grading the certainty of the evidence in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022), and the GRADE handbook (Schünemann 2013), and use the GRADEproGDT software (GRADEpro GDT). We will justify all decisions to downgrade the certainty of evidence using footnotes, and we will make comments to aid the reader's understanding of the review where necessary.

1. Template for summary of findings table.

Sulfonylurea compared with control interventions for people with ischemic stroke
Patient or population: people with ischemic stroke (NIHSS of > 7) Settings: hospital Intervention: sulfonylurea Comparison: placebo/hypothermia/usual care/other
Outcomes		Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
		Assumed risk	Corresponding risk
		Control	Sulfonylurea
Neurological outcome (NIHSS or equivalent)	at 3 months
	more than 3 months
Functional outcome (mRS or equivalent)	at 3 months
	more than 3 months
Death during follow‐up
Hypoglycemia during follow‐up
Early neurological deterioration during follow‐up
Pneumonia during follow‐up
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; mRS: modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.

Appendices

Appendix 1. Ovid MEDLINE(R) ALL

1. cerebrovascular disorders/ or basal ganglia cerebrovascular disease/ or brain ischemia/ or exp brain infarction/ or hypoxia‐ischemia,brain/ or carotid artery diseases/ or carotid artery thrombosis/ or carotid artery, internal, dissection/ or intracranial arterial diseases/ or cerebral arterial diseases/ or infarction, anterior cerebral artery/ or infarction, middle cerebral artery/ or infarction, posterior cerebral artery/ or exp "intracranial embolism and thrombosis"/ or exp stroke/ or vertebral artery dissection/

2. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$)).tw.

3. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$)).tw.

4. 1 or 2 or 3

5. exp Sulfonylurea Compounds/

6. Sulfonylurea Compounds/ or Sulfonylurea Receptors/

7. (sulfonurea or sulfonyl urea or sulfonylcarbamide or sulphonurea or sulphonylurea).mp.

8. (acetohexamide or carboxytolbutamide or carbutamide or chlorpropamide or diabiphage or gliamilide or glibenclamide or glibornuride or glibutimine or glicaramide or gliclazide or glicondamide or gliflumide or glimepiride or glipalamide or glipentide or glipizide or glipizide plus metformin or gliquidone or glisamuride or glisolamide or glisoxepide or glucosulfa or glybuthiazol or glybuzole or glycyclamide or glyhexamide or glyoctamide or glyparamide or glypinamide or glyprothiazol or glysobuzole or hydroxyhexamide or hydroxytolbutamide or metahexamide or tolazamide or tolbutamide).mp.

9. randomized controlled trial.pt.

10. controlled clinical trial.pt.

11. randomized.ab.

12. placebo.ab.

13. drug therapy.fs.

14. randomly.ab.

15. trial.ti.

16. groups.ab.

17. 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16

18. exp animals/ not humans.sh.

19. 17 not 18

20. 5 or 6 or 7 or 8

21. 4 and 19 and 20

Contributions of authors

Drafting the protocol: Linlin Fan, Jin Xu, Tao Wang, Xuesong Bai, Wuyang Yang
Developing the search strategy: Jin Xu, Linlin Fan, Kun Yang

Sources of support

Internal sources

• No sources of support provided

External sources

• No sources of support provided

Declarations of interest

Linlin Fan: none known

Jin Xu: none known

Tao Wang: none known

Kun Yang: none known

Xuesong Bai: none known

Wuyang Yang: none known

New