Stroke

Stroke is a major cause of morbidity and premature death in patients with diabetes. The majority of cases of stroke result from thromboembolic occlusion of cerebral arteries with a smaller percentage attributable to intracerebral haemorrhage. Risk factors including obesity, hypertension and dyslipidaemia, which are commonly present in patients with type 2 diabetes, contribute to the elevated risk of stroke. Patients with diabetes tend to have stroke at a younger age compared with the non-diabetic population; this risk is especially marked in patients with type 1 diabetes. Mortality is higher and functional outcomes are generally poorer following stroke in the presence of diabetes. Primary and secondary prevention relies on a comprehensive multi-factorial approach to risk factor modification.

Background

Diabetes mellitus is a modifiable risk factor for stroke.[1] Approximately 20% of patients with diabetes will die as a result of stroke, making this one of the leading causes of death for this population.[2] Symptom onset tends to occur at an earlier age in the presence of diabetes and functional outcomes are worse than for non-diabetics.[2] The increase in risk of ischaemic stroke is especially evident in the under-65 age group. While overall stroke incidence and mortality in developed countries has declined in recent decades the incidence of stroke in young adults has been increasing. Diabetes and obesity have been identified as risk factors for stroke in younger adults. The elevated risk of stroke in patients with type 1 diabetes is particularly evident in the second to fourth decades of life.[3]

The incidence of stroke – classically defined as an acute focal cerebral deficit with no apparent cause other than a vascular origin – is increased several-fold by the presence of diabetes. Estimates in patients with type 2 diabetes range from a 2- to 3-fold increase in men and a 2- to 5-fold increase in women for ischaemic stroke.[4][5] The higher excess risk of diabetes–associated stroke in women compared to men appears to be independent of sex-related differences in other major cardiovascular risk factors.[6] The magnitude of the risk increases with known duration of diabetes. The onset of symptoms tends to occur at an earlier age in the presence of diabetes and functional outcomes are worse.[2][7] Mortality is higher after stroke in patients with diabetes. The risk of post-stroke dementia is also increased by the presence of diabetes.[8]

Diabetes preferentially elevates the risk of ischaemic stroke resulting in a greater ischaemic-to-haemorrhagic stroke ratio compared with the general population. Haemorrhagic transformation of an ischaemic stroke is more common in diabetic patients and is a recognized unwanted effect of thrombolytic therapy.[9] Cerebrovascular transient ischaemic attacks (TIAs), which often herald a completed stroke, are also more common among patients with diabetes. Patients with diabetes tend to have a poorer prognosis after stroke compared with their non-diabetic counterparts.[1][2] Transient reversible hyperglycaemia is also associated with poorer functional recovery from ischaemic stroke.[10] Obesity and the features of the metabolic syndrome, notably hypertension, are associated with an increased risk of non-haemorrhagic stroke in the absence of diabetes.[1][11] In addition to vascular occlusive events and primary intracerebral haemorrhage reversible central neurological defects including hemiparesis may accompany not only hyperglycaemic emergencies, e.g. hyperosmolar non-ketotic hyperglycaemia but also iatrogenic hypoglycaemia.

In addition to hyperglycaemia additional risk factors for stroke, notably hypertension and dyslipidaemia, are frequently present in patients with type 2 diabetes.[7]

Epidemiological studies have demonstrated a small increase in the risk of stroke as a function of increasing glycated haemoglobin concentrations.[12] Obesity, diabetes and possibly other components of the metabolic syndrome[13] are associated with an increased prevalence of atrial fibrillation, itself a major cause of thromboembolic stroke.

Pathophysiology of stroke in diabetes

In experimental models of stroke, hyperglycaemia impairs cerebrovascular structure and function.[7][14] Cerebral oedema, neovascularization, expression of tissue proteases and altered vascular reactivity and tone have been described. Studies of the impact of acute hyperglycaemia in animal models of stroke have demonstrated larger cerebral infarcts and an increase in the risk of haemorrhagic transformation.[14] The extent to which these observations explain the higher risk of death and disability after stroke in patients with diabetes is uncertain.

Management of acute stroke in patients with diabetes

Hyperglycaemia occurs in about 30-40% of patients admitted with acute ischaemic stroke which may reflect pre-existing diabetes or stress hyperglycaemia. Patients with either diabetes or transient hyperglycaemia experiencing an acute ischaemic stroke are more likely to die or be severely disabled and less likely to benefit from intravenous tissue plasminogen activator.[7]

The risk-to-benefit ratio of controlling blood glucose using insulin in the context of acute stroke remains uncertain. A recently updated meta-analysis of randomized controlled of intravenous insulin with the objective of maintaining blood glucose within a specific range in the first hours of acute ischaemic stroke did not show benefit in terms of functional outcome, death, or improvement in final neurological deficit.[15] Moreover, this approach significantly increased the number of episodes of hypoglycaemia.[15]In the US, guidelines now exist for the evaluation and management of patients with diabetes and ischaemic stroke or TIA that are similar for non-diabetic patients.[16] It has also been recommended that all people admitted with acute stroke should have a blood glucose determination and hyperglycaemia should be treated with subcutaneous insulin but if glucose levels remain high, intravenous insulin infusion can be used initially for the first 24-48 hours.

Experimental therapies under evaluation as adjunctive neuroprotective therapies include dipeptidyl peptidase-4 inhibitors,[17] the glucagon-like-1 receptor agonist class of glucose-lowering agents.[18]

Primary and secondary prevention of stroke in patients with diabetes

Stroke can threaten independence, self-care capacity and quality of life and its prevention should be a major public health target. Clinical guidelines are available for the primary prevention of stroke.[19] For patients with diabetes healthy lifestyle measures, blood pressure control, statin use and antiplatelet therapy should be addressed as part of a comprehensive strategy to reduce risk of cardiovascular morbidity and mortality.

To date, intensive long-term glycaemic control has not been shown to reduce the risk of stroke among patients with type 2 diabetes.[20] Glycaemic targets and therapeutic strategies for their attainment should be appropriate for the particular circumstances and life expectancy of the individual patient.[21]

References

  1. ^ Kurukulasuriya LR, Govindarajan G, Sowers J. Stroke prevention in diabetes and obesity. Expert Rev Cardiovasc Ther 2006;4:487-502.

  2. ^ Phipps MS, Jastreboff AM, Furie K, Kernan WN. The diagnosis and management of cerebrovascular disease in diabetes. Curr Diab Rep 2012;12:314-23.

  3. ^ Sundquist K, Li X. Type 1 diabetes as a risk factor for stroke in men and women aged 15-49: a nationwide study from Sweden. Diabet Med 2006;23:1261-7.

  4. ^ Lehto S, Ronnemaa T, Pyorala K, Laakso M. Predictors of stroke in middle-aged patients with non-insulin-dependent diabetes. Stroke 1996;27:63-8.

  5. ^ Karapanayiotides T, Piechowski-Jozwiak B, van Melle G, Bogousslavsky J, Devuyst G. Stroke patterns, etiology, and prognosis in patients with diabetes mellitus. Neurology 2004;62:1558-62.

  6. ^ Peters SA, Huxley RR, Woodward M. Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes. Lancet 2014;383:1973-80.

  7. ^ Ergul A, Kelly-Cobbs A, Abdalla M, Fagan SC. Cerebrovascular complications of diabetes: focus on stroke. Endocr Metab Immune Disord Drug Targets 2012;12:148-58.

  8. ^ Biessels GJ, Strachan MW, Visseren FL, Kappelle LJ, Whitmer RA. Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions. The lancet Diabetes & endocrinology 2014;2:246-55.

  9. ^ Khatri P, Wechsler LR, Broderick JP. Intracranial hemorrhage associated with revascularization therapies. Stroke 2007;38:431-40.

  10. ^ Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001;32:2426-32.

  11. ^ Maruyama K, Uchiyama S, Iwata M. Metabolic syndrome and its components as risk factors for first-ever acute ischemic noncardioembolic stroke. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2009;18:173-7.

  12. ^ Zhang Y, Hu G, Yuan Z, Chen L. Glycosylated hemoglobin in relationship to cardiovascular outcomes and death in patients with type 2 diabetes: a systematic review and meta-analysis. PLoS ONE 2012;7:e42551.

  13. ^ Menezes AR, Lavie CJ, Dinicolantonio JJ, et al. Cardiometabolic risk factors and atrial fibrillation. Rev Cardiovasc Med 2013;14:e73-81.

  14. ^ Ergul A, Li W, Elgebaly MM, Bruno A, Fagan SC. Hyperglycemia, diabetes and stroke: focus on the cerebrovasculature. Vascul Pharmacol 2009;51:44-9.

  15. ^ Bellolio MF, Gilmore RM, Ganti L. Insulin for glycaemic control in acute ischaemic stroke. Cochrane Database Syst Rev 2014;1:CD005346

  16. ^ Jauch EC, Saver JL, Adams HP, Jr., et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870-947.

  17. ^ Magkou D, Tziomalos K. Antidiabetic treatment, stroke severity and outcome. World journal of diabetes 2014;5:84-8.

  18. ^ Holscher C. Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases. J Endocrinol 2014;221:T31-41.

  19. ^ Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:3754-832.

  20. ^ Marso SP, Kennedy KF, House JA, McGuire DK. The effect of intensive glucose control on all-cause and cardiovascular mortality, myocardial infarction and stroke in persons with type 2 diabetes mellitus: a systematic review and meta-analysis. Diab Vasc Dis Res 2010;7:119-30.

  21. ^ International Diabetes Federation Clinical Guidelines Task Force. Global guidance for type 2 diabetes. [http://www.idf.org/sites/default/files/IDF T2DM Guideline.pdf. 2012.](http://www.idf.org/sites/default/files/IDF T2DM Guideline.pdf. 2012. "http://www.idf.org/sites/default/files/IDF T2DM Guideline.pdf. 2012.")

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