Diabetes as a Risk Factor in Atherosclerotic Cerebrovascular Disease Tim Bodnar Diabetes mellitus (DM) has been described as an epidemic in progress. By 2050 its prevalence among adults in the United States is predicted to increase from 1 in 10 to 1 in 5. Additionally, in the adolescent population its incidence is on the rise. DM results from either the absolute deficiency of insulin (type 1 [T1DM]) or resistance to the action of insulin (type 2 [T2DM]). The diagnosis of T2DM is confirmed by two levels of fasting blood glucose (BG) higher than 126 mg/dL, by a 2-hour postprandial glucose of 200 mg/dL, and by the newer criteria of hemoglobin A1c (A1c) 6.5% or higher. Two different abnormal criteria together can also make the diagnosis. In stroke, as with other medical or surgical illnesses, high BG levels can occur without a history of DM. In the recent VISTA (Virtual International Stroke Trials Archive) analysis, 43% of stroke patients had admission hyperglycemia and 36% of those with elevated BG levels had no history of DM. This stress hyperglycemia is postulated to be either a protective mechanism during early stroke or an epiphenomenon that reflects the size and severity of a stroke. Conversely, numerous reports link hyperglycemia to poor stroke outcome in both DM and stress hyperglycemia. The health burden of DM is related to its microvascular and macrovascular complications. Cardiovascular disease (CVD) is increased two- to threefold in persons with DM, independent of other risk factors, and stroke and coronary artery disease are major causes of death and morbidity, especially in those older than 65 years. In T1DM, CVD occurs 10 to 12 years after the initial diagnosis, but in T2DM it can occur as early as in the prediabetes stage. Although CVD is not as extensively studied in T1DM, its presence is often reported with nephropathy. In T2DM the presentation spectrum is wide. Diabetes and Cerebrovascular Disease Patients with DM have an increased risk of cerebral infarctions. Prospective epidemiologic data have found the incidence of ischemic stroke to be two- to threefold higher in DM, independent of other risk factors. Other risk factors include hypertension, hyperlipidemia, atrial fibrillation, and obesity and are found to be additive. Women with DM have a higher stroke risk than men. Stroke Characteristics in Diabetes In both T1DM and T2DM, the commonest stroke phenotype is an ischemic stroke. The lacunar (small cerebral artery) subtype is consistently the most common, especially multiple lacunar strokes. Hemorrhagic strokes are six times less common, and subarachnoid hemorrhages are rare in this population. Although carotid and basilar artery occlusion are a complication of the heavy burden of atherosclerotic disease in DM, large-vessel infarcts are less common. In some studies A1c is independently related to the severity of carotid occlusion as well as to macroalbuminuria. The incidence of transient ischemic attacks (TIAs) in DM is variably reported, though the majority find a low incidence. It is postulated that irreversible and permanent damage caused by hyperglycemic neuronal changes lead to strokes rather than TIAs. Ischemic strokes in the setting of hyperglycemia are at high risk for hemorrhagic transformation, especially with reperfusion therapy. Various BG cutoffs ranging over 150 mg/dL are reported to increase this risk. DM patients also have a high incidence of stroke mortality, early recurrence, and physical disability, especially with brain stem or cerebellar infarction. Pathophysiology of Stroke in Diabetes and Hyperglycemia Although classified as a macrovascular complication, DM causes both extracranial atherosclerotic and cortical microangiopathic changes. Carotid occlusion is common, especially in the elderly. Endothelial damage from subclinical inflammation of the vessel wall (high levels of interleukin [IL]-6, tumor necrosis factor [TNF], and TNF-α), oxidative stress increasing reactive oxygen species, lipoprotein oxidation, altered platelet aggregation, inhibition of fibrinolysis, and hypercoagulability are some vasculature features in DM. Prolonged hyperglycemia increases permanent glycosylation end products. Vessel wall reactivity to nitric oxide (NO) and free radical production is altered. The brain microvasculature is also damaged by hyalinosis and altered glucose oxidation, all these factors contributing to arterial damage. An acute ischemic event is usually mitigated by collateral circulation. The irreversibly damaged central area is surrounded by the hypoperfused penumbra within which viable cells switch to anaerobic respiration. Early hyperglycemia is favorable to this process, but if perfusion is not restored, continued production and accumulation of lactate leads to cell death, enlarging the infarct. Initial use of intravenous insulin is reported to have multifactorial benefits that include stress hormone reduction and vessel wall relaxation, which lower blood pressure (BP). Prevention of Stroke in Patients with Diabetes In DM, primary and secondary prevention of cerebrovascular disease requires a multifactorial approach. The STENO-2 study has unequivocally shown that controlling BG and additional risk factors addressed later results in a greater reduction of cerebrovascular events and overall CV mortality. Glycemic Control Although there is strong evidence for a reduction in microvascular complications (nephropathy, neuropathy, and retinopathy) with intensive glycemic control in T1DM and T2DM, true benefit in preventing macrovascular complications (coronary artery disease, stroke, and peripheral arterial disease) is less certain. Intensive BG control is reported to have some long-term benefit in minimizing macrovascular complications only if it is implemented early in the course of T1DM and possibly for T2DM. However, intensive control in older adults with T2DM was not clearly shown to prevent CV outcomes. In fact, studies raise the concern for a high rate of hypoglycemia and increased mortality, although the two were not definitively linked. The American Diabetes Association (ADA) therefore suggests target A1c of less than 7% for most adults with DM but an appropriately lower A1c goal of less than 8% for adults with advanced microvascular or macrovascular disease, the elderly, and those with significant comorbidities and/or a limited life expectancy. Therefore, stroke patients (focusing on secondary prevention) with DM should have a target A1c between 7% and 8%. T1DM BG targets are achieved with intensive insulin therapy: either multiple daily injections (one injection of basal insulin [glargine, detemir, NPH] and multiple injections of prandial insulin [lispro, aspart and glulisine]) or a continuous subcutaneous insulin infusion (insulin pump), both ideally managed by an endocrinologist. T2DM BG targets are usually achieved with a combination of oral and injectable agents. Some agents are preferable in stroke patients. Studies have linked metformin to CV benefits, independent of its BG-lowering ability. It is now considered first-line therapy for T2DM, but kidney function must be evaluated before metformin is used. When metformin monotherapy becomes inadequate, addition of a second oral agent, either a sulfonylurea, dipeptidyl peptidase 4 (DPP-4) inhibitor, or thiazolidinedione (TZD), can achieve further A1c reduction (roughly 1% for each additional medication). Sulfonylureas are effective but can cause prolonged hypoglycemia and therefore must be used cautiously in the elderly. Pioglitazone, a TZD, might have additional benefits in secondary prevention of CV events; however, weight gain, edema, and growing concern about increased risk of fractures and bladder cancer limit its use. The other TZD, rosiglitazone, was withdrawn in Europe and is highly restricted in the United States because of elevated risk of myocardial infarction. DPP-IV inhibitors are newer drugs and when used alone have a low risk of hypoglycemia, but they are contraindicated in pancreatic disorders. Initiating insulin therapy in T2DM need not wait for failure of BG control on multiple oral agents. Insulin may be added to an oral agent, and a stepwise progression is recommended, starting with basal insulin and later adding short-acting insulin at one meal (basal plus), then at multiple meals as required for controlling hyperglycemia. Only gold members can continue reading. Log In or Register to continue Share this:Click to share on Twitter (Opens in new window)Click to share on Facebook (Opens in new window) Related Related posts: Embolic Protection Devices to Prevent Stroke during Percutaneous Angioplasty and Stenting Management of Acute Limb Ischemia Complicating Aortic Reconstruction Treatment of Dyslipidemia and Hypertriglyceridemia Intraoperative Assessment of the Technical Adequacy of Carotid Endarterectomy Stay updated, free articles. 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Diabetes as a Risk Factor in Atherosclerotic Cerebrovascular Disease Tim Bodnar Diabetes mellitus (DM) has been described as an epidemic in progress. By 2050 its prevalence among adults in the United States is predicted to increase from 1 in 10 to 1 in 5. Additionally, in the adolescent population its incidence is on the rise. DM results from either the absolute deficiency of insulin (type 1 [T1DM]) or resistance to the action of insulin (type 2 [T2DM]). The diagnosis of T2DM is confirmed by two levels of fasting blood glucose (BG) higher than 126 mg/dL, by a 2-hour postprandial glucose of 200 mg/dL, and by the newer criteria of hemoglobin A1c (A1c) 6.5% or higher. Two different abnormal criteria together can also make the diagnosis. In stroke, as with other medical or surgical illnesses, high BG levels can occur without a history of DM. In the recent VISTA (Virtual International Stroke Trials Archive) analysis, 43% of stroke patients had admission hyperglycemia and 36% of those with elevated BG levels had no history of DM. This stress hyperglycemia is postulated to be either a protective mechanism during early stroke or an epiphenomenon that reflects the size and severity of a stroke. Conversely, numerous reports link hyperglycemia to poor stroke outcome in both DM and stress hyperglycemia. The health burden of DM is related to its microvascular and macrovascular complications. Cardiovascular disease (CVD) is increased two- to threefold in persons with DM, independent of other risk factors, and stroke and coronary artery disease are major causes of death and morbidity, especially in those older than 65 years. In T1DM, CVD occurs 10 to 12 years after the initial diagnosis, but in T2DM it can occur as early as in the prediabetes stage. Although CVD is not as extensively studied in T1DM, its presence is often reported with nephropathy. In T2DM the presentation spectrum is wide. Diabetes and Cerebrovascular Disease Patients with DM have an increased risk of cerebral infarctions. Prospective epidemiologic data have found the incidence of ischemic stroke to be two- to threefold higher in DM, independent of other risk factors. Other risk factors include hypertension, hyperlipidemia, atrial fibrillation, and obesity and are found to be additive. Women with DM have a higher stroke risk than men. Stroke Characteristics in Diabetes In both T1DM and T2DM, the commonest stroke phenotype is an ischemic stroke. The lacunar (small cerebral artery) subtype is consistently the most common, especially multiple lacunar strokes. Hemorrhagic strokes are six times less common, and subarachnoid hemorrhages are rare in this population. Although carotid and basilar artery occlusion are a complication of the heavy burden of atherosclerotic disease in DM, large-vessel infarcts are less common. In some studies A1c is independently related to the severity of carotid occlusion as well as to macroalbuminuria. The incidence of transient ischemic attacks (TIAs) in DM is variably reported, though the majority find a low incidence. It is postulated that irreversible and permanent damage caused by hyperglycemic neuronal changes lead to strokes rather than TIAs. Ischemic strokes in the setting of hyperglycemia are at high risk for hemorrhagic transformation, especially with reperfusion therapy. Various BG cutoffs ranging over 150 mg/dL are reported to increase this risk. DM patients also have a high incidence of stroke mortality, early recurrence, and physical disability, especially with brain stem or cerebellar infarction. Pathophysiology of Stroke in Diabetes and Hyperglycemia Although classified as a macrovascular complication, DM causes both extracranial atherosclerotic and cortical microangiopathic changes. Carotid occlusion is common, especially in the elderly. Endothelial damage from subclinical inflammation of the vessel wall (high levels of interleukin [IL]-6, tumor necrosis factor [TNF], and TNF-α), oxidative stress increasing reactive oxygen species, lipoprotein oxidation, altered platelet aggregation, inhibition of fibrinolysis, and hypercoagulability are some vasculature features in DM. Prolonged hyperglycemia increases permanent glycosylation end products. Vessel wall reactivity to nitric oxide (NO) and free radical production is altered. The brain microvasculature is also damaged by hyalinosis and altered glucose oxidation, all these factors contributing to arterial damage. An acute ischemic event is usually mitigated by collateral circulation. The irreversibly damaged central area is surrounded by the hypoperfused penumbra within which viable cells switch to anaerobic respiration. Early hyperglycemia is favorable to this process, but if perfusion is not restored, continued production and accumulation of lactate leads to cell death, enlarging the infarct. Initial use of intravenous insulin is reported to have multifactorial benefits that include stress hormone reduction and vessel wall relaxation, which lower blood pressure (BP). Prevention of Stroke in Patients with Diabetes In DM, primary and secondary prevention of cerebrovascular disease requires a multifactorial approach. The STENO-2 study has unequivocally shown that controlling BG and additional risk factors addressed later results in a greater reduction of cerebrovascular events and overall CV mortality. Glycemic Control Although there is strong evidence for a reduction in microvascular complications (nephropathy, neuropathy, and retinopathy) with intensive glycemic control in T1DM and T2DM, true benefit in preventing macrovascular complications (coronary artery disease, stroke, and peripheral arterial disease) is less certain. Intensive BG control is reported to have some long-term benefit in minimizing macrovascular complications only if it is implemented early in the course of T1DM and possibly for T2DM. However, intensive control in older adults with T2DM was not clearly shown to prevent CV outcomes. In fact, studies raise the concern for a high rate of hypoglycemia and increased mortality, although the two were not definitively linked. The American Diabetes Association (ADA) therefore suggests target A1c of less than 7% for most adults with DM but an appropriately lower A1c goal of less than 8% for adults with advanced microvascular or macrovascular disease, the elderly, and those with significant comorbidities and/or a limited life expectancy. Therefore, stroke patients (focusing on secondary prevention) with DM should have a target A1c between 7% and 8%. T1DM BG targets are achieved with intensive insulin therapy: either multiple daily injections (one injection of basal insulin [glargine, detemir, NPH] and multiple injections of prandial insulin [lispro, aspart and glulisine]) or a continuous subcutaneous insulin infusion (insulin pump), both ideally managed by an endocrinologist. T2DM BG targets are usually achieved with a combination of oral and injectable agents. Some agents are preferable in stroke patients. Studies have linked metformin to CV benefits, independent of its BG-lowering ability. It is now considered first-line therapy for T2DM, but kidney function must be evaluated before metformin is used. When metformin monotherapy becomes inadequate, addition of a second oral agent, either a sulfonylurea, dipeptidyl peptidase 4 (DPP-4) inhibitor, or thiazolidinedione (TZD), can achieve further A1c reduction (roughly 1% for each additional medication). Sulfonylureas are effective but can cause prolonged hypoglycemia and therefore must be used cautiously in the elderly. Pioglitazone, a TZD, might have additional benefits in secondary prevention of CV events; however, weight gain, edema, and growing concern about increased risk of fractures and bladder cancer limit its use. The other TZD, rosiglitazone, was withdrawn in Europe and is highly restricted in the United States because of elevated risk of myocardial infarction. DPP-IV inhibitors are newer drugs and when used alone have a low risk of hypoglycemia, but they are contraindicated in pancreatic disorders. Initiating insulin therapy in T2DM need not wait for failure of BG control on multiple oral agents. Insulin may be added to an oral agent, and a stepwise progression is recommended, starting with basal insulin and later adding short-acting insulin at one meal (basal plus), then at multiple meals as required for controlling hyperglycemia. Only gold members can continue reading. Log In or Register to continue Share this:Click to share on Twitter (Opens in new window)Click to share on Facebook (Opens in new window) Related Related posts: Embolic Protection Devices to Prevent Stroke during Percutaneous Angioplasty and Stenting Management of Acute Limb Ischemia Complicating Aortic Reconstruction Treatment of Dyslipidemia and Hypertriglyceridemia Intraoperative Assessment of the Technical Adequacy of Carotid Endarterectomy Stay updated, free articles. Join our Telegram channel Join Tags: Current Therapy in Vascular and Endovascular Surgery Aug 25, 2016 | Posted by admin in CARDIOLOGY | Comments Off on Diabetes as a Risk Factor in Atherosclerotic Cerebrovascular Disease Full access? Get Clinical Tree
