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Cerebrovascular disease in type 2 diabetes
International Congress Series 1303 (2007) 65 – 69
www.ics-elsevier.com
Cerebrovascular disease in type 2 diabetes Markku Laakso ⁎, Johanna Kuusisto Department of Medicine, University of Kuopio, Kuopio, 70210 Finland
Abstract. Type 2 diabetes is associated with at least 2-fold elevated risk for all macrovascular complications, coronary heart disease, stroke and peripheral vascular disease. The prevalence and incidence of hemorrhagic stroke is not higher among subjects with type 2 diabetes than in nondiabetic subjects. Therefore, an excess risk of stroke is due to high occurrence of ischemic strokes. High LDL cholesterol, elevated blood pressure, smoking, low HDL cholesterol, high levels of total triglycerides and insulin, central obesity, impaired glucose tolerance and atrial fibrillation have been associated with the risk of stroke. Diabetic patients with stroke should receive effective antihypertensive therapy, lipid-lowering medication, medication to obtain good glycemic control, and anti-platelet therapy. Surgical revascularization is indicated in patients with hemodynamically significant internal carotid artery atherosclerosis independently of symptoms. Patients with atrial fibrillation should be on anticoagulation therapy. © 2007 Published by Elsevier B.V. Keywords: Type 2 diabetes; Cerebrovascular disease; Hyperglycaemia
1. Introduction Diabetes mellitus affects about 3–5% of western populations. The prevalence of this disorder is rapidly increasing almost in all countries, and diabetes will be one of the main threats to human health in the 21st century. Changes in the human environment and in human behavior and lifestyle, in conjunction with genetic susceptibility, have resulted in a dramatic increase in the incidence and prevalence of diabetes in the world. Most of this increase is due to an epidemic of type 2 diabetes (T2DM) because this subtype accounts for 90% of cases globally. Chronic hyperglycemia is associated with long-term complications, especially in the eyes, kidneys, nerves, heart, and blood vessels. More than half of patients with T2DM die ⁎ Corresponding author. Tel.: +358 17 172151; fax: +358 17 173993. E-mail address: [email protected] (M. Laakso). 0531-5131/ © 2007 Published by Elsevier B.V. doi:10.1016/j.ics.2007.03.017
66
M. Laakso, J. Kuusisto / International Congress Series 1303 (2007) 65–69
of cardiovascular diseases (CVD), especially of coronary heart disease (CHD) and stroke. Therefore, the ‘epidemic’ of T2DM will be followed by the ‘epidemic’ of diabetes-related CVD. T2DM is preceded by a long period of asymptomatic hyperglycemia, associated with the clustering or cardiovascular risk factors. In this pre-diabetic state, postprandial or postglucose levels are mildly elevated, whereas fasting blood glucose can usually be maintained within the near-normal range. Very often these risk individuals also have the metabolic syndrome [1], a clustering of other cardiovascular risk factors, e.g. abdominal obesity, elevated levels of total triglycerides, low levels of high-density lipoprotein (HDL) cholesterol and elevated blood pressure. These individuals are at a high risk or developing CVD, including stroke. Type 2 diabetes is associated with at least 2-fold elevated risk for all macrovascular complications, coronary heart disease (CHD), stroke and peripheral vascular disease. Classical risk factors, high low-density lipoprotein (LDL) cholesterol, elevated blood pressure, and smoking, increase the risk of CVD similarly to non-diabetic subjects [2]. However, the absolute risk for CVD is substantially higher among patients with T2DM. 2. Clinical characteristics of stroke among patients with type 2 diabetes Barker et al. [3] reported that beyond the fourth decade of life the frequency and severity of cerebral atherosclerosis was doubled in diabetic subjects compared to non-diabetic individuals. Grunnet et al. [4] found that in subjects aged from 30 to 70 years nearly twice as many diabetic subjects as non-diabetic subjects had moderate or severe cerebral atherosclerosis, whereas above 70 years of age this difference became less striking. Patients with type 2 diabetes have more extracranial atherosclerosis. Several clinical series of diabetic patients and population-based studies have shown that diabetic patients have about 2-fold higher risk for stroke compared to control subjects [2]. Stroke has special characteristics in patients with T2DM compared to non-diabetic subjects presented in Table 1 (modified from [5]). The prevalence and incidence of hemorrhagic stroke is not higher among subjects with T2DM than in non-diabetic subjects. Therefore, an excess risk of stroke is due to high occurrence of ischemic strokes. In patients with T2DM the ratio of ischemic stroke/hemorrhagic stroke is 10:1, whereas in nondiabetic subjects it is 5:1. Furthermore, the relative risk for stroke in patients with T2DM is especially high in subjects b 55 years [6] and in women. Diabetes doubles the risk of
Table 1 Clinical characteristics of stroke in patients with type 2 diabetes Ratio of ischemic stroke vs. hemorrhagic stroke, 10:1 10-fold higher stroke risk than in non-diabetic subjects, if age b55 years Risk for women higher than for men Infratentorial infarcts more common than in non-diabetic subjects Lacunar infarcts more common than in non-diabetic subjects Infarcts located in brainstem, cerebellar or midbrain region more common than in non-diabetic subjects Infarction size not different from that in non-diabetic individuals
M. Laakso, J. Kuusisto / International Congress Series 1303 (2007) 65–69
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recurrence of stroke [7], and increases total and stroke-related mortality [8]. Localization of stroke is also different between diabetic and non-diabetic subjects. Intratentoral and lacunar infarcts are more common in patients with T2DM than in non-diabetic individuals, as well as stroke-related dementia [9]. The size of infarct in stroke patients is not different between diabetic and non-diabetic subjects. 3. Risk factors for stroke In addition to classic risk factors, high LDL cholesterol, elevated blood pressure and smoking, low HDL cholesterol, high levels of triglycerides and insulin, central obesity, impaired glucose tolerance and atrial fibrillation have been associated with the risk of stroke [10,11]. Thus, insulin resistance must be a central component in the risk of stroke. In fact, insulin resistance syndrome has been shown to predict stroke in population-based studies [12]. In insulin-resistant states skeletal muscle glucose uptake is impaired, leading to high insulin levels in circulating blood since the pancreas compensates for impaired insulin action by secreting more insulin. Glucose and free fatty acid (FFA) levels are elevated which increases the risk of atherothrombosis. Insulin resistance in adipose tissue leads to increased lipolysis and high FFA flux into the liver where it stimulates the production of very low density lipoprotein (VLDL) particles, and thus dyslipidemia (high triglycerides, low HDL cholesterol, small and dense LDL particles) [1]. Furthermore, adipose tissue secretes important adipocytokines, for example tumor necrosis factor-α, interleukin-6 and adiponectin. In people with high amount of visceral fat, the levels of cytokines, adhesion molecules, and inflammatory markers are elevated whereas adiponectin concentration is low [13]. All these changes contribute to accelerated atherothrombosis. In response to cytokines the liver produces C-reactive protein, plasminogen activator inhibitor 1 and fibrinogen which lead to enhanced thrombus formation and impaired fibrinolysis. Finally, in insulin resistant states endothelial dysfunction is present, since nitric oxide production is not stimulated. In T2DM the degree of hyperglycemia and long duration of diabetes are risk factors for stroke [14]. Hyperglycemia has several deleterious effects on the risk of atherothrombosis. Glucose toxicity further impairs insulin signaling, glucose metabolism and endothelial function. Furthermore, hyperglycemia stimulates the MAP kinase pathway leading to elevated synthesis of adhesion molecules and endothelin 1, as well as to the stimulation of vascular smooth muscle cell proliferation, and changes in the arterial wall. Hyperglycemia also leads to the formation of advanced glycation end products, increased oxidative stress, and abnormalities in other cardiovascular risk factors [15]. Finally, in diabetes there are abnormalities in platelet function and coagulation. These abnormalities increase intrinsic platelet activation and decrease endogenous inhibitors of platelet activity, and augment blood coagulation [16]. Although several potential risk factors for accelerated atherothrombosis have been identified, it is possible to measure only a few of them in clinical practice. UK Prospective Diabetes Study (UKPDS) evaluated risk factors for stroke case fatality (Table 2). This study demonstrated that from modifiable risk factors particularly elevated blood pressure and hemoglobin A1c were strong predictors for fatal stroke [17]. Our study has shown that in addition to risk factors found
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M. Laakso, J. Kuusisto / International Congress Series 1303 (2007) 65–69
Table 2 Risk factors predicting stroke case fatality in the UK Prospective Diabetes Study in multivariate model [17] Risk factor
Odds ratio and their 95% confidence intervals
p value
Gender (women vs. men) Hemoglobin A1c (per 1%) Systolic blood pressure (per 10 mm Hg) Subsequent stroke vs. first stroke White cell count (per 10− 9 l)
2.33 (1.11–4.91) 1.37 (1.09–1.72) 1.29 (1.04–1.54) 12.6(4.34–36.7) 0.82 (0.67–0.97)
0.0253 0.0071 0.0040 b0.0001 0.0218
in the UKPDS, dyslipidemia (low HDL cholesterol, and high triglycerides) [18] and proteinuria [19] are strong risk factors for stroke in type 2 diabetic patients. 4. Prevention of stroke Diabetic patients with stroke should receive effective antihypertensive therapy, lipidlowering medication, medication to obtain good glycemic control, and anti-platelet therapy. Surgical revascularization is indicated in patients with hemodynamically significant internal carotid artery atherosclerosis independently of symptoms [15]. Patients with atrial fibrillation should be on anticoagulation therapy. Intervention trials have provided support for rigorous blood pressure control in the prevention of stroke in diabetic patients. In the UKPDS tight blood pressure with atenolol or captopril resulted in 44% relative risk reduction in fatal and nonfatal stroke compared with the control group [20]. Also treatment with calcium channels blockers, diuretics, other ACE inhibitors and angiotensin receptor blockers has been shown to prevent stroke events [21]. Blood pressure reduction per se rather than the choice of a specific agent is of primary importance. A prospective meta-analysis of data from 90 056 individuals of 14 randomized statin trials has been recently published [22]. The relative risk reduction of ischemic stroke by statin treatment was 19% (95% confidence interval (CI) 11–26%), but no effect on hemorrhagic stroke was found. The relative risk reduction was of similar magnitude in nondiabetic and diabetic subjects. Meta-analysis of 6 trials on the effect of glucose lowering in type 2 diabetic patients included 4472 patients and 303 cerebrovascular events [23]. This meta-analysis showed that the relative risk of stroke was reduced by 42% (95% CI 26–54%) by intensive glucose control. The first study aiming to investigate the effect of improving insulin sensitivity on cardiovascular disease was the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events) [24]. This trial randomized 5238 patients with T2DM, who had evidence of macrovascular disease, to receive pioglitazone 45 mg or matching placebo. The primary endpoint of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle was not significantly reduced (hazard ratio 0.90, 95% CI 0.80–1.02, p = 0.095). However, the number of subjects with stroke was considerably less in the pioglitazone group than in the placebo group (76 vs. 96). Aspirin therapy reduces the risk of stroke in adults who are at increased risk for cardiovascular disease. Therefore, all patients with T2DM should be on aspirin therapy, if contraindications are not present [25]. A dose of 100 mg is recommended, but diabetic
M. Laakso, J. Kuusisto / International Congress Series 1303 (2007) 65–69
69
patients may need a larger dose. Patients with atrial fibrillation benefit from anticoagulation. Finally, diabetic patients with hemodynamically significant internal carotid artery atherosclerosis benefit from surgical revascularization. References [1] M. Laakso, Insulin resistance and coronary heart disease, Curr. Opin. Lipidol. 7 (1996) 217–226. [2] K. Pyörälä, M. Laakso, M. Uusitupa, Diabetes and atherosclerosis: an epidemiologic view, Diabetes/Metabolism Rev. 3 (1987) 463–524. [3] A.B. Baker, J. Kinnard, A. Iannone, Cerebrovascular disease: VIII. Role of nutritional factors, Neurology 13 (1963) 486–491. [4] M.L. Grunnet, Cerebrovascular: diabetes and cerebral atherosclerosis, Neurology 13 (1963) 486–491. [5] I. Idris, G.A. Thompson, J.C. Sharma, Diabetes mellitus and stroke, Int. J. Clin. Pract. 60 (2006) 48–56. [6] R.X. You, et al., Risk factors for stroke due to cerebral infarction in young adults, Stroke 28 (1997) 1913–1918. [7] G.J. Hankey, et al., Long-term risk of first recurrent stroke in the Perth Community Stroke Study, Stroke 29 (1998) 2491–5000. [8] J. Tuomilehto, et al., Diabetes mellitus as a risk factor for death from stroke, Stroke 27 (1996) 210–215. [9] J.A. Luchsinger, et al., Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort, Am. J. Epidemiol. 154 (2001) 635–641. [10] A.R. Folsom, et al., Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke, Diabetes Care 22 (1999) 1077–1083. [11] R.L. Sacco, et al., High-density lipoprotein cholesterol and ischemic stroke in patients with diagnosed with TIA, Neurology 28 (2001) 280–285. [12] M. Pyörälä, et al., Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study, Arterioscler. Thromb. Vasc. Biol. 20 (2000) 538–544. [13] U. Salmenniemi, et al., Multiple abnormalities in glucose and energy metabolism, and coordinated changes in levels of adiponectin, cytokines and adhesion molecules in subjects with the metabolic syndrome, Circulation 110 (2004) 3842–3848. [14] J. Kuusisto, et al., Non-insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects, Stroke 25 (1994) 1157–1564. [15] J.A. Beckman, M.A. Creager, Diabetes and atherosclerosis. Epidemiology, pathophysiology, and management, JAMA 287 (2002) 2570–2581. [16] A.I. Vinik, et al., Platelet dysfunction in type 2 diabetes, Diabetes Care 24 (2001) 1476–1485. [17] R.J. Stevens, et al., Risk factors for myocardial infarction case fatality and stroke case fatality in type 2 diabetes. UKPDS 66, Diabetes Care 27 (2004) 201–207. [18] S. Lehto, et al., Predictors of stroke in middle-aged patients with non-insulin-dependent diabetes, Stroke 27 (1996) 63–68. [19] H. Miettinen, et al., Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects, Stroke 27 (1996) 2033–2039. [20] T.M. Davis, et al., Risk factors for stroke in type 2 diabetes mellitus. United Kingdom Prospective Diabetes Study (UKPDS) 29, Arch. Intern. Med. 159 (1999) 1097–1103. [21] J.R. Sowers, Treatment of hypertension in patients with diabetes, Arch. Intern. Med. 164 (2004) 1850–1857. [22] Cholesterol Treatment Trialist' (CTT) Collaborators, Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins, Lancet 366 (2005) 1267–1278. [23] C. Stettler, et al., Glycemic control and macrovascular disease in type 1 and 2 diabetes mellitus: meta-analysis of randomized trials, Am. Heart. J. 152 (2006) 27–38. [24] J.A. Dormandy, et al., Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial, Lancet 366 (2005) 1279–1289. [25] JA. Coldwell, Aspirin therapy in diabetes, Diabetes Care (2004) S72–S73 27 (Suppl).
www.ics-elsevier.com
Cerebrovascular disease in type 2 diabetes Markku Laakso ⁎, Johanna Kuusisto Department of Medicine, University of Kuopio, Kuopio, 70210 Finland
Abstract. Type 2 diabetes is associated with at least 2-fold elevated risk for all macrovascular complications, coronary heart disease, stroke and peripheral vascular disease. The prevalence and incidence of hemorrhagic stroke is not higher among subjects with type 2 diabetes than in nondiabetic subjects. Therefore, an excess risk of stroke is due to high occurrence of ischemic strokes. High LDL cholesterol, elevated blood pressure, smoking, low HDL cholesterol, high levels of total triglycerides and insulin, central obesity, impaired glucose tolerance and atrial fibrillation have been associated with the risk of stroke. Diabetic patients with stroke should receive effective antihypertensive therapy, lipid-lowering medication, medication to obtain good glycemic control, and anti-platelet therapy. Surgical revascularization is indicated in patients with hemodynamically significant internal carotid artery atherosclerosis independently of symptoms. Patients with atrial fibrillation should be on anticoagulation therapy. © 2007 Published by Elsevier B.V. Keywords: Type 2 diabetes; Cerebrovascular disease; Hyperglycaemia
1. Introduction Diabetes mellitus affects about 3–5% of western populations. The prevalence of this disorder is rapidly increasing almost in all countries, and diabetes will be one of the main threats to human health in the 21st century. Changes in the human environment and in human behavior and lifestyle, in conjunction with genetic susceptibility, have resulted in a dramatic increase in the incidence and prevalence of diabetes in the world. Most of this increase is due to an epidemic of type 2 diabetes (T2DM) because this subtype accounts for 90% of cases globally. Chronic hyperglycemia is associated with long-term complications, especially in the eyes, kidneys, nerves, heart, and blood vessels. More than half of patients with T2DM die ⁎ Corresponding author. Tel.: +358 17 172151; fax: +358 17 173993. E-mail address: [email protected] (M. Laakso). 0531-5131/ © 2007 Published by Elsevier B.V. doi:10.1016/j.ics.2007.03.017
66
M. Laakso, J. Kuusisto / International Congress Series 1303 (2007) 65–69
of cardiovascular diseases (CVD), especially of coronary heart disease (CHD) and stroke. Therefore, the ‘epidemic’ of T2DM will be followed by the ‘epidemic’ of diabetes-related CVD. T2DM is preceded by a long period of asymptomatic hyperglycemia, associated with the clustering or cardiovascular risk factors. In this pre-diabetic state, postprandial or postglucose levels are mildly elevated, whereas fasting blood glucose can usually be maintained within the near-normal range. Very often these risk individuals also have the metabolic syndrome [1], a clustering of other cardiovascular risk factors, e.g. abdominal obesity, elevated levels of total triglycerides, low levels of high-density lipoprotein (HDL) cholesterol and elevated blood pressure. These individuals are at a high risk or developing CVD, including stroke. Type 2 diabetes is associated with at least 2-fold elevated risk for all macrovascular complications, coronary heart disease (CHD), stroke and peripheral vascular disease. Classical risk factors, high low-density lipoprotein (LDL) cholesterol, elevated blood pressure, and smoking, increase the risk of CVD similarly to non-diabetic subjects [2]. However, the absolute risk for CVD is substantially higher among patients with T2DM. 2. Clinical characteristics of stroke among patients with type 2 diabetes Barker et al. [3] reported that beyond the fourth decade of life the frequency and severity of cerebral atherosclerosis was doubled in diabetic subjects compared to non-diabetic individuals. Grunnet et al. [4] found that in subjects aged from 30 to 70 years nearly twice as many diabetic subjects as non-diabetic subjects had moderate or severe cerebral atherosclerosis, whereas above 70 years of age this difference became less striking. Patients with type 2 diabetes have more extracranial atherosclerosis. Several clinical series of diabetic patients and population-based studies have shown that diabetic patients have about 2-fold higher risk for stroke compared to control subjects [2]. Stroke has special characteristics in patients with T2DM compared to non-diabetic subjects presented in Table 1 (modified from [5]). The prevalence and incidence of hemorrhagic stroke is not higher among subjects with T2DM than in non-diabetic subjects. Therefore, an excess risk of stroke is due to high occurrence of ischemic strokes. In patients with T2DM the ratio of ischemic stroke/hemorrhagic stroke is 10:1, whereas in nondiabetic subjects it is 5:1. Furthermore, the relative risk for stroke in patients with T2DM is especially high in subjects b 55 years [6] and in women. Diabetes doubles the risk of
Table 1 Clinical characteristics of stroke in patients with type 2 diabetes Ratio of ischemic stroke vs. hemorrhagic stroke, 10:1 10-fold higher stroke risk than in non-diabetic subjects, if age b55 years Risk for women higher than for men Infratentorial infarcts more common than in non-diabetic subjects Lacunar infarcts more common than in non-diabetic subjects Infarcts located in brainstem, cerebellar or midbrain region more common than in non-diabetic subjects Infarction size not different from that in non-diabetic individuals
M. Laakso, J. Kuusisto / International Congress Series 1303 (2007) 65–69
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recurrence of stroke [7], and increases total and stroke-related mortality [8]. Localization of stroke is also different between diabetic and non-diabetic subjects. Intratentoral and lacunar infarcts are more common in patients with T2DM than in non-diabetic individuals, as well as stroke-related dementia [9]. The size of infarct in stroke patients is not different between diabetic and non-diabetic subjects. 3. Risk factors for stroke In addition to classic risk factors, high LDL cholesterol, elevated blood pressure and smoking, low HDL cholesterol, high levels of triglycerides and insulin, central obesity, impaired glucose tolerance and atrial fibrillation have been associated with the risk of stroke [10,11]. Thus, insulin resistance must be a central component in the risk of stroke. In fact, insulin resistance syndrome has been shown to predict stroke in population-based studies [12]. In insulin-resistant states skeletal muscle glucose uptake is impaired, leading to high insulin levels in circulating blood since the pancreas compensates for impaired insulin action by secreting more insulin. Glucose and free fatty acid (FFA) levels are elevated which increases the risk of atherothrombosis. Insulin resistance in adipose tissue leads to increased lipolysis and high FFA flux into the liver where it stimulates the production of very low density lipoprotein (VLDL) particles, and thus dyslipidemia (high triglycerides, low HDL cholesterol, small and dense LDL particles) [1]. Furthermore, adipose tissue secretes important adipocytokines, for example tumor necrosis factor-α, interleukin-6 and adiponectin. In people with high amount of visceral fat, the levels of cytokines, adhesion molecules, and inflammatory markers are elevated whereas adiponectin concentration is low [13]. All these changes contribute to accelerated atherothrombosis. In response to cytokines the liver produces C-reactive protein, plasminogen activator inhibitor 1 and fibrinogen which lead to enhanced thrombus formation and impaired fibrinolysis. Finally, in insulin resistant states endothelial dysfunction is present, since nitric oxide production is not stimulated. In T2DM the degree of hyperglycemia and long duration of diabetes are risk factors for stroke [14]. Hyperglycemia has several deleterious effects on the risk of atherothrombosis. Glucose toxicity further impairs insulin signaling, glucose metabolism and endothelial function. Furthermore, hyperglycemia stimulates the MAP kinase pathway leading to elevated synthesis of adhesion molecules and endothelin 1, as well as to the stimulation of vascular smooth muscle cell proliferation, and changes in the arterial wall. Hyperglycemia also leads to the formation of advanced glycation end products, increased oxidative stress, and abnormalities in other cardiovascular risk factors [15]. Finally, in diabetes there are abnormalities in platelet function and coagulation. These abnormalities increase intrinsic platelet activation and decrease endogenous inhibitors of platelet activity, and augment blood coagulation [16]. Although several potential risk factors for accelerated atherothrombosis have been identified, it is possible to measure only a few of them in clinical practice. UK Prospective Diabetes Study (UKPDS) evaluated risk factors for stroke case fatality (Table 2). This study demonstrated that from modifiable risk factors particularly elevated blood pressure and hemoglobin A1c were strong predictors for fatal stroke [17]. Our study has shown that in addition to risk factors found
68
M. Laakso, J. Kuusisto / International Congress Series 1303 (2007) 65–69
Table 2 Risk factors predicting stroke case fatality in the UK Prospective Diabetes Study in multivariate model [17] Risk factor
Odds ratio and their 95% confidence intervals
p value
Gender (women vs. men) Hemoglobin A1c (per 1%) Systolic blood pressure (per 10 mm Hg) Subsequent stroke vs. first stroke White cell count (per 10− 9 l)
2.33 (1.11–4.91) 1.37 (1.09–1.72) 1.29 (1.04–1.54) 12.6(4.34–36.7) 0.82 (0.67–0.97)
0.0253 0.0071 0.0040 b0.0001 0.0218
in the UKPDS, dyslipidemia (low HDL cholesterol, and high triglycerides) [18] and proteinuria [19] are strong risk factors for stroke in type 2 diabetic patients. 4. Prevention of stroke Diabetic patients with stroke should receive effective antihypertensive therapy, lipidlowering medication, medication to obtain good glycemic control, and anti-platelet therapy. Surgical revascularization is indicated in patients with hemodynamically significant internal carotid artery atherosclerosis independently of symptoms [15]. Patients with atrial fibrillation should be on anticoagulation therapy. Intervention trials have provided support for rigorous blood pressure control in the prevention of stroke in diabetic patients. In the UKPDS tight blood pressure with atenolol or captopril resulted in 44% relative risk reduction in fatal and nonfatal stroke compared with the control group [20]. Also treatment with calcium channels blockers, diuretics, other ACE inhibitors and angiotensin receptor blockers has been shown to prevent stroke events [21]. Blood pressure reduction per se rather than the choice of a specific agent is of primary importance. A prospective meta-analysis of data from 90 056 individuals of 14 randomized statin trials has been recently published [22]. The relative risk reduction of ischemic stroke by statin treatment was 19% (95% confidence interval (CI) 11–26%), but no effect on hemorrhagic stroke was found. The relative risk reduction was of similar magnitude in nondiabetic and diabetic subjects. Meta-analysis of 6 trials on the effect of glucose lowering in type 2 diabetic patients included 4472 patients and 303 cerebrovascular events [23]. This meta-analysis showed that the relative risk of stroke was reduced by 42% (95% CI 26–54%) by intensive glucose control. The first study aiming to investigate the effect of improving insulin sensitivity on cardiovascular disease was the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events) [24]. This trial randomized 5238 patients with T2DM, who had evidence of macrovascular disease, to receive pioglitazone 45 mg or matching placebo. The primary endpoint of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle was not significantly reduced (hazard ratio 0.90, 95% CI 0.80–1.02, p = 0.095). However, the number of subjects with stroke was considerably less in the pioglitazone group than in the placebo group (76 vs. 96). Aspirin therapy reduces the risk of stroke in adults who are at increased risk for cardiovascular disease. Therefore, all patients with T2DM should be on aspirin therapy, if contraindications are not present [25]. A dose of 100 mg is recommended, but diabetic
M. Laakso, J. Kuusisto / International Congress Series 1303 (2007) 65–69
69
patients may need a larger dose. Patients with atrial fibrillation benefit from anticoagulation. Finally, diabetic patients with hemodynamically significant internal carotid artery atherosclerosis benefit from surgical revascularization. References [1] M. Laakso, Insulin resistance and coronary heart disease, Curr. Opin. Lipidol. 7 (1996) 217–226. [2] K. Pyörälä, M. Laakso, M. Uusitupa, Diabetes and atherosclerosis: an epidemiologic view, Diabetes/Metabolism Rev. 3 (1987) 463–524. [3] A.B. Baker, J. Kinnard, A. Iannone, Cerebrovascular disease: VIII. Role of nutritional factors, Neurology 13 (1963) 486–491. [4] M.L. Grunnet, Cerebrovascular: diabetes and cerebral atherosclerosis, Neurology 13 (1963) 486–491. [5] I. Idris, G.A. Thompson, J.C. Sharma, Diabetes mellitus and stroke, Int. J. Clin. Pract. 60 (2006) 48–56. [6] R.X. You, et al., Risk factors for stroke due to cerebral infarction in young adults, Stroke 28 (1997) 1913–1918. [7] G.J. Hankey, et al., Long-term risk of first recurrent stroke in the Perth Community Stroke Study, Stroke 29 (1998) 2491–5000. [8] J. Tuomilehto, et al., Diabetes mellitus as a risk factor for death from stroke, Stroke 27 (1996) 210–215. [9] J.A. Luchsinger, et al., Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort, Am. J. Epidemiol. 154 (2001) 635–641. [10] A.R. Folsom, et al., Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke, Diabetes Care 22 (1999) 1077–1083. [11] R.L. Sacco, et al., High-density lipoprotein cholesterol and ischemic stroke in patients with diagnosed with TIA, Neurology 28 (2001) 280–285. [12] M. Pyörälä, et al., Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study, Arterioscler. Thromb. Vasc. Biol. 20 (2000) 538–544. [13] U. Salmenniemi, et al., Multiple abnormalities in glucose and energy metabolism, and coordinated changes in levels of adiponectin, cytokines and adhesion molecules in subjects with the metabolic syndrome, Circulation 110 (2004) 3842–3848. [14] J. Kuusisto, et al., Non-insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects, Stroke 25 (1994) 1157–1564. [15] J.A. Beckman, M.A. Creager, Diabetes and atherosclerosis. Epidemiology, pathophysiology, and management, JAMA 287 (2002) 2570–2581. [16] A.I. Vinik, et al., Platelet dysfunction in type 2 diabetes, Diabetes Care 24 (2001) 1476–1485. [17] R.J. Stevens, et al., Risk factors for myocardial infarction case fatality and stroke case fatality in type 2 diabetes. UKPDS 66, Diabetes Care 27 (2004) 201–207. [18] S. Lehto, et al., Predictors of stroke in middle-aged patients with non-insulin-dependent diabetes, Stroke 27 (1996) 63–68. [19] H. Miettinen, et al., Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects, Stroke 27 (1996) 2033–2039. [20] T.M. Davis, et al., Risk factors for stroke in type 2 diabetes mellitus. United Kingdom Prospective Diabetes Study (UKPDS) 29, Arch. Intern. Med. 159 (1999) 1097–1103. [21] J.R. Sowers, Treatment of hypertension in patients with diabetes, Arch. Intern. Med. 164 (2004) 1850–1857. [22] Cholesterol Treatment Trialist' (CTT) Collaborators, Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins, Lancet 366 (2005) 1267–1278. [23] C. Stettler, et al., Glycemic control and macrovascular disease in type 1 and 2 diabetes mellitus: meta-analysis of randomized trials, Am. Heart. J. 152 (2006) 27–38. [24] J.A. Dormandy, et al., Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial, Lancet 366 (2005) 1279–1289. [25] JA. Coldwell, Aspirin therapy in diabetes, Diabetes Care (2004) S72–S73 27 (Suppl).