Stroke in Patients With Diabetes

Stroke is the third leading cause of death in industrialized countries, only preceded by cardiovascular disease and cancer. It is also a major cause of morbidity and hospital admission and the cause of more long-term disability than any other disease. Currently, more than 600,000 strokes occur each year; approximately 80% result from cerebral infarct, and about 100,000 occur in patients with previous stroke (recurrent stroke). Approximately 160,000 stroke-related deaths occur each year; it is the third leading cause of mortality in persons older than age 65 years. Current acute stroke therapies that may be beneficial at the individual level have limited benefit in a public health setting. Thus, a population-based stroke risk factor reduction approach, especially in high-risk patients, such as those with diabetes and hypertension, is of great importance in preventing this debilitating disease. Diabetes mellitus is a very important modifiable stroke risk factor of increasing significance as the prevalence of diabetes increases. Crude incidence of stroke among patients with diabetes is up to three times higher than that of the general population, with especially high risk rates in the southeastern United States. Emerging evidence also suggests that diabetes is a greater source of stroke risk in some ethnic groups, like African Americans. Hypertension often coexists with diabetes, compounding the risks of stroke in this population. Data from the United Kingdom Prospective Diabetes Study showed a 44% relative risk reduction for stroke in the group whose blood pressure was controlled (mean blood pressure 144/82 mm Hg) compared with the group with poorer control (mean blood pressure 154/87 mm Hg). In the systolic hypertension in Europe trial, 492 patients randomized were diabetic; when treated with dihydropyridine calcium antagonist-based therapy, subjects had a 27% reduction in stroke compared with a 12% reduction in the nondiabetic cohort. In the Micro-HOPE subanalysis of the Heart Outcome Prevention Evaluation HOPE study involving 3577 diabetic patients, the risk of stroke was reduced by 33% with an angiotensin-converting enzyme inhibitor-based regimen compared to a program that did not include an angiotensin-converting enzyme inhibitor. In the Losartan Intervention For Endpoint reduction in hypertension study there was a 25% greater reduction in strokes in the group randomized to an angiotensin receptor blocker compared with a β blocker. Finally, both the Systolic Hypertension in the Elderly Program and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial have clearly shown the benefits of diuretic therapy to control systolic blood pressure and reduce strokes in patients with diabetes and hypertension. These data on the treatment of hypertension to prevent stroke in diabetic patients help support the recent American Diabetes Association (ADA) and Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommendations of a goal blood pressure of >130/80 mm Hg in persons with diabetes. Although meta-analysis of epidemiologic studies have not shown a clear relationship between total cholesterol and stroke, recent trials with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have shown significant benefit in reducing stroke risks, including in patients with diabetes. These trials include the Long-Term Intervention with Pravastatin in Ischemia Disease (LIPID), the Cholesterol and Recurrent Events trial, the Scandinavian Simvastatin Survival, and the Heart Protection Study (HPS). Lipid-lowering therapy has also been shown to be effective in reducing stroke in patients with impaired fasting glucose. An analysis of 1077 diabetic patients and 940 patients with impaired fasting glucose in the LIPID trial showed that lipid-lowering therapy with a statin significantly reduced stroke in patients with established cardiovascular disease, as well as those with diabetes. The National Cholesterol Education Program Adult Treatment Panel III currently recommends lowering low-density lipoprotein cholesterol level to 100 mg/dL. This underscores the pleiotropic effects of statins, including the anti-inflammatory antithrombotic effects of these agents. This supports the notion that statin therapy should be considered routinely for all diabetic patients, regardless of low-density lipoprotein cholesterol level. There is also support for additional strategies that target high-density lipoprotein with niacin and fibric acid derivatives, for example, in this patient population. Other stroke-prevention therapies may also be indicated in the diabetic population. The Antiplatelet Trialists Collaboration, which involved 135,000 patients, including diabetics, showed aspirin to be protective against ischemic stroke. However, in the subanalysis of the diabetic patients in the Hypertension Optimal Treatment Trial, there was no beneficial stroke prevention effect. Nevertheless, the ADA currently recommends aspirin therapy for adults with diabetes unless otherwise contraindicated. Atrial fibrillation is a powerful risk factor for stroke, particularly in patients with diabetes. In a multivariant analysis of six major clinical trials of patients with atrial fibrillation, diabetes was found to be an independent risk factor for stroke together with hypertension, increased age, and previous history of transient ischemic attack. Further, this meta-analysis revealed a 64% stroke risk reduction with warfarin compared with placebo. Thus, anticoagulation therapy is important in diabetic patients with atrial fibrillation. Although there are no studies addressing smoking cessation and a possible reduction in stroke in diabetic patients, both ADA and the American Heart Association recommend complete smoking cessation to decrease the risk of stroke. The effect of alcohol as a risk factor for stroke remains controversial. Chronic heavy drinking and recurrent intoxication have been associated with an increased risk of cerebral infarction among young adults; however, accumulative evidence indicates that moderate alcohol intake may be protective against stroke. For example, in a population-based, case-control study involving 677 patients with first ischemic stroke, moderate alcohol intake, up to two drinks per day, reduced the risk for stroke by 50% after adjusting for diabetes, hypertension, current smoking, and cardiac disease. The current recommendation is to eliminate heavy alcohol drinking and reduce it to moderate (<2 drinks/d). Collectively, current information underscores the importance of a comprehensive risk-factor reduction approach in diabetic patients. Rigorous control of blood pressure, especially systolic pressure and pyophylactic statin therapy, are especially important components of this risk factor approach.