associated with a decrease in stroke risk by 19%, while as in the trial the same blood pressure reduction (by ACE-inhibitor captopril or beta-blocker atenolol) led to much greater actual decrease in stroke incidence - by 44% (179). These results suggest the possibility of some protective action of these agents beyond their antihypertensive efficacy. This assumption is supported by the results of the HOPE trial, which showed a greater than anticipated reduction of stroke incidence following treatment with ACE inhibitor ramipril (174).

Nevertheless, it remains unclear whether some classes of antihyperten-sive agents provide a stronger protection against stroke in diabetic patients than others. There was no difference in the reduction of stroke incidence between groups of subjects who were treated with captopril or atenolol in the UKPDS (180). In two trials directly comparing the efficacy of different antihypertensive medications on the incidence of cardiovascular events in patients with DM [ABCD - amlodipine vs. enalapril (181) and FACET - felodipine vs. fosinopril (182)], no significant difference in the stroke rate was noted. Similarly, no significant difference in the incidence of cerebrovascular events was observed in diabetic patients treated with the calcium-channel blocker diltiazem or captopril, on one side, or a diuretic and beta blocker, on the other side in the NORDIL and CAPPP trials, respectively (183-185). Moreover, a similar incidence of stroke in three groups of patients treated with newer medications (ACE inhibitors or calcium antagonists) or older ones (beta blockers and diuretics) was reported in the STOP-Hypertension-2 trial (186, 187). In a meta-analysis of three trials (ABCD, FACET, STOP-2) no significant difference in stroke incidence was found between ACE inhibitors or calcium channel blockers in patients with DM (188). No difference in stroke incidence between groups of patients with arterial hypertension assigned either to amlodip-ine, chlorthalidone or lisinopril treatment was noted in 13,101 patients with DM and 1,399 subjects with IFG in the largest hypertension trial ALLHAT although in those without DM stroke was more common in those treated with lisinopril compared to chlorthalidone (189). In the meta-analysis of 14 trials addressing the efficacy of calcium channel blockers in patients with DM and arterial hypertension, it was shown that compared with the conventional therapy, calcium antagonists may have reduced the risk of stroke by 13% and had the similar effect on stroke prevention compared to blockers of the renin-angiotensin system (190). In the LIFE trial reduction of stroke risk by 21.2% was reported in patients with DM treated with the angiotensin-receptor (AT1) blocker losartan compared to those treated with the beta-blocker atenolol. However, this difference did not reach the level of statistical significance, possibly due to inadequate statistical power (191). Recently, no benefits in stroke reduction were found for telmisar-

tan or its combination with ramipril compared to ramipril alone in the large ONTARGET trial which enrolled more than 9 thousand patients with DM (192).

However, in the subgroup of 5,137 diabetic patients enrolled into ASCOT trial the treatment with amlodipine combined with perindopril if necessary led to the reduction of the stroke incidence by 25% compared to treatment with beta-blocker atenolol combined with diuretic bendroflumethiazide in the total group of patients studied. Moreover, the amlodopine-perindopril regimen was associated with a 30% reduction of the risk of new cases of DM (193).

In summary, effective antihypertensive treatment is highly beneficial for reduction of stroke risk in diabetic patients, but the advantages of any particular class of antihypertensive medications are not substantially proven.

Treatment of Dyslipidemia

High cholesterol levels are associated with an increased risk of stroke regardless of the presence of DM. In the Asia Pacific Cohort Studies Collaboration each 1 mmol/l increase of total cholesterol was associated with a 23% increased risk of ischemic stroke in subjects with DM and 31% in those without (194). A significant reduction of the risk of stroke was observed in the CARDS trial which enrolled 2,838 patients with DM randomized to receive atorvastatin 10 mg daily or placebo. After only 3.9 years of follow-up, atorvastatin treatment was associated with a 50% reduction in non-hemorrhagic stroke and a 48% reduction for all strokes combined (195). In the cohort of 2,532 patients with DM followed for 3.3 years, who were enrolled in ASCOT-LLA trial, the administration of atorvastatin in a dose of 10 mg daily resulted in the reduction of LDL by 1 mmol/l and a reduction of the risk of stroke by 33% which was not, however, statistically significant, probably due to low absolute number of events that occurred (196). Pravastatin, 40mg/day, reduced the risk of stroke by 39% in 1,077 diabetic patients and by 42% in 944 subjects with IFG in the LIPID trial which lasted for 6 years (197). In the CARE trial, which included 586 diabetic subjects, treatment with pravastatin over a 5-year period led to a decrease in the relative risk of stroke by 14% in diabetic and by 37% in non-diabetic people (198). In the 4S trial including 202 diabetic patients treatment with sim-vastatin over 5.4 years resulted in a reduction of cerebrovascular events in the diabetic cohort by 62% and by 23% in people without DM (199). In the Heart Protection Study, which enrolled almost 6,000 patients with DM, a 24% reduction of the risk of stroke was found in diabetic cohort (200). It seems that the beneficial effect of statins is dose-dependent. The lower the LDL level that is achieved the stronger the cardiovascular protection. In the cohort of 1,501 diabetic patients with coronary heart disease enrolled in

TNT trial the prescription of atorvastatin in a dose of 80 mg daily resulted in a reduction of the risk of cerebrovascular accidents by 31% compared to those who were treated with atorvastatin in doses of 10 mg daily (201). Recently, the results of the meta-analysis of 14 randomized trials of statins in 18,686 patients with DM had been published. It was calculated that statins use in diabetic patients can result in a 21% reduction of the risk of any stroke per 1 mmol/l reduction of LDL achieved which was not significantly different from 16% reduction observed in non-diabetics (202). This reduction was irrespective from prior history of vascular disease and other baseline characteristics.

There is no evidence from trials that supports efficacy of fibrates for stroke prevention in diabetic patients. In the large FIELD trial which enrolled 9,795 patients with type 2 DM use of fenofibrate did not result in significant reduction of the risk either of total or non-hemorrhagic stroke (203). No reduction of stroke risk by fibrates was shown also in a meta-analysis of eight trials enrolled 12,249 patients with type 2 DM (204).

Antiplatelet Therapy

Significant reductions in stroke risk in diabetic patients receiving antiplatelet therapy were found in large-scale controlled trials (205). It appears that based on the high incidence of stroke and prevalence of stroke risk factors in the diabetic population the benefits of routine aspirin use for primary and secondary stroke prevention outweigh its potential risk of hem-orrhagic stroke especially in patients older than 30 years having at least one additional risk factor (206). However, the HOT trial did not show any beneficial effect of aspirin treatment on stroke incidence despite confirmed efficacy in preventing myocardial infarction in diabetic patients (173). Nevertheless, both guidelines issued by the AHA/ADA or the ESC/EASD on the prevention of cardiovascular disease in patients with DM support the use of aspirin in a dose of 50-325 mg daily for the primary prevention of stroke in subjects older than 40 years of age and additional risk factors, such as DM (207,208). The use of aspirin in those younger than 40 years old without additional risk factor should not be advocated as the tool for primary stroke prevention.

The newer antiplatelet agent, clopidogrel, was more efficacious in prevention of ischemic stroke than aspirin with greater risk reduction in the diabetic cohort especially in those treated with insulin compared to non-diabetics in CAPRIE trial (209). However, the combination of aspirin and clopidogrel does not appear to be more efficacious and safe compared to clopidogrel or aspirin alone based on the results of MATCH and CHARISMA programs (210-212). The combined treatment with aspirin and dipyridamole was associated with a decreased incidence of recurrent stroke, but this reduction was not statistically significant in the subgroup of diabetic subjects (213).

The advantage of the combination of aspirin and dipyridamole over aspirin alone for the prevention of vascular events in patients with ischemic stroke was shown in ESPRIT trial (214). In the recently published meta-analysis of five trials that enrolled 7,612 patients the combination of aspirin and dipyridamole was more effective than aspirin alone in patients with TIA or ischemic stroke of presumed arterial origin in the secondary prevention of stroke and other vascular events in all subgroups including patients with DM (215).

Multifactorial Treatment

Gaede et al. (216) have shown in the Steno 2 study that intensive multifac-torial intervention aimed at correction of hyperglycemia, hypertension, dys-lipidemia, and microalbuminuria along with aspirin use resulted in a reduction of cardiovascular morbidity including non-fatal stroke (20 vs. 3 cases in conventionally and intensively treated patients, respectively). Moreover, recently the results of the extended 13.3 years follow-up of this study were presented and the reduction of cardiovascular mortality by 57% and morbidity by 59% along with the reduction of the number of non-fatal stroke (6 vs. 30 events) in intensively treated group was convincingly demonstrated (217).

Antihypertensive, hypolipidemic treatment, use of aspirin should thus be recommended as either primary or secondary prevention of stroke for patients with DM. The adoption of a healthy life style has proven to be beneficial in preventing cardiovascular disease in diabetic patients. Moderate-to-vigorous physical activity was inversely related to the risk of ischemic stroke in women with DM in the Nurses' Health Study (218).

Such an aggressive approach to the stroke prevention explains probably the decrease in incidence in first and recurrent stroke in women with DM (but not in men) recently revealed over 19-year period in the Northern Sweden MONICA Project Stroke registry and this decrease was significantly greater than in non-diabetic women (219).

Treatment of Carotid Stenosis

Available results regarding the efficacy of carotid endarterectomy as a stroke preventive measure in patients with high-grade asymptomatic carotid stenosis are inconclusive, highly dependent on surgical risk, and have not been specifically assessed in patients with DM. In general, the Stroke Council of American Heart Association recommended that endarterectomy might be considered in patients with high-grade asymptomatic carotid stenosis performed by a surgeon, with <3% morbidity/mortality rate (220). The risk of carotid endarterectomy could be an issue especially in patients with DM as the 30-day and 1-year mortality after such treatment was significantly higher in diabetics mainly due to cardiac complications, while post-operative morbidity did not differ (221). DM was also associated with increased risk of ipsilateral stroke following carotid endarterectomy (222). However, other studies have demonstrated that carotid endarterectomy could be performed in diabetic subjects with favorable perioperative morbidity and mortality rates and stroke-free and survival rates were not different from non-diabetic populations (223, 224).

Carotid endarterectomy should be considered in symptomatic patients -those who have stenosis of more than 50% and suffered from TIA or stroke on the side of the stenosis. In the large meta-analysis by Rothwell et al. (225), which included 974 patients with diabetes, it was revealed that such intervention was the most effective in reducing the risk of stroke in males, in those older than 75 years, and in patients operated within first 2 weeks after the last ischemic episode while there was no significant difference in the efficacy of the operation between patients with and without DM. The interventions to prevent stroke and their efficacy in patients with DM are summarized in Table 6.

Table 6

Prevention of stroke in diabetic patients: summary

Evidence Intervention

Correction of arterial hypertension aiming at blood pressure below 130/80 mmHg (level of evidence A)

Correction of dyslipidemia using statins with the goal of LDL below 100 mg/dl (2.6 mM/l) as primary prevention or 70 mg/dl (1.8 mM/l) as the secondary prevention (level of evidence A)

Use of antiplatelet medications (secondary prevention) (level of evidence A)

Carotid endarterectomy for symptomatic stenosis >70% (level of evidence A)

Cessation of smoking (level of evidence A)

Normalization of body mass (level of evidence C)

Physical exercise (level of evidence C)

Carotid endarterectomy for symptomatic stenosis 50-69% (level of evidence B)

Use of antiplatelet medications (primary prevention) (level of evidence B)

Strong evidence for

Weaker evidence for


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