Prevention Of Stroke In Patients With Dm

The results of large-scale randomized controlled clinical trials provide important leads for the prevention of stroke in high-risk populations including people with DM. A large number of diabetic patients were enrolled in most trials, thereby allowing post hoc analyses specific for DM.

Regarding prevention of stroke in patients with DM, it may be less relevant than in non-DM subjects to distinguish between primary and secondary prevention as all patients with DM are considered to be high-risk subjects regardless of the history of cerebrovascular accidents or the presence of clinical and subclinical vascular lesions. However, the aggressiveness of the preventive measures should be most pronounced in those who have DM and history of stroke or TIA. Obvious targets for the prevention of stroke in patients with DM are the correction of DM-specific risk factors, mainly hyperglycemia, and other diabetes non-specific factors, such as arterial hypertension or dyslipidemia. While in most trials addressing the correction of these latter factors the relative risk reduction was similar between patients with or without DM, the absolute risk reduction of stroke was usually higher in those with DM due to significantly higher risk in this subgroup of subjects.

Glycemic Control

In the long-term 17 years follow-up of type 1 DM patients who received intensive or standard insulin treatment in the Diabetes Control and Complications Trial, the combined risk of stroke, myocardial infarction, and cardiovascular death was 57% lower in those treated intensively (156), but the data did not allow to draw conclusions regarding the long-term treatment effect on stroke as a single end-point (156). It is interesting to note that the difference in the risk of cardiovascular disease between the two treatment arms appeared long after the end of the randomized treatment period which suggests the presence of the "metabolic memory" and emphasizes the need of active treatment from the early stages of the disease.

In contrast, the UKPDS did not support the hypothesis that control of glycemia could prevent stroke in type 2 DM patients. Conversely, an 11% statistically non-significant increase in stroke incidence was found in the intensively treated diabetic patients compared to the conventionally treated diabetic patients (157). Recently the results of three large clinical trials (ADVANCE, ACCORD, VADT) that aimed to prevent cardiovascular disease in patients with DM through strict glycemic control have been presented. None of them was able to demonstrate a reduction of the risk of cardiovascular disease in patients intensively treated to achieve good glycemic control (158,159). Furthermore, in ACCORD trial, in the group of intensively treated subjects who achieved mean HbA1c levels of 6.4% a significant increase of cardiovascular mortality compared to standard-treated group was observed while the rate of non-fatal stroke was similar between the groups (159).

The influence of the mode of antihyperglycemic treatment on the risk of stroke is uncertain. Mortality from cerebrovascular disease increased to a similar extent in patients treated by oral hypoglycemic medications or insulin compared to those on diet only (160). Although the incidence of stroke was higher in diabetic subjects treated with insulin than in those receiving oral medications or diet this difference disappeared after adjustment for other confounding factors (11). Stroke incidence did not differ in patients treated with chlorpromamide, glibenclamide, or insulin in the UKPDS. However, in overweight diabetic patients, intensive therapy with metformin was more effective in preventing stroke compared to other intensive treatment modalities, achieving a stroke reduction by 42% compared to the conventionally treated group (161). Although in the UKPDS an early addition of metformin in sulfonylurea-treated patients did not lead to an increased stroke incidence (161), another study showed a 2.3fold increased mortality from stroke in patients treated with both medications compared to those treated with sulfonylurea alone (162). However, it is not known whether such a harmful effect of this combined treatment reflects adverse interactions of both medications or more severe DM requiring the prescription of both drugs to achieve optimal metabolic control.

The PROACTIVE trial showed that pioglitazone was able to decrease the risk of recurrent stroke in patients with DM by 47%, while there was no effect on the prevention of a first stroke (163). One of the possible underlying mechanisms of such protective action could be the slowing of the progression of carotid artery intima-media thickness shown for pioglitazone compared to glimepiride in CHICAGO trial (164). However, the risks associated with the use of medications of this class (thiazolidinediones) such as increased risk of heart failure, myocardial infarction, edema, bone fractures, and weight gain probably do not allow recommending their wide use for stroke prevention.

Earlier it was suggested that oral sulfonylurea medications could adversely influence the outcome of ischemic events. However, sulfony-lurea medications were not independent predictors for increased mortality, deterioration of stroke, or stroke severity and even could have beneficial effect of the outcome of non-lacunar stroke in diabetic subjects (165, 166).

Treatment of Hypertension

There are no doubts that there is a linear relation between elevated systolic blood pressure and the risk of stroke, both in people with or without DM. Recently, at the Asia Pacific Cohort Study Cooperation, it was calculated that each 10mmHg increase in systolic blood pressure was associated with 29% higher risk of ischemic stroke and 56% of hemorrhagic stroke among those with DM (167). Although DM and arterial hypertension represent significant independent risk factors for stroke if they co-occur in the same patient the risk increases dramatically. A prospective study of almost 50 thousand subjects in Finland followed up for 19 years revealed that the hazard ratio for stroke incidence was 1.4, 2.0, 2.5, 3.5, and 4.5 and for stroke mortality was 1.5, 2.6, 3.1, 5.6, and 9.3, respectively, in subjects with an isolated modestly elevated blood pressure (systolic 140-159/diastolic 90-94 mmHg), isolated more severe hypertension (systolic >159mmHg, diastolic >94 mmHg, or use of antihypertensive drugs), with isolated DM only, with both DM and modestly elevated blood pressure, and with both DM and more severe hypertension, relative to subjects without either of the risk factors (168).

Correction of arterial hypertension effectively prevents stroke. The results of trials comparing active antihypertensive treatment and placebo addressing the incidence of stroke in patients with DM are summarized in Table 5. Control of arterial hypertension as the approach to decrease of stroke incidence is at least as or in some trials even more effective in diabetic patients than in the general population (170, 171). Moreover, while in the placebo arms of these trials the risk for stroke in diabetic patients was increased, it became indistinguishable from non-diabetic subjects in actively treated hypertensive diabetic patients suggesting that effective antihypertensive treatment was able to eliminate the excess cardiovascular risk in people with DM (170-172). The incidence of ischemic stroke was similar in treated hypertensive and normotensive diabetic patients, whereas it was significantly higher in those with untreated hypertension (40). Guidelines addressing the treatment of arterial hypertension agree that the goal for blood pressure in patients with DM should be less than 130/80 mmHg (177, 178) although it has to be noted that these recommendations are based on the results of the epidemiological observations and are not yet supported by clinical trials which generally failed to achieve this tight control of blood pressure.

In diabetic patients, the efficacy of antihypertensive treatment in the UKPDS trial was higher than expected based on the data from epidemiological analysis. The calculation made based on epidemiological data indicated that 10 mmHg reduction of mean systolic blood pressure would be

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Supplements For Diabetics

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