Treatment Opportunities

Currently there are no established specific treatment measures to prevent or ameliorate cognitive impairments in patients with diabetes. However, some of the factors that are discussed in the previous sections of this chapter, in particular blood glucose levels and vascular risk factors, are potential targets for intervention and are increasingly being examined in treatment studies that include cognition as an outcome measure.

There are indications that cognitive dysfunction in patients with type 2 diabetes is partially reversible with improvement of glycemic control

(144-148), though not invariably (149). These observations will need to be confirmed in properly designed randomized clinical trials on the effects of intensified glucose-lowering therapy versus standard treatment (150). A recent randomized trial comparing the effects of rosiglitazone to glyburide therapy found similar and statistically significant cognitive improvement in both treatment groups on measures of working memory, but not on learning and cognitive speed (144). The magnitude of the improvement was correlated with the degree to which fasting plasma glucose improved (correlation coefficient r = 0.30). The DCCT trial, however, showed no differences in cognitive functioning after 6.5 years between type 1 diabetes patients who received conventional treatment versus those who received intensive treatment (151). Cognitive performance also remained similar in the two groups after 18 years of follow-up (133).

Regarding the effects of improved glycemic control on cognition, it is difficult to disentangle the interplay between (1) patient factors, which demand a particular therapy, (2) potential direct effects of treatment on the brain, and (3) indirect effects of treatment on the brain, through modulation of glucose levels. This complex interplay, which prohibits inferences on causality, is clearly reflected in observations from the Rotterdam study, where patients receiving insulin treatment had the highest risk of developing dementia [OR 4.3 (95% CI 1.7-10.5)], oral glucose-lowering medication was associated with an intermediate risk [OR 2.4 (95% CI 1.4-4.1)] and the lowest risk was found in patients who received no drug treatment [OR 1.3 (95% CI 0.7-2.3)] (152).

It is yet uncertain whether reductions in the level of vascular risk factors will prevent cognitive decline in patients with type 2 diabetes. Studies in the general population thus far do not consistently demonstrate that modifications of vascular risk factors can delay cognitive decline or dementia (153-155), despite the fact that such treatment effectively prevents macrovascular events such as stroke or myocardial infarction. Limitations of the available studies, including timing and duration of the interventions, may be a source of this uncertainty and vascular risk factors remain a promising target for therapy. Results from further studies on this topic are therefore eagerly awaited. A study in a small cohort of hyperlipidemic patients with type 2 diabetes who were treated with atorvastatin showed that verbal memory improvement was associated with improvement of the diabetic dyslipi-demia profile, regardless of high- or low-dose atorvastatin (156).

Other approaches include physical activity, lowering of glucocorticoid levels, and reducing oxidative stress. Certain types of physical activity, including light and moderate exercise, appear to be beneficial to cognitive functioning in patients with type 2 diabetes (157). In a small randomized, placebo-controlled study administration of the 11^-hydroxysteroid dehydro-

genase inhibitor carbenoxolone improved verbal memory after 6 weeks in 12 patients with type 2 diabetes (158). Moreover, reduction of oxidative stress by taking high-dose antioxidant supplements after a high-fat meal prevented an acute post-prandial decline in delayed verbal memory in 16 patients with type 2 diabetes (159).

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