In these analyses of the ADVANCE study, patients with type 2 diabetes and mildly impaired cognitive function, as assessed by the MMSE were at increased risk of cardiovascular events and death. Patients with more severe cognitive dysfunction were at even greater risk of such events and were also at increased risk of severe hypoglycaemia. For all these outcomes, there was an inverse and continuous correlation with the MMSE score, in that the lower the MMSE score the higher the event risk. There was no evidence to suggest that cognitive dysfunction modified the response to BP-lowering or glucose-control treatments in the management of cardiovascular risk. Thus, patients with cognitive dysfunction appeared to benefit to the same extent as patients with normal cognitive function from interventions that reduce the risks of cardiovascular outcomes. As previously reported, in this group of patients with type 2 diabetes neither BP lowering nor intensive glucose control had any effect on the development of cognitive impairment and dementia [17, 18].
Our findings of increased mortality and cardiovascular disease risks associated with baseline cognitive impairment are in agreement with observations in the general elderly population [10, 11, 13, 22], and in older patients with diabetes . Adjusting for level of education did not materially alter these risks (data not shown, but available on request), making it unlikely that our results were merely an extension of a low level of intelligence, which by itself carries an increased cardiovascular risk [23, 24]. Much of the increased risk may be explained by the higher prevalence of cardiovascular risk factors among patients with cognitive dysfunction. However, although attenuated, the association between impaired cognitive function and major clinical outcomes in our study remained statistically significant even after controlling for these risk factors. This may be caused in part by incomplete adjustment for and consequent overestimation of covariates measured with substantial error, and in part to covariates that were unmeasured or otherwise unknown, such as subclinical vascular disease or poor compliance with pharmacological and non-pharmacological treatments .
A potential biological factor that could explain the link between cognitive dysfunction and cardiovascular events concerns chronic hyperinsulinaemia or insulin resistance. Chronic hyperinsulinaemia has been associated with both cognitive dysfunction  and increased risk of cardiovascular death . There has also been an association between low beta cell function, a determinant of type 2 diabetes and thus of chronic hyperinsulinaemia later in life, and Alzheimer’s disease . Insulin resistance, a well-known risk factor for atherosclerosis , has been associated with vascular dementia . Although once considered insulin-insensitive, the brain is now thought to depend on intact insulin signalling for several aspects of its function, including memory formation. Chronic hyperinsulinaemia and peripheral insulin resistance may impair insulin signalling by reducing cerebral insulin uptake  and insulin action , respectively. They may also impair memory function and precede Alzheimer’s disease by increasing the levels of inflammatory factors and β-amyloid in the brain .
Patients with severe cognitive dysfunction were at twofold higher risk of severe hypoglycaemia than patients with normal cognitive function. Thus while both patients and physicians share concern that severe hypoglycaemia may be implicated in the aetiology of cognitive impairment , they should also be aware of a possible causal relationship in the opposite direction. The higher risk of severe hypoglycaemia was independent of recognised risk factors such as old age, low HbA1c, long duration of diabetes and cardiovascular risk factors. However, it is conceivable that incomplete adherence to or inappropriate use of the glucose-control regimen, which could not be assessed with certainty, might have played a role. Management of diabetes is complex and heavily dependent on active involvement of patients with respect to drug compliance, glucose testing, meal planning and insulin dose titration. This is a demanding process that could cause greater difficulties for patients with severe cognitive impairment. Nevertheless, our analyses did not reveal increased relative risks of hypoglycaemia associated with intensive glucose-control intervention in patients with mild or severe cognitive dysfunction. However, information on mild hypoglycaemia was only collected on the basis of self-reporting, which may be less reliable in the cognitively impaired. Furthermore, there were too few severe hypoglycaemic episodes overall to have adequate power for this subgroup analysis.
There are limited data on the efficacy of risk-factor management in people with impaired cognitive function. Among elderly people with hypertension, BP-lowering treatment was recently reported to reduce the risk of stroke to the same extent as in patients with mildly impaired or normal cognitive function . Our data support these findings in that the relative benefits of BP-lowering treatment and risks of intensive glucose control in patients with type 2 diabetes were largely independent of the level of cognitive function. The greater baseline risk of different outcomes in patients with cognitive dysfunction may translate these similar relative treatments effects into both greater absolute benefits and greater absolute risks (for example severe hypoglycaemia). In this respect, there was some suggestion that cognitive function modified the effect of glucose lowering on survival, in that patients with lower MMSE scores benefited less than those with higher scores. Although this finding was probably caused by chance, it supports the importance of balancing potential benefits and risks for each patient when making treatment decisions. In any case, there seems little justification in denying patients risk-modifying treatment solely on the basis of cognitive impairment.
Some limitations of this study merit consideration. First, the MMSE was originally designed as a screening test for dementia and not especially for the assessment of milder degrees of cognitive dysfunction . However, this limitation may be less relevant for the use of MMSE in cohort or epidemiological studies. Second, at baseline most patients had maximal MMSE scores (i.e. normal cognitive function) with only a small proportion (<2%) demonstrating severe impairment of cognitive function. Thus there was limited statistical power to analyse risks associated with severe cognitive dysfunction. Yet when analysing risks of clinical outcomes by using MMSE as a continuous variable, similar results were yielded, substantiating the validity of our results, at least with respect to mild cognitive dysfunction. As indicated previously, there was insufficient power to analyse the risk of severe hypoglycaemia by randomised glucose-control assignment in cognitive function subgroups.
In conclusion, our data show that cognitive dysfunction further increases the already greater risk of cardiovascular events and death, but does not adversely modify the response to BP- or glucose-lowering treatment in patients with type 2 diabetes. This is clinically relevant, as cognitive decline is common among patients with type 2 diabetes and may influence management . Our data do not support commonly held views [8, 15, 16] suggesting general restraints with regard to cardiovascular risk management in patients with cognitive impairment. Therefore, rather than denying patients with type 2 diabetes risk-modifying treatment on the basis of cognitive dysfunction, such patients deserve a similar careful balancing of all potential risks and benefits associated with treatment to that of patients with intact cognitive function. Future guidelines may need to address this growing patient group in their directives for clinical care.