Cognitive decline and T2DM—a disconnect in the evidence?

1. Cognitive decline and T2DM—a disconnect in the evidence? Strachan, M. W. J. & Price, J. F. Nat. Rev. Endocrinol. 10, 258–260 (2014)

2. Cognition & Diabetes • Unequivocal evidence exists of a link between type 2 diabetes mellitus (T2DM), cognitive decline and dementia • This association has been the subject of numerous observational investigations and one such study has even suggested that diabetes mellitus is one of the largest potentially modifiable risk factors in the aetiology of dementia • 2 Observational studies have suggested potential mechanisms that underlie this association

3. Cognition & Diabetes • Given the complexity of the phenotype of T2DM, it is not surprising that multiple factors have been implicated; foremost amongst these are the classic vascular risk factors • However, few randomised clinical trials have tested interventions that might improve or slow the decline of cognitive function in patients with T2DM • The Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is important as it is by some margin the largest intervention study on cognitive impairment in diabetes mellitus

4. Cognition & Diabetes Potential mediators of cognitive impairment in patients with type 2 diabetes mellitus

5. The Background • The ACCORD study was a landmark trial investigating the effect of intensive management of blood glucose on cardiovascular outcomes in people with T2DM who were already at high risk of CV events • The study included 10,251 participants who were randomly assigned to undergo either intensive or less intensive glycaemic control • Of these, just under half of the participants were randomly assigned to an intensive blood pressure control strategy or a less intensive strategy. The remaining participants took part in a trial of blinded administration of fenofibrate versus placebo

6. The Background • The glycaemic control arm of the study was terminated prematurely because of an increased incidence of cardiovascular events in the intensive therapy arm • The trials investigating blood pressure and lipid levels continued to their planned end date • After 4.7 years, neither fenofibrate nor intensive blood pressure control8 had a statistically significant effect on the composite primary cardiovascular end point • However, a small reduction in the incidence of stroke was observed in the intensive blood pressure control group

7. The MIND substudy • The MIND substudy was established to investigate the effect of the intensive interventions on cognitive function • Recruitment started after the main studies had been established and individuals <55 years old were not eligible • Therefore, 5,575 of the main ACCORD participants were eligible and subsequently 2,977 individuals were recruited • Of these participants, 1,439 were enrolled in the blood pressure trial and 1,538 in the lipid trial; baseline characteristics were very similar to the overall ACCORD study population

8. The MIND substudy • Cognitive function was assessed at baseline and after 20 months and 40 months using a battery of cognitive tests that examined verbal memory, processing speed and executive function • MRI scanning of the brain at baseline and after 40 months was also undertaken in 503 participants; the main outcome measure was total brain volume (TBV)

9. The MIND substudy • The primary outcome measure of cognitive function (the score in the Digit Symbol Substitution Test) was similar in all the baseline groups and declined over the period of the study • However, no significant difference was found in adjusted mean scores after 40 months between either the intensive and standard blood pressure arms or the fenofibrate and placebo arms • No intervention effect was seen in any of the other cognitive tests performed

10. The MIND substudy • The group that underwent intensive blood pressure control had a significantly lower TBV than the group that received standard care, whereas no significant difference in TBV was seen between the two arms of the lipid trial • Participants who received the combination of standard blood pressure control and intensive glycaemic control experienced ~50% of the decline in TBV observed in the other groups in the blood pressure trial

11. The MIND substudy Implications • The fact that intensive blood pressure control and fibrate therapy do not seem to have an effect on cognitive decline in patients with T2DM is disappointing, but is perhaps not altogether surprising • A Cochrane review of randomised trials of antihypertensive therapy concluded there was no convincing evidence that any therapy to reduce blood pressure in later life prevented the development of dementia or cognitive impairment

12. The MIND substudy Implications • Similarly, a Cochrane review of randomised trials of statin therapy in people at increased risk of Alzheimer disease or dementia found no effect on prevention of dementia • The TBV data in ACCORD MIND imply that intensive control of blood pressure might actually be disadvantageous • However, these data must be treated with caution, as TBV cannot as yet be regarded as a surrogate marker of cognitive decline

13. Conclusion • Associations seen in observational studies might not necessarily reflect causal relationships, as a result of confounding factors • Conversely, we must not be too quick to dismiss the usefulness of findings from observational studies on the basis of the findings from a limited number of clinical trials • In the medium to long term, observational studies continue to be required to guide the development of new interventions and the design of more sophisticated trials