ACCORD MIND is the first randomised trial in older persons with T2D to test the effect of intensive compared to standard glycaemic therapeutic strategies on multiple cognitive domains and on structural changes in the brain. Overall, there is no evidence that in this patient group with long-standing T2D, high CVD risk and mean age 62 years, an intensive glycaemic therapeutic strategy provides benefit to cognitive function. There was a significant but small difference in TBV favoring the intensive strategy. This difference would not support using intensive therapy as a means to reduce brain atrophy when taking into account the effects this intervention had in the main ACCORD trial, including increased mortality, no overall benefit on CVD events, an increase in hypoglycaemic events and weight gain (7
The MIND 30% sub-sample of ACCORD participants, the separation in HbA1c levels, and differences in mortality rates between the treatment strategy groups were similar to the main trial. There was reasonable balance of baseline characteristics between treatment groups. Adherence and retention to the cognitive assessment protocol was high, minimizing the likelihood of bias. The cognitive battery was successfully administered in a standardized manner in a large number of geographically and demographically diverse clinics; there were fewer missing 40-month DSST assessments than expected (11.1% (n=333) actual vs. 15% expected), and these were distributed similarly across the treatment arms (11.2% (n=165) intensive vs. 11.1% (n=168) standard strategies). The overall conclusions did not change with different assumptions about the missing 40-month scans.
Several factors may have attenuated treatment differences in cognitive scores. Not all participants completed 40 months on intensive therapy, but most had at least 34 months of therapy. Methodologic factors, such as practice effects, may contribute but these effects should be similar in both treatment arms. Possibly the tests did not measure the appropriate functions but those functions have been repeatedly shown to be affected in T2D (9
) and the tests are appropriate for a large-scale heterogeneous study population. For the deaths to have influenced our conclusion in favor of intensive therapy, the 47 decedents in the intensive group would have had to have considerably higher follow-up cognitive scores than the 39 decedents in the standard group. We think this is unlikely because it assumes the 8 excess deaths would have had to specifically occur in persons whose MIND outcomes would have benefited from intensive therapy.
There are several other explanations to consider. High patient motivation and the optimal diabetes care provided to all participants may have brought glucose into sufficient control to have mitigated some cerebral pathology caused by T2D (3
). Indeed optimal treatment has been raised as a reason for the null effect on cognition in the DCCT/EDIC trial (32
). Age may also be a factor insofar as treatment differences would be more apparent had they been given during a period when participants were experiencing more rapid decline in cognition (33
). It has been suggested that up to age 70 years, there is little measurable cognitive decline in persons with T2D, although after that the rates of decline begin to diverge between those who remain cognitively stable and those who will develop MCI or AD. Possibly intensive treatment was not efficacious given the relatively advanced disease and the elevated risk for CVD.
The annualized decline in TBV (3.9 cm3
) in the intensive group is 26% less than the annualized TBV change in the standard treatment group (5.31 cm3
). From another perspective, a study of persons mean age 76 years, found TBV of cognitively stable persons declined 0.4%/yr compared to 0.8%/yr in those who converted to Mild Cognitive Impairment or dementia (34
). This is compared to an annual decline of 0.42% in the intensive and 0.57% in the standard group. The increase in AWM volume in participants < 60 years in the intensive group requires further study. We found no evidence that major factors, edema or weight gain, influenced the results, although there may have been some other unknown or unmeasured side effect that may result in TBV treatment differences.
Taking cognitive and MRI findings together it is reasonable to hypothesize that in this age group structural brain changes occur before cognitive change and that over time cognitive differences between treatment arms will emerge. With additional on-going follow-up of the cohort, we will be able to determine whether, above overall good glyceamic control, the different treatment strategies resulted in different rates of cognitive change.
At this time, there is scant evidence to quantify the clinical impact of the observed treatment differences. It is reasonable to suggest that a larger decline in brain capacity will lead to earlier loss of function and possibly dementia – the MIND participants at an average of 62 years old are already experiencing an annual decline of TBV in the range reported for persons 15 years older (34
), when the incidence of dementia increases logarithmically. In addition, there are few data quantifying the trajectory of brain changes in persons with T2D who are similar in age to MIND participants, the functional effects of accumulating small decrements in brain structure and function, and the determinants of who, in a general population, will go on to dementia. Most data on persons with diabetes describe trajectories in (younger) type 1 diabetes (35
), or in cohorts that are at least 10 years older(1
). However, the age of MIND participants is the critical period when disease processes in the brain begin to accelerate eventually leading to the observed two times risk of dementia in persons with T2D compared to normotensives –and it is this transition phase where there are clearly gaps in our knowledge that need to be filled if we are to design effective prevention strategies.
Cognitive function influences the ability of patients to follow complex disease management protocols, and impaired cognition predicts CVD and severe hypoglycaemic events (36
). Early prevention strategies reducing the risk for cognitive impairment are needed as the longevity of this diabetic group increases along with the number reaching an age when cognitive disorders become clinically apparent. Optimal therapeutic strategies for brain health in older persons with T2D are needed and should be evaluated in the context of the risks and benefits on other sequelae of T2D.