Journal Club Julie Shah, MD Milton S Hershey Medical Center Penn State University

Memory in Diabetes sub study embedded in the Action to Control Cardiovascular risks in Diabetes ( ACCORD)

Background ♥Elderly patient with T2Dm have at least twice the likelihood of developing late-life cognitive impairment or dementia ♥Possible mechanisms involve vascular, neurodegenerative or neurovascular processes

Hypothesis ♥At 40- months, patients randomized to receive intensive glycemic treatment strategy (targeting HbA1c of < 6.0%) would have a better cognitive function and larger brain volume than patients randomized to receive standard strategy targeting HbA1c %

♥Participants from ACCORD trial were eligible for the MIND study if they were recruited between Aug 2003 and Dec ♥Excluded patients < 55yr of age and participants form VA network ♥Additionally, within MIND a subset of participants were recruited for the MRI substudy

Methods ♥Intensive glycemic group-  treatment target HbA1c <6%  started on 2 or more classes of antiglycemic medications and new drug was added monthly if HbA1c was > 6% ♥Standard treatment group-  treatment target HbA1c %  Treatment was intensified if HbA1c >8%

Methods ♥Battery of cognitive tests were administered at baseline, 20 months and 40 months after randomization. ♥Primary cognitive outcome was Digital symbol substitution test (DSST)- test psychomotor speed, reasoning and memory ♥Secondary cognitive outcomes-  Rey auditory verbal learning test (RAVLT)- measures memory  Stroop test- executive functioning ♥MRI cohort- Brain MRI performed at baseline and 40-months with primary endpoint as Total brain volume (TBV) and secondary outcome Abnormal white matter (AWM)- indicates ischemic, demyelinating or inflammatory processes

Digit Symbol Substitution Test

Results 2977 enrolled for MIND study Intensive intervention = 1469 Standard intervention = completed study1416 completed study 632 participants eligible for MRI substudy Intensive intervention = 301Standard intervention = completed study273 completed study Total 2794

♥In Feb 2008, the intensive intervention arm was stopped due to increased risk for mortality. ♥These pts were moved to the standard treatment arm. By then pts in cognitive study had received treatment for median of 39months and MRI substudy had received treatment for 35 mo

Results 6.6%7.5% 0.41%0.57%

Discussion ♥Overall, there is NO evidence to suggest that intensive glycemic treatment strategies provide benefit to cognitive function. ♥There is a small difference in TBV favoring intensive treatment; however, ACCORD trial suggested that there was increased mortaltity, no overall cardiovascular benefit, increased risk of hypoglycemia and weight gain ♥It is possible that optimal diabetes care provided to all pts may have brought glucose down to sufficient control which may have thus attenuated treatment difference in cognitive scores.

♥Taking cognitive and MRI finding together, it may be reasonable to postulate that structural changes occur before cognitive changes and that over time cognitive differences between treatment groups may emerge. ♥With additional followup of this cohort we will be able to establish if different treatment strategies result on different rates of cognitive changes.