title: Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy.
abstract: BACKGROUND
  People with type 2 diabetes are at risk of cognitive impairment and brain atrophy. We aimed to compare the effects on cognitive function and brain volume of intensive versus standard glycaemic control.
  
  
  METHODS
  The Memory in Diabetes (MIND) study was done in 52 clinical sites in North America as part of Action to Control Cardiovascular Risk in Diabetes (ACCORD), a double two-by-two factorial parallel group randomised trial. Participants (aged 55-80 years) with type 2 diabetes, high glycated haemoglobin A(1c) (HbA(1c)) concentrations (>7·5%; >58 mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive glycaemic control targeting HbA(1c) to less than 6·0% (42 mmol/mol) or a standard strategy targeting HbA(1c) to 7·0-7·9% (53-63 mmol/mol). Randomisation was via a centralised web-based system and treatment allocation was not masked from clinic staff or participants. We assessed our cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, at baseline and at 20 and 40 months. We assessed total brain volume (TBV), our primary brain structure outcome, with MRI at baseline and 40 months in a subset of participants. We included all participants with follow-up data in our primary analyses. In February, 2008, raised mortality risk led to the end of the intensive treatment and transition of those participants to standard treatment. We tested our cognitive function hypotheses with a mixed-effects model that incorporated information from both the 20 and 40 month outcome measures. We tested our MRI hypotheses with an ANCOVA model that included intracranial volume and factors used to stratify randomisation. This study is registered with ClinicalTrials.gov, number NCT00182910.
  
  
  RESULTS
  We consecutively enrolled 2977 patients (mean age 62·5 years; SD 5·8) who had been randomly assigned to treatment groups in the ACCORD study. Our primary cognitive analysis was of patients with a 20-month or 40-month DSST score: 1378 assigned to receive intensive treatment and 1416 assigned to receive standard treatment. Of the 614 patients with a baseline MRI, we included 230 assigned to receive intensive treatment and 273 assigned to receive standard treatment in our primary MRI analysis at 40 months. There was no significant treatment difference in mean 40-month DSST score (difference in mean 0·32, 95% CI -0·28 to 0·91; p=0·2997). The intensive-treatment group had a greater mean TBV than the standard-treatment group (4·62, 2·0 to 7·3; p=0·0007).
  
  
  CONCLUSIONS
  Although significant differences in TBV favoured the intensive treatment, cognitive outcomes were not different. Combined with the non-significant effects on other ACCORD outcomes, and increased mortality in participants in the intensive treatment group, our findings do not support the use of intensive therapy to reduce the adverse effects of diabetes on the brain in patients with similar characteristics to those of our participants.
  
  
  BACKGROUND
  US National Institute on Aging and US National Heart, Lung, and Blood Institute.
authors.affiliation: Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. launerl@nia.nih.gov
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.forename: Michael E
authors.initials: ME
authors.lastname: Miller
authors.forename: Jeff D
authors.initials: JD
authors.lastname: Williamson
authors.forename: Ron M
authors.initials: RM
authors.lastname: Lazar
authors.forename: Hertzel C
authors.initials: HC
authors.lastname: Gerstein
authors.forename: Anne M
authors.initials: AM
authors.lastname: Murray
authors.forename: Mark
authors.initials: M
authors.lastname: Sullivan
authors.forename: Karen R
authors.initials: KR
authors.lastname: Horowitz
authors.forename: Jingzhong
authors.initials: J
authors.lastname: Ding
authors.forename: Santica
authors.initials: S
authors.lastname: Marcovina
authors.forename: Laura C
authors.initials: LC
authors.lastname: Lovato
authors.forename: James
authors.initials: J
authors.lastname: Lovato
authors.forename: Karen L
authors.initials: KL
authors.lastname: Margolis
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Connor
authors.forename: Edward W
authors.initials: EW
authors.lastname: Lipkin
authors.forename: Joy
authors.initials: J
authors.lastname: Hirsch
authors.forename: Laura
authors.initials: L
authors.lastname: Coker
authors.forename: Joseph
authors.initials: J
authors.lastname: Maldjian
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Sunshine
authors.forename: Charles
authors.initials: C
authors.lastname: Truwit
authors.forename: Christos
authors.initials: C
authors.lastname: Davatzikos
authors.forename: R Nick
authors.initials: RN
authors.lastname: Bryan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D011345:Fenofibrate / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D009929:Organ Size / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D011345:Fenofibrate; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents