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Original Investigation |

Cognitive Function and Brain Structure in Persons With Type 2 Diabetes Mellitus After Intensive Lowering of Blood Pressure and Lipid Levels:  A Randomized Clinical Trial

Jeff D. Williamson, MD, MHS1; Lenore J. Launer, PhD2; R. Nick Bryan, MD3; Laura H. Coker, PhD4; Ronald M. Lazar, PhD5; Hertzel C. Gerstein, MD6,7; Anne M. Murray, MD8; Mark D. Sullivan, MD9; Karen R. Horowitz, MD10; Jingzhong Ding, PhD1; Santica Marcovina, PhD11; Laura Lovato, MS12; James Lovato, MS12; Karen L. Margolis, MD13; Christos Davatzikos, PhD3; Joshua Barzilay, MD14; Henry N. Ginsberg, MD15; Peter E. Linz, MD16; Michael E. Miller, PhD12; for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes (MIND) Investigators
[+] Author Affiliations
1Roena B. Kulynych Center for Memory and Cognition Research, Department of Internal Medicine, Wake Forest University, Winston-Salem, North Carolina
2Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
3Department of Radiology, University of Pennsylvania Health System, Philadelphia
4Division of Public Health Sciences, Department of Social Sciences and Health Policy, Wake Forest University, Winston-Salem, North Carolina
5Departments of Neurology and Neurological Surgery, Columbia University College of Physicians and Surgeons, New York, New York
6Department of Medicine, McMaster University, Hamilton, Ontario, Canada
7Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada
8Hennepin County Medical Center and Chronic Disease Research Group, Minneapolis, Minnesota
9Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle
10Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio
11Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle
12Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina
13Division of Epidemiology and Community Health, University of Minnesota Medical School, Minneapolis
14Kaiser Permanente, Crescent Center Medical Office, Tucker, Georgia
15Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York
16Cardiology Division, Naval Medical Center San Diego, San Diego, California
JAMA Intern Med. 2014;174(3):324-333. doi:10.1001/jamainternmed.2013.13656.
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Importance  Persons with type 2 diabetes mellitus (T2DM) are at increased risk for decline in cognitive function, reduced brain volume, and increased white matter lesions in the brain. Poor control of blood pressure (BP) and lipid levels are risk factors for T2DM-related cognitive decline, but the effect of intensive treatment on brain function and structure is unknown.

Objective  To examine whether intensive therapy for hypertension and combination therapy with a statin plus a fibrate reduces the risk of decline in cognitive function and total brain volume (TBV) in patients with T2DM.

Design, Setting, and Participants  A North American multicenter clinical trial including 2977 participants without baseline clinical evidence of cognitive impairment or dementia and with hemoglobin A1c (HbA1c) levels less than 7.5% randomized to a systolic BP goal of less than 120 vs less than 140 mm Hg (n = 1439) or to a fibrate vs placebo in patients with low-density lipoprotein cholesterol levels less than 100 mg/dL (n = 1538). Participants were recruited from August 1, 2003, through October 31, 2005, with the final follow-up visit by June 30, 2009.

Main Outcome Measures  Cognition was assessed at baseline and 20 and 40 months. A subset of 503 participants underwent baseline and 40-month brain magnetic resonance imaging to assess for change in TBV and other structural measures of brain health.

Results  Baseline mean HbA1c level was 8.3%; mean age, 62 years; and mean duration of T2DM, 10 years. At 40 months, no differences in cognitive function were found in the intensive BP-lowering trial or in the fibrate trial. At 40 months, TBV had declined more in the intensive vs standard BP-lowering group (difference, −4.4 [95% CI, −7.8 to −1.1] cm3; P = .01). Fibrate therapy had no effect on TBV compared with placebo.

Conclusions and Relevance  In participants with long-standing T2DM and at high risk for cardiovascular events, intensive BP control and fibrate therapy in the presence of controlled low-density lipoprotein cholesterol levels did not produce a measurable effect on cognitive decline at 40 months of follow-up. Intensive BP control was associated with greater decline in TBV at 40 months relative to standard therapy.

Trial Registration  clinicaltrials.gov Identifier: NCT00000620

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Figure 1.
Cohort Participation in the Primary Cognitive Outcome of the Blood Pressure (BP) and Lipid Trials

Participants were enrolled in the Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. DSST indicates Digit Symbol Substitution Test.

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Figure 2.
Cohort Participation in the Primary Magnetic Resonance Imaging (MRI) Outcome of the Blood Pressure (BP) and Lipid Trials

Participants were enrolled in the Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Standard and intensive BP interventions and active and placebo lipid treatments are described in the legend to Figure 1. TBV indicates total brain volume.aAgreeing to the MRI procedure indicates that participants signed a consent for MRI. Enrolled in the MIND MRI substudy indicates that they underwent a baseline MRI.

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Figure 3.
40-Month Decline in Total Brain Volume (TBV) in the Blood Pressure (BP) and Lipid Trials

Whiskers mark 95% confidence intervals. Intensive and standard glycemia therapy groups are described in the Supplement (eAppendix). Standard and intensive BP interventions and active and placebo lipid treatments are described in the legend to Figure 1.aP < .001 for heterogeneity of glycemia effect.bP = .86 for heterogeneity of glycemia effect.

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