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.
OBJECTIVE
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.


METHODS
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.


METHODS
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] cm(3); P = .01). Fibrate therapy had no effect on TBV compared with placebo.


CONCLUSIONS
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.
Roena B. Kulynych Center for Memory and Cognition Research, Department of Internal Medicine, Wake Forest University, Winston-Salem, North Carolina.
Jeff D
JD
Williamson
Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
Lenore J
LJ
Launer
Department of Radiology, University of Pennsylvania Health System, Philadelphia.
R Nick
RN
Bryan
Division of Public Health Sciences, Department of Social Sciences and Health Policy, Wake Forest University, Winston-Salem, North Carolina.
Laura H
LH
Coker
Departments of Neurology and Neurological Surgery, Columbia University College of Physicians and Surgeons, New York, New York.
Ronald M
RM
Lazar
Department of Medicine, McMaster University, Hamilton, Ontario, Canada7Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada.
Hertzel C
HC
Gerstein
Hennepin County Medical Center and Chronic Disease Research Group, Minneapolis, Minnesota.
Anne M
AM
Murray
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.
Mark D
MD
Sullivan
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio.
Karen R
KR
Horowitz
Roena B. Kulynych Center for Memory and Cognition Research, Department of Internal Medicine, Wake Forest University, Winston-Salem, North Carolina.
Jingzhong
J
Ding
Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle.
Santica
S
Marcovina
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Laura
L
Lovato
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
James
J
Lovato
Division of Epidemiology and Community Health, University of Minnesota Medical School, Minneapolis.
Karen L
KL
Margolis
Department of Radiology, University of Pennsylvania Health System, Philadelphia.
Christos
C
Davatzikos
Kaiser Permanente, Crescent Center Medical Office, Tucker, Georgia.
Joshua
J
Barzilay
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York.
Henry N
HN
Ginsberg
Cardiology Division, Naval Medical Center San Diego, San Diego, California.
Peter E
PE
Linz
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Michael E
ME
Miller
D000368:Aged; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000473:pathology / Q000523:psychology*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy*; D006973:Hypertension / Q000188:drug therapy*; D008055:Lipids / Q000097:blood*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids