Impact of Type 2 Diabetes and Postmenopausal Hormone Therapy on Incidence of Cognitive Impairment in Older Women.
OBJECTIVE
In older women, higher levels of estrogen may exacerbate the increased risk for cognitive impairment conveyed by diabetes. We examined whether the effect of postmenopausal hormone therapy (HT) on cognitive impairment incidence differs depending on type 2 diabetes.


METHODS
The Women's Health Initiative (WHI) randomized clinical trials assigned women to HT (0.625 mg/day conjugated equine estrogens with or without [i.e., unopposed] 2.5 mg/day medroxyprogesterone acetate) or matching placebo for an average of 4.7-5.9 years. A total of 7,233 women, aged 65-80 years, were classified according to type 2 diabetes status and followed for probable dementia and cognitive impairment (mild cognitive impairment or dementia).


RESULTS
Through a maximum of 18 years of follow-up, women with diabetes had increased risk of probable dementia (hazard ratio [HR] 1.54 [95% CI 1.16-2.06]) and cognitive impairment (HR 1.83 [1.50-2.23]). The combination of diabetes and random assignment to HT increased their risk of dementia (HR 2.12 [1.47-3.06]) and cognitive impairment (HR 2.20 [1.70-2.87]) compared with women without these conditions, interaction P = 0.09 and P = 0.08. These interactions appeared to be limited to women assigned to unopposed conjugated equine estrogens.


CONCLUSIONS
These analyses provide additional support to a prior report that higher levels of estrogen may exacerbate risks that type 2 diabetes poses for cognitive function in older women. The role estrogen plays in suppressing non-glucose-based energy sources in the brain may explain this interaction.
Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC mespelan@wakehealth.edu.
Mark A
MA
Espeland
Departments of Pharmacology and Pharmaceutical Sciences, Biomedical Engineering, and Neurology, University of Southern California, Los Angeles, CA.
Roberta Diaz
RD
Brinton
Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
Christina
C
Hugenschmidt
Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
JoAnn E
JE
Manson
Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
Suzanne
S
Craft
Departments of Epidemiology and Biostatistics, Psychiatry, and Neurology, University of California, San Francisco, San Francisco, CA.
Kristine
K
Yaffe
Veterans Affairs Palo Alto Health Care System, Stanford University School of Medicine, Stanford, CA Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA.
Julie
J
Weitlauf
Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Winston-Salem, NC.
Leslie
L
Vaughan
Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN.
Karen C
KC
Johnson
Veterans Affairs Palo Alto Health Care System, Stanford University School of Medicine, Stanford, CA Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA.
Claudia B
CB
Padula
Department of Internal Medicine, Ohio State University, Columbus, OH.
Rebecca D
RD
Jackson
Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD.
Susan M
SM
Resnick
D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D003072:Cognition Disorders / Q000139:chemically induced* / Q000503:physiopathology; D003704:Dementia / Q000139:chemically induced* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000503:physiopathology*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D004967:Estrogens / Q000097:blood; D004966:Estrogens, Conjugated (USP) / Q000009:adverse effects; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D015994:Incidence; D017258:Medroxyprogesterone Acetate / Q000009:adverse effects; D017698:Postmenopause; D016032:Randomized Controlled Trials as Topic; D012306:Risk
D004967:Estrogens; D004966:Estrogens, Conjugated (USP); D017258:Medroxyprogesterone Acetate; D005947:Glucose