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Diabetes in Midlife and Cognitive Change Over 20 Years: A Cohort StudyDiabetes in Midlife and Cognitive Change Over 20 Years

Andreea M. Rawlings, MS; A. Richey Sharrett, MD, DrPH; Andrea L.C. Schneider, PhD; Josef Coresh, MD, PhD, MHS; Marilyn Albert, PhD; David Couper, PhD, MS; Michael Griswold, PhD; Rebecca F. Gottesman, MD, PhD; Lynne E. Wagenknecht, Dr PH, MPH; B. Gwen Windham, MD; and Elizabeth Selvin, PhD, MPH
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From Johns Hopkins Bloomberg School of Public Health and Johns Hopkins University School of Medicine, Baltimore, Maryland; University of North Carolina, Chapel Hill, North Carolina; University of Mississippi Medical Center, Jackson, Mississippi; and Wake Forest University, Winston-Salem, North Carolina.

Note: Ms. Rawlings had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Acknowledgment: The authors thank the staff and participants of the ARIC study for their important contributions (staff members are listed in Appendix 2).

Grant Support: ARIC is a collaborative study supported by contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C from the National Heart, Lung, and Blood Institute (NHLBI). Neurocognitive (ARIC-NCS) data are collected with support from NHLBI grants U01HL096812, HL096814, HL096899, HL096902, and HL096917, and previous magnetic resonance imaging examinations of the brain were funded by NHLBI grant R01HL70825. Ms. Rawlings and Dr. Schneider were supported by training grant T32HL007024 from NHLBI. Dr. Selvin was supported by grant R01DK089174 from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Gottesman was supported by grant R01AG040282 from the National Institute on Aging.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0737.

Reproducible Research Statement:Study protocol and data set: Protocols and data for the parent ARIC-NCS may be obtained by approved persons through written agreements with the ARIC Steering Committee and the research sponsor (NHLBI). Statistical code: Available from Dr. Selvin (e-mail, eselvin@jhu.edu).

Requests for Single Reprints: Elizabeth Selvin, PhD, MPH, Associate Professor of Epidemiology & Medicine, Welch Center for Prevention, Epidemiology and Clinical Research and the Johns Hopkins Bloomberg School of Public Health, 2024 East Monument Street, Suite 2-600, Baltimore, MD 21287; e-mail, lselvin@jhsph.edu.

Current Author Addresses:Ms. Rawlings and Drs. Schneider, Coresh, and Selvin: Department of Epidemiology and the Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, 2024 East Monument Street, Suite 2-600, Baltimore, MD 21287.

Dr. Sharrett: Department of Epidemiology and the Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room W6009, Baltimore, MD 21205.

Dr. Albert: Department of Neurology, Johns Hopkins University School of Medicine, Reed Hall West, Room 101B, 1620 McElderry Street, Baltimore, MD 21287.

Dr. Couper: Department of Biostatistics, University of North Carolina, 137 East Franklin Street, Suite 203, Chapel Hill, NC 27514.

Dr. Griswold: Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, 2500 North State Street, G551-07, Jackson, MS 39216.

Dr. Gottesman: Department of Neurology, Johns Hopkins University School of Medicine, Phipps 122 c/o Edna Gilliam, Meyer 6-109, 600 North Wolfe Street, Baltimore, MD 21287.

Dr. Wagenknecht: Division of Public Health Sciences, School of Medicine, Wake Forest University, Medical Center Boulevard, Room 2346, Winston-Salem, NC 27157.

Dr. Windham: Geriatrics Division, Department of Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216.

Author Contributions:Conception and design: A.L.C. Schneider, J. Coresh, B.G. Windham, E. Selvin.

Analysis and interpretation of the data: A.M. Rawlings, A.R. Sharrett, A.L.C. Schneider, J. Coresh, M. Griswold, R.F. Gottesman, L.E. Wagenknecht, E. Selvin.

Drafting of the article: A.M. Rawlings, E. Selvin.

Critical revision of the article for important intellectual content: A.M. Rawlings, A.R. Sharrett, A.L.C. Schneider, J. Coresh, M. Albert, D. Couper, M. Griswold, R.F. Gottesman, L.E. Wagenknecht, B.G. Windham, E. Selvin.

Final approval of the article: A.M. Rawlings, A.R. Sharrett, A.L.C. Schneider, J. Coresh, M. Albert, D. Couper, M. Griswold, R.F. Gottesman, L.E. Wagenknecht, B.G. Windham, E. Selvin.

Provision of study materials or patients: J. Coresh.

Statistical expertise: A.M. Rawlings, A.L.C. Schneider, D. Couper, M. Griswold, E. Selvin.

Obtaining of funding: J. Coresh, L.E. Wagenknecht.

Collection and assembly of data: A.M. Rawlings, J. Coresh, D. Couper, L.E. Wagenknecht.

Ann Intern Med. 2014;161(11):785-793. doi:10.7326/M14-0737
Text Size: A A A

Background: Type 2 diabetes is associated with dementia risk, but evidence is limited for possible associations of diabetes and prediabetes with cognitive decline.

Objective: To determine whether diabetes in midlife is associated with 20-year cognitive decline and to characterize long-term cognitive decline across clinical categories of hemoglobin A1c (HbA1c) levels.

Design: Prospective cohort study.

Setting: The community-based ARIC (Atherosclerosis Risk in Communities) study.

Participants: 13 351 black and white adults aged 48 to 67 years at baseline (1990 to 1992).

Measurements: Diabetes was defined by self-reported physician diagnosis or medication use or HbA1c level of 6.5% or greater. Undiagnosed diabetes, prediabetes, and glucose control in persons with diagnosed diabetes were defined by clinical categories of HbA1c level. Delayed word recall, digit symbol substitution, and word fluency tests were used to assess cognitive performance and were summarized with a global Z score.

Results: Diabetes in midlife was associated with a 19% greater cognitive decline over 20 years (adjusted global Z-score difference, −0.15 [;95% CI, −0.22 to −0.08];) compared with no diabetes. Cognitive decline was significantly greater among persons with prediabetes (HbA1c level of 5.7% to 6.4%) than among those with an HbA1c level less than 5.7%. Participants with poorly controlled diabetes (HbA1c level ≥7.0%) had greater decline than those whose diabetes was controlled (adjusted global Z-score difference, −0.16; P = 0.071). Longer-duration diabetes was also associated with greater late-life cognitive decline (P for trend < 0.001). Rates of decline did not differ significantly between white and black persons (P for interaction = 0.44).

Limitation: Single HbA1c measurement at baseline, 1 test per cognitive domain, and potential geographic confounding of race comparisons.

Conclusion: Diabetes prevention and glucose control in midlife may protect against late-life cognitive decline.

Primary Funding Source: National Institutes of Health.


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Figure 2.

Difference in global cognitive Z score decline by clinical category of HbA1c level compared with decline in persons without diabetes and HbA1c level <5.

“Adjusted for attrition” refers to the inverse probability of attrition weighting used to account for participant death or dropout during follow-up. Estimates and 95% CIs are from generalized linear models fit using generalized estimating equations for global cognitive Z score, with adjustment for age; age2; race–field center; sex; education; cigarette smoking status; alcohol consumption; hypertension; history of coronary heart disease; history of stroke; apolipoprotein E ϵ4 genotype; body mass index; interactions between each of these variables and time (except alcohol consumption and history of coronary heart disease, which were not significant); and interactions between race–field center and sex, hypertension, and education. HbA1c level was categorized by using the standard clinical cut points based on American Diabetes Association criteria (<5.7% [n = 9031], 5.7% to 6.4% [n = 2365], and ≥6.5% [n = 7011] in participants without a diagnosis of diabetes and <7.0% [n = 415] and ≥7.0% [n = 829] in those with diagnosed diabetes). HbA1c = hemoglobin A1c.

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Appendix Figure.

Propensity score distribution for persons with and without diabetes, in the full cohort (top) and among matched participants (bottom).

Propensity scores were calculated from logistic models that included sex, age, race–field center, education, cigarette smoking status, alcohol consumption, hypertension status, prevalent coronary heart disease, prevalent stroke, and body mass index.

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Diabetes in Midlife and Cognitive Change Over 20 Years
Posted on December 19, 2014
Lucile Parker Gregg, MD, James P LoGerfo, MD, MPH, FACP
University of Washington
Conflict of Interest: None Declared
Cognitive decline is an ever-increasingly important clinical issue in the United States as the population ages, and studying the relationship between cognitive decline and diabetes, also increasingly prevalent, could potentially be of great benefit. Rawlings and colleagues sought to evaluate this relationship in their two-decade cohort study (1) correlating diabetes in midlife and cognitive decline in black and white participants from the Atherosclerosis Risk in Communities (ARIC) study.

Both cognitive decline and diabetes are complex conditions with many associated factors. Consequently, the risk of confounding factors is high, and this study left out some important points relevant to the interpretation of the data presented. First, the study included no evaluation of physical activity, which is known to be associated with cognitive decline and age-related white matter changes in the elderly (2). Second, hypertension may have had a significant role in the outcomes of this study. The study design included hypertension as a binary covariate, recorded only as present or absent in each patient. In this study, not only was hypertension more common in the diabetic cohort, but also the diabetic cohort included a much higher percentage of black participants. Health disparities literature shows that even as recently 2011 blood pressure control between black and white people remains unequal (3), so it is conceivable that such disparities existed during the 1980s when this study began, thereby emphasizing the confounding effect of blood pressure level on the cognitive decline seen in this subgroup.

Finally, and perhaps most importantly, while this is among the more thorough epidemiologic studies about this subject, the suggestion that glucose control to an A1c below 7.0% in midlife could protect against cognitive decline is of concern in face of the risks of aggressive glycemic control. The ACCORD trial (4) examined patients not dissimilar from those in this study; they had a baseline hemoglobin A1c of 8.1%, and the average A1c achieved by the standard therapy group and the intensive therapy group is similar to the grouping of patients in this study to an A1c of less than 7.0% or greater to or equal than 7.0%. That study was stopped after 3.5 years due to excess mortality in the intensively treated group. A potential improvement in cognitive decline does not outweigh the increase in mortality from intensive glycemic control.

1. Rawlings AM, Sharrett AR, Schneider AL, Coresh J, Albert M, Couper D, et al. Diabetes in Midlife and Cognitive Change Over 20 Years: A Cohort Study. Ann Intern Med. 2014;161:785-793.
2. Rosness TA, Strand BH, Bergem ALM, Engedal K, Bjertness E. Associations between Physical Activity in Old Age and Dementia-Related Mortality: A Population-Based Cohort Study. Dementia and Geriatric Cognitive Disorders EXTRA 2014;4(3):410-418.
3. Ayanian JZ, Landon BE, Newhouse JP, Zaslavsky AM. Racial and Ethnic Disparities among Enrolees in Medicare Advantage Plans. N Engl J Med 2014;371:2288-2297.
4. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med 2008;358:2545-2559.
Author's Response
Posted on February 10, 2015
Andreea M. Rawlings, MS, A. Richey Sharrett, MD, DrPH, Elizabeth Selvin, PhD, MPH
Johns Hopkins University
Conflict of Interest: None Declared
Drs. Gregg and LoGerfo raise several important points. First, we agree that physical activity may be a confounder in the association of mid-life diabetes with late-life cognitive decline. Unfortunately, physical activity was not assessed at the baseline visit for our study (ARIC visit 2, 1990-1992). We did, however, evaluate physical activity assessed using the Baecke Questionnaire at ARIC visit 1 (1987-1989) but this variable was not a significant risk factor for cognitive decline and its inclusion in our final model did not materially alter our results.

Second, we agree that care should be taken to address the potential confounding by hypertension, and that disparities in blood pressure control by race could impact our results. The relationship between hypertension and cognitive decline has recently been explored in ARIC(1). This study by Gottesman et al found significant associations between blood pressure and cognitive decline in whites but not blacks, likely due to higher rates of loss-to-follow-up in the latter group. By contrast, we observed similar associations of diabetes with cognitive decline in blacks and whites before and after adjustment for blood pressure and hypertension medication use.

Lastly, we also agree that targeting very low HbA1c values in persons with diabetes may be problematic for many reasons. As Drs. Gregg and LoGerfo point out, the ACCORD trial showed increased risk of death among persons in the intensive glycemic control (A1c target <6%) vs standard control group (A1c of 7 to 7.9%). Our observational study is reassuring. We found that middle-aged adults with diabetes who had good glycemic control (HbA1c <7%) at baseline (1990-1992) were less likely to have late-life (20-year) cognitive decline as compared to their counterparts who had poor mid-life glycemic control (HbA1c >7%). Indeed, in observational studies, middle-aged adults with diabetes in the community with HbA1c <7% consistently have better outcomes and survival as compared to persons with poorly controlled diabetes(2–4).

Our findings not only highlight the importance of diabetes prevention for the preservation of cognition but also suggest that persons with diabetes who maintain good glycemic control may benefit in the long run. Given the infeasibility of conducting long-term trials, evidence generated by long-term observational studies is likely the best we will have for suggesting ways for preventing cognitive decline.

(word count=371)

1. Gottesman RF, Schneider ALC, Albert M, Alonso A, Bandeen-Roche K, Coker L, et al. Midlife Hypertension and 20-Year Cognitive Change. JAMA Neurol. 2014 Aug 4 [cited 2014 Aug 5]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/25090106
2. Selvin E. Meta-Analysis: Glycosylated Hemoglobin and Cardiovascular Disease in Diabetes Mellitus. Ann Intern Med [Internet]. American College of Physicians; 2004 Sep 21 [cited 2015 Feb 9];141(6):421. Available from: http://annals.org/article.aspx?articleid=717820
3. Khaw KT, Wareham N, Luben R, Bingham S, Oakes S, Welch A, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of european prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ [Internet]. 2001 Jan 6 [cited 2015 Feb 9];322(7277):15–8. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=26599&tool=pmcentrez&rendertype=abstract
4. Selvin E, Ning Y, Steffes MW, Bash LD, Klein R, Wong TY, et al. Glycated hemoglobin and the risk of kidney disease and retinopathy in adults with and without diabetes. Diabetes [Internet]. 2011 Jan [cited 2015 Feb 6];60(1):298–305. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3012185&tool=pmcentrez&rendertype=abstract

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Summary for Patients

Diabetes in Midlife and Cognitive Change Over 20 Years

The full report is titled “Diabetes in Midlife and Cognitive Change Over 20 Years. A Cohort Study.” It is in the 2 December 2014 issue of Annals of Internal Medicine (volume 161, pages 785-793). The authors are A.M. Rawlings, A.R. Sharrett, A.L.C. Schneider, J. Coresh, M. Albert, D. Couper, M. Griswold, R.F. Gottesman, L.E. Wagenknecht, B.G. Windham, and E. Selvin.


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