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Risk of Dementia in Seniors with Newly Diagnosed 1868 Diabetes Care Volume 38, October 2015 Nisha Nigil Haroon,1 Peter C. Austin,2 Risk of Dementia in Seniors With Baiju R. Shah,1,2 Jianbao Wu,2 Newly Diagnosed Diabetes: A Sudeep S. Gill,2,3 and Gillian L. Booth1,2 Population-Based Study Diabetes Care 2015;38:1868–1875 | DOI: 10.2337/dc15-0491 OBJECTIVE To study whether diabetes onset in late life is a risk factor for dementia. RESEARCH DESIGN AND METHODS We conducted a population-based matched cohort study using provincial health data from Ontario, Canada. Seniors with (n = 225,045) and without newly diag- nosed diabetes (n = 668,070) between April 1995 and March 2007 were followed until March 2012 for a new diagnosis of dementia. Cox proportional hazards modeling was used to compare the risk of dementia between groups after adjust- EPIDEMIOLOGY/HEALTH SERVICES RESEARCH ing for baseline cardiovascular disease, chronic kidney disease (CKD), hyperten- sion, and other risk factors. RESULTS Over this period, we observed 169,114 new cases of dementia. Individuals with diabetes had a modestly higher incidence of dementia (2.68 vs. 2.62 per 100 person-years) than those without diabetes. In the fully adjusted Cox model, the risk of dementia was 16% higher among our subgroup with diabetes (hazard ratio [HR] 1.16 [95% CI 1.15–1.18]). Adjusted HRs for dementia were 1.20 (95% CI 1.17– 1.22) and 1.14 (95% CI 1.12–1.16) among men and women, respectively. Among seniors with diabetes, the risk of dementia was greatest in those with prior cerebrovascular disease (HR 2.03; 95% CI 1.88–2.19), peripheral vascular disease (HR 1.47; 95% CI 1.19–1.82), and CKD (HR 1.44; 95% CI 1.38–1.51), and those with one or more hospital visits for hypoglycemia (HR 1.73; 95% CI 1.62–1.84). 1Department of Medicine, University of Toronto, CONCLUSIONS Toronto, Canada 2Institute for Clinical Evaluative Sciences (ICES), In this population-based study, newly diagnosed diabetes was associated with a Toronto, Canada 16% increase in the risk of dementia among seniors. Preexisting vascular disease 3Department of Medicine, Queen’s University, and severe hypoglycemia were the greatest risk factors for dementia in seniors Kingston, Canada with diabetes. Corresponding author: Gillian L. Booth, boothg@ smh.ca. Received 7 March 2015 and accepted 2 July The incidence and prevalence of diabetes have increased substantially in recent 2015. years (1). Diabetes is a risk factor for blindness, kidney failure, coronary artery This article contains Supplementary Data online disease (CAD), stroke, and some cancers. However, medical advances over the at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc15-0491/-/DC1. past two decades have led to reductions in cardiovascular risk, resulting in longer life expectancy (2). This has led to the emergence of geriatric complications in A slide set summarizing this article is available online. elderly people with diabetes, including Alzheimer disease and related dementias. ’ © 2015 by the American Diabetes Association. With the aging of the world s population, both diabetes and dementia are expected Readers may use this article as long as the work is to become global epidemics. Currently, ;44 million people have dementia, and this properly cited, the use is educational and not for number is expected to reach 135 million by the year 2050 (3). profit, and the work is not altered. care.diabetesjournals.org Haroon and Associates 1869 There is a growing body of evidence Our secondary aim was to identify fac- those with evidence of physician-diag- supporting an association between dia- tors that predict a higher risk of demen- nosed dementia at baseline, based on phy- betes and dementia (4–11). Since the tia in elderly patients with diabetes, as sician billing claims and hospitalizations. two entities appear to share antecedent an aid to individualized risk assessment fi cardiometabolic risk factors, dementia and prevention. Outcome De nitions Individuals were followed until 31 may be yet another vascular complica- March 2012 for a new diagnosis of de- tion of diabetes. Cardiovascular risk fac- RESEARCH DESIGN AND METHODS mentia, our primary outcome. This was tors in midlife such as hypertension Setting and Data Sources defined based on one or more hospital- (HTN), dyslipidemia, and obesity have We conducted a population-based ization records or two outpatient physi- been implicated in the risk of dementia matched cohort study to assess the as- cian billing claims (within 6 months) in later life, although few studies have sociation between new-onset diabetes listing a relevant ICD-9 code (prior to 1 had sufficient follow-up to draw firm and dementia using provincial health April 2002: 290.x [except 290.8 or 290.9, conclusions (4,7,9). The demonstration administrative databases from Ontario, indicating senile psychosis], 331.0, of selective central nervous system ab- ’ Canada. Virtually all of Ontario s13.5 331.2, or 797) or ICD-10 code (1 April normalities in insulin signaling have led million residents receive coverage for 2002 onwards: F00, F01, F02.3, F03, to the notion that Alzheimer disease ’ health services under the province s F05.1, F09, G30, G31.1, or R54) (17– represents “type 3” diabetes (12–14). publicly funded universal health care 20). This algorithm was validated in a In animal models, insulin resistance at system. The Registered Persons Data- population of ;2,000 participants en- the level of the brain leads to tau hyper- base contains information on demo- rolled in the Canadian Study of Health phosphorylation and b-amyloid accu- graphics, location of residence, and and Aging and found to have positive and mulation, both of which may promote vital status of all individuals registered negative predictive values of 73 and the development of Alzheimer disease ’ under the province s health plan (i.e., all 94%, respectively, using results from ex- (15). Moreover, insulin may have direct Ontario residents, including new immi- tensive cognitive testing as the gold effects on cortical function. Hyperglyce- $ grants 3 months since arrival). Records standard (18). mia, itself, may exert direct effects can be linked anonymously across data- through advanced glycation end prod- bases in order to track each individual’s Baseline Variables ucts, oxidative stress, inflammation, health care utilization and health out- We collected data on baseline covari- and microvascular alterations such as comes over time. This study was ap- ates including age, sex, income, HTN, capillary basement membrane thicken- proved by the Institute for Clinical and history of CAD, cerebrovascular dis- ing, similar to abnormalities seen in the Evaluative Sciences and the institu- ease (CVD), peripheral vascular disease kidney and retina (13,14). tional review board of Sunnybrook (PVD), and chronic kidney disease (CKD) Epidemiological evidence also supports Health Sciences Centre in Toronto. in the 36 months prior to the index date, a direct link between diabetes and demen- using previously defined diagnostic al- tia (5–11). A meta-analysis published in Study Population and Eligibility gorithms (21–24) (Supplementary Table 2011, based on 19 longitudinal studies, Our study cohort consisted of Ontario 1). HTN was defined using an algorithm found a nearly 1.5-fold higher incidence seniors with newly diagnosed (incident) based on hospitalization and physicians’ of Alzheimer disease and a 2.5 times higher diabetes and a matched comparison co- claims data, similar to that of diabetes, likelihood of vascular dementia in those hort without diabetes, who were 66– which has a positive and negative pre- with preexisting diabetes (5). However, el- 105 years of age between 1 April 1995 dictive value of 87 and 88%, respectively igible studies had heterogeneous results and 31 March 2007. Individuals who (21). Prior CAD included hospitalizations and differed substantially with respect to had a new record in the Ontario Diabe- for acute myocardial infarction, percu- their definitions of exposure and outcome tes Database (ODD) during this window taneous transluminal coronary angio- events. Moreover, many studies were served as our exposure group. The ODD plasty, or coronary artery bypass surgery. limited by relatively small sample sizes, is a validated administrative data-derived Our definition of CVD included hospitaliza- insufficient numbers of outcome events, registry that has a sensitivity and spec- tion for stroke, transient ischemic attack, and lack of data on diabetes duration or ificity of 86 and 97% (respectively) for or carotid endarterectomy. We identified vascular risk factors. identifying individuals with physician- patients undergoing lower extremity ar- It is still unknown whether the onset diagnosed diabetes (16). Only individu- terial bypass surgery or percutaneous of diabetes in late life can accelerate als with health care coverage for a transluminal angioplasty as having PVD. In- cognitive decline. The primary aim minimum of 3 years were included to en- formation on individual-level income was of our study was to examine whether sure that new entries into the ODD were not available in our data sources; hence incident diabetes is a risk factor for truly incident cases. We then identified the median household income level of dementia in elderly individuals. We three matches without diabetes with the each individual’s neighborhood of resi- hypothesized that exposure to even same age, sex, and region of residence for dence, derived from the nearest Canadian short-term hyperglycemia in late life every person with newly diagnosed diabe- census year (1996, 2001, or 2006) was at- can trigger or accelerate cognitive de- tes in our cohort, using their entry date into tributed to them using their postal code. cline and therefore that incident diabe- the ODD as the baseline (index) date for Among individuals with diabetes, we tes is a risk factor for dementia after both groups.
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