Introduction
Study | Sample | Design | Number | Baseline mean age | Lipids | Cognitive measures | Adjustment variables | Association with cognitive function |
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Bruce et al. [14] (2008) | Patients with type 2 diabetes participating in the Fremantle Diabetes Study; Australia | 8-year retrospective, observational | 302 | Mean 76 ± 5 years | Total cholesterol and HDL at baseline and 8 years earlier | Dementia and MCI identified from screening instruments/clinical interview | Waist-hip ratio | No associations in unadjusted cross-sectional or prospective analyses. Higher total cholesterol 8 years earlier protective of cognitive impairment short of dementia (but not dementia or all cognitive impairment) at baseline (finding independent of waist-hip ratio) |
Chen et al. [9] (2011) | Patients with type 2 diabetes; China | Cross-sectional, observational | 101 | Mean 63 ± 8 years | Total cholesterol, LDL, and HDL | MCI identified on the basis of cognitive screening instrument | None | Higher triglycerides, total cholesterol, and LDL in MCI group compared with group free of MCI. Negative correlation of total cholesterol with scores on cognitive screening instrument in patients with MCI. No finding for HDL. |
Chen et al. [11] (2012) | Patients with type 2 diabetes; China | Cross-sectional, observational | 157 | Mean 55 ± 7 years | Triglycerides, total cholesterol, LDL, and HDL | MCI identified on the basis of cognitive screening instrument | None | No association |
Cukierman-Yaffe et al. [13] (2009) | Patients with type 2 diabetes participating in ACCORD-MIND; North America | Cross-sectional analysis of trial on blood pressure, lipids, and glycemic control | 2,977 | Mean 63 ± 6 years | Hyperlipidemia defined as use of lipid-lowering medication or untreated LDL cholesterol | Digit Symbol Coding (primary outcome), MMSE, Rey Auditory Verbal Learning, and Stroop (secondary outcomes) | Age | Association of hyperlipidemia with better performance on Digit Symbol Coding. No findings for other cognitive tests. |
Perlmutter et al. [10] (1988) | Patients with type 2 diabetes; USA | Cross-sectional, observational | 246 | Range 55-74 years | Triglycerides and total cholesterol | Digit Symbol Coding, Digit Span, and simple reaction time | Plasma glucose, HbA1c, body mass index, and history of hypertension | Lower cognitive function in ‘high’ compared with ‘low’ triglyceride groups (fully adjusted analysis); association of cholesterol with triglyceride (unadjusted analysis). |
Umegaki et al. [16] (2014) | Patients with type 2 diabetes; Japan | Six-year prospective, observational | 79 | Mean 74 ± 5 years | Mean of HDL and LDL measured at baseline and annual follow-ups | Composite score from MMSE, Digit Symbol Coding, Stroop, and word recall. Analyses of ‘decliners’ versus ‘non-decliners’ on the basis of composite score and individual cognitive tests. | Age, education, estimated glomerular filtration rate, renin-angiotensin system inhibitor use, paraventricular hyperintensities, and deep white matter hyperintensities | Lower mean 6-year HDL in ‘decliners’ compared with ‘non-decliners’ on composite score and Stroop (unadjusted analysis). No finding for LDL. Mean 6-year HDL significant predictor in model of risk of decline on composite score (fully adjusted analysis). |
Williamson et al. [17] (2014) | Patients with type 2 diabetes participating in ACCORD-MIND lipid arm, receiving simvastatin + fenofibrate or simvastatin + placebo; North America | 40-month trial on blood pressure, lipids, and glycemic control | 1,538 | Mean 62 ± 6 years | Successful manipulation of cholesterol levels (groups differed on cholesterol following intervention). | Total brain volume at baseline and 40 months, Digit Symbol Coding (primary outcome), MMSE, Rey Auditory Verbal Learning, and Stroop (secondary outcomes) at baseline and 20 and 40 months | Glycemia treatment arm, visit effect, clinical center, and history of cardiovascular disease | No difference in 20- or 40-month cognitive decline or 40-month change in total brain volume between intervention and control groups of lipid trial |
Van Harten et al. [12] (2007) | Patients with type 2 diabetes; The Netherlands | Cross-sectional, observational | 92 | Mean 73 ± 6 years | Total cholesterol/HDL ratio | Cognitive screening instruments, composite scores of four cognitive domains derived from scores on battery of 10 cognitive tests | Duration of diabetes, HbA1c, insulin use, hypertension, and polyneuropathy | No association |
Yanagawa et al. [15] (2011) | Patients with diabetes receiving exercise program four times per week versus none; Japan | 12-week trial on physical exercise intervention | 16 | Mean 71 ± 4 years | HDL and LDL (no intervention effect on HDL and LDL) | MMSE, word recall, Digit Symbol Coding, Stroop, and Trail-Making Test | Age, education, and body mass index | No difference in cognitive function between treatment groups following intervention |
Study | Sample | Design | Number | Baseline mean age | Blood pressure | Cognitive measures | Adjustment variables | Association with cognitive function |
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Chen et al. [11] (2012) | Patients with type 2 diabetes; China | Cross-sectional, observational | 157 | Mean 55 ± 7 years | Hypertension defined on the basis of systolic blood pressure and diastolic blood pressure | MCI identified on the basis of cognitive screening instrument | None | Higher prevalence of hypertension in group with MCI compared with group free of MCI. Negative correlation of presence with hypertension with cognitive scores. No findings for blood pressure as continuous measure. |
Bruce et al. [14] (2008) | Patients with type 2 diabetes participating in the Fremantle Diabetes Study; Australia | 8-year retrospective, observational | 302 | Mean 76 ± 5 years | Systolic blood pressure and diastolic blood pressure at baseline and 8 years earlier | Dementia and MCI identified from screening instruments/clinical interview | Age and duration of diabetes | Prospective analyses: higher diastolic blood pressure 8 years earlier associated with increased risk of AD (but not MCI or any dementia) at follow-up. No findings in cross-sectional analyses. |
Bruce et al. [21] (2008) | Patients with type 2 diabetes participating in the Fremantle Diabetes Study; Australia | 8-year retrospective, 2-year prospective, observational | 205 | Mean 75 ± 4 years | Systolic blood pressure and diastolic blood pressure measured 8 years prior to baseline cognitive assessment | Dementia and MCI identified from screening instruments/clinical interview at baseline and 2-year follow-up. ‘Cognitive decline’ defined as downward conversion between ‘normal’, MCI, and dementia. | None | No association |
Cukierman-Yaffe et al. [13] (2009) | Patients with type 2 diabetes participating in ACCORD-MIND; North America | Cross-sectional analysis of trial on blood pressure, lipids, and glycemic control | 2,977 | Mean 63 ± 6 years | Hypertension defined as use of anti-hypertensive medication or self-report of hypertension | Digit Symbol Coding (primary outcome), MMSE, Rey Auditory Verbal Learning, and Stroop (secondary outcomes) | Age | Association of hypertension with poorer performance on Digit Symbol Coding. No findings for other cognitive tests. |
Hassing et al. [19] (2004) | OCTO-Twin Study of people without diabetes/hypertension, diabetes or hypertension alone, or co-morbid diabetes/hypertension; Sweden | 6-year prospective, observational | 258 | Mean 83 ± 2 years | Hypertension defined as use of anti-hypertensive medication or on the basis of systolic blood pressure and diastolic blood pressure from medical records | MMSE administered at baseline and at 2-year intervals, dementia diagnosis prevalent at baseline, and incident dementia diagnosis | Age, sex, education, smoking, angina, MI, CHF, stroke, and TIA | Co-morbid diabetes/hypertension associated with steeper decline on MMSE (compared with group free of both conditions). |
Statistically non-significant trend for higher prevalence and incidence of dementia in co-morbid diabetes/hypertension group than in remaining groups. | ||||||||
Johnson et al. [22] (2012) | National cohort of veterans with diabetes; USA | 2-year retrospective, observational study of hospital records | 377,838 | Mean 76 ± 6 years | ICD codes for hypertension at baseline (2 years before analysis of incident dementia) | ICD codes for incident dementia diagnosis | Age, ethnicity, geographic area, duration of diabetes, co-morbidity according to HCC scores, and medication use | 8 % increased risk of developing dementia during follow-up in patients with co-morbid hypertension at baseline. |
Decreased risk in patients on anti-hypertensive medication (effect size dependent on medication), except for increased risk in patients receiving α-adrenoceptor blockers. | ||||||||
Manschot et al. [20] (2006) | Patients with type 2 diabetes participating in the Utrecht Diabetic Encephalopathy Study; The Netherlands | Cross-sectional, observational | 122 | Mean 66 ± 6 years | Hypertension defined on the basis of systolic blood pressure and diastolic blood pressure or use of anti-hypertensive medication | Composite scores on five cognitive domains from 11 cognitive tests, estimate of pre-morbid ability, cortical atrophy, and white matter lesions | Age, sex, and estimated pre-morbid ability | Statistically non-significant trend for lower scores on all cognitive domains except memory in patients with hypertension. Higher blood pressure associated with higher scores on memory domain and with greater severity of white matter lesions. |
Manschot et al. [25] (2007) | Patients with type 2 diabetes participating in the Utrecht Diabetic Encephalopathy Study; The Netherlands | Cross-sectional, observational | 122 | Mean 66 ± 6 years | Hypertension defined on the basis of systolic blood pressure and diastolic blood pressure or use of anti-hypertensive medication | Composite score from 11 cognitive tests, estimate of pre-morbid ability, cortical atrophy, and white matter lesions | Age, sex, and estimated pre-morbid ability | Statistically non-significant trend for lower cognitive function in patients with hypertension (reaches statistical significance in final model including age, estimated pre-morbid ability, lipid-lowering drugs, and history of any vascular event). Higher blood pressure associated with greater severity of white matter lesions. |
Umegaki et al. [16] (2014) | Patients with type 2 diabetes; Japan | 6-year prospective, observational | 79 | Mean 74 ± 5 years | Mean of systolic blood pressure and diastolic blood pressure measured at baseline and annual follow-ups | Composite score from MMSE, Digit Symbol Coding, Stroop, and word recall. Analyses of ‘decliners’ versus ‘non-decliners’ on bases of composite score and individual cognitive tests. | None | No association |
Williamson et al. [17] (2014) | Patients with type 2 diabetes participating in ACCORD-MIND blood pressure arm, with systolic blood pressure goal of 120 versus 140 mmHg; North America | 40-month trial on blood pressure, lipids, and glycemic control | 1,439 | Mean 62 ± 6 years | Successful manipulation of blood pressure (groups differed on blood pressure following intervention) | Total brain volume at baseline and 40 months, Digit Symbol Coding (primary outcome), MMSE, Rey Auditory Verbal Learning, and Stroop (secondary outcomes) at baseline and 20 and 40 months | Glycemia treatment arm, visit effect, clinical center, and history of cardiovascular disease | No difference in 20- or 40-month cognitive decline treatment and control groups. Greater reduction in total brain volume in intervention than in control group. |
Study | Sample | Design | Number | Baseline mean age | Hyperglycemia/ hyperinsulinemia | Cognitive measures | Adjustment variables | Association with cognitive function |
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Abbatecola et al. [30] (2006) | Patients with diabetes free of vascular disease, receiving repaglinide or glibenclamide; Italy | 12-month trial on glycemic control | 156 | Mean 74 ± 2 years | Variation in post-prandial blood glucose, fasting plasma glucose, and HbA1c. (No difference between groups in reduction of HbA1c and plasma glucose during trial. Decline in variation in post-prandial glucose only in group treated with repaglinide.) | Composite score of attention/executive function (Trail-Making Test, Digit Span, and verbal fluency), MMSE, cortical atrophy, and white matter lesions | Age, education, physical activity, depression, blood pressure, cIMT, insulin resistance, and body mass index | Association of higher variation in fasting plasma glucose and post-prandial blood glucose with lower cognitive function across groups at baseline (fully adjusted analyses). Composite score and MMSE declined in glibenclamide but not in repaglinide group during trial (analyses controlling only for HbA1c and variation in fasting plasma glucose). |
Bruce et al. [14] (2008) | Patients with type 2 diabetes participating in the Fremantle Diabetes Study; Australia | 8-year retrospective, observational | 302 | Mean 76 ± 5 years | HbA1c at baseline and 8 years earlier | Dementia and MCI identified from screening instruments/clinical interview | None | No association |
Bruce et al. [21] (2008) | Patients with type 2 diabetes participating in the Fremantle Diabetes Study; Australia | 8-year retrospective, 2-year prospective, observational. | 205 | Mean 75 ± 4 years | HbA1c 8 years prior to baseline cognitive assessment | Dementia and MCI identified from screening instruments/clinical interview at baseline and at 2-year follow-up. ‘Cognitive decline’ defined as downward conversion between ‘normal’, MCI, and dementia. | None | No association |
Chen et al. [9] (2011) | Patients with type 2 diabetes; China | Cross-sectional, observational | 101 | Mean 63 ± 8 years | HbA1c | MCI identified on the basis of cognitive screening instrument | None | Higher HbA1c in group with MCI compared with group free of MCI |
Chen et al. [11] (2012) | Patients with type 2 diabetes; China | Cross-sectional, observational | 157 | Mean 55 ± 7 years | HbA1c | MCI identified on the basis of cognitive screening instrument | None | No association |
Cukierman-Yaffe et al. [13] (2009) | Patients with type 2 diabetes participating in ACCORD-MIND; North America | Cross-sectional analysis of trial on blood pressure, lipids, and glycemic control | 2,977 | Mean 63 ± 6 years | HbA1c and fasting plasma glucose | Digit Symbol Coding (primary outcome), MMSE, Rey Auditory Verbal Learning, and Stroop (secondary outcomes) | Total of 18 demographic and clinical risk factors | Higher HbA1c associated with lower Digit Symbol Coding. Findings for other cognitive tests did not survive full adjustment. No findings for fasting plasma glucose. |
Launer et al. [28] (2011) | Patients with type 2 diabetes participating in ACCORD-MIND trial, with HbA1c targets of <6.0 % versus 7.0 % to 7.9 %; North America | 40-month trial on blood pressure, lipids and glycemic control | 2,977 | Mean 62 ± 6 years | Successful manipulation of glycemic control. (Treatment groups differed in glycemic control following intervention.) | Total brain volume and abnormal white matter at baseline and 40 months. Digit Symbol Coding (primary outcome), MMSE, Rey Auditory Verbal Learning, and Stroop (secondary outcomes) at baseline and 20 and 40 months. | Second trial assignment (lipid or blood pressure trials), group allocation within second trial assignment, clinical center, and history of cardiovascular disease | No difference in 20- or 40-month cognitive decline between intervention groups (fully adjusted analyses). Total brain volume declined at slower rate in intensively treated compared with standard treatment groups (independent of adjustment variables and of age, sex, duration of diabetes, Digit Symbol Coding). Greater abnormal white matter in intensively treated compared with standard treatment group at 40 months. |
Manschot et al. [20] (2006) | Patients with type 2 diabetes participating in the Utrecht Diabetic Encephalopathy Study; The Netherlands | Cross-sectional, observational | 122 | Mean 66 ± 6 years | HbA1c | Composite scores on five cognitive domains from 11 cognitive tests, estimate of pre-morbid ability, cortical atrophy, and white matter lesions | Age, sex, and estimated pre-morbid ability | Association of higher HbA1c with steeper estimated lifetime decline in processing speed. No association of HbA1c with brain imaging data. |
Manschot et al. [25] (2007) | Patients with type 2 diabetes participating in the Utrecht Diabetic Encephalopathy Study; The Netherlands | Cross-sectional, observational | 122 | Mean 66 ± 6 years | HbA1c and plasma insulin | Composite score from 11 cognitive tests, estimate of pre-morbid ability, cortical atrophy, and white matter lesions | Age, sex, and estimated pre-morbid ability | Association of higher HbA1c with steeper estimated lifetime decline in overall cognitive function. Association of higher insulin with greater severity of white matter lesions. |
Ravona-Springer et al. [27] (2014) | Patients with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline Study; Israel | 12-year retrospective observational | 835 | Mean 73 ± 5 years | Data on HbA1c from diabetes register (mean 18 ± 10 measurements per patient). Six HbA1c trajectories identified (for example, high/increasing and high/stable). | Measured at 12 years only: CDR, MMSE, and battery of seven cognitive tests. Sum of z-scores calculated for four cognitive domains. | Age, sex, education, cardiovascular disease, years in diabetes register, anti-diabetes treatment, and depression | Associations of HbA1c trajectories with level of overall cognitive function, semantic categorization, and executive function. Relatively poorest cognitive function in high/decreasing group and high/increasing groups. Relatively highest performance in low/stable group. |
Ryan et al. [29] (2006) | Patients with type 2 diabetes, receiving rosiglitazone or glibenclamide; USA | 24-week trial | 145 | Mean 60 ± 1 years | Successful manipulation of glycemic control and insulin sensitivity. (Treatment groups differed in fasting plasma glucose and fasting serum insulin following intervention.) | CANTAB, Digit Symbol Coding, Rey Auditory Verbal Learning, and estimate of pre-morbid ability | Age, center, pre-morbid ability, and baseline measurement of fasting plasma glucose/insulin | Cognitive function improved equally in both treatment groups (fully adjusted analysis). Correlation of reduction in fasting plasma glucose with improvements in working memory across groups (unadjusted analysis). No finding for insulin. |
Seaquist et al. [41] (2013) | Patients with type 2 diabetes participating in ACCORD-MIND, with HbA1c targets of less than 6.0 % versus 7.0 % to 7.9 %; North America | 40-month trial on blood pressure, lipids, and glycemic control | 2,977 | Mean 62 ± 6 years | Treatment with insulin at enrolment and during trial | Digit Symbol Coding at baseline and 20 and 40 months | Total of 21 demographic, lifestyle, and clinical covariates | Association of insulin use at enrolment with lower baseline cognitive function. Loss of statistical significance upon full adjustment. No association of insulin use during trial with 40-month cognitive decline in standard treatment group. Association of insulin use with steeper 40-month cognitive decline in intensive treatment group; loss of statistical significance upon full adjustment. |
Umegaki et al. [16] (2014) | Patients with type 2 diabetes; Japan | 6-year prospective, observational | 79 | Mean 74 ± 5 years | Mean of HbA1c and plasma immunoreactive insulin at baseline and annual follow-ups. | Composite score from MMSE, Digit Symbol Coding, Stroop, and word recall. Analyses of ‘decliners’ versus ‘non-decliners’ on bases of composite score and individual cognitive tests. | None | No associations for HbA1c or insulin, except for higher mean 6-year insulin in ‘decliners’ compared with ‘non-decliners’ on Stroop. |
Yanagawa et al. [15] (2011) | Patients with diabetes receiving exercise program four times/week versus none; Japan | 12-week trial on physical exercise intervention | 16 | Mean 71 ± 4 years | HbA1c, fasting blood glucose, GIR, MCR in euglycemic clamp, and immunoreactive insulin. (No intervention effect on any of these measurements.) | MMSE, word recall, Digit Symbol Coding, Stroop, and Trail-Making Test | Age, education, and body mass index | No difference in cognitive function between groups following intervention. Across groups, changes in HbA1c and changes in GIR correlated with changes in word recall. Changes in fasting blood glucose correlated with changes in Trail-Making. |
Vascular and metabolic risk factors
Dyslipidemia
Hypertension
Hyperglycemia
Hypoglycemia
Study | Sample | Design | Number | Baseline mean age | Hypoglycemia | Cognitive measures | Adjustment variables | Association with cognitive function |
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Aung et al. [33] (2012) | Patients with type 2 diabetes participating in the Edinburgh Type 2 Diabetes Study; Scotland | Cross-sectional, observational | 1,066 | Mean 68 ± 4 years | Baseline self-report of history of SH (defined as episode requiring assistance) | MMSE, composite score from seven cognitive tests, and estimate of pre-morbid ability | Age, sex, duration of diabetes, anti-diabetes medication, depression, alcohol, smoking, blood pressure, HbA1c, stroke, TIA, MI, angina, and retinopathy. Analyses of estimated lifetime decline additionally adjusted for estimated pre-morbid ability. | History of SH associated with lower cognitive function and steeper estimated lifetime decline (fully adjusted analyses). Linear negative relationship between number of episodes of SH in the year before cognitive testing and cognitive function (analysis controlling for age and sex). |
Bruce et al. [14] (2008) | Patients with type 2 diabetes participating in the Fremantle Diabetes Study; Australia | 8-year retrospective, observational | 302 | Mean 76 ± 5 years | Hypoglycemia resulting in coma or hospitalization, self-reported at baseline and 8 years earlier | Dementia and MCI identified from screening instruments/clinical interview | None | Cross-sectional analysis: increased prevalence of history of hypoglycemia in groups with poorer cognitive function. No findings in prospective analyses. |
Bruce et al. [21] (2008) | Patients with type 2 diabetes participating in the Fremantle Diabetes Study; Australia | 8-year retrospective, 2-year prospective, observational | 205 | Mean 75 ± 4 years | Hypoglycemia resulting in coma or hospitalization, self-reported 8 years prior to baseline cognitive assessment | Dementia and MCI identified from screening instruments/clinical interview at baseline and at 2-year follow-up. ‘Cognitive decline’ defined as downward conversion between ‘normal’, MCI, and dementia. | None | No association |
Bruce et al. [34] (2009) | Patients with type 2 diabetes participating in the Fremantle Diabetes Study; Australia | 5-year prospective, observational | 302 | Mean 76 ± 5 years | 1. Self-reported medical assistance or unconsciousness or both. | Dementia and MCI identified from screening instruments/clinical interview. ‘All cognitive impairment’ summarizes groups of dementia and MCI. | Based on preliminary associations of covariates with cognition, the following adjustment variables were selected for: analyses of MCI: age, sex, education, and cardiovascular disease; for analyses of dementia: duration of diabetes and peripheral arterial disease; for analyses of all cognitive impairment: cardiovascular disease, peripheral arterial disease, and duration of diabetes. | Cross-sectional analyses: presence of MCI and all cognitive impairment associated with history of all three measures of hypoglycemia (fully adjusted analyses). No finding for dementia. Prospective analyses: no association of baseline history of hypoglycemia and risk of ‘cognitive decline’ in patients free of cognitive impairment at baseline (unadjusted). Increased risk of first-ever incident HSH in group with dementia at baseline (adjusted for insulin use, body mass index, inability to self-manage medication, and history of severe hypoglycemia). No finding on risk of subsequent hypoglycemia in patients with MCI at baseline. |
2. Episodes rated by medical staff as ‘doctor-verified’. 3. Codes for ambulance or emergency treatment for hypoglycemia in hospital records (HSH). | ‘Cognitive decline’ defined as conversion between unimpaired, MCI, and dementia. | |||||||
de Galan et al. [35] (2009) | Patients with type 2 diabetes participating in ADVANCE arm on glycemic control, receiving standard target versus target HbA1c ≤6.5 %; Australia | 5-year trial on effects of intensified blood pressure control and intensified glycemic control | 11,140 | Mean 66 ± 6 years | Incident SH defined as blood glucose <2.8 mmol/L or symptoms consistent with hypoglycemia with absence of another cause and requiring external assistance. Incident mild hypoglycemia defined as self-treated episode. | At baseline and 2-year intervals: MMSE followed by clinical interview for patients with MMSE <24 or suspected dementia. ‘Normal’ cognitive function defined as MMSE ≥28; ‘mild dysfunction’ as MMSE = 24-27; ‘severe dysfunction’ as MMSE <24. Additional use of MMSE as continuous measure. | Age, sex, treatment arm, education, duration of diabetes, blood pressure, hypertension, HbA1c, cholesterol, body mass index, macrovascular disease, microvascular disease, smoking, and alcohol | Prospective analyses (unadjusted): increased risk of SH (but not any hypoglycemia) in groups with ‘mild dysfunction’ and ‘severe dysfunction’ (versus ‘normal’ group). For ‘severe dysfunction’, but not ‘mild dysfunction’, finding survived full adjustment. Each unit-lower baseline MMSE score associated with 10 % increased risk of SH (adjusted for age, sex, education, and treatment group). Increased risk of hypoglycemia in treatment group with intensified glycemic control, but finding similar across cognitive groups. No difference in cognitive decline between treatment groups. |
Feinkohl et al. [38] (2014) | Patients with type 2 diabetes participating in the Edinburgh Type 2 Diabetes Study; Scotland | 4-year prospective, observational | 1,066 | Mean 68 ± 4 years | Self-reported history of episode requiring assistance at baseline (prevalent SH) and during follow-up (incident SH) | MMSE, composite score from seven cognitive tests, and estimate of pre-morbid ability | Age, sex, cholesterol, blood pressure, smoking, HbA1c, TIA, stroke, MI, and angina | History of SH and incident SH both associated with lower cognitive function at year 4 and with increased rate of 4-year cognitive decline. Incident SH associated with steeper estimated lifetime decline. Baseline lower cognitive function predicted increased risk of incident SH. |
Launer et al. [28] (2011) | Patients with type 2 diabetes participating in ACCORD and ACCORD-MIND, with HbA1c targets of less than 6.0 % versus 7.0 % to 7.9 %; North America | 40-month trial on blood pressure, lipids, and glycemic control | 2,977 | Mean 62 ± 6 years (ACCORD-MIND) | Increased risk of episode of hypoglycemia requiring medical assistance and of episode of hypoglycemia requiring any assistance in treatment arm with intensified glycemic control in ACCORD (n = 10,251) | Total brain volume at baseline and 40 months. Digit Symbol Coding (primary outcome), MMSE, Rey Auditory Verbal Learning, and Stroop (secondary outcomes) at baseline and 20 and 40 months. | Second trial assignment (lipid or blood pressure trials), group allocation within second trial assignment, clinical center, and history of cardiovascular disease | No difference in 20- or 40-month cognitive decline between treatment groups in ACCORD-MIND substudy of ACCORD (fully adjusted analyses). Total brain volume declined at slower rate in intensively treated compared with standard treatment group (independent of adjustment variables, and of age, sex, duration of diabetes, and Digit Symbol Coding score). Greater abnormal white matter in intensively treated compared with standard treatment group at 40 months. |
Lin and Sheu [40] (2013) | Patients with diabetes (>45 years); Taiwan | 3-year retrospective ascertainment of hypoglycemia. Dementia ascertained in subsequent 4 years | 15,000 | Mean 64 ± 10 years | ICD codes for any hypoglycemia from inpatient and outpatient medical records | ICD codes for dementia from inpatient and outpatient medical records | Age, sex, insulin use, cardiovascular disease, hypertension, ischemic heart disease, chronic kidney disease, and cholesterol | Hypoglycemia associated with increased risk of subsequent dementia diagnosis. Linear relationship of number of episodes with dementia risk. |
Punthakee et al. [36] (2012) | Patients with type 2 diabetes participating in ACCORD-MIND, with HbA1c targets of <6.0 % versus 7.0 % to 7.9 %; North America | 40-month trial on blood pressure, lipids and glycemic control | 2,956 | Mean 62 ± 6 years | 1. SH defined as self-reported <2.8 mmol/L or symptoms that resolved with use of glucose or similar. 2. HMA defined as episode requiring medical assistance (hospitalization; care in emergency department/ by emergency personnel). 3. HAA defined as episode requiring any assistance. | Digit Symbol Coding (primary outcome), MMSE, Rey Auditory Verbal Learning, and Stroop (secondary outcomes) at baseline and 20 and 40 months | Age, education, language of test administration, depression, second trial assignment (lipid or blood pressure trials), group allocation within second trial assignment, duration of diabetes, stroke, HbA1c, ethnicity, body mass index, peripheral neuropathy, urine albumin-to-creatinine ratio, and baseline use of insulin | Cross-sectional analyses (unadjusted): association of history of HMA with lower cognitive function at baseline. Lower baseline cognitive function predicted increased risk of first-ever HMA and HAA (but not recurrent HMA or HAA) during follow-up across intervention groups (fully adjusted analyses). Association between 20-month cognitive decline and risk of first-ever HMA in subsequent 22 months (finding restricted to group scoring in lowest tertile of Digit Symbol Coding at baseline; analysis adjusted only for second trial assignment, group allocation within second trial assignment). |
Whitmer et al. [39] (2009) | Patients with type 2 diabetes; USA | 18-year retrospective, observational | 17,000 | Mean 65 ± 7 years | ICD codes for emergency treatment or hospitalization for hypoglycemia, 1980 to 2002; additional analysis of 1980 to 1985. | ICD codes for any dementia in inpatient and outpatient medical records 2003 to 2007; additional analysis of 2005 to 2007. | Age, sex, education, ethnicity, duration of diabetes, anti-diabetes treatment, duration of insulin use, HbA1c, body mass index, hyperlipidemia, count scores of co-morbidity based on ICD codes for hypertension, cardiovascular disease, stroke, and end-stage renal disease | In 5- and 18-year analyses: hypoglycemia (versus none) 1980 to 2002 or 1980 to 1985 associated with increased risk of subsequent dementia (analyses of dementia 2003 to 2007). Association of ≥2 episodes of hypoglycemia (but not of single episode of hypoglycemia) versus none with increased risk of dementia in analysis of dementia 2005 to 2007. Findings similar for codes of any hypoglycemia and for episodes resulting in hospitalization. |
Yaffe et al. [37] (2013) | Patients with diabetes participating in Health ABC; USA | 12-year prospective, observational | 783 | Mean 74 ± 3 years | Hospital records identifying hypoglycemia as primary or secondary diagnosis related to hospitalization during follow-up. | Participants cognitively unimpaired at baseline. Identification of dementia cases on the basis of hospital records showing ICD codes for dementia as primary or secondary diagnosis related to hospitalization, or dementia medication on medication inventory during annual visit; MMSE administered at 2-year intervals. | Age, sex, education, ethnicity, diabetes at baseline, insulin use, HbA1c, APOE e4 status, baseline MMSE, MI, stroke, and hypertension | Cross-sectional analysis (unadjusted): association of history of hypoglycemia with lower cognitive function. Prospective analyses: hypoglycemia associated with increased risk of dementia (fully adjusted analysis; survived additional adjustment for slope of MMSE over time). Dementia associated with increased risk of hypoglycemia (analysis adjusted for adjustment variables, minus HbA1c and APOE e4). |