Table 1: Studies of Dyslipidaemia and Cognitive Function in Type 2 Diabetes

Supplemental Data{2 Column Table}Table S1. Studies of inflammation and cognitive function in type 2 diabetesStudy Sample Design Num Baseline Measuremen Cognitive measures Adjus Association with ber mean t of tment cognitive function age inflammation variab les Chen et Patients with Cross-sectional, 101 Mean CRP MCI identified on the None Higher CRP in al. [9] type 2 observational 63 ± 8 basis of cognitive group with MCI (2011) diabetes; years screening instrument compared with China group free of MCI. Keller et Patients with 4-year 1,06 Mean Plasma Composite score from Age Higher baseline al. [45] type 2 prospective, 6 68 ± 4 fibrinogen at seven cognitive tests and fibrinogen (2012) diabetes observational years baseline sex associated with participating steeper cognitive in the decline Edinburgh Type 2 Diabetes Study;Scotland Keller et Patients with 4-year 1,06 Mean Plasma IL-6 Composite score from Age Higher baseline IL- al. [46] type 2 prospective, 6 68 ± 4 at baseline seven cognitive tests and 6 associated with (2012) diabetes observational years sex steeper cognitive participating decline. in the Edinburgh Type 2 Diabetes Study;Scotland Marioni Patients with Cross-sectional, 1,06 Mean Plasma Composite score from Age Higher fibrinogen et al. type 2 observational 6 68 ± 4 fibrinogen seven cognitive tests and associated with [43] diabetes years sex lower cognitive (2011) participating function. in the Edinburgh Type 2 Diabetes Study;Scotland Marioni Patients with Cross-sectional, 1,06 Mean Plasma IL-6, Composite score from Age, Higher IL-6 et al. type 2 observational 6 68 ± 4 TNF-α, and seven cognitive tests sex, associated with [44] diabetes years CRP and estimate of pre- educa lower cognitive (2010) participating morbid ability tion, function and in the cardio steeper estimated Edinburgh vascu lifetime decline Type 2 lar (fully adjusted Diabetes diseas analyses). Study; e, Association of Scotland durati higher TNF-α with on of lower cognitive diabet function and es, estimated lifetime HbA1 decline only in c, and analyses adjusted estim for age, sex, and ated estimated pre- pre- morbid ability. No morbi consistent finding d for CRP. abilit y Umegak Patients with 6-year 79 Mean Mean of Composite score from None No association. i et al. type 2 prospective, 74 ± 5 CRP MMSE, Digit Symbol [16] diabetes; observational years measured at Coding, Stroop, and (2014) Japan baseline and word recall. Analyses of annual ‘decliners’ versus ‘non- follow-ups decliners’ on bases of composite score and individual cognitive tests. CRP, C-reactive protein; IL-6, interleukin-6; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; TNF-α, tumor necrosis factor-alpha. {2 Column Table}Table S2. Studies of microvascular disease and cognitive function in type 2 diabetesStudy Sample Design Numbe Baseline Measuremen Cognitive Adjustment Association r mean age t of measures variables with microvascul cognitive ar disease function de Bresser et Patients with 4-year 122 Mean 66 ± 6 Ophthalmol Composite Age, sex, No al. [49] type 2 diabetes prospective, years ogist- score from and pre- association.(2010) participating in observationa identified 11 cognitive morbid the Utrecht l presence tests, ability for Diabetic versus estimate of analyses of Encephalopath absence of pre-morbid cognitive y Study; retinopathy ability, total function. The according to brain Age and sexNetherlands ‘standard volume, for analyses clinical lateral of imaging practice’ at ventricular data. baseline volume, white matter hyperintensi ty volumes, and cerebral infarcts de Galan Patients with 5-year trial 11,140 Mean 66 ± 6 ‘Major At baseline None Cross- et al. [35] type 2 diabetes on effects of years diabetic eye and 2-year sectional (2009) participating in intensified disease’ intervals: analysis: ADVANCE blood MMSE increased arm on pressure followed by prevalence glycemic control and clinical of major control, intensified interview diabetic eye receiving glycemic for patients disease in standard target control with MMSE groups with versus target <24 or cognitive HbA1c ≤6.5%; suspected dysfunction. Australia 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. Hugenschmid Patients with 40-month 1,862 Mean 62 ± 6 Presence of Digit Age, sex, Cross- t et al. [50] type 2 diabetes prospective, years no Symbol ethnicity, sectional (2014) participating in observationa retinopathy, Coding education, association ACCORD-Eye l of mild non- (primary smoking, of and ACCORD- proliferative outcome), geographic retinopathy MIND retinopathy, MMSE, Rey region, with lower substudies of or of Auditory duration of gray matter ACCORD; moderate/se Verbal diabetes, volume but North America vere Learning, HbA1c, not with retinopathy and Stroop cholesterol, cognitive at baseline; (secondary triglycerides function. based on outcomes) , blood Prospective ETDRS at baseline pressure, association chart and 20 and anti- of 40 months. hypertensive retinopathy Total brain medication with steeper volume, use, 40-month white matter depression, (but not 20- volume, alcohol, and month) gray matter neuropathy. decline on volume, and Additional MMSE and abnormal adjustment Digit white matter for visual Symbol volume at acuity for Coding. baseline and analyses of Statistically 40 months. cognitive non- function and significant for total trend for intracranial association volume for of baseline analyses of retinopathy brain with greater volumes. increase in white matter abnormalitie s during 40- month follow-up. Manschot et Patients with Cross- 122 Mean 66 ± 6 Presence Composite Age, sex, No al. [25] type 2 diabetes sectional, years versus score from and association (2007) participating in observationa absence of 11 cognitive estimated of the Utrecht l retinopathy tests, pre-morbid retinopathy Diabetic based on estimate of ability with Encephalopath scores on pre-morbid estimated y Study; diabetic ability, lifetime The retinopathy cortical decline in Netherlands severity atrophy, and cognitive scale white matter function. (Wisconsin lesions Association Epidemiolog of ic Study of retinopathy Diabetic with Retinopathy presence of ) at baseline cortical atrophy (analysis additionally controlling for lipid- lowering drugs and cerebral infarcts). ACCORD, Action to Control Cardiovascular Risk in Diabetes; ACCORD-MIND, Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ETDRS, Early Treatment of Diabetic Retinopathy Study; MMSE, Mini-Mental State Examination. {2 Column Table}Table S3. Studies of markers of macrovascular disease and cognitive function in type 2 diabetesStudy Sample Design Numbe Baselin Macrovascular Cognitive Adjustme Association r e mean disease measures nt with cognitive age variables function Bruce et Patients with 8-year 302 Mean ‘Cerebrovascular Dementia and None Cross- al. [14] type 2 retrospectiv 76 ± 5 disease’ (stroke MCI identified sectional (2008) diabetes e, years and TIA), ‘CHD’ from screening analyses: participating observation (MI, angina, instruments/clinic increased in the al coronary artery al interview prevalence of Fremantle bypass, and cerebrovasculDiabetes evidence of MI on ar disease Study; ECG), and across Australia peripheral arterial cognitive disease at baseline groups, with and 8 years earlier highest prevalence in dementia group, followed by MCI group and unimpaired group. Increased prevalence of PAD in group with any cognitive impairment (in model controlling for sex, duration of diabetes, and stroke) and in group with dementia(in model controlling for age, sex, and duration of diabetes). Prospective analyses: cerebrovascul ar disease (unadjusted analysis) and PAD (model controlling for age, sex, duration of diabetes, and waist-hip ratio) 8 years earlier both associated with poorer cognitive outcome. No findings for CHD. Bruce et Patients with 8-year 205 Mean Cerebrovascular Dementia and None No al. [21] type 2 retrospectiv 75 ± 4 disease and MCI identified association.(2008) diabetes e, 2-year years peripheral arterial from screening participating prospective, disease assessed 8 instruments/clinic in the observation years prior to al interview at Fremantle al baseline cognitive baseline and at 2- Diabetes assessment year follow-up. Study; ‘Cognitive Australia decline’ defined as downward conversion between ‘normal’, MCI, and dementia. Chen et al. Patients with Cross- 101 Mean ABI and cIMT MCI identified on None Lower ABI [9] (2011) type 2 sectional, 63 ± 8 the basis of and higher diabetes; observation years screening cIMT in China al instrument group with MCI compared with group free of MCI. Chen et al. Patients with Cross- 157 Mean cIMT MCI identified on None Higher cIMT [11] type 2 sectional, 55 ± 7 the basis of in group with (2012) diabetes; observation years cognitive MCI China al screening compared instrument with group free of MCI. Inverse correlation between cognitive scores and cIMT. Cukierma Patients with Cross- 2,977 Mean Stroke, ‘CVD’ Digit Symbol Age Association of n-Yaffe type 2 sectional 63 ± 6 (stroke, MI, angina Coding (primary stroke with et al. [13] diabetes analysis of years with ischemic outcome), lower (2009) participating trial on changes, and MMSE, Rey cognitive in ACCORD- blood coronary Auditory Verbal function. MIND; pressure, procedure) Learning, and Association ofNorth lipids, and Stroop CVD (without America glycemic (secondary stroke) with control outcomes) lower verbal memory but higher MMSE scores. de Galan Patients with 5-year 11,140 Mean Stroke, MI, major At baseline and Age, sex, Cross- et al. [35] type 2 prospective 66 ± 6 coronary event 2-year intervals: education, sectional, (2009) diabetes trial on years (non-fatal MI, MMSE followed and unadjusted participating effects of death from by clinical treatment analyses: in ADVANCE intensified coronary event), interview for allocation association of arm on blood and major CVD patients with stroke and glycemic pressure event (MI, stroke, MMSE <24 or major CVD control; control and and cardiovascular suspected event with Australia intensified death) during dementia. lower glycemic follow-up ‘Normal’ cognitive control cognitive function. No function defined finding for as MMSE ≥28; MI. ‘mild Prospective dysfunction’ as analyses MMSE = 24-27; (adjusted):‘severe baseline mild dysfunction’ as and severe MMSE <24. impairment Additional use of (versus MMSE as unimpaired) continuous associated measure. with increased risk of major CVD event, stroke, and major coronary event during follow-up. Lower MMSE at baseline associated with increased risk of major CVD event. Feinkohl Patients with 4-year 1,066 Mean MI, stroke, angina, MMSE, Age, sex, Cross- et al. [51] type 2 prospective, 68 ± 4 ABI, and cIMT at composite score cholestero sectional (2013) diabetes observation years baseline from seven l, blood analyses: participating al cognitive tests, pressure, stroke, in the and estimate of smoking, angina, and Edinburgh pre-morbid and MI associated Type 2 ability estimated with lower Diabetes pre- cognitive Study; morbid function. Scotland ability Prospective analyses: stroke, higher cIMT, and lower ABI associated with increased late-life cognitive decline and increased estimated lifetime decline. Manschot Patients with Cross- 122 Mean ‘Any Composite scores Age, sex, Association of et al. [20] type 2 sectional, 66 ± 6 macrovascular on five cognitive and infarcts with (2006) diabetes observation years event’ defined as domains from 11 estimated steeper participating al MI, stroke, or cognitive tests, pre- estimated in the Utrecht surgery/endovascul estimate of pre- morbid lifetime Diabetic ar treatment for morbid ability, ability decline in Encephalopat coronary, carotid cortical atrophy, processing hy Study; or peripheral and white matter speed. The arterial disease. lesions Association ofNetherlands Cerebral infarcts any on MRI. macrovascular event with steeper estimated lifetime decline in processing speed and memory. Manschot Patients with Cross- 122 Mean ‘Any Composite score Age, sex, ‘Any et al. [25] type 2 sectional, 66 ± 6 macrovascular from 11 cognitive and macrovascular (2007) diabetes observation years event’ (MI, stroke, tests, estimate of estimated event’ and participating al and pre-morbid pre- infarcts both in the Utrecht surgery/endovascul ability, cortical morbid associated Diabetic ar treatment for atrophy, and ability with steeper Encephalopat coronary, carotid, white matter estimated hy Study; or peripheral lesions lifetime The arterial disease) cognitive Netherlands and cerebral decline. infarcts on MRI. Finding on Measurement of ‘any vascular cIMT. event’ attenuated following exclusion of patients with stroke. For ‘any vascular event’, but not infarcts, association persisted in final model adjusting for age, estimated pre-morbid ability, hypertension, smoking, and lipid-lowering drugs. No finding for cIMT. ABI, ankle brachial index; ACCORD-MIND, Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; CHD, coronary heart disease; cIMT, carotid intima-media thickness; CVD, cardiovascular disease; ECG, electrocardiogram; MCI, mild cognitive impairment; MI, myocardial infarction; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; PAD, peripheral arterial disease; TIA, transient ischemic attack. {2 Column Table}Table S4. Studies of natriuretic peptides and cognitive function in the general population and in type 2 diabetesStudy Sample Design Number Baseli Natriuretic Cognitiv Adjustment Association ne peptide e variables with mean measures cognitive age function Daniels et Rancho Cross-sectional, 950 Mean NT-proBNP, MMSE, Age, sex, ‘High’ NT- al. [52] Bernardo observational 77 ± 8 categorized as Trail- education, proBNP (2011) Study; USA years ‘high’ (≥450 Making hypertension, group likely pg/mL) versus Test, and body mass to score low ‘low’ (<450 Category index, exercise, on MMSE pg/mL) and Fluency. alcohol, and Trail- additionally as ‘Low’ smoking, Making quartiles of the performa cholesterol, and compared distribution nce on creatinine with ‘low’ each group. defined Findings as similar whenMMSE excluding ≤24, participants Trail- with stroke Making and ≥300 cardiovascul seconds, ar disease. and Findings for Category Category Fluency Fluency ≤12 restricted to words. largely Cognitiv unadjusted e tests analyses. additiona Additionally lly used increased as prevalence quartiles of scoring in of lower respectiv quartiles of e cognitive distributi scores with on. increasing quartiles of NT-proBNP (unadjusted analyses). Feinkohl et Patients with 4-year 1,066 Mean NT-proBNP at MMSE, Age, sex, Association al. [51] type 2 prospective, 68 ± 4 baseline composit cholesterol, of higher (2013) diabetes observational years e score blood pressure, baseline NT- participating from and smoking proBNP in the seven with steeper Edinburgh cognitive late-life Type 2 tests, and cognitive Diabetes estimate decline and Study; of pre- steeper Scotland morbid estimated ability lifetime decline. Finding on 4-year decline lost statistical significance when controlled for estimated pre-morbid ability or for stroke, cIMT, and ABI. Kerola et Kuopio 75+ 5-year 464 Mean BNP at baseline Diagnosi Age, education, Association al. cohort; prospective, 80 ± 4 s of AD, and of higher [53] (2010) Finland observational years VaD, and hypertension BNP with MMSE lower MMSE and with steeper decline on MMSE (unadjusted analyses). Association of higher BNP and increased risk of AD and VaD diagnosis during follow-up (adjusted analyses). Hiltunen et Kuopio 75+ 5-year 601 Range BNP at baseline Diagnosi Cross-sectional Presence of al. cohort; prospective, 75-96 s of analyses: age, any [54] (2013) Finland observational years dementia sex, dementia medication, associated heart failure, with higher and blood BNP in pressure. youngest Prospective tertile and analyses: age, lower BNP education, and in oldest hypertension. tertile. Higher baseline BNP associated with increased risk of dementia during follow-up in youngest tertile only. Tynkkynen National 14-year 7,158 Mean NT-proBNP at Medical Age, sex, Higher et al. [56] FINRISK prospective, 48 ± baseline records cholesterol, baseline NT-(2015) Study; observational 13 for body mass proBNP Finland years diagnosis index, ischemic associated (range with any heart disease, with 25 to dementia and diabetes increased 74) or AD, or risk of any dementia incident medicati dementia on across all participants. Finding driven by males. No finding on incident AD. Vaes et al. Leiden 85+ Cross-sectional, 274 All 90 NT-proBNP MMSE. Height, weight, No [55] (2009) cohort; observational years categorized ‘Poor renal function, association.The old according to sex- cognitive hemoglobin, Netherlands specific tertiles of function’ and distribution defined cardiovascular as medication MMSE <19. ABI, ankle-brachial index; AD, Alzheimer’s disease; BNP, brain natriuretic peptide; cIMT, carotid intima-media thickness; FINRISK,Finland Cardiovascular Risk Study; MMSE, Mini-Mental State Examination; NT-proBNP, N-terminal pro-brain natriuretic peptide; VaD, vascular dementia. {2 Column Table}Table S5. Studies of depression and cognitive function in type 2 diabetesStudy Sample Design Nu Baselin Measuremen Cognitive measures Adjust Association with m e mean t of ment cognitive function be age depression variabl r es Cukierma Patients Cross-sectional 2, Mean Scores ≥10 Digit Symbol Coding Age Association of n-Yaffe with type 2 analysis of trial 97 63 ± 6 on 9-item (primary outcome), depression with et al. [13] diabetes on blood 7 years Patient MMSE, Rey Auditory lower MMSE (2009) participatin pressure, lipids, Health Verbal Learning, and scores. No g in and glycemic Questionnair Stroop (secondary findings for other ACCORD- control e or self- outcomes) cognitive tests.MIND; reported North depressionAmerica Katon et Patients 3- to 5-year 19 Range ICD codes ICD codes for dementia in Sociod Co-morbid al. [60] with type 2 retrospective, ,0 30-75 for diagnosis hospital records, restricted emogra depression/diabet(2012) diabetes observational 00 years of to incident cases occurring phic es associated with participatin depression/u 3 to 5 years after baseline factors, increased risk of g in the se of anti- clinical dementia Diabetes depressants risk diagnosis and Aging in hospital factors, compared with Study; records health diabetes alone.USA risk factors, and health use Sullivan Patients 40-month trial 2, Mean Scores ≥10 Digit Symbol Coding Age, Association of et al. [61] with type 2 on blood 97 age 63 on 9-item (primary outcome), sex, depression at (2013) diabetes pressure, lipids, 7 ± 6 Patient MMSE, Rey Auditory ethnicit baseline with participatin and glycemic years Health Verbal Learning, and y, steeper cognitive g in control Questionnair Stroop (secondary educati decline across ACCORD- e at baseline outcomes) at baseline and on, cognitive tests.MIND; 20 and 40 months glycem North ia America treatme nt arm, blood pressur e versus lipid treatme nt arm, blood pressur e treatme nt, lipid treatme nt, clinical center, cardiov ascular event, body mass index, HbA1c, cholest erol, smokin g, alcohol, and insulin use Trento et Patients Cross-sectional, 49 Mean Zung Self- MMSE Age, Statistically non- al. [58] with 2 observational 8 68 ± 7 Rating sex, significant trend (2012) diabetes; years Depression duratio for association of Italy Questionnair n of higher depression e diabete scores with lower s, MMSE scoresHbA1c, and insulin use Watari et Patients Cross-sectional, 40 Range Clinical MMSE, 12 cognitive tests Age, Statistically non- al. [59] with type 2 observational 30-80 interview to resulting in composite sex, significant trend (2006) diabetes; years. diagnose scores of and for lower overall USA Mean depression attention/processing speed, educati cognitive function60 ± 12 memory, executive on and statistically years. function, verbal memory, significant lower and non-verbal memory attention/processi ng speed in co- morbid depression/diabet es group than in no depression/diabet es group. ACCORD, Action to Control Cardiovascular Risk in Diabetes; ACCORD-MIND, ACCORD-MIND, Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes; ICD, International Classification of Diseases; MMSE, Mini-Mental State Examination.

Table 1: Studies of Dyslipidaemia and Cognitive Function in Type 2 Diabetes

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