Web Extra Material for Microvascular Disease and Risk of Cardiovascular Events Among Individuals With Type 2 Diabetes: a Population-Level Cohort Study

Web extra material 1Diagnostic and investigation READ codes for microalbuminuria

READ Code READ Term

R110300 Microalbuminuria

46w0.00 Urine microalbumin positive

46W0.00 Urine microalbumin positive

C10EL00 Type 1 diabetes mellitus with persistent microalbuminuria

C10FM00 Type 2 diabetes mellitus with persistent microalbuminuria

467A.00 24 hour urine protein output

467E.00 Urine protein level

467H.00 Random urine protein level

46N3.00 Urine total protein

46N4.00 Urine albumin

46N5.00 24 hour urine protein excretion test

46N6.00 24 hour urine albumin output

46N7.00 Urine protein/creatinine index

46N8.00 Urine microalbumin profile

46TC.00 Urine albumin:creatinine ratio

46TD.00 Urine microalbumin:creatinine ratio

Web extra material 2Diagnostic and investigation READ codes for retinopathy

READ Code READ Term

2BBa.00 O/E- non-referable retinopathy

2BBF.00 Retinal abnormality - diabetes related

2BBk.00 O/E - right eye stable treated prolif diabetic retinopathy

2BBl.00 O/E - left eye stable treated prolif diabetic retinopathy

2BBo.00 O/E - sight threatening diabetic retinopathy

2BBP.00 O/E - right eye background diabetic retinopathy

2BBQ.00 O/E - left eye background diabetic retinopathy

2BBr.00 Impaired vision due to diabetic retinopathy

2BBR.00 O/E - right eye preproliferative diabetic retinopathy

2BBS.00 O/E - left eye preproliferative diabetic retinopathy

2BBT.00 O/E - right eye proliferative diabetic retinopathy

2BBV.00 O/E - left eye proliferative diabetic retinopathy

2BBY.00 O/E - referable retinopathy

C109600 Non-insulin-dependent diabetes mellitus with retinopathy

C109611 Type II diabetes mellitus with retinopathy

C109612 Type 2 diabetes mellitus with retinopathy

C10F600 Type 2 diabetes mellitus with retinopathy

C10F611 Type II diabetes mellitus with retinopathy

F420.00 Diabetic retinopathy

F420000 Background diabetic retinopathy

F420100 Proliferative diabetic retinopathy

F420200 Preproliferative diabetic retinopathy

F420600 Non proliferative diabetic retinopathy

F420700 High risk proliferative diabetic retinopathy

F420800 High risk non proliferative diabetic retinopathy

F420z00 Diabetic retinopathy NOS

F422z00 Proliferative retinopathy NOS

2BBL.00 O/E - diabetic maculopathy present both eyes

2BB2.00 O/E - retinal vessel narrowing

2BB3.00 O/E - retinal A-V nipping

2BB4.00 O/E - retinal microaneurysms

2BB5.00 O/E - retinal haemorrhages

2BB6.00 O/E - retinal exudates

2BB7.00 O/E - retinal vascular prolif.

2BB8.00 O/E - vitreous haemorrhages

2BB9.00 O/E - retinal pigmentation

2BBO.00 O/E - Laser photocoagulation scars

2BB1.00 O/E - retina normal

2BBD.00 O/E - Right retina normal

2BBE.00 O/E - Left retina normal

2BBI.00 O/E - no retinopathy

2BBJ.00 O/E - no right diabetic retinopathy

2BBK.00 O/E - no left diabetic retinopathy

3128000 Fundoscopy normal

3128200 Dilated fundoscopy normal

2BB..00 O/E - retinal inspection

2BB..11 O/E - retina

2BBA.00 Examination of retina

2BBb.00 O/E - fundus not adequately seen

2BBZ.00 O/E - retinal inspection NOS

3128.00 Fundoscopy

3128.11 Retinoscopy

3128300 Camera fundoscopy

3128400 Indirect fundoscopy following mydriatic

3128Z00 Fundoscopy NOS

3129.00 Eye fundus photography

312E.00 Direct fundoscopy following mydriatic

312G.00 Indirect fundoscopy following mydriatic

58C1.00 Retinal photography

66AD.00 Fundoscopy - diabetic check

68A7.00 Diabetic retinopathy screening

68A8.00 Digital retinal screening

3128100 Fundoscopy abnormal

2BBB.00 O/E - Right retina not seen

2BBc.00 O/E - No retinal laser photocoagulation scars

2BBC.00 O/E - Left retina not seen

2BBd.00 O/E - Red reflex absent

2BBe.00 O/E - right retina partially assessable

2BBg.00 O/E - right retina fully assessable

2BBG.00 Retinal abnormality - non-diabetes

2BBH.00 Retinal drusen

2BBi.00 O/E - right eye no maculopathy

2BBj.00 O/E - left eye no maculopathy

2BBk.00 O/E - right eye stable treated prolif diabetic retinopathy

2BBM.00 O/E - diabetic maculopathy absent both eyes

Web extra material 3Diagnostic and investigation READ codes for peripheral neuropathy

C106.12 Diabetes mellitus with neuropathy

C106.13 Diabetes mellitus with polyneuropathy

C109A00 Non-insulin dependent diabetes mellitus with mononeuropathy

C109A11 Type II diabetes mellitus with mononeuropathy

C109B00 Non-insulin dependent diabetes mellitus with polyneuropathy

C109B11 Type II diabetes mellitus with polyneuropathy

C10FA00 Type 2 diabetes mellitus with mononeuropathy

C10FA11 Type II diabetes mellitus with mononeuropathy

C10FB00 Type 2 diabetes mellitus with polyneuropathy

C10FB11 Type II diabetes mellitus with polyneuropathy

F171z00 Peripheral autonomic neuropathy due to disease NOS

F366.00 Polyneuropathy

F367.00 Peripheral neuropathy

F372.00 Polyneuropathy in diabetes

F372000 Acute painful diabetic neuropathy

F372100 Chronic painful diabetic neuropathy

F372.11 Diabetic polyneuropathy

F372.12 Diabetic neuropathy

F372200 Asymptomatic diabetic neuropathy

F374z00 Polyneuropathy in disease NOS

F37y100 Axonal sensorimotor neuropathy

F37z.11 Polyneuropathy unspecified

F3y0.00 Diabetic mononeuropathy

Fyu6B00 [X]Other mononeuropathies of lower limb

Fyu7C00 [X] Polyneuropathy, unspecified

29B2000 O/E - anaesthesia in legs

29B2100 O/E - anaesthesia of extremities

29B2.11 O/E - loss of touch sensation

29B3.00 O/E - hypoaesthesia present

29B8.00 10g monofilament sensation absent

29B9.00 10g monofilament sensation R foot abnormal

29BA.00 10g monofilament sensation L foot abnormal

29H2.00 O/E - vibration sense reduced

29H3.00 O/E - vibration sense absent

29H4.00 O/E - Vibration sense of right foot abnormal

29H6.00 O/E - Vibration sense of left foot abnormal

29H8.00 O/E - vibration sense left foot reduced

29H9.00 O/E - vibration sense right foot reduced

29HA.00 O/E - Vibration sense of right foot absent

29HB.00 O/E - Vibration sense of left foot absent

29B1.00 O/E - tactile sensation normal

29B4.00 O/E - hyperaesthesia present

29B7.00 10g monofilament sensation present

29BB.00 10g monofilament sensation R foot normal

29BC.00 10g monofilament sensation L foot normal

29H1.00 O/E - vibration sense normal

29H5.00 O/E - Vibration sense of right foot normal

29H7.00 O/E - Vibration sense of left foot normal

66Ac.00 Diabetic peripheral neuropathy screening

29B..00 O/E - tactile sensation

311A.00 Monofilament foot sensation test

29B..11 O/E - touch sensation

29H..00 O/E - vibration sense

Web extra material 4Baseline characteristics among individuals with a single manifestation of microvascular disease versus those without microvascular disease

Microvascular disease present†

Nonen=12385

Nephropathyn=9607

p value Neuropathyn=6456

p value Retinopathyn=2568

p value

Age, years 62.6 (11.3) 70.1 (11.8) <0·001 69.3 (10.4) <0·001 64.2 (10.9) <0·001

Women 5405 (43.6) 5148 (53.6) <0.001 2540 (39.3) <0.001 1066 (41.5) 0.050

White ethnicity 3104 (74.3) 2486 (75.2) 0.144 1655 (74.3) 1.000 589 (76.7) <0·001

BMI, kg/m2 31.0 (6.2) 30.7 (6.4) <0·001 30.5 (6.3) <0·001 30.7 (6.2) 0.008

HbA1c, % 7.23 (1.25) 7.18 (1.30) 0·004 7.20 (1.21) 0.104 7.46 (1.33) <0·001Duration diabetes, years 5.7 (4.5) 6.6 (5.1) <0·001 7.5 (5.5) <0·001 8.4 (6.5) <0·001

Systolic blood pressure, mmHg 135.5 (12.6) 136.7 (13.8) <0·001 136.8 (12.8) <0·001 136.9 (12.8) <0·001

Diastolic blood pressure, mmHg 78.1 (7.6) 75.9 (8.3) <0·001 76.4 (7.6) <0·001 77.3 (7.7) <0·001

Total cholesterol, mmol/L 4.36 (0.89) 4.35 (0.92) 0.211 4.23 (0.85) <0·001 4.26 (0.85) <0·001

HDL cholesterol, mmol/L 1.27 (0.37) 1.27 (0.38) 0·588 1.28 (0.36) 0.139 1.27 (0.38) 0.680

LDL cholesterol, mmol/L 2.38 (0.85) 2.32 (0.86) <0·001 2.26 (0.82) <0·001 2.31 (0.84) <0·001

Smoking history 8999 (72.9) 7099 (74.2) 0.030 5039 (78.1) <0·001 1829 (71.3) 0.114

Statin use 8631 (69.7) 7131 (74.2) <0·001 4658 (72.1) <0.001 1769 (68.9) 0.435

ACEi/ARB 7479 (60.4) 7885 (82.1) <0·001 4327 (67.0) <0·001 1691 (65.8) <0·001Blood pressure treatment 9216 (74.4) 8791 (91.5) <0·001 5346 (82.8) <0·001 2009 (78.2) <0·001

Antiplatelet 6790 (54.8) 6201 (64.5) <0·001 4228 (65.5) <0·001 1534 (59.7) <0·001

† Microvascular diseases considered include retinopathy, nephropathy and peripheral neuropathy. Data are mean (SD) or number (%). BMI indicates body mass index; HbA1c, glycosylated haemoglobin; HDL, high-density lipoprotein; LDL, low density lipoprotein; eGFR, estimated glomerular filtration rate; ACEi/ARB, angiotensin converting enzyme inhibitor/ angiotensin receptor blocker.

Web extra material 5Adjusted hazard ratios* (95% CIs) for the primary outcome among individuals with a single manifestation of microvascular disease versus those without

Composite event

HR 95% CI p

Nephropathy 1.35 1.15-1.58 <0.001

Neuropathy 1.40 1.19-1.66 <0.001

Retinopathy 1.39 1.09-1.76 0.007

Age, years 1.06 1.06-1.07 <0.001

Female gender 0.69 0.61-0.79 <0.001

Systolic BP, mmHg 1.01 1.01-1.02 <0.001

Diastolic BP, mmHg 0.99 0.99-1.00 0.043

LDL, mmol/L 1.16 1.08-1.24 <0.001

HDL, mmol/L 0.75 0.62-0.91 0.003

HbA1c, 7% 1.09 1.03-1.14 0.002

Diabetes duration, years 1.00 0.99-1.01 0.763* Adjusted for age, gender, systolic BP, diastolic BP, LDL-C, HDL-C, HbA1c, BMI, duration of diabetes, smoking status, antiplatelet therapy, lipid-lowering treatment, RAS blockade, other blood pressure treatment, ethnicity, index of multiple deprivation. Numerical data were entered into models as continuous data.

Web extra material 6Adjusted hazard ratios for the primary outcome among individuals with nephropathy as a single manifestation of microvascular disease versus those without*

* Adjusted for age, gender, systolic BP, diastolic BP, LDL-C, HDL-C, HbA1c, BMI, duration of diabetes, smoking status, antiplatelet therapy, lipid-lowering treatment, RAS blockade, other blood pressure treatment, ethnicity, index of multiple deprivation

Web extra material 7Adjusted hazard ratios for the primary outcome among individuals with peripheral neuropathy as a single manifestation of microvascular disease versus those without.*

* Adjusted for age, gender, systolic BP, diastolic BP, LDL-C, HDL-C, HbA1c, BMI, duration of diabetes, smoking status, antiplatelet therapy, lipid-lowering treatment, RAS blockade, other blood pressure treatment, ethnicity, index of multiple deprivation

Web extra material 8Adjusted hazard ratios for the primary outcome among individuals with retinopathy as a single manifestation of microvascular disease versus those without.*

* Adjusted for age, gender, systolic BP, diastolic BP, LDL-C, HDL-C, HbA1c, BMI, duration of diabetes, smoking status, antiplatelet therapy, lipid-lowering treatment, RAS blockade, other blood pressure treatment, ethnicity, index of multiple deprivation

Web extra material 9

Adjusted hazard ratios* (95% CIs) for the primary outcome among individuals with nephropathy as a single manifestation of microvascular disease defined by its components

Composite event

HR 95% CI p

Low eGFR 1.18 0.95-1.46 0.128

Microalbuminuria 1.51 1.22-1.86 <0.001

Low eGFR and microalbuminuria 1.58 1.21-2.06 <0.001* Adjusted for age, gender, systolic BP, diastolic BP, LDL-C, HDL-C, HbA1c, BMI, duration of diabetes, smoking status, antiplatelet therapy, lipid-lowering treatment, RAS blockade, other blood pressure treatment, ethnicity, index of multiple deprivation

Web extra material 10Unadjusted survival by cumulative burden of microvascular disease.

Log-rank test for the linear association between cumulative burden of microvascular disease for all-cause mortality p<0.001.

Web extra material 11

Unadjusted and Adjusted Hazard Ratios for All-Cause Mortality by Burden of Microvascular Disease*

Number microvascular disease states

0n=12 385

1n=18 631

2n=13 886

3n=4125

All-cause mortality

n 1203 (9.7%) 3609 (19.4 %) 4304 (31.0%) 1561 (37.8%)

Event rate per 1000 person years 17.01 35.78 61.64 78.91

Unadjusted hazard ratio 1.00 2.11 (1.98-2.25) 3.65 (3.42-3.89) 4.68 (4.34-5.05)

Adjusted hazard ratio (95% CI)* 1.00 1.30 (1.20-1.42) 1.61 (1.48-1.75) 1.81 (1.64-2.01)* Adjusted for age, gender, systolic BP, diastolic BP, LDL-C, HDL-C, HbA1c, BMI, duration of diabetes, smoking status, antiplatelet therapy, lipid-lowering treatment, RAS blockade, other blood pressure treatment, ethnicity, index of multiple deprivation

Web extra material 12Adjusted hazard ratio for and all-cause mortality events by cumulative burden of microvascular disease and per 1 SD difference in values for established risk factors*

1 SD of each established risk factor is: BP 13.5/8.4 mmHg; LDL 0.9 mmol/L; BMI 6.3 kg/m2 ; HbA1c 1.3%.* Adjusted for age, gender, systolic BP, diastolic BP, LDL-C, HDL-C, HbA1c, BMI, duration of diabetes, smoking status, antiplatelet therapy, lipid-lowering treatment, RAS blockade, other blood pressure treatment, ethnicity, index of multiple deprivation

Web extra material 13Adjusted hazard ratio for the primary outcome by cumulative burden of microvascular disease and comparison with established risk factor goals*

* Adjusted for age, gender, systolic BP, diastolic BP, LDL-C, HDL-C, HbA1c, BMI, duration of diabetes, smoking status, antiplatelet therapy, lipid-lowering treatment, RAS blocake, other blood pressure treatment, ethnicity, index of multiple deprivation

Web extra material 14Unadjusted Kaplan-Meier estimates of freedom from the primary outcome by presence of individual microvascular disease states among patients with complete (A) and incomplete (B) data on three microvascular diseases.

Retinopathy

Neuropathy

BA

BA

Nephropathy

BA