Post on 21-Sep-2020
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