ESM1 for Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective cohort study Statistical modelling details We used Cox proportional-hazards regressions to investigate relationships between biometric factors (HbA 1c, cholesterol, systolic and diastolic blood pressure) and patient mortality and first new diabetesrelated complications, in yearly time windows. For many patients, data for time-varying variables - most particularly biometric measurements - were missing for the year of their death. We therefore only included data for these variables up to the year prior to death, as predictors of death in the subsequent year. For new macrovascular and microvascular diabetes complications, in patients with no history of macrovascular or microvascular complications respectively, missing data in the year of diagnosis of a complication was not an issue and they were modelled without a time lag. Separate analyses were executed for each of the two complication types and each of the mortality outcomes: all-cause CPRD (Clinical Practice Research Datalink), all-cause ONS (Office of National Statistics), diabetes ONS, coronary (ischaemic) heart disease ONS, cerebrovascular (stroke) ONS and cerebrovascular excluding bleeds ONS. Each model included HbA 1c, cholesterol, systolic and diastolic blood pressure as potentially explanatory variables. Additional covariates included to control for potential confounding were: age, sex, each co-morbidity (asthma, coronary heart disease, chronic kidney disease, chronic obstructive pulmonary disease, depression, dementia, severe mental illness, heart failure, hypertension, stroke, cancer, epilepsy, osteoarthritis, osteoporosis, and hypothyroidism), BMI, microvascular and macrovascular complications (except where the outcome was complications; but microvascular included as predictor when the outcome was macrovascular), smoking, and practice characteristics (diabetes prevalence, list size, region and area deprivation as measured by the 2010 Index of Multiple Deprivation). We did not control the analyses for prescribed medication to avoid over-complicating the research question, since our focus was the relationship between biometrics and outcomes irrespective of medication. In the macrovascular (myocardial infarction, stroke, peripheral vascular disease or amputation) complications analysis, we did not include stroke as a covariate since there was complete overlap with the outcome, but we included coronary heart disease and heart failure since they do not overlap fully with myocardial infarction. Some overlap is not a problem since the survival cohort is necessarily constrained to patients without a macrovascular complication at entry; hence we were able to control the analysis for cases of coronary heart disease or heart failure without a myocardial infarction. 1
Similarly, in the microvascular (retinopathy, neuropathy, nephropathy (chronic kidney disease stages 4-5) or foot ulcer) complications analysis we did not include chronic kidney disease as a covariate. Due to the nature of the modelled variables (e.g. a comorbidity was either present for a patient because of a relevant code or not) data was complete except for the biometric measurements (BMI, HbA 1c, blood pressure and cholesterol levels) and smoking status. For BMI, we used an interpolation algorithm to clean and impute values between observations over time, which will be made available in Stata in the near future. The algorithm used all available BMI, height and weight information from 2000/1 to 2011/12, in linear regression modelling, to impute BMI values for patients in each yearly time point. Extrapolations are not allowed and, for each patient, at least two measurements at different time points are required for the algorithm to generate information. For all analyses, biometric measurements were categorised and for the main analyses missing data were coded as an additional category (see Figures 1-5 and Table 2). HbA 1c was categorised as: <6.25% (<45mmol/mol); from 6.25% to 6.75% (45-50mmol/mol); above 6.75% and up to 7.25% (50-56mmol/mol); above 7.25% and up to 7.75% (56-61mmol/mol); above 7.75% and up to 8.25% (61-67mmol/mol); and >8.25% (>67mmol/mol). Cholesterol categories were: <2.5mmol/l; from 2.5mmol/l to 3.5mmol/l; above 3.5mmol/l and up to 4.5mmol/l; above 4.5mmol/l and up to 5.5mmol/l; above 5.5mmol/l and up to 6.5mmol/l; and >6.5mmol/l. For systolic blood pressure we categorised to: <115mmHg; from 115mmHg to 125mmHg; above 125mmHg and up to 135mmHg; above 135mmHg and up to 145mmHg; above 145mmHg and up to 155mmHg; above 155mmHg and up to 165mmHg; above 165mmHg and up to 175mmHg; and >175mmHg. For diastolic blood pressure the categories were: <72.5mmHg; from 72.5mmHg to 77.5mmHg; above 77.5mmHg and up to 82.5mmHg; above 82.5mmHg and up to 87.5mmHg; above 87.5mmHg and up to 92.5mmHg; and >92.5mmHg. Finally BMI was categorised to: <18.5; from 18.5 to 25; above 25 and up to 30; above 30 and up to 40; and >40. However, we also employed twofold, a multiple imputation algorithm for longitudinal data which uses data within (e.g. a diagnosis of hypertension which is used to impute blood pressure values) and across time (e.g. measurements of blood pressure in other years) to impute missing biometric measurements [1]. HbA 1c, cholesterol, systolic and diastolic blood pressure and BMI (interpolated) were specified as time-dependent variables with missing values, age at entry and sex as fully observed timeindependent variables, and all co-morbidities were used as fully observed time-dependent variables. Through this approach we generated five complete datasets with which we conducted sensitivity analyses using multiple imputation techniques. Note that we used an initial interpolation stage only for BMI since it is different from the other metrics, in the sense that it is much more stable over time, 2
and we felt that interpolated values were potentially more reliable than imputed values based on other parameters. Additional sensitivity analyses for all-cause mortality were run in a subsample of patients aged up to 65 (to verify patterns in a younger population), with a 2- and 3-year time lag on mortality (to verify results were not affected by changes in the biometrics immediately prior to death, possibly due to frailty), across different polypharmacy-levels subgroups (to assess severity confounding) and by gender. The results for these are provided in a supplementary excel file. In all survival analysis models we used a yearly time window, allowed multiple records for patients, used the diagnosis year as the time a patient becomes at risk, specified patient entries and exits from the database and used patient as a clustering variable to obtain standard errors that account for intragroup correlation. When more than one biometric value was available within a year for a patient, we used the mean value for the analyses. We used Schoenfeld residuals to test for the proportionalhazards assumption and included time-varying covariates when needed to stabilise the models. To allow an easy interpretation of the coefficients for the biometric measurement, we did not include any time-varying covariates for them although it was indicated in some of the models (see main paper Table 2 and ESM-1 Tables 2-3). All analyses were performed using Stata v13 and commands stcox and mi estimate [2]. Results: BMI Interestingly, high BMI appears to have a prophylactic effect in all analyses. However, in univariate analyses where we focused on the relationship between BMI and death or complications the direction of the effect is reversed (available from the authors). High BMI is a risk factor because it leads to comorbidities and affects the other biometric measurements (HbA 1c, total cholesterol and blood pressure). In the full analyses where we control for all these factors this relationship between BMI and the other biometrics is masked and we are likely observing the prophylactic effect of a higher BMI in the old and very old. The causal relationships between all the biometrics could be mapped and tested through a Structural Equation Modelling (SEM) approach, but SEM survival analysis models are underdeveloped and analysing with this framework would be a serious challenge. References [1] Welch C, Bartlett J, Petersen I (2014) Application of multiple imputation using the two-fold fully conditional specification algorithm in longitudinal clinical data. Stata J 14: 418-431 [2] StataCorp L. P. (2013) Stata Statistical software for Windows. In: 3
Table A1: Comorbidities for type II diabetes patients, over 6 years (2006/7-2011/12), including mean age (SD) Female Male All Freq Cuml Age Freq Cuml Age Freq Cuml Age Conditions* None 8.6 8.6 56.8(13.8) 16.7 16.7 56.7(12.1) 13.1 13.1 56.8(12.7) One 22.7 31.3 62.9(13.1) 30.8 47.4 62.2(11.5) 27.2 40.3 62.4(12.1) Two 26.2 57.5 67.3(12.4) 25.5 73.0 66.7(11.1) 25.8 66.1 67.0(11.7) Three 20.5 78.0 70.9(11.5) 15.0 88.0 70.2(10.3) 17.4 83.5 70.6(11.0) Four 12.2 90.2 73.4(10.5) 7.5 95.5 72.9(9.4) 9.6 93.1 73.2(10.0) Five 6.1 96.3 75.1(9.7) 3.0 98.5 74.6(8.9) 4.4 97.5 74.9(9.4) Six+ 3.7 100.0 76.8(9.0) 1.5 100.0 75.4(8.4) 2.5 100.0 76.3(8.8) * Including: asthma, coronary heart disease, chronic kidney disease, chronic obstructive pulmonary disease, depression, dementia, severe mental illness, heart failure, hypertension, stroke, cancer, epilepsy, osteoarthritis, osteoporosis, hypothyroidism 4
Main analyses coding missing data as a category ESM-1 Figure 1 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on coronary heart disease related mortality (verified through the Office of National Statistics) in the following year (main analysis)* * The second category in all graphs in the reference category. Ischaemic heart disease (ICD-10 codes I21-I22) underlying cause or in the top three causes of death. Missing category for diastolic blood pressure omitted because perfectly collinear with missing for systolic. 5
ESM-1 Figure 2 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on cerebrovascular disease related mortality (verified through the Office of National Statistics) in the following year (main analysis)* * The second category in all graphs in the reference category. Stroke (ICD-10 codes I60-I64) underlying cause or in the top three causes of death. Missing category for diastolic blood pressure omitted because perfectly collinear with missing for systolic. 6
ESM-1 Figure 3 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on developing a new macrovascular diabetes complication in the current year, when none before (main analysis)* * The second category in all graphs in the reference category. Missing category for diastolic blood pressure omitted because perfectly collinear with missing for systolic. 7
ESM-1 Figure 4 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on developing a new microvascular diabetes complication in the current year, when none before (main analysis)* * The second category in all graphs in the reference category. Missing category for diastolic blood pressure omitted because perfectly collinear with missing for systolic. 8
ESM-1 Figure 5 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on all-cause mortality (verified through the Office of National Statistics) in the following year (main analysis)* * The second category in all graphs in the reference category Missing category for diastolic blood pressure omitted because perfectly collinear with missing for systolic. 9
ESM-1 Figure 6 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on diabetes related mortality* (verified through the Office of National Statistics) in the following year (main analysis)* * The second category in all graphs in the reference category Diabetes (ICD-10 codes E10-E16) underlying cause or in the top three causes of death Missing category for diastolic blood pressure omitted because perfectly collinear with missing for systolic. 10
ESM-1 Figure 7 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on cerebrovascular related mortality excluding bleeds (verified through the Office of National Statistics) in the following year (main analysis)* * The second category in all graphs in the reference category Stroke, excluding bleeds, (ICD-10 codes I60-I62 & I64) underlying cause or in the top three causes of death Missing category for diastolic blood pressure omitted because perfectly collinear with missing for systolic. 11
ESM-1 Table 2: Hazard ratios from Cox proportionate hazards survival analysis for all ONS deaths, all ONS diabetes related deaths, all ONS cerebrovascular (excluding bleeds) related deaths (main analysis)* All-cause mortality Diabetes related mortality Cerebrovascular (excl bleeds) related mortality Age 1.069(1.065,1.074) 1.084(1.078,1.091) 1.097(1.081,1.113) Male 1.239(1.195,1.284) 1.151(1.068,1.240) 0.894(0.782,1.022) Complications Macrovascular 1.347(1.295,1.401) 1.548(1.426,1.680) 1.628(1.419,1.868) Microvascular 1.159(1.120,1.200) 1.333(1.242,1.432) 1.047(0.920,1.192) Smoking Never smoked Reference Ex-smoker 1.098(1.050,1.148) 0.988(0.903,1.080) 1.052(0.901,1.230) Current smoker 1.501(1.409,1.598) 1.317(1.158,1.499) 1.268(1.001,1.605) Missing 0.532(0.384,0.737) 0.511(0.262,0.997) 1.396(0.615,3.167) Practice characteristics DM prevalence 0.945(0.926,0.964) 0.929(0.890,0.970) 0.948(0.881,1.019) List size (1000s) 0.996(0.993,0.999) 0.998(0.991,1.005) 1.000(0.988,1.011) Region North East 0.857(0.767,0.958) 1.029(0.828,1.278) 0.694(0.443,1.086) Yorkshire & The Humber 0.958(0.884,1.039) 0.970(0.818,1.150) 1.053(0.788,1.407) East Midlands 0.963(0.874,1.061) 0.808(0.652,1.001) 1.085(0.777,1.515) West Midlands 0.946(0.891,1.004) 1.084(0.962,1.221) 0.907(0.727,1.132) East of England 0.934(0.878,0.992) 0.991(0.875,1.124) 0.961(0.770,1.199) South West 0.917(0.864,0.974) 0.857(0.756,0.972) 0.912(0.734,1.132) South Central 0.981(0.921,1.045) 0.912(0.797,1.044) 0.990(0.785,1.248) London 0.836(0.786,0.890) 0.762(0.667,0.872) 0.999(0.801,1.244) South East Coast 0.851(0.740,0.978) 0.849(0.744,0.968) 0.788(0.620,1.000) Deprivation quintile Comorbidities 1 (most affluent) Reference 2 1.090(1.032,1.152) 1.167(1.039,1.312) 1.183(0.966,1.450) 3 1.087(1.027,1.150) 1.153(1.023,1.300) 1.249(1.017,1.534) 4 1.106(1.046,1.170) 1.182(1.049,1.331) 1.113(0.902,1.375) 5 1.195(1.127,1.267) 1.274(1.125,1.442) 1.243(0.998,1.547) Asthma 1.061(1.002,1.123) 0.933(0.822,1.058) 0.943(0.751,1.183) Coronary heart disease 1.053(1.014,1.093) 0.939(0.868,1.016) 0.848(0.739,0.974) Chronic kidney disease 1.160(1.060,1.269) 1.186(1.050,1.340) 1.135(1.002,1.285) Chronic obstructive pulmonary disease 1.796(1.579,2.044) 1.371(1.211,1.551) 1.105(0.875,1.395) Depression 1.055(1.015,1.096) 1.066(0.985,1.153) 1.033(0.898,1.188) Dementia 1.601(1.501,1.708) 1.816(1.612,2.047) 1.707(1.385,2.104) Serious mental illness 1.444(1.244,1.675) 1.346(1.120,1.617) 1.050(0.744,1.482) Heart failure 1.916(1.705,2.153) 1.643(1.497,1.803) 1.599(1.355,1.887) Hypertension 1.023(0.987,1.060) 0.993(0.922,1.070) 1.096(0.956,1.257) Stroke 1.091(1.043,1.141) 1.082(0.989,1.185) 2.831(2.475,3.238) 12
All-cause mortality Diabetes related mortality Cerebrovascular (excl bleeds) related mortality Cancer 2.823(2.555,3.118) 1.498(1.367,1.641) 1.221(1.033,1.442) Epilepsy 1.385(1.217,1.575) 1.420(1.085,1.859) 2.152(1.519,3.049) Osteoarthritis 0.926(0.895,0.959) 0.938(0.873,1.008) 0.993(0.880,1.120) Osteoporosis 1.106(1.035,1.182) 1.098(0.959,1.257) 1.105(0.881,1.388) Hypothyroidism 0.990(0.942,1.040) 1.032(0.933,1.141) 0.850(0.705,1.023) BMI <18.5 1.998(1.805,2.211) 2.178(1.759,2.697) 1.754(1.203,2.557) 18.5 & 25 Reference >25 & 30 0.637(0.609,0.667) 0.669(0.604,0.740) 0.711(0.603,0.839) >30 & 40 0.555(0.516,0.597) 0.653(0.584,0.730) 0.554(0.456,0.673) >40 0.838(0.763,0.922) 1.106(0.913,1.339) 0.522(0.332,0.821) Missing BMI 3.119(2.971,3.274) 3.585(3.233,3.976) 2.685(2.251,3.202) HbA1c (%) <6.25 (<45mmol/mol) 1.147(1.091,1.205) 1.078(0.962,1.207) 1.117(0.924,1.351) 6.25 & 6.75 (45-50mmol/mol) Reference >6.75 & 7.25 (50-56mmol/mol) 0.941(0.890,0.994) 0.992(0.877,1.121) 1.087(0.884,1.337) >7.25 & 7.75 (56-61mmol/mol) 0.932(0.877,0.991) 0.977(0.853,1.117) 1.196(0.956,1.497) >7.75 & 8.25 (61-67mmol/mol) 1.076(1.005,1.153) 1.285(1.115,1.480) 1.333(1.036,1.715) >8.25 (>67mmol/mol) 1.203(1.138,1.272) 1.494(1.330,1.679) 1.315(1.059,1.633) Missing HbA 1c 0.975(0.907,1.047) 0.927(0.796,1.078) 1.249(0.954,1.634) Total cholesterol (mmol/l) <2.5 1.426(1.274,1.595) 1.405(1.105,1.785) 1.197(0.741,1.932) 2.5 & 3.5 Reference >3.5 & 4.5 0.893(0.856,0.932) 0.890(0.811,0.976) 0.889(0.757,1.043) >4.5 & 5.5 0.907(0.862,0.955) 0.914(0.818,1.021) 0.957(0.795,1.153) >5.5 & 6.5 0.966(0.895,1.041) 0.981(0.834,1.154) 0.980(0.746,1.288) >6.5 1.178(1.056,1.315) 1.184(0.937,1.495) 1.250(0.857,1.823) Missing total cholesterol 1.111(1.045,1.182) 1.271(1.120,1.442) 0.868(0.677,1.112) Systolic BP (mmhg) <115 1.161(1.091,1.235) 1.219(1.066,1.394) 1.218(0.936,1.585) 115 & 125 Reference >125 & 135 0.840(0.800,0.882) 0.888(0.798,0.989) 1.059(0.869,1.292) >135 & 145 0.763(0.726,0.803) 0.780(0.698,0.872) 0.993(0.813,1.214) >145 & 155 0.774(0.729,0.822) 0.825(0.723,0.940) 1.039(0.826,1.306) >155 & 165 0.795(0.735,0.859) 0.812(0.687,0.959) 0.921(0.684,1.240) >165 & 175 0.816(0.729,0.914) 0.896(0.709,1.133) 1.205(0.827,1.756) >175 0.866(0.751,0.998) 0.934(0.705,1.237) 1.517(0.998,2.306) Missing systolic BP 0.637(0.586,0.693) 0.690(0.578,0.823) 0.600(0.428,0.840) Diastolic BP (mmhg) <72.5 1.062(1.018,1.108) 1.100(1.003,1.206) 0.847(0.725,0.990) 72.5 & 77.5 Reference >77.5 & 82.5 0.963(0.914,1.013) 0.951(0.849,1.066) 0.894(0.743,1.075) 13
All-cause mortality Diabetes related mortality Cerebrovascular (excl bleeds) related mortality >82.5 & 87.5 0.915(0.852,0.983) 0.969(0.829,1.132) 0.833(0.646,1.074) >87.5 & 92.5 1.031(0.934,1.138) 1.231(1.007,1.505) 1.097(0.788,1.527) 92.5 1.078(0.941,1.236) 1.016(0.754,1.370) 1.311(0.865,1.988) Missing diastolic BP omitted Model info No. of subjects 118291 118291 118291 No. of failures 14939 3495 1169 Years at risk (no. of observations) 418792 418792 418792 Log pseudolikelihood -132118-29772 -9980 * Models include time-varying covariates so that the proportionate hazard assumption can be met; missing data for biometric measurements have been categorised as such enabling us to use all available records. Office of National Statistics (ONS) deaths in the following year, using data from all available practices. Office of National Statistics (ONS) deaths in the following year where the underlying cause (or in top 3 causes) is diabetes (ICD-10 codes E10-E16), using data for approximately 60% of the practices for which the data has been linked. Office of National Statistics (ONS) deaths in the following year where the underlying cause (or in top 3 causes) is stroke excluding bleeds (ICD-10 codes I60-I62 & I64), using data for approximately 60% of the practices for which the data has been linked. Variables for which additional time-varying components have been added and therefore interpretation of the main effects is not straightforward. Displaying better fit when included an additional logarithmic time-varying component, which implies that the associated hazard increases over time at a logarithmic rate. ONS data only available for England. omitted since missing cases for SBP and DBP overlap completely. 14
Sensitivity analyses multiple imputation for missing data using the twofold algorithm ESM-1 Figure 8 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on all-cause CPRD mortality in the following year (sensitivity analysis)* * The second category in all graphs in the reference category. 15
ESM-1 Figure 9 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on coronary heart disease related mortality (verified through the Office of National Statistics) in the following year (sensitivity analysis)* * The second category in all graphs in the reference category. Ischaemic heart disease (ICD-10 codes I21-I22) underlying cause or in the top three causes of death. 16
ESM-1 Figure 10 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on cerebrovascular related mortality (verified through the Office of National Statistics) in the following year (sensitivity analysis)* * The second category in all graphs in the reference category. Stroke (ICD-10 codes I60-I64) underlying cause or in the top three causes of death. 17
ESM-1 Figure 11 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on developing a new macrovascular diabetes complication in the current year, when none before (sensitivity analysis)* * The second category in all graphs in the reference category. 18
ESM-1 Figure 12 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on developing a new microvascular diabetes complication in the current year, when none before (sensitivity analysis)* * The second category in all graphs in the reference category. 19
ESM-1 Table 3: Hazard ratios from Cox proportionate hazards survival analysis for all CPRD deaths, all ONS coronary heart disease related deaths, all ONS cerebrovascular related deaths and new diabetes complications (sensitivity analysis)* All-cause mortality Coronary heart disease related mortality Cerebrovascular related mortality Macrovascular complication(s) Microvascular complication(s) Age 1.081(1.077,1.085) ** 1.099(1.084,1.116) ** 1.113(1.097,1.129) ** 1.031(1.027,1.034) ** 1.006(1.004,1.008) ** Male 1.182(1.149,1.216) 1.468(1.294,1.666) 0.923(0.814,1.048) 1.418(1.353,1.486) 1.104(1.057,1.154) ** Complications Macrovascular 1.268(1.182,1.361) ** 2.219(1.946,2.532) 1.678(1.476,1.909) Microvascular 1.137(1.106,1.168) 1.208(1.074,1.359) 1.086(0.963,1.224) 1.427(1.364,1.494) Smoking Never smoked Reference Ex-smoker 1.115(1.025,1.212) ** 1.143(0.966,1.351) 0.977(0.844,1.132) 1.326(1.148,1.532) ** 0.984(0.960,1.009) Current smoker 1.824(1.630,2.040) ** 1.903(1.536,2.359) 1.237(0.988,1.549) 2.019(1.697,2.403) ** 0.937(0.905,0.970) Missing 0.854(0.655,1.112) 0.345(0.048,2.495) 1.536(0.672,3.509) 3.209(1.602,6.428) ** 0.676(0.539,0.848) Practice characteristics DM prevalence 0.938(0.907,0.970) ** 0.984(0.917,1.055) 0.955(0.891,1.023) 0.943(0.920,0.968) 1.135(1.106,1.164) ** List size (1000s) 0.999(0.997,1.001) 0.997(0.986,1.008) 1.001(0.991,1.012) 0.995(0.991,1.000) 1.025(1.022,1.028) ** Region North West Reference North East 0.864(0.784,0.952) 0.625(0.418,0.934) 0.729(0.487,1.090) 1.450(1.262,1.667) 1.761(1.650,1.880) Yorkshire- Humber 0.905(0.840,0.976) 0.950(0.735,1.228) 1.003(0.760,1.326) 0.840(0.734,0.961) 1.026(0.961,1.096) East Midlands 0.831(0.768,0.900) 0.832(0.611,1.132) 1.029(0.750,1.414) 0.907(0.796,1.033) 1.322(1.248,1.400) West Midlands 0.942(0.892,0.994) 0.790(0.647,0.964) 0.913(0.743,1.120) 0.773(0.704,0.850) 1.253(1.201,1.308) East of England 0.901(0.852,0.953) 0.792(0.645,0.972) 0.940(0.763,1.158) 0.843(0.766,0.928) 0.673(0.610,0.742) ** South West 0.923(0.874,0.974) 0.768(0.630,0.937) 0.944(0.771,1.155) 0.805(0.732,0.885) 1.439(1.379,1.501) South Central 0.955(0.906,1.007) 0.839(0.678,1.038) 0.952(0.765,1.185) 0.834(0.763,0.912) 0.977(0.902,1.058) ** London 0.836(0.792,0.882) 0.662(0.535,0.821) 0.962(0.781,1.187) 0.828(0.760,0.903) 1.098(1.055,1.144) South East Coast 0.785(0.698,0.883) ** 0.345(0.197,0.605) ** 0.836(0.671,1.042) 0.827(0.755,0.907) 0.982(0.939,1.027) Northern Ireland 0.965(0.896,1.038) 0.991(0.877,1.120) 0.437(0.364,0.525) ** Scotland 1.045(0.993,1.100) 0.976(0.896,1.064) 1.254(1.167,1.347) ** 20
All-cause mortality Coronary heart disease related mortality Cerebrovascular related mortality Macrovascular complication(s) Microvascular complication(s) Wales 1.037(0.988,1.089) 0.876(0.805,0.953) 0.999(0.926,1.078) ** Deprivation quintile Comorbidities 1 (most affluent) Reference 2 1.103(1.058,1.151) 0.934(0.774,1.128) 1.117(0.924,1.351) 1.048(0.977,1.126) 0.956(0.925,0.987) 3 1.079(1.035,1.126) 0.981(0.812,1.185) 1.140(0.939,1.384) 1.077(1.004,1.155) 0.885(0.856,0.914) 4 1.104(1.060,1.151) 0.917(0.760,1.106) 1.066(0.877,1.296) 1.052(0.982,1.128) 0.893(0.855,0.933) ** 5 1.142(1.093,1.193) 1.004(0.824,1.222) 1.196(0.975,1.467) 0.997(0.926,1.074) 0.885(0.833,0.941) ** Asthma 1.029(0.985,1.074) 0.915(0.747,1.120) 0.935(0.757,1.155) 1.027(0.956,1.104) 1.007(0.974,1.042) Coronary heart disease 0.994(0.966,1.024) ** 1.308(1.155,1.481) 0.814(0.715,0.928) 2.972(2.749,3.212) ** 1.027(1.002,1.053) Chronic kidney disease 1.161(1.083,1.244) 1.522(1.350,1.715) 1.110(0.988,1.247) 1.155(1.098,1.215) Chronic obstructive pulmonary disease 1.839(1.670,2.025) ** 1.099(0.897,1.348) 1.003(0.800,1.256) 1.513(1.261,1.814) ** 1.053(1.007,1.102) Depression 1.080(1.048,1.113) 1.011(0.886,1.155) 1.061(0.929,1.211) 1.131(1.076,1.188) 1.070(1.018,1.125) ** Dementia 2.106(1.853,2.394) ** 1.192(0.900,1.577) 1.954(1.602,2.384) 1.229(1.079,1.399) 0.791(0.726,0.860) Serious mental illness 1.599(1.424,1.796) ** 1.266(0.891,1.801) 1.145(0.828,1.585) 1.181(1.031,1.353) 0.928(0.865,0.997) Heart failure 1.883(1.819,1.950) 2.194(1.903,2.529) 1.777(1.525,2.071) 1.731(1.608,1.864) 1.347(1.292,1.404) Hypertension 0.989(0.962,1.017) 1.086(0.957,1.234) 1.074(0.944,1.220) 1.156(1.101,1.213) 1.061(1.039,1.084) Stroke 1.190(1.151,1.231) 0.931(0.802,1.082) 2.895(2.552,3.284) 1.132(1.049,1.222) ** Cancer 3.017(2.792,3.261) ** 0.968(0.815,1.148) 1.201(1.026,1.406) 1.085(1.013,1.163) 1.040(1.005,1.077) Epilepsy 1.645(1.468,1.843) ** 0.843(0.483,1.470) 2.287(1.646,3.177) 1.536(1.271,1.857) 0.990(0.897,1.093) Osteoarthritis 0.915(0.891,0.940) 0.811(0.720,0.913) 0.994(0.887,1.114) 1.068(1.019,1.119) 1.072(1.049,1.097) Osteoporosis 1.097(1.040,1.157) 1.326(1.048,1.679) 1.109(0.894,1.375) 1.144(1.030,1.270) 1.051(0.993,1.111) Hypothyroidism 0.988(0.951,1.028) 0.835(0.695,1.004) 0.885(0.744,1.052) 1.013(0.945,1.086) 1.025(0.992,1.060) BMI <18.5 1.657(1.544,1.778) 1.473(1.011,2.147) 1.466(1.013,2.123) 1.245(0.996,1.556) 0.766(0.648,0.905) 18.5 & 25 Reference >25 & 30 0.689(0.650,0.730) ** 0.910(0.783,1.058) 0.800(0.685,0.934) 0.865(0.815,0.918) 0.970(0.909,1.034) ** 21
All-cause mortality Coronary heart disease related mortality Cerebrovascular related mortality Macrovascular complication(s) Microvascular complication(s) >30 & 40 0.653(0.618,0.690) ** 0.971(0.831,1.136) 0.694(0.589,0.817) 0.738(0.654,0.832) ** 0.858(0.803,0.915) ** >40 1.012(0.947,1.081) 1.511(1.113,2.049) 0.779(0.538,1.127) 0.683(0.614,0.760) 0.806(0.732,0.888) ** HbA1c (%) <6.25 (<45mmol/mol) 1.233(1.188,1.280) 1.089(0.903,1.313) 1.179(0.981,1.418) 0.984(0.915,1.059) 0.957(0.926,0.990) 6.25 & 6.75 (45-50mmol/mol) Reference >6.75 & 7.25 (50-56mmol/mol) 0.975(0.936,1.017) 0.941(0.773,1.144) 1.050(0.865,1.273) 1.042(0.968,1.120) 1.025(0.993,1.059) >7.25 & 7.75 (56-61mmol/mol) 0.975(0.930,1.022) 0.969(0.776,1.211) 1.164(0.947,1.431) 1.091(1.007,1.182) 1.061(1.024,1.099) >7.75 & 8.25 (61-67mmol/mol) 1.109(1.055,1.166) 1.104(0.881,1.384) 1.295(1.009,1.661) 1.187(1.091,1.292) 1.088(1.046,1.132) >8.25 (>67mmol/mol) 1.262(1.208,1.318) 1.355(1.121,1.637) 1.339(1.081,1.659) 1.455(1.357,1.559) 1.239(1.201,1.279) Total cholesterol (mmol/l) <2.5 1.406(1.290,1.533) 1.144(0.740,1.767) 1.072(0.673,1.707) 1.417(1.211,1.657) 1.193(1.081,1.317) 2.5 & 3.5 Reference >3.5 & 4.5 0.883(0.851,0.917) 1.012(0.869,1.178) 0.878(0.760,1.014) 0.901(0.853,0.953) 0.952(0.928,0.977) >4.5 & 5.5 0.927(0.887,0.969) 1.197(1.015,1.413) 0.946(0.801,1.117) 0.903(0.846,0.964) 0.917(0.889,0.945) >5.5 & 6.5 1.015(0.955,1.079) 1.633(1.300,2.053) 0.962(0.761,1.216) 0.878(0.796,0.968) 0.881(0.843,0.921) >6.5 1.146(1.051,1.249) 2.528(1.863,3.432) 1.240(0.876,1.757) 1.240(1.094,1.405) 0.916(0.857,0.979) Systolic BP (mmhg) <115 1.297(1.236,1.362) 1.323(1.054,1.661) 1.201(0.934,1.544) 1.172(1.060,1.296) 1.008(0.959,1.060) 115 & 125 reference >125 & 135 0.838(0.805,0.871) 0.791(0.658,0.950) 1.018(0.847,1.223) 0.962(0.898,1.030) 1.069(1.035,1.104) >135 & 145 0.744(0.714,0.776) 0.930(0.778,1.113) 0.902(0.743,1.095) 0.941(0.877,1.009) 1.098(1.063,1.134) >145 & 155 0.742(0.706,0.780) 0.898(0.729,1.107) 0.952(0.765,1.184) 1.070(0.987,1.160) 1.186(1.141,1.232) >155 & 165 0.750(0.705,0.799) 1.245(0.980,1.582) 0.850(0.643,1.123) 1.280(1.159,1.413) 1.237(1.178,1.300) >165 & 175 0.808(0.740,0.883) 1.065(0.723,1.569) 1.051(0.732,1.510) 1.516(1.322,1.739) 1.259(1.169,1.356) >175 0.845(0.755,0.946) 1.293(0.838,1.994) 1.431(0.962,2.130) 1.690(1.415,2.017) 1.418(1.292,1.556) Diastolic BP (mmhg) <72.5 1.052(1.018,1.087) 1.057(0.914,1.224) 0.853(0.738,0.985) 0.977(0.923,1.035) 1.043(1.015,1.072) 72.5 & 77.5 reference 22
All-cause mortality Coronary heart disease related mortality Cerebrovascular related mortality Macrovascular complication(s) Microvascular complication(s) >77.5 & 82.5 1.023(0.982,1.065) 0.950(0.797,1.132) 0.949(0.801,1.124) 0.911(0.855,0.970) 0.942(0.915,0.970) >82.5 & 87.5 1.030(0.975,1.088) 0.899(0.704,1.148) 0.941(0.746,1.186) 0.850(0.781,0.924) 0.961(0.928,0.996) >87.5 & 92.5 1.115(1.026,1.212) 0.833(0.574,1.208) 1.241(0.897,1.717) 0.839(0.746,0.944) 0.937(0.894,0.982) 92.5 1.264(1.136,1.408) 1.410(0.958,2.074) 1.468(0.987,2.182) 0.981(0.851,1.132) 0.886(0.830,0.945) Model info (5 imputation datasets) No. of subjects 195481 118291 118291 183140 183610 No. of failures 24752 1340 1323 8901 39553 Years at risk (no. of observations) 689140 418792 418792 710068 641955 F 406.7 34.1 51.6 93.2 43.4 * Models include time-varying covariates so that the proportionate hazard assumption can be met; missing data for biometric measurements have been categorised as such enabling us to use all available records. CPRD estimated deaths in the following year, using data from all available practices. Office of National Statistics (ONS) deaths in the following year where the underlying cause (or in top 3 causes) is ischaemic heart disease (ICD-10 codes I21-I22), using data for approximately 60% of the practices for which the data has been linked. Office of National Statistics (ONS) deaths in the following year where the underlying cause (or in top 3 causes) is stroke (ICD-10 codes I60-I64), using data for approximately 60% of the practices for which the data has been linked. New macrovascular complication (peripheral vascular disease, myocardial infarction, stroke or amputation) in the current year, when none previously, using data from all available practices. Stroke was not included as a covariate in this analysis since it overlaps fully with the outcome. Coronary heart disease and heart failure were included since they do not overlap fully with myocardial infarction. New microvascular complication (retinopathy, neuropathy, nephropathy, chronic kidney disease stages 4-5 or foot ulcer) in the current year, when none previously, using data from all available practices. Chronic kidney disease was not included as a covariate in this analysis since there is great overlap with the outcome. Variables for which additional time-varying components have been added and therefore interpretation of the main effects is not straightforward. Displaying better fit when included an additional logarithmic time-varying component, which implies that the associated hazard increases over time at a logarithmic rate. ONS data only available for England. 23
ESM-1 Figure 13 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on all-cause mortality (verified through the Office of National Statistics) in the following year (sensitivity analysis)* * The second category in all graphs in the reference category 24
ESM-1 Figure 14 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on diabetes related mortality* (verified through the Office of National Statistics) in the following year (sensitivity analysis)* * The second category in all graphs in the reference category Diabetes (ICD-10 codes E10-E16) underlying cause or in the top three causes of death 25
ESM-1 Figure 15 a-d: Hazard ratios (CIs) for HbA1c, cholesterol, systolic blood pressure and diastolic blood pressure levels on cerebrovascular related mortality excluding bleeds (verified through the Office of National Statistics) in the following year (sensitivity analysis)* * The second category in all graphs in the reference category Stroke, excluding bleeds, (ICD-10 codes I60-I62 & I64) underlying cause or in the top three causes of death 26
ESM-1 Table 4: Hazard ratios from Cox proportionate hazards survival analysis (multiple imputation) for all ONS deaths, all ONS diabetes related deaths, all ONS cerebrovascular (excluding bleeds) related deaths (sensitivity analysis)* Cerebrovascular All-cause mortality Diabetes related mortality (excl bleeds) related mortality Age 1.084(1.079,1.089) 1.104(1.097,1.112) 1.112(1.095,1.129) Male 1.179(1.138,1.223) 1.086(1.007,1.171) 0.848(0.742,0.970) Complications Macrovascular 1.403(1.349,1.459) 1.624(1.496,1.762) 1.708(1.491,1.958) Microvascular 1.140(1.101,1.180) 1.305(1.216,1.401) 1.035(0.911,1.177) Smoking Never smoked Reference Ex-smoker 1.019(0.974,1.066) 0.913(0.834,0.998) 0.981(0.840,1.147) Current smoker 1.519(1.427,1.616) 1.344(1.182,1.530) 1.271(1.004,1.610) Missing 0.765(0.549,1.065) 0.767(0.393,1.497) 1.756(0.768,4.012) Practice characteristics DM prevalence 0.946(0.927,0.966) 0.931(0.891,0.973) 0.943(0.876,1.014) List size (1000s) 0.998(0.995,1.001) 1.001(0.994,1.007) 1.001(0.990,1.013) Region North East 0.857(0.766,0.960) 1.012(0.815,1.258) 0.687(0.439,1.075) Yorkshire & The Humber 0.988(0.912,1.070) 1.008(0.851,1.195) 1.098(0.822,1.465) East Midlands 0.976(0.888,1.072) 0.816(0.659,1.010) 1.080(0.774,1.507) West Midlands 0.950(0.895,1.008) 1.092(0.969,1.231) 0.906(0.726,1.130) East of England 0.954(0.898,1.013) 1.016(0.896,1.152) 0.975(0.782,1.217) South West 0.920(0.867,0.977) 0.860(0.759,0.975) 0.901(0.725,1.119) South Central 0.986(0.925,1.050) 0.924(0.808,1.058) 0.988(0.784,1.245) London 0.841(0.790,0.896) 0.765(0.668,0.875) 1.000(0.801,1.248) South East Coast 0.859(0.750,0.983) 0.874(0.766,0.996) 0.795(0.625,1.010) Deprivation quintile 1 (most affluent) Reference 2 1.086(1.028,1.148) 1.167(1.038,1.311) 1.160(0.946,1.421) 3 1.087(1.027,1.150) 1.149(1.019,1.296) 1.227(0.999,1.508) 4 1.100(1.040,1.163) 1.179(1.047,1.327) 1.097(0.889,1.354) 5 1.184(1.116,1.257) 1.263(1.115,1.431) 1.213(0.973,1.512) Comorbidities Asthma 1.028(0.972,1.087) 0.889(0.784,1.008) 0.913(0.729,1.143) Coronary heart disease 1.004(0.967,1.042) 0.887(0.819,0.960) 0.816(0.710,0.938) Chronic kidney disease 1.129(1.032,1.235) 1.133(1.003,1.280) 1.094(0.966,1.239) Chronic obstructive pulmonary disease 1.845(1.631,2.086) 1.360(1.203,1.537) 1.113(0.883,1.403) Depression 1.089(1.048,1.132) 1.102(1.017,1.193) 1.063(0.924,1.224) Dementia 1.952(1.831,2.081) 2.275(2.018,2.565) 1.966(1.593,2.426) Serious mental illness 1.533(1.317,1.783) 1.520(1.262,1.830) 1.167(0.833,1.635) Heart failure 2.023(1.808,2.263) 1.792(1.633,1.967) 1.728(1.466,2.036) Hypertension 0.985(0.951,1.022) 0.950(0.881,1.025) 1.063(0.927,1.218) 27
Cerebrovascular All-cause mortality Diabetes related mortality (excl bleeds) related mortality Stroke 1.180(1.129,1.232) 1.184(1.083,1.294) 3.025(2.650,3.453) Cancer 2.823(2.555,3.119) 1.503(1.372,1.647) 1.223(1.035,1.444) Epilepsy 1.504(1.319,1.715) 1.547(1.181,2.025) 2.354(1.669,3.319) Osteoarthritis 0.902(0.871,0.933) 0.910(0.847,0.977) 0.976(0.865,1.102) Osteoporosis 1.122(1.049,1.199) 1.112(0.970,1.274) 1.108(0.884,1.390) Hypothyroidism 0.996(0.948,1.046) 1.039(0.940,1.148) 0.852(0.708,1.026) BMI <18.5 1.617(1.457,1.794) 1.678(1.337,2.105) 1.547(1.059,2.261) 18.5 & 25 Reference >25 & 30 0.717(0.685,0.751) 0.757(0.684,0.837) 0.815(0.697,0.953) >30 & 40 0.671(0.626,0.719) 0.813(0.733,0.903) 0.711(0.600,0.843) >40 1.065(0.978,1.160) 1.387(1.154,1.666) 0.714(0.475,1.073) HbA1c (%) <6.25 (<45mmol/mol) 1.207(1.152,1.265) 1.164(1.040,1.303) 1.123(0.929,1.357) 6.25 & 6.75 (45-50mmol/mol) Reference >6.75 & 7.25 (50-56mmol/mol) 0.947(0.897,1.000) 1.009(0.895,1.138) 1.051(0.859,1.285) >7.25 & 7.75 (56-61mmol/mol) 0.958(0.903,1.016) 1.009(0.886,1.149) 1.152(0.927,1.431) >7.75 & 8.25 (61-67mmol/mol) 1.085(1.016,1.159) 1.299(1.130,1.495) 1.270(0.978,1.647) >8.25 (>67mmol/mol) 1.265(1.197,1.336) 1.617(1.442,1.814) 1.338(1.067,1.679) Total cholesterol (mmol/l) <2.5 1.421(1.259,1.604) 1.421(1.096,1.842) 1.181(0.734,1.899) 2.5 & 3.5 Reference >3.5 & 4.5 0.895(0.851,0.941) 0.898(0.825,0.978) 0.887(0.761,1.034) >4.5 & 5.5 0.950(0.904,1.000) 0.967(0.860,1.088) 0.940(0.784,1.127) >5.5 & 6.5 1.022(0.937,1.116) 1.046(0.902,1.211) 0.999(0.775,1.286) >6.5 1.164(1.043,1.299) 1.197(0.960,1.491) 1.123(0.771,1.635) Systolic BP (mmhg) <115 1.232(1.156,1.314) 1.313(1.147,1.504) 1.280(0.982,1.667) 115 & 125 Reference >125 & 135 0.805(0.765,0.846) 0.844(0.757,0.941) 1.016(0.834,1.237) >135 & 145 0.721(0.684,0.760) 0.726(0.651,0.810) 0.941(0.766,1.156) >145 & 155 0.720(0.678,0.765) 0.746(0.654,0.852) 0.960(0.760,1.212) >155 & 165 0.734(0.678,0.794) 0.730(0.618,0.862) 0.849(0.628,1.149) >165 & 175 0.767(0.683,0.861) 0.829(0.656,1.048) 1.171(0.805,1.703) >175 0.839(0.728,0.966) 0.895(0.675,1.188) 1.487(0.981,2.253) Diastolic BP (mmhg) <72.5 1.041(0.998,1.085) 1.066(0.974,1.166) 0.838(0.718,0.979) 72.5 & 77.5 Reference >77.5 & 82.5 1.015(0.964,1.070) 1.022(0.912,1.145) 0.950(0.792,1.140) >82.5 & 87.5 0.999(0.931,1.071) 1.078(0.927,1.254) 0.937(0.729,1.204) >87.5 & 92.5 1.152(1.043,1.272) 1.397(1.148,1.701) 1.214(0.860,1.714) 92.5 1.278(1.118,1.461) 1.217(0.896,1.651) 1.565(1.041,2.351) 28
Model info (5 imputation datasets) All-cause mortality Diabetes related mortality Cerebrovascular (excl bleeds) related mortality No. of subjects 118291 118291 118291 No. of failures 14939 3495 1169 Years at risk (no. of observations) 418792 418792 418792 F 282.4 90.0 48.8 * Models include time-varying covariates so that the proportionate hazard assumption can be met; missing data for biometric measurements have been categorised as such enabling us to use all available records. Office of National Statistics (ONS) deaths in the following year, using data from all available practices. Office of National Statistics (ONS) deaths in the following year where the underlying cause (or in top 3 causes) is diabetes (ICD-10 codes E10-E16), using data for approximately 60% of the practices for which the data has been linked. Office of National Statistics (ONS) deaths in the following year where the underlying cause (or in top 3 causes) is stroke excluding bleeds (ICD-10 codes I60-I62 & I64), using data for approximately 60% of the practices for which the data has been linked. Variables for which additional time-varying components have been added and therefore interpretation of the main effects is not straightforward. Displaying better fit when included an additional logarithmic time-varying component, which implies that the associated hazard increases over time at a logarithmic rate. ONS data only available for England. 29