MEDCODE READCODE READTERM

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1 Supplementary Table 1A. Codes used to identify MI events in the CPRD MEDCODE READCODE READTERM 241 G Acute myocardial infarction G Attack - heart 2491 G Coronary thrombosis G Cardiac rupture following myocardial infarction (MI) 1204 G Heart attack 1677 G MI - acute myocardial infarction G Thrombosis - coronary G Silent myocardial infarction G Acute anterolateral infarction 5387 G Other specified anterior myocardial infarction G Acute anteroapical infarction G Acute anteroseptal infarction G301z00 Anterior myocardial infarction NOS 8935 G Acute inferolateral infarction G Acute inferoposterior infarction G Posterior myocardial infarction NOS G Lateral myocardial infarction NOS G True posterior myocardial infarction 3704 G Acute subendocardial infarction 9507 G Acute non-q wave infarction G Acute non-st segment elevation myocardial infarction 1678 G Inferior myocardial infarction NOS G Acute Q-wave infarct G30A.00 Mural thrombosis G30B.00 Acute posterolateral myocardial infarction G30X.00 Acute transmural myocardial infarction of unspecif site G30X000 Acute ST segment elevation myocardial infarction G30y.00 Other acute myocardial infarction G30y000 Acute atrial infarction G30y100 Acute papillary muscle infarction G30y200 Acute septal infarction G30yz00 Other acute myocardial infarction NOS G30z.00 Acute myocardial infarction NOS G Coronary thrombosis not resulting in myocardial infarction G Postoperative myocardial infarction G Postoperative transmural myocardial infarction anterior wall G Postoperative transmural myocardial infarction inferior wall G Postoperative subendocardial myocardial infarction G38z.00 Postoperative myocardial infarction, unspecified G Post infarction pericarditis Gyu3400 [X]Acute transmural myocardial infarction of unspecif site

2 Supplementary Table 1B. Codes in HES used to identify MI events ICD-10 code I21.0 ST elevation (STEMI) myocardial infarction of anterior wall I21.01 ST elevation (STEMI) myocardial infarction involving left main coronary artery I21.02 ST elevation (STEMI) myocardial infarction involving left anterior descending coronary artery I21.09 ST elevation (STEMI) myocardial infarction involving other coronary artery of anterior wall I21.1 ST elevation (STEMI) myocardial infarction of inferior wall I21.11 ST elevation (STEMI) myocardial infarction involving right coronary artery I21.19 ST elevation (STEMI) myocardial infarction involving other coronary artery of inferior wall I21.2 ST elevation (STEMI) myocardial infarction of other sites I21.21 ST elevation (STEMI) myocardial infarction involving left circumflex coronary artery I21.29 ST elevation (STEMI) myocardial infarction involving other sites I21.3 ST elevation (STEMI) myocardial infarction of unspecified site I21.4 Non-ST elevation (NSTEMI) myocardial infarction I22.0 Subsequent ST elevation (STEMI) myocardial infarction of anterior wall I22.1 Subsequent ST elevation (STEMI) myocardial infarction of inferior wall I22.2 Subsequent non-st elevation (NSTEMI) myocardial infarction I22.8 Subsequent ST elevation (STEMI) myocardial infarction of other sites I22.9 Subsequent ST elevation (STEMI) myocardial infarction of unspecified site I25.2 Old myocardial infarction Incidence rate estimates Supplementary Table 2. Cohort Patients, n MI events, n Person years IR (95% CI) Complete cohort, diagnosed in 101,799 5, , (8.09, 8.55) Early cohort, diagnosed in 32,551 1, , (10.9, 12.1) Recent cohort, diagnosed in ,382 2, , (6.11, 6.66) Incidence rates (IR) per 1000 patient years.

3 Estimated HRs for categorized variables Supplementary Table 3. Cohort HbA 1c variable All * Categories of HbA 1c % (mmol/mol) Baseline 0.84 (0.74, 0.96) 1.09 (1.00, 1.18) 1.29 (1.18, 1.41) 1.36 (1.23, 1.50) 1.24 (1.14, 1.34) Latest 1.19 (1.09, 1.30) 1.10 (1.02, 1.18) 1.38 (1.26, 1.52) 1.74 (1.55, 1.96) 1.85 (1.65, 2.07) Updated mean 0.88 (0.78, 1.00) 1.06 (0.99, 1.14) 1.40 (1.29, 1.53) 1.67 (1.50, 1.87) 1.79 (1.57, 2.03) All women * Baseline 0.89 (0.72, 1.11) 1.16 (1.00, 1.33) 1.35 (1.16,1.58) 1.42 (1.19, 1.69) 1.32 (1.14, 1.52) Latest 1.36 (1.17, 1.58) 1.17 (1.04, 1.33) 1.47 (1.25,1.73) 1.73 (1.41, 2.13) 1.98 (1.64, 2.41) Updated mean 0.99 (0.81, 1.21) 1.13 (1.00, 1.28) 1.53 (1.32, 1.76) 1.72 (1.42, 2.08) 1.92 (1.54, 2.39) All men * Baseline 0.82 (0.70, 0.96) 1.04 (0.95, 1.16) 1.25 (1.11, 1.39) 1.32 (1.17, 1.50) 1.19 (1.07, 1.31) Latest 1.10 (0.98, 1.23) 1.06 (0.97, 1.16) 1.34 (1.20, 1.50) 1.73 (1.51, 2.00) 1.77 (1.54, 2.03) Updated mean 0.83 (0.71, 0.96) 1.03 (0.94, 1.12) 1.34 (1.20, 1.48) 1.64 (1.43, 1.87) 1.71 (1.46, 2.00) Early * Baseline 0.80 (0.61, 1.04) 1.26 (1.06, 1.50) 1.45 (1.22, 1.72) 1.63 (1.36, 1.95) 1.40 (1.19, 1.65) Latest 1.01 (0.84, 1.22) 1.22 (1.06, 1.39) 1.48 (1.27, 1.74) 1.88 (1.56, 2.26) 1.79 (1.48, 2.17) Updated mean 0.89 (0.69, 1.14) 1.28 (1.10, 1.47) 1.59 (1.37, 1.86) 1.81 (1.51, 2.17) 2.01 (1.65, 2.46) Recent * Baseline 0.94 (0.78, 1.12) 1.07 (0.95, 1.20) 1.30 (1.13, 1.49) 1.20 (1.00, 1.42) 1.12 (0.98, 1.27) Latest 1.23 (1.08, 1.40) 1.08 (0.97, 1.20) 1.26 (1.08, 1.48) 1.33 (1.06, 1.68) 1.76 (1.44, 2.14) Updated mean 0.98 (0.83, 1.15) 0.98 (0.89, 1.09) 1.25 (1.09, 1.43) 1.35 (1.12, 1.64) 1.42 (1.14, 1.76) *Time period of diabetes diagnosis for the patients included in cohort Estimated HRs with 95% CI of the categorized HbA 1c variables. The HRs are adjusted for age, gender, systolic blood pressure and history of myocardial infarction. The reference category of the HRs is HbA 1c 6% to <7% (42-53 mmol/mol).

4 Frequencies of patients and MI events across HbA1c categories Supplementary Table 4A. All, first HbA 1c Women, first HbA 1c Men, first HbA 1c First Patients MI events Patients MI events Patients MI events HbA 1c n % n row% n % n row% n % n row% <6% 7, , , % 25, , , , % 21, , , , % 13, , , % 10, , , % 23, , , , Supplementary Table 4B. All, last HbA 1c Women, last HbA 1c Men, last HbA 1c Last Patients MI events Patients MI events Patients MI events HbA 1c n % n row% n % n row% n % n row% <6% 11, , , % 38, , , , , % 27, , , , % 11, , , % 5, , , % 6, , , Supplementary Table 4C. All, first HbA 1c Early cohort, first HbA 1c Recent cohort, first HbA 1c First Patients MI events Patients MI events Patients MI events HbA 1c n % n row% n % n row% n % n row% <6% 7, , , % 25, , , , % 21, , , , % 13, , , % 10, , , % 23, , , , Supplementary Table 4D. All, last HbA 1c Early cohort, last HbA 1c Recent cohort, last HbA 1c Last Patients MI events Patients MI events Patients MI events HbA 1c n % n row% n % n row% n % n row% <6% 11, , , % 38, , , , % 27, , , , % 11, , , % 5, , , % 6, , , Tables A-D show the numbers of patients and MI events within each HbA 1c categories. Tables A and B contain data for the complete cohort, and for women and men separately. In Table A categorization is according to the patients baseline HbA 1c (first HbA 1c ), and in Table B according to their last HbA 1c registration during follow-up. Tables C and D show beside the complete cohort the numbers for the early and recent sub-cohorts; table C categorized according to their baseline registration, table D according to their last available registration of HbA 1c.

5 Distribution of the MI-cases according to updated latest and updated mean variable, respectively Supplementary Table 5. TABLE 5A First reg. Updated latest variable Last registration, HbA 1c category % (mmmol/mol) <6% (<42) 6-7% (42-53) 7-8% (53-64) 8-9% (64-75) 9-10% (75-86) 10% ( 86) <6% (<42) % (42-53) % (53-64) % (64-75) % (75-86) % ( 86) Column sum TABLE 5B First reg. Updated mean variable Last registration, HbA 1c category % (mmmol/mol) <6% (<42) 6-7% (42-53) 7-8% (53-64) 8-9% (64-75) 9-10% (75-86) 10% ( 86) <6% (<42) % (42-53) % (53-64) % (64-75) % (75-86) % ( 86) Column sum The percentage of the 5104 MI cases (complete cohort) according to first and last registration of HbA1cvariable, where row-category is the first, and column category is the last registration. The distribution of updated latest variable is shown in Table A, and updated mean variable in table B.

6 Supplementary Table 6. Model Model 1 Model 2 HbA 1c - variable Complete cohort diagnosed in Early sub-cohort diagnosed in Recent sub-cohort diagnosed in Baseline 1.05 (1.03,1.06) 1.06 (1.04,1.09) 1.03 (1.00,1.05) Updated latest 1.11 (1.09,1.13) 1.13 (1.10,1.17) 1.07 (1.04,1.10) Updated mean 1.15 (1.13,1.18) 1.17 (1.13,1.21) 1.08 (1.05,1.12) Baseline 1.05 (1.03, 1.06) 1.06 (1.04, 1.09) 1.03 (1.01, 1.05) Updated latest 1.11 (1.09, 1.13) 1.14 (1.10, 1.17) 1.07 (1.04, 1.10) Updated mean 1.16 (1.13, 1.18) 1.17 (1.13, 1.21) 1.08 (1.05, 1.12) Estimated HRs of each HbA 1c variable in proportional hazard regression models. Model 1 is the basis model which adjusts for age, gender, history of MI, and systolic blood-pressure. Model 2 is in addition adjusted for smoking, and use of statins. For the complete cohort all models are stratified for time period (before and after January 1, 2004).

7 Subgroup analysis of the early and recent sub-cohorts Among the 32,551 patients in the early cohort 12,511 (38.4%) had baseline information on BMI, LDL and HDL. The number of MI events among these was 536, 34.0% of the total of 1575 MI events in the early cohort. In the recent cohort consisting of 67,382 patients, 49,936 (71.1%) had baseline information on BMI, LDL and HDL. The number of MI events was 1472, 69.2% of the total of 2120 events in the recent cohort. Supplementary Table 7A. HbA 1c Early cohort basis model Early cohort subgroup analysis Recent cohort basis model Recent cohort subgroup analysis Baseline 1.06 (1.04,1.09) 1.06 (1.02, 1.10) 1.03 (1.00,1.05) 1.01 (0.98,1.03) Latest 1.13 (1.10,1.17) 1.13 (1.06,1.20) 1.07 (1.04,1.10) 1.03 (0.99, 1.08) Updated mean Supplementary Table 7B (1.13,1.21) 1.16 (1.09,1.23) 1.08 (1.05,1.12) 1.04 (1.00,1.09) Cohort Categories of HbA HbA 1c variable 1c % (mmol/mol) Early, basis <6% (42) 7%-8% (53-64) 8%-9% (64-75) 9%-10% (75-86) 10% (86) model Baseline 0.80 (0.61, 1.04) 1.26 (1.06, 1.50) 1.45 (1.22, 1.72) 1.63 (1.36, 1.95) 1.40 (1.19, 1.65) Latest 1.01 (0.84, 1.22) 1.22 (1.06, 1.39) 1.48 (1.27, 1.74) 1.88 (1.56, 2.26) 1.79 (1.48, 2.17) Updated mean 0.89 (0.69, 1.14) 1.28 (1.10, 1.47) 1.59 (1.37, 1.86) 1.81 (1.51, 2.17) 2.01 (1.65, 2.46) Subgroup analysis <6% (42) 7%-8% (53-64) 8%-9% (64-75) 9%-10% (75-86) 10% (86) Baseline 0.62 (0.40, 0.95) 1.11 (0.85, 1.45) 1.28 (0.97,1.69) 1.45 (1.07, 1.95) 1.24 (0.96, 1.61) Latest 0.90 (0.66, 1.23) 1.18 (0.96, 1.47) 1.48 (1.13,1.94) 1.87 (1.32, 2.64) 1.32 (0.87, 2.64) Updated mean 0.76 (0.51, 1.14) 1.25 (0.99, 1.57) 1.63 (1.27, 2.10) 1.74 (1.27, 2.40) 1.49 (0.99, 2.24) Recent, basis model <6% (42) 7%-8% (53-64) 8%-9% (64-75) 9%-10% (75-86) 10% (86) Baseline 0.94 (0.78, 1.12) 1.07 (0.95, 1.20) 1.30 (1.13, 1.49) 1.20 (1.00, 1.42) 1.12 (0.98, 1.27) Latest 1.23 (1.08, 1.40) 1.08 (0.97, 1.20) 1.26 (1.08, 1.48) 1.33 (1.06, 1.68) 1.76 (1.44, 2.14) Updated mean 0.98 (0.83, 1.15) 0.98 (0.89, 1.09) 1.25 (1.09, 1.43) 1.35 (1.12, 1.64) 1.42 (1.14, 1.76) Subgroup <6% (42) 7%-8% (53-64) 8%-9% (64-75) 9%-10% (75-86) 10% (86) analysis Baseline 0.99 (0.81, 1.22) 1.11 (0.96, 1.27) 1.19 (1.00, 1.42) 1.07 (0.86, 1.34) 1.02 (0.87, 1.19) Latest 1.22 (1.05, 1.42) 0.96 (0.84, 1.09) 1.12 (0.91, 1.37) 1.23 (0.92, 1.65) 1.47 (1.14, 1.91) Updated mean 1.00 (0.83, 1.20) 0.93 (0.82, 1.06) 1.09 (0.92, 1.29) 1.27 (1.00, 1.61) 1.13 (0.84, 1.53) Estimated HRs of HbA 1c variables as continuous linear effects are shown in table 7A. Table 7B shows the HRs for the categorized variables. Basis models were adjusted for age, gender, SBP, and history of MI, and include all the patients in the early and recent sub-cohorts, respectively. In the subgroup analyses the models were in addition adjusted for smoking, statin use, BMI, LDL and HDL. The reference category, in Table B, of the HRs is 6% to <7% (42-53 mmol/mol).

8 Adjusting for diabetic treatment in the proportional hazard models We acknowledge that some readers would request to see the estimated HRs of HbA 1c after additional adjustment by diabetes treatment, as pointed out by one of the reviewers, but we want to emphasize the problematic side of it and why the results in table 8 below should be interpreted with caution: The problem stems from the fact that HbA 1c, our exposure of interest, is correlated with treatment of diabetes. The likely causal pathway is that diabetes treatment influences the level of HbA 1c, and HbA 1c influences outcome. We have no reason to believe that the treatment in itself would have a direct effect on outcome. By adjusting for a factor which is not a risk factor in itself, but correlated with the exposure of interest, the resulting exposure estimates can be disturbed or diluted in an unpredictable way. From a statistical modeling perspective it is thus clear that the treatment adjustment in this context does not improve the estimated HbA 1c associations. Supplementary table 8. Estimated HRs of the categorized HbA 1c variables with treatment added to the adjusting factors in the basic regression model. The treatment variable has four classes: diet, one OAD, several OADs, and insulin (with or without OAD). Cohort HbA 1c variable All * Categories of HbA 1c % (mmol/mol) Baseline 0.86 (0.75, 0.97) 1.03 (0.95, 1.13) 1.17 (1.06, 1.29) 1.22 (1.09, 1.35) 1.08 (0.99, 1.19) Latest 1.21 (1.10, 1.32) 1.07 (0.99, 1.14) 1.30 (1.18, 1.43) 1.60 (1.42, 1.80) 1.68 (1.50, 1.89) Updated mean 0.90 (0.80, 1.02) 1.02 (0.95, 1.10) 1.30 (1.19, 1.42) 1.51 (1.35, 1.69) 1.58 (1.39, 1.80) *Time period of diabetes diagnosis for the patients included in cohort