Supplementary table 1: Codes used to identify MACE from the EHR  ICD-9 ICD-10 CPT

Myocardial Infarction

410.00, 410.0, 410.01, 410.02, 410.1, 410.10, 410.11, 410.12, 410.20, 410.2, 410.21, 410.22, 410.30, 410.31, 410.32, 410.40, 410.4, 410.41, 410.42, 410.50, 410.51, 410.52, 410.60, 410.61, 410.62, 410.7, 410.70, 410.71, 410.72, 410.8,410.80, 410.81, 410.82, 410.9, 410.90, 410.91, 410.92, 411.0, 412, 429.7, 429.71, 429.79

I21.*, I22.*, I23.*, I24.0, I24.8, I24.9, I25.*

Heart Failure

398.91, 428.0, 428, 428.1, 428.20, 428.2, 428.21, 428.22, 428.23, 428.3, 428.30, 428.31, 428.32, 428.33, 428.40, 428.4,428.41, 428.42, 428.43, 428.9

I50.*

Ischemic Stroke 433.01, 433.11, 433.21, 433.31, 433.81,433.91, 434.01, 434.11, 434.91 I63.*

Percutaneous Coronary Intervention

00.66, 17.55, 36.02, 36.03, 36.04, 36.05,36.06, 36.07, 36.09, 36.01 I97.89

C9600, C9601, C9602, C9604, C9605, C9606, C9607, G0290

Coronary Artery Bypass Grafting

36.10, 36.11, 36.12, 36.13, 36.14, 36.15,36.16, 36.19 I25.7*

Implantable Cardioverter-Defibrillator 89.49, 37.94, 37.95, 37.96, 37.97, 37.98

Z95.810, Z45.02, T82.128A, T82.118A

C1721, C1722, C1777, C1882, C1895, C1896

* indicates all the sub-codes under each ICD-10 category. ICD: International Classification of Diseases; CPT: Current Procedural Terminology

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Supplementary table 2: Number of prescription and patients by anti-diabetic medication classes Medication Class Number of prescriptions  Number of Patients Metformin 484209 60791 (72.6%)Insulin 771113 49310 (58.9%)Sulfonylureas 305068 38251 (45.7%)DPP-4 Inhibitors 70304 16262 (19.4%)Insulin Sensitizing Agents 75437 12298 (14.7%)Meglitinide Analogues 34501 7088 (8.5%)GLP-1 Receptor Agonists 22251 5987 (7.1%)SGLT2 Inhibitors 14830 5453 (6.5%)Glucose 9317 4698 (5.6%)Glucagon 8609 4197 (5.0%)Antidiabetic Combinations 20333 4128 (4.9%)Alpha-Glucosidase Inhibitors 2927 829 (1.0%)Antidiabetic - Amylin Analogs 974 255 (0.3%)

DPP-4: dipeptidyl peptidase-4; GLP-1: glucagon-like peptide 1; SGLT2: sodium-glucose transport protein2

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Supplementary table 3: The estimated parameters of the covariates in a linear model of ΔHbA1cVariables Estimate SE t value PIndex age 0.0048 0.0015 3.125 0.0018Baseline HbA1c 0.6914 0.0123 56.06 <2e-16MF monotherapy 0.7667 0.0761 10.07 <2e-16PC15 2.8245 1.1780 2.398 0.0166PC16 2.4166 1.1096 2.178 0.02949PC18 -2.9830 1.1508 -2.592 0.0096PC19 -4.3804 1.2319 -3.556 0.0004Adjusted R2: 0.5063; p-value: < 2.2e-16

Supplementary table 4: Summary of latent mixed models assuming 2-4 latent classesLatent class number Log likelihood BIC  %Class

1 %Class2 %Class3 %Class4

2 -60688.55 121461.5 9.05 90.95 / /3 -59470.01 119052.5 4.29 88.45 7.26 /4 -59470.01 119080.6 4.40 7.48 88.12 0

Supplementary table 5: The association of the variants of previous reported loci with the decrease of HbA1crsID CHR:BP A1/A2 Beta L95 U95 P Geners12486657 3:170738349 A/T 0.098 0.019 0.18 0.016 SLC2A

2 rs57413756 3:170738665 G/C 0.098 0.019 0.18 0.016 SLC2A

2 rs7643425 3:170737395 G/A 0.098 0.019 0.18 0.016 SLC2A

2 rs35297160 3:170738981 G/C 0.098 0.018 0.18 0.017 SLC2A

2 rs6806926 3:170743747 A/T 0.093 0.014 0.17 0.022 SLC2A

2 rs11917504 3:170736708 T/A 0.091 0.012 0.17 0.024 SLC2A

2 rs4987923 11:108116412 G/C -0.28 -0.46 -0.097 0.0026 ATMrs4987924 11:108116482 C/A -0.28 -0.46 -0.097 0.0026 ATMrs1800058 11:108160350 T/C -0.27 -0.45 -0.090 0.0035 ATM

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rs17092269 11:108210795 G/A -0.27 -0.45 -0.090 0.0035 ATM22

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Supplementary Figure 1

Supplementary figure 1: the flowchart of the eMERGE T2DM algorithm (http://phenotype.mc.vanderbilt.edu/phenotype/type-2-diabetes-mellitus) implemented in Geisinger.

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Supplementary Figure 2

Supplementary figure 2. Baseline HbA1c is positively correlated with the ΔHbA1c. A) Scatter plot of the Baseline HbA1c and the ΔHbA1c; B) The estimated parameters of the linear model between ΔHbA1c and the Baseline HbA1c.

Supplementary Figure 3

Supplementary figure 3. Density and Histogram of the Baseline HbA1c (pink), the minimum of the on-treatment HbA1c (cyan), and the ΔHbA1c (right panel, grey) in GWAS sample.

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Supplementary figure 4

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Supplementary figure 4: The individual HbA1c trajectories for patients in each latent class. The thick colored line represented the regressed line of all the patients in each group.

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Supplementary Figure 5

Supplementary figure 5: The Manhattan plot and QQ plot of the sensitivity GWAS of the decrease of HbA1c without adjusting the baseline HbA1c

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