Events / Person-Years (Annual Rate) Hazard Ratio More Intensive Figure 1 Events / Person-Years (Annual Rate) Hazard Ratio More Intensive Less Intensive Trials More Intensive Less Intensive Better Better (95% CI) Primary Kidney Outcome ACCORD 383/21641 (1.8%) 484/21554 (2.2%) 0.79 (0.69-0.90) ADVANCE 233/25728 (0.9%) 301/25675 (1.2%) 0.77 (0.65-0.91) UKPDS 127/10852 (1.2%) 54/4515 (1.2%) 0.98 (0.71-1.35) VADT 18/3818 (0.5%) 26/3878 (0.7%) 0.70 (0.39-1.28) Overall 761/62039 (1.2%) 865/55622 (1.6%) 0.80 (0.72-0.88) (I2=0.0%, p=0.583) Primary Eye Outcome ACCORD 131/6135 (2.1%) 167/6104 (2.7%) 0.79 (0.64-0.98) ADVANCE 35/2992 (1.2%) 49/2901 (1.7%) 0.83 (0.56-1.22) UKPDS 200/5300 (3.8%) 88/2251 (3.9%) 0.95 (0.74-1.23) VADT 62/450 (13.8%) 63/453 (13.9%) 0.94 (0.66-1.34) Overall 428/14877 (2.9%) 367/11709 (3.1%) 0.87 (0.76-1.00) (I2=0.0%, p=0.688) Primary Nerve Outcome ACCORD 2055/14979 (13.7%) 2210/14923 (14.8%) 0.92 (0.87-0.98) ADVANCE 1373/23752 (5.8%) 1299/23876 (5.4%) 1.07 (0.99-1.15) UKPDS 453/12247 (3.7%) 208/5087 (4.1%) 0.93 (0.78-1.10) Overall 3881/50978 (7.6%) 3717/43887 (8.5%) 0.98 (0.87-1.09) (I2=78.1%, p=0.011) 0.25 0.5 1 2 p is for Cochran’s Q test Hazard Ratio

A B Figure 2 Events (Annual Rate) Hazard Ratio More Intensive Less Intensive More Intensive Less Intensive Better Better (95% CI) Primary Kidney Outcome 761 (1.2%) 865 (1.6%) 0.80 (0.72-0.88) End Stage Kidney Disease 113 (0.2%) 143 (0.2%) 0.61 (0.26-1.44) Renal Death 18 (0.0%) 22 (0.1%) 0.77 (0.41-1.46) eGFR<30ml/min/1.73m2 175 (0.3%) 149 (0.3%) 1.16 (0.93-1.44) Macroalbuminuria 509 (0.9%) 603 (1.2%) 0.74 (0.61-0.90) Secondary Outcomes 0.90 (0.84-0.95) Microalbuminuria 2121 (5.2%) 2210 (6.3%) B Less Intensive More Intensive Better Better Secondary Outcomes Macro to Norm 80 (3.5%) 603 (1.2%) 1.01 (0.61-1.66) Macro to Micro/Norm 353 (22.0%) 332 (18.1%) 1.23 (1.03-1.48) Micro to Norm 1430 (13.0%) 1176 (10.7%) 1.15 (1.03-1.28) Norm to Norm 7004 (75.5%) 5784 (72.4%) 1.16 (1.08-1.25) 0.25 0.5 1 2 Hazard Ratio

Figure 3 Events (Annual Rate) More Intensive Less Intensive Hazard Ratio More Intensive Less Intensive Better Better (95% CI) Primary Eye Outcome 428(2.9%) 367(3.1%) 0.87(0.76-1.00) Photocoagulation/ Vitrectomy 675(1.1%) 665(1.3%) 0.96(0.86-1.07) Proliferative Retinopathy 223(0.7%) 210(0.7%) 0.93(0.65-1.33) ETDRS Progression ≥3 steps 339(2.1%) 288(2.3%) 0.86(0.73-1.01) Secondary Outcomes Macular Edema 187(0.5%) 205(0.6%) 0.83(0.68-1.02) Blindness . 397(0.7%) 380(0.7%) 1.03(0.89-1.18) Vision Deterioration 4663(9.3%) 4615(10.7%) 0.97(0.92-1.03) Cataract Extraction 763(2.1%) 828(2.8%) 0.90(0.81-0.99) 0.25 0.5 1 2 Hazard Ratio

Supplementary Figure 1 Events (Annual Rate) More Intensive Less Intensive Hazard Ratio More Intensive Less Intensive Better Better (95% CI) Primary Nerve Outcome 3881 (7.6%) 3717 (8.5%) 0.98 (0.87-1.09) Loss of Vibratory Sensation 808 (2.7%) 789 (3.5%) 0.91 (0.82-1.00) Loss of Ankle Reflexes 2804 (6.1%) 2722 (7.0%) 0.97 (0.85-1.09) Loss of Light touch 994 (1.8%) 1029 (2.1%) 0.91 (0.78-1.07) 0.25 0.5 1 2 Hazard Ratio

Supplementary Figure 2A (Primary Kidney Outcome) Events (Annual Rate) More Intensive Less Intensive Hazard Ratio P Subgroups More Intensive Less Intensive Better Better (95% CI) interaction OVERALL Male Female Age < mean (62.3y) Age ≥ mean (62.3y) Age < 70y Age ≥ 70y HbA1c < 7.5% HbA1c 7.5-8.5% HbA1c > 8.5% Caucasian Asian Hispanic Black Duration of diabetes < 5y Duration of diabetes ≥ 5y No existing CVD Existing CVD eGFR 1st third (<73 ml/min) eGFR 2nd third (73-90 ml/min) eGFR 3rd third (>90 ml/min) 761(1.2%) 480(1.3%) 291(1.2%) 392(1.2%) 379(1.3%) 607(1.2%) 164(1.5%) 260(1.0%) 223(1.3%) 277(1.6%) 472(1.2%) 47(2.2%) 92(1.6%) 139(1.1%) 256(1.0%) 513(1.4%) 496(1.1%) 275(1.6%) 348(1.7%) 192(0.9%) 223(1.1%) 865(1.6%) 568(1.7%) 301(1.4%) 402(1.5%) 467(1.6%) 684(1.5%) 185(1.7%) 239(1.1%) 282(1.7%) 338(2.0%) 520(1.5%) 41(1.9%) 101(1.9%) 171(1.5%) 225(1.2%) 642(1.8%) 547(1.4%) 322(1.9%) 413(2.2%) 224(1.2%) 229(1.2%) 0.80(0.72-0.88) 0.80(0.63-1.02) 0.84(0.58-1.23) 0.83(0.67-1.04) 0.78(0.68-0.90) 0.79(0.68-0.92) 0.93(0.62-1.39) 0.90(0.75-1.08) 0.72(0.58-0.90) 0.81(0.64-1.02) 0.81(0.69-0.94) 0.76(0.18-3.27) 0.79(0.59-1.06) 0.75(0.60-0.94) 0.80(0.64-0.99) 0.80(0.71-0.90) 0.78(0.67-0.90) 0.84(0.72-0.99) 0.75(0.54-1.03) 0.86(0.71-1.03)   0.816 0.645 0.415 0.251 0.682 0.952 0.398 0.517 0.25 0.5 1 2 Hazard Ratio

Supplementary Figure 2B (Primary Eye Outcome) Events (Annual Rate) More Intensive Less Intensive Hazard Ratio P Subgroups More Intensive Less Intensive Better Better (95% CI) interaction OVERALL Male Female Age < mean (62.3y) Age ≥ mean (62.3y) Age < 70y Age ≥ 70y HbA1c < 7.5% HbA1c 7.5-8.5% HbA1c > 8.5% Caucasian Asian Hispanic Black Duration of diabetes < 5y Duration of diabetes ≥ 5y No existing CVD Existing CVD eGFR 1st third (<73 ml/min) eGFR 2nd third (73-90 ml/min) eGFR 3rd third (>90 ml/min) 428(2.9%) 281(3.0%) 147(2.6%) 280(3.0%) 148(2.7%) 399(3.0%) 29(2.0%) 140(2.1%) 101(2.4%) 181(4.9%) 283(2.8%) 28(6.1%) 54(3.9%) 55(2.2%) 223(2.8%) 204(3.0%) 336(2.8%) 91(3.1%) 113(2.7%) 142(2.7%) 172(3.2%) 367(3.1%) 268(3.6%) 99(2.3%) 232(3.4%) 135(2.8%) 328(3.2%) 39(2.7%) 85(1.8%) 110(3.0%) 167(5.2%) 210(2.8%) 23(5.1%) 57(4.8%) 62(2.9%) 135(2.7%) 230(3.4%) 274(3.1%) 93(3.3%) 91(2.8%) 119(2.9%) 155(3.6%) 0.87(0.76-1.00) 0.76(0.64-0.90) 1.08(0.81-1.43) 0.83(0.68-1.01) 0.90(0.71-1.14) 0.86(0.74-1.00) 0.78(0.48-1.26) 0.95(0.72-1.26) 0.72(0.55-0.94) 0.87(0.67-1.14) 0.89(0.74-1.07) 1.02(0.44-2.36) 0.92(0.42-2.02) 0.76(0.52-1.10) 0.64(0.35-1.19) 0.85(0.66-1.10) 0.78(0.63-0.97) 1.02(0.76-1.36) 0.96(0.71-1.30) 0.80(0.62-1.03) 0.83(0.66-1.04)   0.035 0.639 0.719 0.687 0.391 0.563 0.178 0.461 0.25 0.5 1 2 Hazard Ratio

Supplementary Figure 2C (Primary Nerve Outcome) Events (Annual Rate) More Intensive Less Intensive Hazard Ratio P Subgroups More Intensive Less Intensive Better Better (95% CI) interaction OVERALL Male Female Age < mean (62.3y) Age ≥ mean (62.3y) Age < 70y Age ≥ 70y HbA1c < 7.5% HbA1c 7.5-8.5% HbA1c > 8.5% Caucasian Asian Hispanic Black Duration of diabetes < 5y Duration of diabetes ≥ 5y No existing CVD Existing CVD eGFR 1st third (<73 ml/min) eGFR 2nd third (73-90 ml/min) eGFR 3rd third (>90 ml/min) 3881(7.6%) 2489(8.4%) 1392(6.5%) 1853(6.8%) 2028(8.5%) 3078(7.3%) 803(9.4%) 1463(6.0%) 1265(9.3%) 1103(9.2%) 2797(8.5%) 111(9.6%) 399(9.7%) 458(3.9%) 1311(5.3%) 2553(9.7%) 2681(7.0%) 1200(9.4%) 1349(7.9%) 1257(7.2%) 1258(7.7%) 3717(8.5%) 2363(9.2%) 1354(7.4%) 1682(8.1%) 2035(8.8%) 2890(8.2%) 827(9.7%) 1309(6.6%) 1267(10.4%) 1116(10.0%) 2638(9.8%) 129(11.3%) 413(12.4%) 401(3.6%) 1089(6.3%) 2607(9.8%) 2538(8.1%) 1178(9.3%) 1253(8.3%) 1237(8.5%) 1214(8.7%) 0.98(0.87-1.09) 0.99(0.86-1.14) 0.95(0.88-1.03) 1.00(0.88-1.13) 0.96(0.85-1.09) 0.98(0.86-1.10) 0.97(0.88-1.07) 0.99(0.89-1.10) 0.95(0.82-1.11) 0.98(0.89-1.08) 0.97(0.92-1.03) 0.86(0.67-1.11) 0.89(0.77-1.02) 0.87(0.55-1.40) 0.94(0.82-1.07) 1.01(0.89-1.14) 0.96(0.81-1.15) 1.00(0.93-1.09) 1.00(0.91-1.10) 0.93(0.85-1.02) 0.99(0.80-1.21) 0.656 0.694 0.901 0.847 0.870 0.449 0.714 0.978 0.25 0.5 1 2 Hazard Ratio