Supplementary Data Supplementary Table 1. Baseline Characteristics by Quintiles of Systolic and Diastolic Blood Pressures Quintiles of Systolic Blood Pressure Quintiles of Diastolic Blood Pressure Q1 Q2 Q3 Q4 Q5 Q1 Q2 Q3 Q4 Q5 N= 7324 N= 7395 N= 7177 N= 5771 N= 6342 N= 5970 N= 11511 N= 2424 N= 6773 N= 7331 59.1 62.5 64.9 66.5 69.2 67.2 65.0 (12.1) 64.6 63.2 61.4 Age, years (12.7) (12.0) (11.3) (10.9) (10.6) (12.6) (11.5) (11.6) (11.4) Female, n 3070 (42) 3214 (44) 3334 (47) 2862 (50) 3524 (56) 3087 (52) 5635 (49) 1163 (48) 3159 (47) 2960 (40) Body mass index, 29.6 (5.4) 30.5 (5.5) 30.4 (5.3) 30.5 (5.4) 29.9 (5.3) 28.7 (5.1) 29.6 (5.2) 29.9 (5.1) 30.9 (5.3) 31.6 (5.6) kg/m 2 HbA1c, % 7.3 (1.5) 7.3 (1.3) 7.3 (1.3) 7.3 (1.4) 7.4 (1.3) 7.2 (1.3) 7.3 (1.4) 7.3 (1.3) 7.4 (1.4) 7.4 (1.4) Systolic BP, mm Hg 123 (7) 137 (3) 146 (3) 156 (3) 174 (11) 135 (18) 142 (16) 147 (15) 150 (15) 159 (17) Diastolic BP, mm Hg 75 (8) 80 (7) 82 (8) 84 (8) 88 (10) 68 (5) 78 (2) 82 (1) 85 (1) 94 (5) Triglycerides, mm 2 (1.5) 2.0 (1.5) 2.1 (1.5) 2.1 (1.5) 2.0 (1.3) 1.8 (1.4) 2.0 (1.4) 2.1 (1.5) 2.1 (1.5) 2.3 (1.6) Total cholesterol, mm 5.2 (1.1) 5.3 (1.1) 5.4 (1.1) 5.5 (1.1) 5.6 (1.1) 5.2 (1.1) 5.3 (1.1) 5.4 (1.0) 5.5 (1.1) 5.6 (1.2) LDL cholesterol, mm 1.5 (1.0) 1.5 (0.9) 1.5 (0.9) 1.5 (0.9) 1.5 (0.8) 1.6 (0.9) 1.5 (0.9) 1.5 (0.9) 1.5 (0.9) 1.4 (0.9) HDL cholesterol, mm 3.2 (0.9) 3.2 (0.9) 3.3 (0.9) 3.3 (0.9) 3.4 (1.0) 3.1 (0.9) 3.2 (0.9) 3.3 (0.9) 3.3 (0.9) 3.4 (0.9) Creatinine, µm 80 (23) 82 (22) 82 (21) 84 (24) 86 (25) 84 (26) 83 (23) 82 (24) 82 (22) 83 (23) egfr, ml/min/1.73 84 (20) 80 (19) 78 (19) 75 (19) 71 (19) 75 (20) 77 (19) 78 (19) 79 (19) 80 (19) m 2 Smoker, n 1,168 (23) 1,022 (19) 830 (16) 628 (15) 635 (15) 726 (18) 1,437 (18) 294 (16) 842 (17) 984 (19) Antihypertensive 1,838 (25) 2,624 (36) 3,078 (43) 2,808(49) 3,329 (53) 2,071 (35) 4,029 (35) 1,079 (45) 2,931 (43) 3,567 (49) drugs, n Alpha-blockers 21 (0) 28 (0) 43 (1) 45 (1) 46 (1) 34 (1) 50 (0) 13 (1) 36 (1) 50 (1) ARBs 399 (5) 621 (8) 733 (10) 614 (11) 750 (12) 478 (8) 886 (8) 221 (9) 639 (9) 893 (12) ACE-inhibitors 636 (9) 858 (12) 1,089 (15) 1,062(18) 1,337 (21) 709 (12) 1,273 (11) 373 (15) 1,123 (17) 1,504 (21) Calcium antagonists 438 (6) 745 (10) 922 (13) 844 (15) 981 (16) 670 (11) 1,172 (10) 320 (13) 854 (13) 914 (13) Thiazides 312 (4) 544 (7) 631 (9) 536 (9) 590 (9) 392 (7) 784 (7) 230 (10) 579 (9) 628 (9) Beta-blockers 1,001 (14) 1,400 (19) 1,511 (21) 1,395(24) 1,727 (27) 1,109 (19) 2,205 (19) 575 (24) 1,428 (21) 1,717 (23) Lipid-lowering drugs, 1,258 (17) 1,490 (20) 1,341 (19) 1,047(18) 843 (13) 1,155 (19) 2,017 (18) 485 (20) 1,166 (17) 1,156 (16) n Insulin, n 658 (9) 559 (8) 552 (8) 437 (8) 525 (8) 660 (11) 994 (9) 171 (7) 485 (7) 421 (6)
Oral glucose-lowering 2,420 (33) 2,561 (35) 2,451 (34) 2,048 (36) 2,263 (36) 1,883 (32) 3,945 (34) 836 (35) 2,437 (36) 2,642 (36) drugs, n Education Elementary school 2,442 (36) 2,776 (41) 2,831 (44) 2,408(47) 2,772 (53) 2,320 (45) 4,585 (45) 979 (44) 2,596 (42) 2,749 (41) Secondary school 2,225 (33) 2,120 (31) 2,035 (31) 1,545(30) 1,402 (27) 1,510 (30) 3,012 (30) 663 (30) 1,970 (32) 2,172 (32) College or graduate exam 2,077 (31) 1,891 (28) 1,641 (25) 1,179 (23) 1,024 (20) 1,295 (25) 2,589 (25) 570 (26) 1,582 (26) 1,776 (27) Marital status Married 3,708 (52) 3,943 (54) 3,808 (54) 2,968(52) 3,174 (51) 2,982 (51) 6,058 (54) 1,302 (54) 3,533 (53) 3,726 (52) Divorced 1,344 (19) 1,212 (17) 1,171 (17) 943 (17) 906 (14) 924 (16) 1,818 (16) 383 (16) 1,122 (17) 1,329 (18) Unmarried 1,425 (20) 1,239 (17) 1,004 (14) 760 (13) 714 (11) 760 (13) 1,591 (14) 342 (14) 1,109 (17) 1,340 (19) Widow/widower 688 (10) 889 (12) 1,098 (16) 1,026 (18) 1,450 (23) 1,169 (20) 1,843 (16) 375 (16) 926 (14) 838 (12) Data are means (standard deviations) or numbers of individuals (percent). BP, blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; egfr, estimated glomerular filtration rate; ARBs, angiotensin receptor-blockers; ACE, angiotensinconverting enzyme. Quintile limits for systolic blood pressure were <130; 130-140; 140-149; 149-160; and >160 mm Hg; and those for diastolic blood pressure were <73; 73-78; 78-81; 81-87; and >87 mm Hg.
Supplementary Table 2. Relations of Quintiles of Systolic and Diastolic Blood Pressures to Risk of Cardiovascular Events and Mortality No antihypertensive Models A Models B Models C Antihypertensive Antihypertensive No antihypertensive No antihypertensive Antihypertensive Risk of Cardiovascular Events Systolic blood pressure Quintile 1 (<130 mm Hg) 1 1 1 1 1 1 Quintile 2 (130-140 mm Hg) 1.20 (1.07-1.36) 0.89 (0.80-0.99) 0.98 (0.86-1.10) 0.87 (0.79-0.97) 1.24 (0.91-1.70) 0.94 (0.76-1.16) Quintile 3 (140-149 mm Hg) 1.38 (1.20-1.59) 0.87 (0.77-0.97) 0.96 (0.83-1.11) 0.82 (0.73-0.92) 1.35 (0.95-1.93) 1.03 (0.83-1.28) Quintile 4 (149-160 mm Hg) 1.91 (1.70-2.14) 1.08 (0.98-1.20) 1.17 (1.04-1.31) 0.93 (0.84-1.03) 1.29 (0.91-1.82) 0.98 (0.79-1.20) Quintile 5 (>160 mm Hg) 2.59 (2.28-2.94) 1.50 (1.36-1.65) 1.28 (1.12-1.45) 1.15 (1.04-1.27) 1.79 (1.17-2.74) 1.37 (1.11-1.70) Diastolic blood pressure Quintile 1 (<73 mm Hg) 1 1 1 1 1 1 Quintile 2 (73-78 mm Hg) 0.79 (0.70-0.89) 0.79 (0.72-0.87) 0.92 (0.81-1.03) 0.92 (0.84-1.02) 1.65 (1.17-2.32) 1.00 (0.83-1.21) Quintile 3 (78-81 mm Hg) 0.79 (0.70-0.89) 0.85 (0.77-0.93) 0.94 (0.83-1.06) 1.05 (0.95-1.16) 1.11 (0.75-1.64) 0.89 (0.72-1.10) Quintile 4 (81-87 mm Hg) 0.72 (0.63-0.82) 0.70 (0.63-0.77) 0.94 (0.82-1.06) 0.99 (0.90-1.09) 1.36 (0.93-1.99) 0.93 (0.76-1.14) Quintile 5 (>87 mm Hg) 0.89 (0.79-1.01) 0.76 (0.70-0.84) 1.23 (1.09-1.39) 1.29 (1.17-1.42) 2.01 (1.35-2.98) 1.24 (1.01-1.52) Risk of Mortality Systolic blood pressure Quintile 1 (<130 mm Hg) 1 1 1 1 1 1 Quintile 2 (130-140 mm Hg) 0.97 (0.87-1.08) 0.71 (0.64-0.79) 0.77 (0.69-0.86) 0.71 (0.64-0.78) 1.00 (0.71-1.41) 0.75 (0.60-0.93) Quintile 3 (140-149 mm Hg) 0.93 (0.81-1.07) 0.59 (0.52-0.66) 0.62 (0.54-0.72) 0.56 (0.50-0.63) 1.02 (0.68-1.53) 0.63 (0.49-0.80) Quintile 4 (149-160 mm Hg) 1.30 (1.17-1.45) 0.80 (0.73-0.88) 0.75 (0.67-0.83) 0.69 (0.63-0.76) 0.90 (0.60-1.35) 0.65 (0.51-0.81) Quintile 5 (>160 mm Hg) 1.63 (1.44-1.85) 0.95 (0.86-1.04) 0.72 (0.63-0.82) 0.71 (0.64-0.78) 0.90 (0.50-1.64) 0.72 (0.56-0.92) Diastolic blood pressure Quintile 1 (<73 mm Hg) 1 1 1 1 1 1 Quintile 2 (73-78 mm Hg) 0.64 (0.57-0.72) 0.71 (0.65-0.78) 0.76 (0.67-0.85) 0.84 (0.76-0.92) 0.97 (0.68-1.39) 0.78 (0.63-0.96) Quintile 3 (78-81 mm Hg) 0.69 (0.62-0.77) 0.76 (0.69-0.84) 0.83 (0.75-0.93) 0.95 (0.86-1.04) 0.77 (0.52-1.16) 0.77 (0.61-0.98) Quintile 4 (81-87 mm Hg) 0.54 (0.48-0.61) 0.53 (0.47-0.58) 0.73 (0.64-0.83) 0.78 (0.70-0.86) 0.94 (0.62-1.4) 0.69 (0.54-0.88) Quintile 5 (>87 mm Hg) 0.63 (0.56-0.72) 0.57 (0.52-0.63) 0.90 (0.79-1.02) 1.01 (0.91-1.11) 0.82 (0.49-1.38) 0.93 (0.73-1.19)
Data are Cox proportional hazard ratios (95% confidence intervals). Model A, unadjusted; model B, adjusting for gender and age; model C, adjusting for gender, age, smoking, education and body mass index. Supplementary Table 3. Systolic and Diastolic Blood Pressures at Lowest Risk of Cardiovascular Events and Mortality Starting Follow-Up Two Years After Baseline Date Risk of Cardiovascular Events No antihypertensive Antihypertensive No antihypertensive Risk of Mortality Antihypertensive Systolic blood pressure at lowest risk 140 134 151 140 Diastolic blood pressure at lowest risk 73 75 78 76 Data are systolic and diastolic blood pressures corresponding to lowest risk of cardiovascular events and mortality from multivariableregression spline models B (adjusting for age and gender; stratified by antihypertensive treatment use) starting follow-up two years after baseline date.
Supplementary Figure 1. Distributions of Systolic and Diastolic Blood Pressures
Supplementary Figure 2. Cumulative Incidence of Cardiovascular Events and Mortality by Quintiles of Blood Pressure Levels A B C D Cumulative incidence of cardiovascular events (panels A & B) and mortality (panels C & D) by quintiles of systolic blood pressure (panels A & C) and diastolic blood pressure (panels B & D), by years of follow-up. All log-rank p-values<0.0001. Quintile blood pressure limits as in Supplementary Table 1.
Supplementary Figure 3. Natures of Associations of Blood Pressure Levels With Risk of Cardiovascular Events by Gender A B C D Risk of cardiovascular events by systolic (panels A & B) and diastolic (panels C & D) blood pressures in untreated (A & C) and antihypertensive drug treated (B & D) persons (pink lines, men; blue lines, women; shaded fields, 95% confidence intervals). Multiplicative interaction terms between gender and systolic blood pressure in untreated p=0.97 and antihypertensive drug treated p=0.34; and between gender and diastolic blood pressure in untreated p=0.38 and treated p=0.01.
Supplementary Figure 4. Natures of Associations of Blood Pressure Levels With Risk of Cardiovascular Events by Age A B C D Risk of cardiovascular events by systolic (panels A & B) and diastolic (panels C & D) blood pressures in untreated (A & C) and antihypertensive drug treated (B & D) persons (pink lines, above median age; blue lines, below median age; shaded fields, 95% confidence intervals). Multiplicative interaction terms between age and systolic blood pressure in untreated p<0.0001 and antihypertensive drug treated p<0.0001; and between age and diastolic blood pressure in untreated p=0.09 and treated p=0.30.
Supplementary Figure 5. Natures of Associations of Blood Pressure Levels With Risk of Cardiovascular Events by Body Mass Index A B C D Risk of cardiovascular events by systolic (panels A & B) and diastolic (panels C & D) blood pressures in untreated (A & C) and antihypertensive drug treated (B & D) persons (pink lines, above median body mass index; blue lines, below median body mass index; shaded fields, 95% confidence intervals). Multiplicative interaction terms between body mass index and systolic blood pressure in untreated p=0.98 and antihypertensive drug treated p=0.03; and between body mass index and diastolic blood pressure in untreated p=0.99 and treated p=0.06.
Supplementary Figure 6. Natures of Associations of Blood Pressure Levels With Risk of Cardiovascular Events by HbA1c A B C D Risk of cardiovascular events by systolic (panels A & B) and diastolic (panels C & D) blood pressures in untreated (A & C) and antihypertensive drug treated (B & D) persons (pink lines, above median HbA1c; blue lines, below median HbA1c; shaded fields, 95% confidence intervals). Multiplicative interaction terms between HbA1c and systolic blood pressure in untreated p=0.90 and antihypertensive drug treated 0.35; and between HbA1c and diastolic blood pressure in untreated p=0.40 and treated p=0.92.
Supplementary Figure 7. Natures of Associations of Blood Pressure Levels With Risk of Cardiovascular Events by egfr A B C D Risk of cardiovascular events by systolic (panels A & B) and diastolic (panels C & D) blood pressures in untreated (A & C) and antihypertensive drug treated (B & D) persons (pink lines, above median egfr; blue lines, below median egfr; shaded fields, 95% confidence intervals). Multiplicative interaction terms between egfr and systolic blood pressure in untreated p<0.0001 and antihypertensive drug treated p=0.0009; and between egfr and diastolic blood pressure in untreated p=0.75 and treated p=0.0004.
Supplementary Figure 8. Natures of Associations of Blood Pressure Levels With Risk of Cardiovascular Events by Antidiabetic Treatment (no treatment vs. oral hypoglycemic treatment vs. insulin treatment) Risk of cardiovascular events by systolic (panels A & B) and diastolic (panels C & D) blood pressures in untreated (A & C) and antihypertensive drug treated (B & D) persons (pink lines, oral hypoglycemictherapy; blue lines, no antidiabetic drugs; green lines, insulin therapy; shaded fields, 95% confidence intervals). Multiplicative interaction terms between antidiabetic and systolic blood pressure in antihypertensive drug untreated p=0.38 and treated p=0.30; and between antidiabetic and diastolic blood pressure in antihypertensive drug untreated p=0.009 and treated p=0.39.