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Original ArticlesEpidemiology and Outcomes
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High Density Lipoprotein Cholesterol and the Risk of All-Cause Mortality among U.S. Veterans

Benjamin Bowe, Yan Xie, Hong Xian, Sumitra Balasubramanian, Mohamed A. Zayed and Ziyad Al-Aly
CJASN October 2016, 11 (10) 1784-1793; DOI: https://doi.org/10.2215/CJN.00730116
Benjamin Bowe
*Clinical Epidemiology Center, Research and Education Service,
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Yan Xie
*Clinical Epidemiology Center, Research and Education Service,
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Hong Xian
*Clinical Epidemiology Center, Research and Education Service,
†Department of Biostatistics, College for Public Health and Social Justice, St. Louis University, St. Louis, Missouri; and
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Sumitra Balasubramanian
*Clinical Epidemiology Center, Research and Education Service,
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Mohamed A. Zayed
*Clinical Epidemiology Center, Research and Education Service,
‡Division of Vascular and Endovascular Surgery, Department of Surgery and
§Section of Vascular Surgery, Surgery Service, and
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Ziyad Al-Aly
*Clinical Epidemiology Center, Research and Education Service,
‖Division of Nephrology, Department of Medicine, Veterans Affairs St. Louis Health Care System, St. Louis, Missouri;
¶Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
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    Figure 1.

    Cohort construction. (A) Flow diagram of cohort assembly. (B) Timeline of cohort selection.

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    Figure 2.

    Risk of all-cause mortality by HDL cholesterol (HDL-C) levels in each eGFR category. Error bars represent 95% confidence intervals.

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    Figure 3.

    Spline analyses of all-cause mortality by HDL cholesterol (HDL-C) levels in the overall cohort, where median HDL-C was used as a reference and the HDL-C probability distribution histogram is represented in gray bars in the background. Dashed red lines represent 95% confidence intervals.

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    Table 1.

    Demographic and clinical characteristics according to HDL cholesterol levels

    CharacteristicOverallHDL-C≤25 mg/dlHDL-C>25 to <34 mg/dlHDL-C≥34 to ≤42 mg/dlHDL-C>42 to <50 mg/dlHDL-C≥50 mg/dl
    No. (%)1,764,98665,431 (3.7)338,327 (19.2)522,373 (29.6)399,303 (22.6)439,552 (24.9)
    Median HDL-C (IQR), mg/dl41.0 (34.0–49.5)23.0 (21.6–25.0)30.0 (28.1–32.0)37.9 (36.0–39.5)45.0 (43.0–47.0)57.0 (53.0–65.0)
    Race (%)
     White1,503,312 (85.2)58,598 (89.6)299,469 (88.5)452,934 (86.7)338,073 (84.7)354,238 (80.6)
     Black224,785 (12.7)5626 (8.6)31,649 (9.4)58,008 (11.1)52,670 (13.2)76,832 (17.5)
     Other36,889 (2.1)1207 (1.8)7209 (2.1)11,431 (2.2)8560 (2.1)8482 (1.9)
    Median age (IQR), yr64.1 (56.1–72.6)61.8 (55.1–71.4)63.1 (55.7–72.0)64.0 (56.1–72.4)64.8 (56.3–72.9)65.0 (56.3–73.1)
    Cancer (%)248,058 (14.1)9567 (14.6)45,499 (13.5)71,324 (13.7)55,676 (13.9)65,992 (15.0)
    Cerebrovascular accident (%)11,633 (0.7)613 (0.9)2704 (0.8)3643 (0.7)2412 (0.6)2261 (0.5)
    Coronary artery disease (%)576,589 (32.7)28,484 (43.5)132,693 (39.2)181,056 (34.7)122,458 (30.7)111,898 (25.5)
    Congestive heart failure (%)146,203 (8.3)10,055 (15.4)37,141 (11.0)44,195 (8.5)28,235 (7.1)26,577 (6.1)
    Chronic lung disease (%)384,971 (21.8)15,966 (24.4)73,546 (21.7)107,299 (20.5)82,971 (20.8)105,189 (23.9)
    Diabetes mellitus (%)557,235 (31.6)31,039 (47.4)138,205 (40.9)179,777 (34.4)113,751 (28.5)94,463 (21.5)
    Dementia (%)61,308 (3.5)2438 (3.7)11,563 (3.4)17,766 (3.4)13,831 (3.5)15,710 (3.6)
    HIV (%)119,926 (6.8)6277 (9.6)26,114 (7.7)35,227 (6.7)25,030 (6.3)27,278 (6.2)
    Hypertension (%)1,278,661 (72.5)50,986 (77.9)258,782 (76.5)385,445 (73.8)283,880 (71.1)299,568 (68.2)
    Hepatitis C (%)81,256 (4.6)5312 (8.1)16,527 (4.9)21,527 (4.1)16,189 (4.1)21,701 (4.9)
    Peripheral artery disease (%)60,387 (3.4)3302 (5.1)14,210 (4.2)18,337 (3.5)12,246 (3.1)12,292 (2.8)
    Average eGFR at T0 (SD), ml/min per 1.73 m274.8 (19.3)71.7 (21.6)72.6 (20.0)73.9 (19.2)75.2 (18.7)77.7 (18.6)
    eGFR at T0 (%), ml/min per 1.73 m2
     ≥9025,249 (1.4)2085 (3.2)7150 (2.1)7640 (1.5)4462 (1.1)3912 (0.9)
     ≥60 to <9098,720 (5.6)5972 (9.1)25,157 (7.4)31,263 (6.0)19,746 (5.0)16,582 (3.8)
     ≥45 to <60272,441 (15.4)11,479 (17.5)57,977 (17.1)85,344 (16.3)60,612 (15.2)57,029 (13.0)
     ≥30 to <45954,680 (54.1)31,176 (47.7)176,095 (52.1)283,942 (54.4)222,440 (55.7)241,027 (54.8)
     ≥15 to <30413,896 (23.5)14,719 (22.5)71,948 (21.3)114,184 (21.9)92,043 (23.1)121,002 (27.5)
    Dialysis during follow-up (%)27,157 (1.5)1727 (2.6)6961 (2.1)8144 (1.6)5152 (1.3)5173 (1.2)
    Kidney transplant during follow-up (%)11,515 (0.7)761 (1.2)2897 (0.9)3357 (0.6)2175 (0.5)2325 (0.5)
    Average LDL-C (SD), mg/dl109.79 (33.8)93.16 (33.9)104.40 (33.3)110.88 (33.6)113.73 (33.6)111.54 (33.5)
    Average triglycerides (SD), mg/dl160.81 (114.3)252.55 (194.2)204.98 (132.5)171.69 (108.0)145.35 (94.2)114.25 (78.3)
    Average serum albumin (SD), g/dl4.09 (0.7)3.88 (0.7)4.00 (0.6)4.08 (0.7)4.13 (0.7)4.16 (0.8)
    Body mass index (%)
     Underweight17,671 (1.0)378 (0.6)1308 (0.4)2604 (0.5)3252 (0.8)10,129 (2.3)
     Normal345,569 (19.6)8,507 (13.0)41,815 (12.4)78,388 (15.0)79,063 (19.8)137,796 (31.4)
     Overweight689,296 (39.6)23,492 (35.9)126,130 (37.3)207,027 (39.6)167,046 (41.8)179,755 (40.9)
     Obese703,450 (39.9)33,054 (50.5)169,074 (50.0)234,354 (44.9)149,942 (37.6)111,872 (25.5)
    Average body surface area (SD), m22.1 (0.2)2.1 (0.2)2.1 (0.2)2.1 (0.2)2.1 (0.2)2.0 (0.2)
    Statin use during follow-up (%)1,282,527 (72.7)45,963 (70.3)256,950 (76.0)397,119 (76.0)295,012 (73.9)287,483 (65.4)
    ACEI/ARB use876,615 (49.7)38,709 (59.2)189,971 (56.2)270,522 (51.8)189,658 (47.5)187,755 (42.7)
    Median follow-up time (IQR), yr9.1 (7.7–9.4)9.1 (5.4–9.3)9.1 (7.3–9.3)9.1 (8.1–9.4)9.2 (8.3–9.4)9.1 (7.4–9.4)
    Death during follow-up (%)541,682 (30.7)26,247 (40.1)109,222 (32.3)152,625 (29.2)113,785 (28.5)139,803 (31.8)
    Microalbumin-to-creatinine ratio (%),a mg/g
     0–<2093,696 (69.8)4133 (65.5)21,558 (67.8)30,232 (69.5)20,322 (71.4)17,451 (72.0)
     20–<30036,687 (27.3)1902 (30.2)9168 (28.9)12,030 (27.6)7429 (26.1)6158 (25.4)
     ≥3003938 (2.9)272 (4.3)1053 (3.3)1264 (2.9)709 (2.5)640 (2.6)
    Average C–reactive proteinb (SD), mg/dl2.0 (4.4)2.4 (4.7)2.2 (4.7)2.0 (4.4)1.9 (4.2)1.9 (4.3)
    • HDL-C, HDL cholesterol; IQR, interquartile range; LDL-C, LDL cholesterol; ACEI, angiotensin–converting enzyme inhibitor; ARB, angiotensin receptor blocker.

    • ↵a Results for a subset of the cohort (n=134,321).

    • ↵b Results for a subset of the cohort with available C–reactive protein data (n=65,112).

    • View popup
    Table 2.

    Risk of all-cause mortality by HDL cholesterol levels in overall cohort and by eGFR category

    eGFR, ml/min per 1.73 m2Hazard Ratio (95% Confidence Interval)
    HDL-C≤25 mg/dlHDL-C>25 to <34 mg/dlHDL-C≥34 to ≤42 mg/dlHDL-C>42 to <50 mg/dlHDL-C≥50 mg/dl
    Overall1.000.87 (0.86 to 0.88)0.84 (0.83 to 0.85)0.84 (0.82 to 0.85)0.92 (0.91 to 0.93)
    ≥15 to <301.000.91 (0.86 to 0.96)0.89 (0.84 to 0.94)0.92 (0.86 to 0.97)0.97 (0.91 to 1.03)
    ≥30 to <451.000.88 (0.85 to 0.91)0.86 (0.83 to 0.89)0.84 (0.81 to 0.87)0.88 (0.85 to 0.92)
    ≥45 to <601.000.85 (0.83 to 0.88)0.83 (0.80 to 0.85)0.81 (0.79 to 0.84)0.87 (0.85 to 0.89)
    ≥60 to <901.000.87 (0.85 to 0.89)0.83 (0.82 to 0.85)0.84 (0.82 to 0.86)0.91 (0.89 to 0.93)
    ≥901.000.85 (0.83 to 0.88)0.84 (0.82 to 0.87)0.85 (0.82 to 0.88)1.01 (0.97 to 1.04)
    • Models were adjusted for age, race, cancer, cerebrovascular accident, chronic lung disease, diabetes mellitus, dementia, hepatitis C, HIV, hypertension, body mass index, LDL cholesterol, triglycerides, serum albumin, angiotensin–converting enzyme inhibitor/angiotensin receptor blocker use, coronary artery disease, congestive heart failure, and peripheral artery disease. Models were additionally adjusted for eGFR, dialysis, kidney transplant, and statin use as time varying. P for interaction of HDL-C and eGFR category is <0.01. HDL-C, HDL cholesterol.

    • View popup
    Table 3.

    Risk of all-cause mortality by HDL cholesterol deciles in eGFR category

    HDL-C DecileMedian (IQR)All-Cause Mortality Hazard Ratio (95% Confidence Interval)
    OveralleGFR≥15 to <30 ml/min per 1.73 m2eGFR≥30 to <45 ml/min per 1.73 m2eGFR≥45 to <60 ml/min per 1.73 m2eGFR≥60 to <90 ml/min per 1.73 m2eGFR≥90 ml/min per 1.73 m2
    Decile 1 (low HDL-C)27.0 (24.0–28.0)1.001.001.001.001.001.00
    Decile 232.0 (31.0–32.9)0.92 (0.91 to 0.93)0.92 (0.88 to 0.97)0.94 (0.92 to 0.97)0.90 (0.88 to 0.92)0.93 (0.91 to 0.94)0.92 (0.90 to 0.95)
    Decile 334.0 (34.0–35.0)0.91 (0.90 to 0.93)0.93 (0.88 to 0.99)0.90 (0.87 to 0.93)0.92 (0.90 to 095)0.91 (0.89 to 0.93)0.92 (0.89 to 0.95)
    Decile 437.0 (36.0–38.0)0.91 (0.90 to 0.92)0.91 (0.87 to 0.96)0.92 (0.89 to 0.95)0.89 (0.87. 0.91)0.91 (0.89 to 0.92)0.92 (0.89 to 0.94)
    Decile 540.0 (39.0–41.0)0.90 (0.89 to 0.91)0.91 (0.86 to 0.96)0.94 (0.91 to 0.97)0.88 (0.86 to 0.90)0.89 (0.87 to 0.90)0.91 (0.89 to 0.94)
    Decile 643.0 (42.0–44.0)0.90 (0.89 to 0.91)0.99 (0.94 to 1.05)0.89 (0.86 to 0.92)0.88 (0.86 to 0.90)0.90 (0.89 to 0.92)0.91 (0.88 to 0.94)
    Decile 746.0 (45.0–47.0)0.91 (0.90 to 0.92)0.89 (0.84 to 0.96)0.92 (0.88 to 0.95)0.89 (0.86 to 0.91)0.91 (0.90 to 0.93)0.92 (0.89 to 0.95)
    Decile 850.0 (48.9–51.0)0.92 (0.91 to 0.93)0.97 (0.91 to 1.03)0.91 (0.87 to 0.94)0.89 (0.86 to 0.91)0.91 (0.90 to 0.93)0.98 (0.95 to 1.01)
    Decile 956.0 (54.0–58.0)0.94 (0.93 to 0.95)0.95 (0.89 to 1.02)0.95 (0.91 to 0.98)0.90 (0.88 to 093)0.93 (0.91 to 0.95)1.01 (0.98 to 1.04)
    Decile 10 (high HDL-C)68.1 (64.0–77.0)1.09 (1.08 to 1.11)1.07 (1.00 to 1.15)0.99 (0.96 to 1.04)1.01 (0.98 to 1.04)1.08 (1.06 to 1.09)1.22 (1.18 to 1.25)
    • Models were adjusted for age, race, cancer, cerebrovascular accident, chronic lung disease, diabetes mellitus, dementia, hepatitis C, HIV, hypertension, body mass index, LDL cholesterol, triglycerides, serum albumin, angiotensin–converting enzyme inhibitor/angiotensin receptor blocker use, coronary artery disease, congestive heart failure, and peripheral artery disease. Models were additionally adjusted for eGFR, dialysis, kidney transplant, and statin use as time varying. IQR, interquartile range; HDL-C, HDL cholesterol.

    • View popup
    Table 4.

    Effect modification of the relationship between HDL cholesterol and risk of death by presence of coronary artery disease

    eGFR (ml/min per 1.73 m2) with or without Coronary Artery DiseaseHazard Ratio (95% Confidence Interval)
    HDL-C≤25 mg/dlHDL-C>25 to <34 mg/dlHDL-C≥34 to ≤42 mg/dlHDL-C>42 to <50 mg/dlHDL-C≥50 mg/dl
    ≥15 to <30
     Without1.000.92 (0.83 to 1.02)0.92 (0.83 to 1.02)0.96 (0.86 to 1.07)0.97 (0.87 to 1.09)
     With1.000.91 (0.85 to 0.97)0.88 (0.82 to 0.93)0.89 (0.83 to 0.96)0.98 (0.91 to 1.05)
    ≥30 to <45
     Without1.000.84 (0.79 to 0.89)0.82 (0.77 to 0.87)0.81 (0.76 to 0.86)0.85 (0.80 to 0.91)
     With1.000.90 (0.86 to 0.93)0.87 (0.84 to 0.91)0.85 (0.81 to 0.89)0.89 (0.85 to 0.93)
    ≥45 to <60
     Without1.000.84 (0.80 to 0.88)0.81 (0.77 to 0.84)0.80 (0.77 to 0.84)0.85 (0.81 to 0.89)
     With1.000.86 (0.83 to 0.89)0.84 (0.81 to 0.87)0.82 (0.79 to 0.85)0.88 (0.85 to 0.92)
    ≥60 to <90
     Without1.000.84 (0.82 to 0.87)0.80 (0.78 to 0.83)0.81 (0.79 to 0.84)0.88 (0.86 to 0.91)
     With1.000.89a (0.87 to 0.92)0.86a (0.84 to 0.89)0.87a (0.84 to 0.89)0.93a (0.90 to 0.96)
    ≥90
     Without1.000.81 (0.78 to 0.85)0.80 (0.77 to 0.83)0.80 (0.77 to 0.84)0.96 (0.92 to 1.00)
     With1.000.93a (0.87 to 0.98)0.92a (0.87 to 0.98)0.94a (0.88 to 0.99)1.08a (1.02 to 1.14)
    • Models were adjusted for age, race, cancer, cerebrovascular accident, chronic lung disease, diabetes mellitus, dementia, hepatitis C, HIV, hypertension, body mass index, LDL cholesterol, triglycerides, serum albumin, angiotensin–converting enzyme inhibitor/angiotensin receptor blocker use, coronary artery disease, congestive heart failure, and peripheral artery disease. Models were additionally adjusted for eGFR, dialysis, kidney transplant, and statin use as time varying. HDL-C, HDL cholesterol.

    • ↵a Significant (<0.05) P value for interaction between HDL-C level and coronary artery disease status.

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Clinical Journal of the American Society of Nephrology: 11 (10)
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High Density Lipoprotein Cholesterol and the Risk of All-Cause Mortality among U.S. Veterans
Benjamin Bowe, Yan Xie, Hong Xian, Sumitra Balasubramanian, Mohamed A. Zayed, Ziyad Al-Aly
CJASN Oct 2016, 11 (10) 1784-1793; DOI: 10.2215/CJN.00730116

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High Density Lipoprotein Cholesterol and the Risk of All-Cause Mortality among U.S. Veterans
Benjamin Bowe, Yan Xie, Hong Xian, Sumitra Balasubramanian, Mohamed A. Zayed, Ziyad Al-Aly
CJASN Oct 2016, 11 (10) 1784-1793; DOI: 10.2215/CJN.00730116
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Keywords

  • hypercholesterolemia
  • mortality risk
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  • lipids
  • mortality
  • epidemiology and outcomes
  • Cardiovascular Diseases
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  • humans
  • United States
  • veterans

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