Web Appendix
MATERIALS AND METHODS
Prescription medications
The usage of prescription medications for lowering blood lipids, glucose, and blood pressure as well as aspirin and clopidogrel in the past month was assessed by questionnaires. Participants were asked whether they had taken or used any prescription medicine in the past month and showed the interviewer the medication containers and the exact name of all the products. If the container was unavailable, the interviewer asked the participants to verbally report this information. Lipid lowering medications were classified into statins, fibrates, bile acid sequestrants, nicotinic acids, cholesterol adsorption inhibitor (i.e. ezetimibe), and others (including probucol and other unspecified medications). Blood pressure lowering medications were classified into angiotensin-converting enzyme inhibitors, angiotensin receptor blockers (ARBs), b-blockers, calcium channel blockers (CCBs), diuretics, aldosterone receptor antagonists, and others (including a-blockers, other antiadrenergic drugs, direct vasodilators, direct renin inhibitors and other unspecified anti-hypertensive medications). Glucose lowering medications were classified into metformin, sulfonylureas, thiazolidinediones, insulin, and others (including a-glucosidase inhibitors, amylin analogs, dipeptidyl peptidase 4 inhibitors, incretin mimetics, meglitinides, and other unspecific anti-diabetic medications). A participant can report the use of more than one medication, either as a single combination pill or several different pills. In this case, the participant was only counted once for any medication use category, and once within each class of medications. For example, a subject who reported the uses of “niacin/simvastatin”, “pravastatin”, “amlodipine, valsartan and hydrochlorothiazide”, and “metformin/pioglitazone” in the past month was only counted once for each of the classes, nicotinic acid, statins, CCBs, ARBs, diuretics, metformin, and thiazolidinediones. A participant, who took two or more different classes of medications for the same therapeutic use (lowering either blood lipids, glucose, or blood pressure), either as a single combination pill or several different pills, was defined as receiving polytherapy.
Laboratory measurement
Serum high-density lipoprotein cholesterol, total cholesterol, and triglycerides were measured with a Hitachi Model 704 multichannel analyzer in 1999-2004, a Roche Hitachi 717 (Roche Diagnostics, Indianapolis, IN) in 2005, both Roche Hitachi 717 and 912 (Roche Diagnostics, Indianapolis, IN) in 2006, and a Roche Modular P chemistry analyzer (Roche Diagnostics, Indianapolis, IN) in 2007-2010. Low-density lipoprotein cholesterol was calculated using the Friedewald equation.
Glycosylated hemoglobin was determined by high performance liquid chromatography using a Primus CLC330 or a Primus CLC385 (Primus Corporation, Kansas City, MO) in 1999-2004, a Tosoh A1c 2.2 Plus Glycohemoglobin Analyzer (Tosoh Medics Inc, San Francisco, CA) in 2005-2006, and an A1c G7 HPLC Glycohemoglobin Analyzer (Tosoh Medics Inc, San Francisco, CA) in 2007-2010. Serum creatinine, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, and total bilirubin levels were measured as the routine laboratory blood parameters using a Hitachi Model 917 multichannel analyzer (Boehringer Mannheim Diagnostics, Indianapolis, IN) in 1999-2000, a Beckman Synchron LX20 system in 2003-2007 and a Beckman UniCel® DxC800 Synchron (Beckman Coulter Inc, Fullerton, CA) in 2008-2010. In 2001-2002, these levels were measured using either a Hitachi Model 917 multichannel analyzer or a Beckman Synchron LX20. The reported values have been adjusted by regression equations to allow comparison across the two methods. Correction for serum creatinine data in 1999-2000 and 2005-2006 was performed according to the NHANES recommendations before calculating the estimated glomerular filtration rate.
Urinary creatinine was determined colorimetrically by the Jaffé rate reaction in a Beckman
Synchron CX3 Clinical Analyzer (Beckman Instruments, Brea, CA) in 1999-2006, and a Roche/Hitachi Modular P Chemistry Analyzer (Roche Diagnostics, Indianapolis, IN) in 2007-2010. Data on urinary creatinine were adjusted using regression equations so that values from two different measurements could be combined and compared. Urinary albumin was measured with a solid-phase fluorescent immunoassay using a Sequoia-Turner Digital Model 450 fluorometer (Mountain View, CA) in 1999-2010.
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Web Table 1. Prevalence of Elevated CRP and Geometric Mean CRP Levels in United States Adults, 1999-2010, After Excluding Subjects With CRP Levels >10 mg/La
1999-2002(n = 7,217) / 2003-2006
(n = 7,419) / 2007-2010
(n = 9,757) / Change, 1999-2002 to 2007-2010 / P Value for 12-year Linear Trendb / P Value for Interactionb
% (SE)b / Meanb / 95% CI / % (SE)b / Meanb / 95% CI / % (SE)b / Meanb / 95% CI
Overall
Elevated CRP, % / 30.1 (0.7) / 28.2 (0.8)** / 25.7 (0.5)*** / -4.4 / <0.001
CRP level, mg/L / 1.52 / 1.45, 1.59 / 1.47*** / 1.40, 1.53 / 1.33*** / 1.28, 1.39 / -0.19 / <0.001
Age, years
20-29 (n = 4,040)
Elevated CRP, % / 20.6 (1.5) / 21.6 (1.5) / 20.7 (1.3) / 0.0 / 0.90 / 0.006
CRP level, mg/L / 1.06 / 0.98, 1.15 / 1.04 / 0.96, 1.12 / 1.02 / 0.93, 1.13 / -0.04 / 0.10 / <0.001
30-39 (n = 4,075)
Elevated CRP, % / 26.7 (1.1) / 24.7 (1.5)* / 24.5 (1.2) / -2.1 / 0.005
CRP level, mg/L / 1.33 / 1.23, 1.44 / 1.29 / 1.20, 1.39 / 1.21** / 1.11, 1.32 / -0.12 / <0.001
40-49 (n = 4,363)
Elevated CRP, % / 28.9 (1.5) / 29.9 (1.5) / 24.6 (1.3) / -4.3 / 0.014
CRP level, mg/L / 1.47 / 1.34, 1.62 / 1.55 / 1.45, 1.65 / 1.34* / 1.24, 1.44 / -0.14 / 0.006
50-59 (n = 3,519)
Elevated CRP, % / 36.2 (1.7) / 30.4 (2.0)** / 27.1 (1.2) / -9.2 / <0.001
CRP level, mg/L / 1.87 / 1.74, 2.01 / 1.62** / 1.49, 1.77 / 1.43** / 1.35, 1.51 / -0.44 / <0.001
60-69 (n = 3,837)
Elevated CRP, % / 39.1 (1.9) / 34.3 (1.7)* / 30.2 (1.3) / -8.9 / <0.001
CRP level, mg/L / 2.08 / 1.96, 2.21 / 1.94** / 1.81, 2.08 / 1.63*** / 1.53, 1.73 / -0.45 / <0.001
70-79 (n = 2,799)
Elevated CRP, % / 37.7 (2.1) / 32.1 (1.9) / 31.8 (1.5) / -5.9 / 0.007
CRP level, mg/L / 2.13 / 2.00, 2.28 / 1.81*** / 1.70, 1.92 / 1.72* / 1.63, 1.82 / -0.41 / <0.001
≥80 (n = 1,760)
Elevated CRP, % / 37.4 (2.7) / 31.0 (1.5) / 27.2 (3.1) / -10.3 / 0.024
CRP level, mg/L / 2.11 / 1.89, 2.34 / 1.87 / 1.75, 2.00 / 1.52* / 1.35, 1.71 / -0.59 / 0.002
Sex
Men (n = 12,614)
Elevated CRP, % / 24.0 (0.9) / 23.8 (0.9) / 21.1 (0.6) / -2.9 / <0.001 / 0.27
CRP level, mg/L / 1.34 / 1.27, 1.42 / 1.34 / 1.28, 1.41 / 1.21*** / 1.16, 1.27 / -0.13 / <0.001 / 0.36
Women (n = 11,779)
Elevated CRP, % / 36.3 (1.0) / 32.7 (1.1)*** / 30.2 (0.7) / -6.1 / <0.001
CRP level, mg/L / 1.73 / 1.62, 1.85 / 1.60** / 1.51, 1.70 / 1.46*** / 1.38, 1.54 / -0.27 / <0.001
Race/ethnicity
Non-Hispanic White (n = 12,292)
Elevated CRP, % / 29.9 (0.9) / 27.3 (0.9)** / 25.0 (0.8) / -4.8 / <0.001 / 0.022
CRP level, mg/L / 1.53 / 1.44, 1.62 / 1.45** / 1.38, 1.53 / 1.31*** / 1.24, 1.39 / -0.21 / <0.001 / 0.026
Non-Hispanic Black (n = 4,461)
Elevated CRP, % / 32.3 (1.5) / 33.1 (1.1) / 33.0 (1.1) / -0.7 / 0.38
CRP level, mg/L / 1.56 / 1.44, 1.70 / 1.63 / 1.52, 1.76 / 1.54* / 1.45, 1.62 / -0.03 / 0.009
Mexican American (n = 4,962)
Elevated CRP, % / 30.1 (1.2) / 31.1 (1.4) / 29.0 (1.9) / -1.1 / 0.004
CRP level, mg/L / 1.50 / 1.38, 1.63 / 1.57 / 1.44, 1.70 / 1.61 / 1.45, 1.78 / 0.11 / 0.083
Other (n = 2,678)
Elevated CRP, % / 29.6 (1.7) / 27.5 (2.4) / 20.8 (1.5) / -8.8 / <0.001
CRP level, mg/L / 1.46 / 1.30, 1.63 / 1.32 / 1.17, 1.50 / 1.11*** / 1.01, 1.21 / -0.35 / <0.001
Body mass index, kg/m2
<25.0 (n = 7,714)
Elevated CRP, % / 15.9 (0.8) / 13.7 (0.9)* / 11.7 (0.6) / -4.2 / <0.001 / 0.054
CRP level, mg/L / 0.91 / 0.85, 0.98 / 0.85* / 0.79, 0.92 / 0.76*** / 0.71, 0.81 / -0.16 / <0.001 / 0.12
25.0-29.9 (n = 8,890)
Elevated CRP, % / 28.4 (1.0) / 25.6 (0.8)** / 21.3 (1.0) / -7.1 / <0.001
CRP level, mg/L / 1.60 / 1.52, 1.68 / 1.52* / 1.47, 1.57 / 1.31*** / 1.24, 1.38 / -0.29 / <0.001
≥30.0 (n = 7,789)
Elevated CRP, % / 51.0 (1.5) / 47.4 (1.4) / 44.9 (0.8) / -6.1 / 0.002
CRP level, mg/L / 2.79 / 2.67, 2.92 / 2.58 / 2.46, 2.71 / 2.42*** / 2.35, 2.48 / -0.38 / <0.001
Abbreviations: CI, confidence interval; CRP, C-reactive protein; SE, standard error.
*P 0.05, **P 0.01, and ***P 0.001 for the 8-year linear trend compared to the previous four-year cycle (i.e. 2003-2006 vs 1999-2002 or 2007-2010 vs 2003-2006).
aAll P values were adjusted for age, sex (except sex-specific estimates), race/ethnicity (except race/ethnicity-specific estimates), body mass index, blood pressure lowering medication, glucose lowering medication, and lipid lowering medication. CRP values were ln-transformed when assessing the trend in mean CRP values. For the subgroups by age and body mass index, categorical subgroup variable, instead of the continuous level, was used in the adjustment model when assessing the P value for interaction.
bData are expressed as % (SE) for elevated CRP. For continuous CRP level, data are expressed as geometric mean (95% CI) due to skewed distribution.
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Web Table 2. Medication Use Pattern by Age and Race/ethnicity in United States Adults, 1999-2010a
Overall1999-2010 / 1999-2002 / 2003-2006 / 2007-2010 / Change, 1999-2002 to 2007-2010 / P Value for Linear Time Trend / P Value for Interactionb
Any blood pressure lowering medication, %
Age, years
20-39 (n = 8,848) / 3.7 (0.2) / 3.1 (0.4) / 3.7 (0.5) / 4.2 (0.4) / 1.1 / 0.21 / 0.14
40-59 (n = 8,830) / 23.7 (0.7) / 21.2 (1.3) / 24.3 (1.0) / 25.4 (1.1) / 4.2 / 0.18
≥60 (n = 9,516) / 60.1 (0.8) / 53.2 (1.4) / 62.1 (1.3) / 63.8 (1.4) / 10.5 / <0.001
Race/ethnicity
Non-Hispanic White (n = 13,547) / 26.7 (0.6) / 22.9 (1.0) / 27.5 (1.1) / 29.6 (1.1) / 6.6 / 0.001 / 0.62
Non-Hispanic Black (n = 5,200) / 28.1 (0.7) / 25.1 (1.3) / 28.8 (1.2) / 30.1 (1.3) / 5.0 / 0.11
Mexican American (n = 5,520) / 11.3 (0.8) / 8.5 (0.8) / 10.4 (1.4) / 14.1 (1.4) / 5.6 / 0.016
Other (n = 2,927) / 16.8 (0.9) / 14.6 (1.2) / 17.3 (2.2) / 18.3 (1.1) / 3.7 / 0.073
Any glucose lowering medication, %
Age, years
20-39 (n = 8,848) / 1.4 (0.1) / 1.1 (0.2) / 1.6 (0.2) / 1.5 (0.2) / 0.4 / 0.14 / 0.92
40-59 (n = 8,830) / 6.3 (0.3) / 5.1 (0.5) / 6.3 (0.5) / 7.5 (0.6) / 2.4 / 0.021
≥60 (n = 9,516) / 14.7 (0.5) / 11.9 (0.6) / 14.3 (0.8) / 17.2 (1.0) / 5.3 / 0.001
Race/ethnicity
Non-Hispanic White (n = 13,547) / 5.8 (0.3) / 4.3 (0.4) / 5.9 (0.4) / 7.1 (0.6) / 2.8 / 0.002 / 0.73
Non-Hispanic Black (n = 5,200) / 9.6 (0.4) / 7.9 (0.8) / 9.1 (0.6) / 11.6 (0.8) / 3.7 / 0.012
Mexican American (n = 5,520) / 6.5 (0.4) / 5.2 (0.5) / 6.4 (0.5) / 7.6 (0.8) / 2.4 / 0.14
Other (n = 2,927) / 7.6 (0.6) / 7.1 (1.1) / 7.8 (1.3) / 7.8 (0.9) / 0.7 / 0.38
Any lipid lowering medication, %
Age, years
20-39 (n = 8,848) / 1.1 (0.1) / 0.7 (0.2) / 0.9 (0.2) / 1.6 (0.3) / 0.9 / 0.002 / 0.010
40-59 (n = 8,830) / 13.1 (0.5) / 9.9 (0.8) / 13.4 (1.0) / 15.5 (0.8) / 5.6 / 0.001
≥60 (n = 9,516) / 35.0 (0.6) / 23.4 (1.0) / 35.4 (1.0) / 44.1 (0.8) / 20.7 / <0.001
Race/ethnicity
Non-Hispanic White (n = 13,547) / 15.6 (0.4) / 10.9 (0.6) / 15.6 (0.8) / 19.9 (0.7) / 9.0 / <0.001 / 0.007
Non-Hispanic Black (n = 5,200) / 9.8 (0.5) / 5.1 (0.5) / 10.4 (0.7) / 13.3 (0.8) / 8.2 / <0.001
Mexican American (n = 5,520) / 6.2 (0.6) / 2.8 (0.3) / 5.2 (0.6) / 9.7 (1.1) / 6.9 / <0.001
Other (n = 2,927) / 10.1 (0.7) / 6.8 (1.0) / 11.6 (1.6) / 11.7 (0.9) / 4.8 / <0.001
Statins, %
Age, years
20-39 (n = 8,848) / 0.9 (0.1) / 0.5 (0.1) / 0.8 (0.2) / 1.4 (0.3) / 0.9 / <0.001 / 0.036
40-59 (n = 8,830) / 11.7 (0.5) / 8.7 (0.7) / 11.8 (0.9) / 14.2 (0.7) / 5.5 / <0.001
≥60 (n = 9,516) / 32.3 (0.5) / 21.8 (0.9) / 32.3 (0.9) / 40.7 (0.8) / 18.9 / <0.001
Race/ethnicity
Non-Hispanic White (n = 13,547) / 14.2 (0.4) / 9.9 (0.6) / 14.0 (0.7) / 18.3 (0.6) / 8.4 / <0.001 / 0.004
Non-Hispanic Black (n = 5,200) / 9.1 (0.5) / 4.5 (0.4) / 9.5 (0.7) / 12.6 (0.7) / 8.1 / <0.001
Mexican American (n = 5,520) / 5.6 (0.5) / 2.4 (0.3) / 4.7 (0.5) / 8.7 (1.0) / 6.3 / <0.001
Other (n = 2,927) / 8.7 (0.6) / 5.6 (0.8) / 10.0 (1.4) / 10.5 (0.9) / 4.8 / <0.001
aData are expressed as % (standard error). All P values were adjusted for age, sex (except sex-specific estimates), race/ethnicity (except race/ethnicity-specific estimates), and body mass index.
bFor the subgroups by age, categorical subgroup variable, instead of the continuous level, was used in the adjustment model when assessing the P value for interaction.
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Web Table 3. Association of Survey Year With Elevated CRP or Geometric Mean Level in United States Adults, 1999-2010, After Excluding Subjects With CRP Levels >10 mg/La
Modelb / Elevated CRP (>3.0 mg/L) / ln CRP (mg/L)Odds ratio / 95% CI / P Value / Regression coefficient / 95% CI / P Value
Unadjusted / 0.95 / 0.93, 0.97 / 0.001 / -0.035 / -0.051, -0.019 / 0.001
1 / 0.92 / 0.90, 0.94 / 0.001 / -0.051 / -0.063, -0.039 / 0.001
2 / 0.92 / 0.90, 0.94 / 0.001 / -0.048 / -0.059, -0.037 / 0.001
3 / 0.95 / 0.92, 0.97 / 0.001 / -0.028 / -0.039, -0.016 / 0.001
4 / 0.95 / 0.93, 0.98 / 0.001 / -0.026 / -0.037, -0.014 / 0.001
5 / 0.95 / 0.93, 0.98 / 0.001 / -0.026 / -0.037, -0.014 / 0.001
6 / 0.97 / 0.95, 1.00 / 0.030 / -0.018 / -0.030, -0.006 / 0.005
Abbreviations: CI, confidence interval; CRP, C-reactive protein.
aMultiple logistics or linear regression was used with elevated CRP or ln CRP as the dependent variable. Data are presented as odds ratio (95% CI) for elevated CRP or regression coefficient (95% CI) for ln CRP level per each two-year cycle increase.