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Non–High-Density Lipoprotein Cholesterol Level as a Predictor of Cardiovascular Disease Mortality
Yadong Cui, MD, PhD;
Roger S. Blumenthal, MD;
Jodi A. Flaws, PhD;
Maura K. Whiteman, BS;
Patricia Langenberg, PhD;
Paul S. Bachorik, PhD;
Trudy L. Bush, PhD, MHS
Arch Intern Med. 2001;161:1413-1419.
ABSTRACT
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Background Non–high-density lipoprotein cholesterol (non–HDL-C) contains
all known and potential atherogenic lipid particles. Therefore, non–HDL-C
level may be as good a potential predictor of risk for cardiovascular disease
(CVD) as low-density lipoprotein cholesterol (LDL-C).
Objectives To determine whether non–HDL-C level could be useful in predicting
CVD mortality and to compare the predictive value of non–HDL-C and LDL-C
levels.
Methods Data are from the Lipid Research Clinics Program Follow-up Study, a
mortality study with baseline data gathered from 1972 through 1976, and mortality
ascertained through 1995. A total of 2406 men and 2056 women aged 40 to 64
years at entry were observed for an average of 19 years, with CVD death as
the main outcome measure.
Results A total of 234 CVD deaths in men and 113 CVD deaths in women occurred
during follow-up. Levels of HDL-C and non–HDL-C at baseline were significant
and strong predictors of CVD death in both sexes. In contrast, LDL-C level
was a somewhat weaker predictor of CVD death in both. Differences of 0.78
mmol/L (30 mg/dL) in non–HDL-C and LDL-C levels corresponded to increases
in CVD risk of 19% and 15%, respectively, in men. In women, differences of
0.78 mmol/L (30 mg/dL) in non–HDL-C and LDL-C levels corresponded to
increases in CVD risk of 11% and 8%, respectively.
Conclusions Non–HDL-C level is a somewhat better predictor of CVD mortality
than LDL-C level. Screening for non–HDL-C level may be useful for CVD
risk assessment.
INTRODUCTION
ELEVATED LEVELS of low-density lipoprotein cholesterol (LDL-C) have
been consistently associated with an increased risk for development of and
death due to cardiovascular disease (CVD).1-5
The National Cholesterol Education Program (NCEP) recommends that LDL-C values
be used to estimate the lipoprotein-related risks for CVD in individuals.1 In addition, current treatment recommendations are
based on discrete LDL-C level. Recently, however, the use of non–high-density
lipoprotein cholesterol (non–HDL-C) level has been suggested as a better
tool for risk and treatment assessments than LDL-C level.6
(Non–HDL-C level is defined as the difference between total cholesterol
(TC) and HDL-C levels.) The rationale for this recommendation is that non–HDL-C
includes all cholesterol present in lipoprotein particles considered to be
atherogenic, including LDL, lipoprotein(a), intermediate-density lipoprotein
(IDL), and very-low-density lipoprotein (VLDL) remnants; and estimation of
LDL-C level using the formula of Friedewald7
(Friedewald formula) can be inaccurate.
Despite the potential usefulness of non–HDL-C level as a predictor
of CVD mortality, only a few studies have demonstrated that elevated non–HDL-C
level is associated with an increased risk for development of CVD.8-13
However, to our knowledge, no study has compared the relative values of LDL-C
and non–HDL-C levels in prediction of CVD. To address this question
directly, we used data from the Lipid Research Clinics (LRC) Program Follow-up
Study, a long-term observational mortality study that includes men and women
with well-defined lipid level measurements at baseline. Our goal was to determine
whether non–HDL-C level predicts CVD mortality in men and women, and
whether it is as good as LDL-C level in predicting CVD death.
SUBJECTS AND METHODS
STUDY POPULATION
All data were obtained from participants in the LRC Program Prevalence
Study.14 Details of the prevalence study design
and data collection have been described elsewhere.14-16
Briefly, from 1972 through 1976, a preliminary screening (visit 1) was conducted
at 10 centers throughout North America. A 15% random sample of persons attending
visit 1 was asked to return for a second visit (visit 2). In addition, all
persons who had elevated lipid levels and/or who were taking medications to
lower lipid levels were asked to return for visit 2. During visit 2, each
participant completed a detailed questionnaire and provided a fasting blood
sample. Triglyceride, TC, LDL-C, and HDL-C levels were measured using the
standardized LRC protocol previously described.17
Briefly, plasma triglyceride level was estimated fluorometrically. Level of
HDL-C was estimated in plasma after precipitation of the apoliprotein B–containing
lipoprotein using heparin and manganese chloride. Lipoproteins then were separated
by centrifugation in a saline density gradient to yield a fraction containing
VLDL and a fraction containing LDL and HDL. Level of LDL-C was calculated
by subtracting HDL-C from the total infranatant cholesterol. Non–HDL-C
level was calculated by subtracting HDL-C from TC levels.
From January 1, 1977, through November 14, 1987, each participant was
contacted annually to determine vital status using a mailed questionnaire.18 Nonrespondents were contacted by telephone or home
visit or were traced, when necessary, using other sources. Confirmation of
any deaths was obtained from death certificates, hospital and physician records,
and next of kin. The cause of death for those identified before November 14,
1987, was determined by a mortality-classification panel after review of relevant
documents.19 The cause of death for those identified
after November 14, 1987, was determined by trained nosologists from death
certificates obtained using the National Death Index.
Individuals aged 40 to 64 years at visit 2 were eligible for this analysis
(n = 4968). Participants not fasting between 12 and 16 hours were excluded
(n = 72). In addition, those with clinically evident CVD at baseline (n =
434) were excluded. Clinically evident CVD was defined as a finding of any
of the following: angina defined by a positive response on the Rose questionnaire,20 use of anginal medications, or hospitalizations due
to myocardial infarction or stroke. Thus, this analysis is based on 4462 participants
(2406 men and 2056 women). Baseline characteristics included current smoking
status, alcohol use during the past week, body mass index (weight in kilograms
divided by the square of height in meters), systolic blood pressure, and fasting
plasma glucose level. Diabetes was defined as a glucose level of greater than
6.94 mmol/L (>125 mg/dL).
ANALYSIS
Analyses were performed using SAS statistical software (SAS Institute
Inc, Cary, NC), separately for men and women. Age-adjusted CVD mortality rates
were calculated based on person-years of follow-up using the distribution
of the random sample as the standard. Relative risk (RR) estimates and 95%
confidence intervals (CIs) adjusted for baseline age were obtained from Cox
proportional hazards models. To assess the linearity of the association between
lipid levels and CVD mortality, and for ease of interpretation and presentation,
lipids were grouped into categories on the basis of clinical recommendations.1, 21 Level of LDL-C was categorized as
follows: less than 3.36 mmol/L (<130 mg/dL), 3.36 to less than 4.14 mmol/L
(130 to <160 mg/dL), 4.14 to less than 4.91 mmol/L (160 to <190 mg/dL),
and at least 4.91 mmol/L ( 190 mg/dL). Cut points for LDL-C level were
increased by 0.78 mmol/L (30 mg/dL) to create analogous cut points for non–HDL-C
levels.1, 21 Total cholesterol
level was separated into the following 4 categories: less than 5.17 mmol/L
(<200 mg/dL), 5.17 to less than 6.21 mmol/L (200 to <240 mg/dL), 6.21
to less than 7.24 mmol/L (240 to <280 mg/dL), and at least 7.24 mmol/L
(280 mg/dL). Because of different distributions of HDL-C levels in men
and women, HDL-C level categories were different by sex. In men, these were
less than 0.91 mmol/L (<35 mg/dL), 0.91 to less than 1.16 mmol/L (35 to
<45 mg/dL), 1.16 to less than 1.42 mmol/L (45 to <55 mg/dL), and at
least 1.42 mmol/L (55 mg/dL); in women, less than 1.16 mmol/L (<45
mg/dL), 1.16 to less than 1.42 mmol/L (45 to <55 mg/dL), 1.42 to less than
1.68 mmol/L (55 to <65 mg/dL), and at least 1.68 mmol/L (65 mg/dL).
Cox proportional hazards models were used to assess the value of non–HDL-C,
LDL-C, TC, and HDL-C levels in predicting CVD mortality. The age-only model,
which served as the model with which all others were compared, included age
alone as a predictor of CVD death. Subsequently, separate models with non–HDL-C,
LDL-C, TC, and HDL-C levels added as continuous variables were fit. The differences
in the -2 logarithm likelihood (-2ln[L]) of each of these 4 lipid
models with the -2ln(L) of the age-only model were calculated. These
differences follow an approximate  2 distribution with 1 df, and provide a statistical test for the predictive value
of a given lipid level. When compared between lipid models, these 2 values assess which lipid level measure added the most predictive
value to the age-only model; higher 2 values indicated better
prediction of CVD mortality by that lipid level.
These models also provided estimates of the RR for CVD death corresponding
to 1-unit (0.026 mmol/L [1 mg/dL]) increase in each lipid level. The risks
for a 0.78-mmol/L (30-mg/dL) difference in non–HDL-C, LDL-C, and TC
levels were calculated as exponentiation of 30 ß, where ß is the
regression coefficient from the Cox models, which allows for comparisons of
the association between each of the lipid levels and CVD death. The risk for
a 0.26-mmol/L (10-mg/dL) difference in HDL-C level was reported as well. All
analyses were repeated using all-cause mortality as the end point to assess
the associations between each lipid variable and all deaths.
RESULTS
BASELINE CHARACTERISTICS
The baseline characteristics of participants are presented in Table 1. Men and women had similar mean
ages and blood pressure levels at entry. In general, women had lower non–HDL-C,
triglyceride, and VLDL-C levels, but higher HDL-C and TC levels than men.
Approximately one third of men and women were cigarette smokers; however,
73% of the men compared with 55% of the women drank alcohol. Nearly 95% of
the population were white, and a small proportion (<5%) had diabetes mellitus.
About 40% of participants were selected because of elevations in lipid levels
or the use of medications to lower lipid levels.
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Table 1. Baseline Characteristics of Study Population*
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CVD MORTALITY BY LIPID LEVELS
During follow-up, 234 CVD deaths occurred in men and 113 in women. In
men, an increased risk for CVD death was associated with increasing non–HDL-C
level (Table 2). Compared with
men with non–HDL-C levels of less than 4.14 mmol/L (<160 mg/dL),
men with levels ranging from 4.91 to less than 5.69 mmol/L (190 to <220
mg/dL) had a 43% increased risk for death due to CVD (RR, 1.43; 95% CI, 0.99-2.07).
The RR was 2.14 (95% CI, 1.50-3.04) in men whose non–HDL-C levels were
at least 5.69 mmol/L (220 mg/dL).
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Table 2. CVD Mortality by Lipid Levels in Men and Women*
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Similarly, there was a positive association between baseline LDL-C levels
and CVD mortality. Men with LDL-C levels of at least 4.91 mmol/L (190
mg/dL) had a 77% increased risk for CVD death (RR, 1.77; 95% CI, 1.22-2.59)
compared with men with LDL-C levels of less than 3.36 mmol/L (<130 mg/dL).
However, men in the lowest LDL-C level category (<2.59 mmol/L [<100
mg/dL]) had a higher CVD mortality than men with LDL-C levels ranging from
2.59 to less than 3.36 mmol/L (100 to <130 mg/dL). Additional analysis
showed that the increased CVD risk seen in men with the lowest LDL-C levels
(<2.59 mmol/L [<100 mg/dL]) was confined to those whose baseline triglyceride
value was greater than 2.26 mmol/L (>200 mg/dL). Like non–HDL-C level,
TC level showed a positive linear relationship with CVD mortality.
An increased risk for CVD death was inversely associated with HDL-C
level (Table 2). Compared with
men with HDL-C levels of less than 0.91 mmol/L (<35 mg/dL), men with levels
ranging from 0.91 to less than 1.16 mmol/L (35 to <45 mg/dL) had a 40%
reduction in the risk for death due to CVD (RR, 0.60; 95% CI, 0.43-0.83).
The reduction was 48% (RR, 0.52; 95% CI, 0.37-0.74) in men whose HDL-C levels
ranged from 1.16 to less than 1.42 mmol/L (45 to <55 mg/dL), and 59% (RR,
0.41; 95% CI, 0.27-0.61) in those whose HDL-C levels were at least 1.42 mmol/L
(55 mg/dL).
In women, an increased risk for CVD death also was positively and linearly
associated with non–HDL-C level (Table 2). Compared with women with non–HDL-C levels of less
than 4.14 mmol/L (<160 mg/dL), the RR was 1.61 (95% CI, 0.91-2.84) in women
with non–HDL-C levels ranging from 4.91 to less than 5.69 mmol/L (190
to <220 mg/dL), and 2.43 (95% CI, 1.47-4.00) with non–HDL-C levels
of at least 5.69 mmol/L (220 mg/dL). However, among women, there was no
significant association between baseline LDL-C or TC levels and subsequent
CVD death (Table 2).
As in men, baseline HDL-C levels in women were strongly and negatively
associated with an increased risk for CVD death. Compared with women with
baseline HDL-C levels of less than 1.16 mmol/L (<45 mg/dL), women with
HDL-C levels ranging from 1.42 to less than 1.68 mmol/L (55 to <65 mg/dL)
had a 46% reduction in risk for CVD death (RR, 0.54; 95% CI, 0.32-0.92), whereas
women with HDL-C levels at least 1.68 mmol/L (65 mg/dL) had a 66% lower
risk for death due to CVD (RR, 0.34; 95% CI, 0.20-0.57).
COMPARISON OF LIPID LEVELS AS PREDICTORS OF CVD DEATH
When analyzed as continuous variables, levels of all 4 lipid variables
examined (non–HDL-C, LDL-C, TC, and HDL-C) significantly predicted CVD
death in men and women (with the exception of LDL-C and TC levels in women)
(Table 3). These associations
were positive for non–HDL-C, LDL-C, and TC levels and negative for HDL-C
level. In men, non–HDL-C and HDL-C levels were equally good predictors
of CVD mortality (2 for non– HDL-C, 24.3, and for HDL-C,
23.2), whereas LDL-C level was less predictive of CVD death (2
for LDL-C, 5.0). From the multivariable model, we estimate that an increase
of 0.78 mmol/L (30 mg/dL) in non–HDL-C, TC, and LDL-C levels would result
in increases in CVD risk of 19%, 16%, and 11%, respectively. Likewise, an
increase of 0.26 mmol/L (10 mg/dL) in HDL-C level would correspond to a 23%
decrease in the risk for CVD mortality.
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Table 3. Comparison of Lipid Levels in Predicting CVD Mortality in
Men and Women*
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In women, HDL-C level was the best lipid predictor, non–HDL-C
level the second best lipid predictor, and LDL-C level the poorest lipid predictor
of CVD death (2 for HDL-C, 18.5; for non–HDL-C, 8.3;
for TC, 2.8; and for LDL-C, 1.8). An increase of 0.78 mmol/L (30 mg/dL) in
non–HDL-C level corresponded to a 15% increase in the risk for CVD death.
An increase of 0.78 mmol/L (30 mg/dL) in LDL-C level corresponded to an 8%
increase in the risk for CVD death, whereas an increase of 0.26 mmol/L (10
mg/dL) in HDL-C level corresponded to a 23% decrease in the risk for CVD mortality.
Further adjustment for other risk factors, such as smoking, alcohol use, body
mass index, race, hypertension, and fasting glucose level, did not significantly
change these lipid level estimates in men or women.
Levels of HDL-C and non–HDL-C were independent predictors of CVD
mortality, as determined by a model that included both lipid levels and age
at baseline. In addition, both lipid levels remained significantly associated
with CVD risk after adjustment for other CVD risk factors (data not shown).
Similar results were seen when the analyses were restricted to the randomly
sampled participants and to women not using hormone therapy. Likewise, the
exclusion of deaths during the first 4 years of follow-up did not significantly
alter the results.
ALL-CAUSE MORTALITY BY LIPID LEVELS
During follow-up, a total of 532 deaths due to all causes occurred in
men and 340 occurred in women. In both sexes, an increased risk for all-cause
mortality was associated with increasing non–HDL-C level (Table 4). These associations were not as strong as those observed
between non–HDL-C level and CVD death (Table 2). Level of LDL-C was a poor predictor of all-cause mortality
in both sexes. Compared with individuals with LDL-C levels of less than 3.36
mmol/L (<130 mg/dL), participants with higher LDL-C levels did not have
a significant increase in risk for death.
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Table 4. All-Cause Mortality by Non–HDL-C and LDL-C Levels in
Men and Women*
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COMMENT
To date, the prognostic value of non–HDL-C level for CVD and total
mortality has not been well characterized, and, to our knowledge, no studies
have specifically compared the predictive utilities of LDL-C and non–HDL-C
levels. We examined the predictive value of non–HDL-C, LDL-C, TC, and
HDL-C levels in the LRC Program Prevalence Follow-up Study. Among these lipoprotein
variables, HDL-C and non–HDL-C levels are good predictors of CVD death
in men and women. In contrast, LDL-C level, which is the main focus of the
NCEP guidelines, was the weakest lipid predictor of CVD death in men and women.
These results suggest that non–HDL-C level is as good as, and in fact
is better than, LDL-C level as a predictor of CVD mortality. Furthermore,
non–HDL-C level could be used in adults to aid in their CVD risk assessment.
Several previous studies have assessed the role of non–HDL-C level
in risk assessment of CVD. In a cohort study of 787 men aged 30 to 61 years
in Finland, non–HDL-C level significantly predicted deaths due to coronary
heart disease (CHD) during a 24-year follow-up.8
Another study in an Italian occupational cohort of men aged 46 to 65 years
found non–HDL-C level to predict coronary deaths.9
A report from the British Regional Heart Study suggested that non–HDL-C
level in men aged 40 to 59 years was a significant independent predictive
risk factor for CHD.10 In a recent nested case-control
study, non–HDL-C level was found to be a significant independent risk
factor for incidence of coronary artery disease.11
Non–HDL-C level has also been shown to predict CVD in special
populations. In a 7-year Finnish cohort study of middle-aged patients with
type 2, high non–HDL-C level as well as low HDL-C level, high triglyceride
level, and elevated fasting plasma glucose level were each independently associated
with a 2-fold increase in the risk for CHD mortality.22
In an analysis from the Systolic Hypertension in the Elderly Program, non–HDL-C
level contributed independently to the risk for nonfatal myocardial infarction
or CHD death in participants who were 60 years or older.12
However, in all these studies, no direct comparison was made between LDL-C
and non–HDL-C levels for predictive values.
One reason that non–HDL-C level may better predict CVD mortality
is that this measurement includes all of the potentially atherogenic lipid
fractions (LDL, lipoprotein[a],23-30
IDL,31-33 and
VLDL remnants31, 34-37).
Although the Friedewald formula and ß quantification include IDL and
lipoprotein(a) in the LDL-C level measurement, they do not include remnant
cholesterol level. The inclusion of remnant cholesterol in the non–HDL-C
level measurement probably improves the predictive value of non–HDL-C
level. In addition, numerous studies indicate that elevated triglyceride level
(>1.7 mmol/L [>150 mg/dL]) is associated with small, dense LDL, which is thought
to be more easily oxidized and, thus, more atherogenic. The higher risk for
CVD death seen in men with LDL-C levels of less than 2.59 mmol/L (<100
mg/dL) was only observed in those who also had triglyceride levels greater
than 2.26 mmol/L (>200 mg/dL), ie, in those in whom increased concentrations
of remnant cholesterol and small, dense LDL would be expected.
For women, the relationship between LDL-C level and CVD mortality is
not significant, even at very high levels of LDL-C. This weak relationship
between LDL-C level and CVD events in women was previously reported by Bass
et al38 with a shorter follow-up.
Non–HDL-C rather than LDL-C level may be particularly useful in
risk assessment for some specific patient populations. For example, patients
with type 2 diabetes have elevations in triglyceride levels, often making
the calculation of LDL-C level by the Friedewald formula potentially inaccurate.
One report has suggested that non–HDL-C level be used as a primary screening
tool in patients with diabetes,39 and we would
concur. Non–HDL-C level might also identify a group of individuals who
have a genetically influenced atherogenic lipoprotein phenotype, characterized
by high VLDL-C and IDL-C levels, a low HDL-C level, and an LDL-C level within
the reference range. About 20% of the American population are estimated to
have this phenotype.21, 40
Our study indicates that a positive linear association also exists between
non–HDL-C level and all-cause mortality, but that, as expected, this
association is weaker than that of non–HDL-C level and CVD mortality.
Some previous studies have suggested a J-shaped curve for the relationship
of TC level with all-cause mortality,41-47
but others have not.48-49 A number
of hypotheses have been proposed to explain such an elevated mortality risk
at low cholesterol levels. For example, some analyses indicate that if smokers
or heavy alcohol users are removed from the analysis, then this relationship
weakens.41, 47, 50
Low levels of HDL-C also have been associated with an increased risk for all-cause
mortality.51-53
Our study yielded similar results for LDL-C (positive) and HDL-C (negative,
data not shown). To our knowledge, no previously reported studies have examined
non–HDL-C level and all-cause mortality in middle-aged men and women.
The ease of measurement of non–HDL-C level compared with LDL-C
level is a practical reason to recommend it as a risk assessment tool. Estimation
of LDL-C level via the Friedewald formula is often inconvenient because it
requires the measurement of 3 different lipid levels in each blood sample
(TC, triglycerides, and HDL-C). In contrast, the estimation of non–HDL-C
level only requires the measurement of TC and HDL-C levels and does not require
assumptions about the relationship of VLDL-C to triglyceride levels.
In interpreting the findings of this study, however, more than 40% of
the participants in the follow-up study had hyperlipidemia.16, 54-55
As a result, the study population is not representative of a general population.
To address this issue, we analyzed the data from random-sample participants
and found similar results to those from all study participants.
CONCLUSIONS
This study indicates that non–HDL-C level has a stronger linear
relationship with CVD mortality than LDL-C level in men and women without
clinical evidence of CVD. These data suggest that non–HDL-C level is
a better predictor of long-term CVD mortality than LDL-C level. They also
show that HDL-C level is a strong predictor of long-term CVD risk for men
and women. Given the increased accuracy in predicting CVD death by means of
non–HDL-C compared with LDL-C levels, initial lipid level evaluation
could consist of measurement of TC and HDL-C levels. The adoption of non–HDL-C
level as a fundamental CVD risk factor that is more inclusive of plasma lipoprotein-related
risk than is LDL-C level may lead to a more effective approach to risk reduction.
AUTHOR INFORMATION
Accepted for publication December 11, 2000.
Portions of this work were presented at the 72nd Scientific Sessions
of the American Heart Association, Atlanta, Ga, November 9, 1999.
We gratefully acknowledge the assistance of Robert I. Levy, MD, for
his insightful review of early versions of the manuscript, and we mourn his
untimely death and that of Dr Bush. We also thank the investigators and staff
of the Lipid Research Clinics Coordinating Center at the University of North
Carolina, Chapel Hill, for their assistance with this project.
Corresponding author and reprints: Roger S. Blumenthal, MD, Director,
Ciccarone Heart Center, The Johns Hopkins University, 600 W Wolfe St, Carnegie
538, Baltimore, MD 21287 (e-mail: rblument{at}jhmi.edu).
From the Department of Epidemiology and Preventive Medicine, School
of Medicine, University of Maryland (Drs Cui, Flaws, Langenberg, and Bush
and Ms Whiteman), and the Division of Cardiology, Johns Hopkins Ciccarone
Preventive Cardiology Center (Dr Blumenthal), and School of Medicine (Dr Bachorik),
The Johns Hopkins University, Baltimore, Md.
Dr Bush died March 14,
2001.
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