8

High-Density Lipoprotein Cholesterol and

Cardiovascular Disease
Four Prospective American Studies
David J. Gordon, MD, PhD, Jeffrey L. Probstfield, MD,
Robert J. Garrison, MS, James D. Neaton, PhD, William P. Castelli, MD,
James D. Knoke, PhD, David R. Jacobs Jr., PhD,
Shrikant Bangdiwala, PhD, and H. Alfred Tyroler, MD

The British Regional Heart Study (BRHS) reported in 1986 that much of the inverse relation of
high-density lipoprotein cholesterol (HDLC) and incidence of coronary heart disease was
eliminated by covariance adjustment. Using the proportional hazards model and adjusting for
age, blood pressure, smoking, body mass index, and low-density lipoprotein cholesterol, we
analyzed this relation separately in the Framingham Heart Study (FHS), Lipid Research Clinics
Prevalence Mortality Follow-up Study (LRCF) and Coronary Primary Prevention Trial
(CPPT), and Multiple Risk Factor Intervention Trial (MRFIT). In CPPT and MRFIT (both
randomized trials in middle-aged high-risk men), only the control groups were analyzed. A
1-mg/dl (0.026 mM) increment in HDLC was associated with a significant coronary heart
disease risk decrement of 2% in men (FHS, CPPT, and MRFIT) and 3% in women (FHS). In
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LRCF, where only fatal outcomes were documented, a 1-mg/dl increment in HDLC was
associated with significant 3.7% (men) and 4.7% (women) decrements in cardiovascular disease
mortality rates. The 95% confidence intervals for these decrements in coronary heart and
cardiovascular disease risk in the four studies overlapped considerably, and all contained the
range 1.9-2.9%. HDLC levels were essentially unrelated to non-cardiovascular disease
mortality. When differences in analytic methodology were eliminated, a consistent inverse
relation of HDLC levels and coronary heart disease event rates was apparent in BRHS as well
as in the four American studies. (Circulation 1989;79:8-15)

T rends relating high plasma levels of high-
density lipoprotein cholesterol (HDLC) and
decreased incidence of cardiovascular dis-
ease endpoints have been observed in prospective
epidemiological studies conducted in several
countries.1-12 The report from one of these studies,
the British Regional Heart Study (BRHS), in which
7,415 men, aged 40-59 years, were followed for an
average of 4.2 years, suggested that HDLC was not
a significant risk factor for ischemic coronary heart
From the Lipid Metabolism-Atherogenesis Branch (D.J.G.),
Division of Heart and Vascular Diseases and Division of Epi-
demiology and Clinical Applications (J.L.P., R.J.G.), NHLBI,
National Institutes of Health, Bethesda, Maryland; Division of
Biometry (J.D.N.) and Division of Epidemiology (D.R.J.), School
of Public Health, University of Minnesota, Minneapolis, Minne-
sota; Framingham Epidemiology Research Section (W.P.C.),
NHLBI, Framingham, Massachusetts; Biostatistics Center
(J.D.K.), George Washington University, Rockville, Maryland;
Collaborative Studies Coordinating Center, Department of Bio-
statistics (S.B.), and Department of Epidemiology (H.A.T.),
University of North Carolina, Chapel Hill, North Carolina.
disease (CHD) after statistical adjustment for other
risk factors.9 Because comparisons of these studies
are confounded by differences in their statistical
methods and in the populations and cardiovascular
endpoints studied, we have undertaken a system-
atic reexamination of two major North American
population-based studies, the Framingham Heart
Study (FHS) and the Lipid Research Clinics Prev-
alence Mortality Follow-up Study (LRCF); and of
the control groups of two large North American
randomized clinical trials, the Lipid Research Clin-
Supported by the National Heart, Lung, and Blood Institute
contracts: N01-HV12159, N01-HV12156, N01-HV32961, NO1-
HV12160, NO1-HV22914, NO1-HV32931, NO1-HV22913, NOI-
HV12158, NO1-HV12161, N01-HV22915, N01-HV12903, NO1-
HV12243, NO1-HV22932, N01-HV22917. NO1-HV22916, NO1-
HV12157, and Y01-HV30010.
Address for correspondence: Dr. David J. Gordon, Lipid
Metabolism-Atherogenesis Branch, Division of Heart and Vas-
cular Diseases, NHLBI, NIH, Federal Building, Room 401, 7550
Wisconsin Avenue, Bethesda, MD 20892.
Received May 3, 1988; revision accepted August 30, 1988.
 Gordon et al High-Density Lipoprotein and Cardiovascular Disease 9

ics Coronary Primary Prevention Trial (CPPT) and
the Multiple Risk Factor Intervention Trial (MRFIT),
using a standardized analytic approach that permits
comparison with the BRHS results.
Patients and Methods
We have confined our consideration to white men
and women between 30 and 69 years of age who
were free of clinical symptoms of CHD and were
neither pregnant nor taking exogenous hormones or
lipid-altering drugs at baseline. Capsule descrip-
tions of each study follow (Table 1).
The Framingham Heart Study
In the FHS, a prospective epidemiological study
of cardiovascular diseases (CVD) initiated in 1948,
5,209 persons between 30 and 59 years of age,
selected from a community of 28,000, were enrolled
and followed biennially.13 The vital status of 97% of
the original cohort is currently known. Approxi-
mately 85% of the surviving cohort participate in
biennial examinations, in which interviews, physi-
cal examinations, and selected laboratory tests
(including plasma cholesterol) are obtained. Fasting
HDLC and triglyceride measurements were intro-
duced in cycle 11 (1969-1971), the baseline for the
present analysis.1 Our analysis included all FHS
participants between 50 and 69 years of age at their
cycle 11 examination. Endpoint diagnoses are based
on a review of medical records by a committee of
FHS investigators. The diagnosis of CHD includes
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correlates of lipid and other cardiovascular risk
factors, performed during 1972-1976 in 10 collabo-
rating North American centers.14 More than 70,000
men and women were sampled from defined popu-
lations, and fasting plasma lipid levels and selected
medical and sociodemographic data were obtained
(visit 1). A 15% random sample plus all whose
plasma lipid levels at visit 1 exceeded predefined
cut points (or who reported using lipid-lowering
drugs) were invited to return for further evaluation,
including fasting lipoprotein determinations (visit
2). In 1977, a mortality follow-up study (LRCF) was
begun in all participants in the Prevalence Study
who were at least 30 years old at visit 2.15 The
protocol includes annual mail and telephone contact
with participants, but no clinical reexamination or
assessment of morbidity. When a death is discov-
ered, a copy of the death certificate is obtained, and
the attending physician and next of kin are inter-
viewed. A panel of clinical cardiologists assigns the
cause of death with a standard algorithm. The vital
status of 99.6% of the original cohort is currently
known.
The Lipid Research Clinics Coronary Primary
Prevention Trial
The CPPT was a multicenter, randomized, double-
blinded trial of the efficacy of lowering low-density
lipoprotein cholesterol (LDLC) levels in reducing
CHD risk in 3,806 asymptomatic middle-aged men

fatal and nonfatal myocardial infarction, sudden car- with primary hypercholesterolemia (plasma choles-
diovascular death, and acute coronary insufficiency. terol .265 mg/dl [6.87 mM]).16,17 The treatment
group received a moderate cholesterol-lowering diet
The Lipid Research Clinics Prevalence Mortality plus cholestyramine; the control group received the
Follow-up Study identical diet plus placebo. The therapeutic diet
The Lipid Research Clinics Prevalence Study (daily cholesterol intake of about 400 mg and a
was an epidemiological study of the distribution and polyunsaturated fat/saturated fat ratio of 0.8) low-
TABLE 1. Description of Studies
Study feature FHS LRCF CPPT MRFIT
Composition Residents of High lipid range Volunteers with Volunteers with
Framingham, over-sampled high LDLC levels high CHD risk
Massachusetts index
Number of subjects
Men 704 3,937 1,808 5,792
Women 714 2,297
Age range (yr) 50-69 30-69 35-59 35-57
Follow-up
Interval 2yr 1 yr 2 mo 1 yr
Baseline Cycle 11 Visit 2 Randomization Randomization
Mean years 10.3 8.5 7.7 6.7
Contact Examination Mail/phone Examination Examination
Treatment None None Diet + placebo Usual care
HDLC methodology
Material Plasma Plasma Plasma Plasma
Fasting Yes Yes Yes Yes
Precipitant Manganese-heparin Manganese-heparin Manganese-heparin Manganese-heparin
Cholesterol Abell-Kendall AutoAnalyzer AutoAnalyzer AutoAnalyzer
FHS, Framingham Heart Study; LRCF, Lipid Research Clinics Prevalence Mortality Follow-up Study; CPPT, Lipid Research Clinics
Coronary Primary Prevention Trial; MRFIT, Multiple Risk Factor Intervention Trial; HDLC, high-density lipoprotein cholesterol;
LDLC, low-density lipoprotein cholesterol; CHD, coronary heart disease.
 10 Circulation Vol 79, No 1, January 1989

ered plasma cholesterol levels by an average 4-6%,
with a trivial effect on HDLC levels.17 The present
analysis is confined to the placebo group.
Participants were examined bimonthly for an
average of 7.4 years; none was lost to follow-up.
The diagnosis of CHD included fatal and nonfatal
myocardial infarction and sudden cardiovascular
death, based on review of hospital records, electro-
cardiograms, and death certificates by a committee
of clinical cardiologists, who used a standard
algorithm.16,17 The average of four prerandomiza-
tion HDLC determinations was used as a baseline.12
The Multiple Risk Factor Intervention Trial
MRFIT was a randomized multicenter clinical
trial conducted in men without clinical CHD mani-
festations but who were at high CHD risk (upper
10-15%) because of a combination of hypertension,
cigarette smoking, and elevated plasma choles-
terol.18,19 Eligible male volunteers (12,866), aged
35-57 years, were randomized into two groups. The
"special intervention" group received stepped-care
therapy for the control of elevated blood pressure, a
dietary program for lowering plasma cholesterol,
and a counseling program to encourage cessation of
cigarette smoking. The control group continued
with their usual source of medical care (e.g., per-
sonal physician). The present analysis is confined to
the "usual care" group.
Participants were examined annually for deter-
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used in measuring HDLC in all four studies.20
Plasma LDLC levels were determined by ultracen-
trifugation20 and plasma very low-density lipopro-
tein cholesterol (VLDLC) levels were estimated as
one fifth the plasma triglyceride level.22
Statistical Methods
CHD incidence and CHD, CVD, and all-cause
mortality rates (events per 1,000 person-years) were
calculated for subgroups of each cohort defined by
HDLC levels as "high" (.50 mg/dl or 1.30 mM),
"medium" (40-50 mg/dl), or "low" (<40 mg/dl or
1.04 mM). In FHS and LRCF, men and women
were analyzed as separate cohorts.
Cox's proportional hazards model23 was used to
quantify the relation of HDLC levels to event rates
and to adjust for other baseline risk factor levels.
The regression coefficient (a) for HDLC was con-
verted to a percent increment in risk corresponding
to a 1 mg/dl (0.026 mM) increment in HDLC as
follows:
a' 100 * (ea_ 1)
=
when the value of a is much less than 1, a' = 100* a.
The logistic regression coefficients relating HDL
and non-HDL (NHDL) cholesterol levels to CHD
incidence in BRHS9 were used to calculate the
logistic coefficients of the algebraically equivalent
alternative model containing HDL and total (TOT)
cholesterol. Because NHDL=TOT-HDL by defi-

mination of risk factors and disease occurrence nition,

for an average of 6.7 years. Vital status was
ascertained in 99.7% of the cohort. The definitions
and mechanisms for endpoint diagnosis were
similar to those in the CPPT.
Laboratory Methods
Lipid and lipoprotein determinations were per-
formed on fresh plasma samples collected after at
least 12 hours of fasting.20 Cholesterol levels were
determined by the Abell-Kendall method21 in FHS
and by the Technicon AutoAnalyzer (standardized
to the Abell-Kendall method)20 in LRCF, CPPT,
and MRFIT. Manganese-heparin precipitation was
a * HDL +b NHDL = (a - b) HDL +b TOT
Thus, the total cholesterol-adjusted coefficient for
HDL cholesterol can be calculated by subtracting
the published coefficient for NHDL cholesterol (b)
from the published coefficient for HDL cholesterol
(a). Each logistic coefficient was then converted to
a percent increment in risk for each 1 mg/dl (0.026
mM) increment in HDLC as described above.
Results
The mean values of HDLC and several other
CHD risk factors in each study are provided in

TABLE 2. Mean Baseline Risk Factor Levels

FHS LRCF CPPT MRFIT
Risk factor Men Women Men Women Men Men
Age (yr) 59.7 60.2 44.6 46.2 47.9 46.2
% Smokers 30.5 33.3 39.2 34.1 36.8 63.4
Systolic blood pressure (mm Hg) 138.8 138.4 126.1 121.7 121.1 135.5
Body mass index (kg/m) 26.4 25.9 26.8 25.2 26.3 27.7
Cholesterol (mg/dl*)
Total 221.1 239.2 222.2 221.7 289.1 240.8
LDL 143.5 154.8 146.5 146.2 213.2 160.4
HDL 45.8 57.3 44.2 56.4 44.9 41.6
FHS, Framingham Heart Study; LRCF, Lipid Research Clinics Prevalence Mortality Follow-up Study; CPPT, Lipid Research Clinics
Coronary Primary Prevention Trial; MRFIT, Multiple Risk Factor Intervention Trial; LDL, low-density lipoprotein; HDL, high-density
lipoprotein.
*38.7 mg/dl = 1 mM.
 Gordon et al High-Density Lipoprotein and Cardiovascular Disease
20
0
11 RC i ]14i1
LRCF
cc
U)
B. Mortality Men
Ui 1E5_
F-
15
z in low HDLC than in high HDLC women. When
FHS FHS
LRCFMRI
CPPT LRFIT
5 -.
0
LMH LMH LMH LMH LMH
HDL-C SUBGROUP
FIGURE 1. Bargraphs of coronary heart disease (CHD)
incidence rates and cause-specific mortality rates in low
(L), middle (M), and high (H) high-density lipoprotein
(HDL-C) subgroups of FHS, LRCF, CPPT and MRFIT
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participants (see "Patients and Methods"). Note that
only fatal CHD events were identified in LRCF, whereas
both fatal and nonfatal CHD events were identified in
the other studies. Note also that non-cardiovascular
disease (non-CVD) mortality rates from FHS were
unavailable for this publication. Respective numbers of
subjects in the L, M, and H subgroups of each study
were FHS (men): 235, 216, 253; LRCF (men): 1,576,
1, 216, 1,145; CPPT: 597, 713, 498; MRFIT: 2,861, 1,807,
1,124; FHS (women): 60, 170, 484; LRCF (women): 302,
520, 1,476. FHS, Framingham Heart Study; LRCF,
Lipid Research Clinics Prevalence Mortality Follow-up
Study; CPPT, Lipid Research Clinics Coronary Primary
Prevention Trial; MRFIT, Multiple Risk Factor Inter-
vention Trial.
Table 2. There were substantial differences among
participants in the four studies, notably the rela-
tively advanced age of the FHS cohorts, the high
LDLC levels of the CPPT cohort, and the high
prevalence of smoking (as well as high mean body
mass index, cholesterol, and blood pressure lev-
els) in MRFIT. Nevertheless, baseline HDLC
levels differed little among cohorts of the same
sex. In both FHS and LRCF, the mean HDLC
level was about 12 mg/dl (0.31 mM) higher in
women than in men.
Crude incidence rates of CHD (Figure 1A) were
generally highest in participants with low HDLC
(<40 mg/dl [1.04 mM]) and lowest in those with
11
"high" HDLC (>50 mg/dl [1.30 mM]). This inverse
trend was most striking in FHS women, where
incidence rates were 2.6 times higher in the former
than latter HDLC stratum. Note that event rates
within a given HDLC category should not be com-
pared across studies without taking into account
their differing CHD risk factor profiles (Table 2) as
well as the absence of data on nonfatal myocardial
infarction in LRCF.
Although CHD, CVD, and all-cause mortality
rates (Figure 1B) also tended to be lowest among
subjects with the highest HDLC levels, the num-
Women
bers of fatal cardiovascular events were relatively
small, and their relation to HDLC levels appeared
* CHD more irregular. However, in both FHS and LRCF,
~~~~~~~~CVD
Non-CVD
CVD mortality rates were at least four times higher
CVD mortality rates in FHS and CRCF women
were compared with those of their male counter-
parts, their survival advantage was confined to the
LRCF
middle and high HDLC categories. No trend relat-
ing HDLC levels to non-CVD mortality rates was
evident in men or women in FHS (not shown),
LRCF, CPPT, and MRFIT (Figure 1B).
LMH
The relation of HDLC to each endpoint was
quantified and adjusted for age, cigarette smoking,
systolic blood pressure, body mass index, and LDLC
levels by proportional hazards regression (Table 3).
Consistent with the univariate results (Figure 1A),
significant inverse associations of HDLC and CHD
incidence were observed in both men (FHS, CPPT,
and MRFIT) and women (FHS). A hypothetical
1-ml/dl (0.026 mM) increment in HDLC was asso-
ciated with a CHD risk decrement of 1.9-2.3% in
men and 3.2% in women.
The regression models for mortality (Table 3)
were also consistent with the corresponding univar-
iate analyses (Figure 1B). In men, the regression
coefficients relating HDLC levels to CHD and total
CVD mortality in FHS, CPPT, and MRFIT were
generally smaller than those for CHD incidence;
none was statistically significant. However, in LRCF
men, these two coefficients were highly significant
(p <0.001) and were more than twice as large as
those in the other three male cohorts. In both
female cohorts, as in LRCF men, a 1-mg/dl (0.026
mM) increment in HDL was associated with a 3.7-
4.7% decrement in CHD and total CVD mortality
rates. The number of FHS and LRCF women dying
of CHD was small (17 in both cohorts combined),
and only the coefficients for total CVD mortality
attained statistical significance. The coefficients relat-
ing HDLC to all-cause mortality were generally
weak, reflecting the dilution of cardiovascular with
unrelated causes of death; only those for LRCF
men and women remained statistically significant.
The 95% confidence intervals for the regression
coefficients relating HDLC levels to CHD incidence
and CVD mortality in the four male and two female
cohorts are compared in Figure 2. Although these
coefficients vary among studies, the corresponding
 12 Circulation Vol 79, No 1, January 1989

TABLE 3. Proportional Hazards Regression Coefficients for

High-Density Lipoprotein Cholesterol
Events
Endpoint (n) Coefficient* Zt p
CHD incidence
Men
FHS 102 -1.90 -2.23 0.025
U 6 1 Vi CPPT 181 -2.33 -2.79 0.005
MRFIT 404 - 2.05 -3.91 < 0.001
E
Women
10 FHS 43 -3.24 -2.53 0.011
E

i:B. CVD Mortality Men Women

CHD mortality
2 Men
FHS 36 -1.97 -1.42 0.15
LRCF 60 -4.15 -3.61 < 0.001
01
CPPT 37 -1.26 -0.70 0.48
-2
MRFIT 120 -1.66 -1.76 0.078
Women
-6
FHS 11 -4.57 -1.76 0.078
-t ..e LRCF 6 -3.68 -1.15 0.25
CVD mortality
Men
FHS 49 -1.47 -1.30 0.19
FHS LRCF CPPT MRFIT FHS LRCF LRCF 95 -3.60 -3.95 < 0.001
STUDY CPPT 46 -0.87 -0.55 0.59
MRFIT 138 -1.22 -1.43 0.15
FIGURE 2. Plots of 95% confidence intervals for the
Women
adjustedproportional hazards regression coefficients (Table FHS 18 -4.44 -2.18 0.029
3) relating high-density lipoprotein cholesterol (HDL-C) LRCF 29 -4.72 -3.15 0.002
levels to coronary heart disease (CHD) incidence rates Total mortality
and cardiovascular disease (CVD) mortality rates in FHS,
Men
LRCF, CPPT, and MRFITparticipants. The shaded region LRCF 192 -1.39
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(-1. 9 to -2.9%) is contained in all 12 confidence intervals.
Note that the regression coefficients for LRCF in Figure
2A are based on CHD mortality only because nonfatal
events were not identified. FHS, Framingham Heart Study;
LRCF, Lipid Research Clinics Prevalence Mortality Follow-
up Study; CPPT, Lipid Research Clinics Coronary Pri-
mary Prevention Trial; MRFIT, Multiple Risk Factor
Intervention Trial.
confidence intervals overlap considerably, and all
include the range 1.9-2.9% as the estimated decre-
ment in risk associated with a 1 mg/dl (0.026 mM)
increment in HDLC level.
The relation of HDLC to CHD incidence in 7,415
men, aged 40-59, followed for 4.2 years in the
BRHS was reported using a logistic regression
model with age, smoking, systolic blood pressure,
and NHDLC included as covariates.9 We have used
these published data to calculate the percent incre-
ment in CHD risk for a 1-mg/dl increment in HDLC
in this model and in a model with TOTC rather than
NHDLC as a covariate (see "Patients and Meth-
ods"). We have then compared these results with
the corresponding results among men in FHS,
LRCF, CPPT, and MRFIT with the same covari-
ates (Table 4). Table 4 also includes the unadjusted
proportional hazards regression coefficients for
HDLC, as well as coefficients adjusted for LDLC
and for both LDLC and VLDLC, in the four
American studies.
-2.32 0.021
CPPT 70 -1.84 -1.40 0.16
MRFIT 241 -0.20 -0.33 0.74
Women
LRCF 81 -2.83 -3.53 < 0.001
CHD, coronary heart disease; CVD, cardiovascular disease;
FHS, Framingham Heart Study; CPPT, Lipid Research Clinics
Coronary Primary Prevention Trial; MRFIT, Multiple Risk Fac-
tor Intervention Trial; LRCF, Lipid Research Clinics Prevalence
Mortality Follow-up Study.
*Adjusted for age, cigarette smoking, systolic blood pressure,
body mass index, and low-density lipoprotein cholesterol, and
expressed as percent risk increment for each 1 mg/dl (0.026 mM)
increment in high-density lipoprotein cholesterol level.
tRatio of untransformed coefficient and its standard error.
In each of the five studies, the inverse relation of
HDLC and CHD incidence was weaker for the
model containing NHDLC than for any of the other
models. However, except in FHS (p=0.06) and
BRHS (p=0.21), the coefficient remained statisti-
cally significant. In FHS and MRFIT, adjustment
for TOTC, LDLC, or both LDLC and VLDLC did
not change the regression coefficient for HDLC
from its unadjusted value. In LRCF, these covari-
ance adjustments actually increased the magnitude
of this coefficient. This coefficient decreased sub-
stantially after covariance adjustment only in the
CPPT. Although LDLC and VLDLC levels were
not obtained in BRHS and the unadjusted regres-
sion coefficient for HDLC was not reported, the
values of the coefficients for HDLC in BRHS for
models containing NHDLC or TOTC as covariates
 Gordon et al High-Density Lipoprotein and Cardiovascular Disease 13

TABLE 4. Alternative Estimates of Regression Coefficients Relating High-Density Lipoprotein Cholesterol Levels and
Coronary Heart Disease Incidence in Men*
Cholesterol covariates
Study None NHDL Total LDL LDL, VLDLt
FHS -1.9 -1.6 -2.0 -1.9 -1.9
LRCFt -2.7 -2.7 -3.3 -3.6 -3.4
CPPT -3.0 -1.8 -2.8 -2.3 -2.1
MRFIT -1.7 - 1.1 -2.0 -2.0 -1.6
BRHS -1.0 -2.0
NHDL, non-high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein; FHS,
Framingham Heart Study; LRCF, Lipid Research Clinics Prevalence Mortality Follow-up Study; CPPT, Lipid
Research Clinics Coronary Primary Prevention Trial; MRFIT, Multiple Risk Factor Intervention Trial; BRHS,
British Regional Heart Study.
*All regression coefficients are expressed as percent risk increment for each 1 mg/dl (0.026 mM) increment in
high-density lipoprotein cholesterol level. All except those in the "None" column have been adjusted for age,
cigarette smoking, systolic blood pressure, and body mass index. A logistic model was used in BRHS, and a
proportional hazards model was used elsewhere.
tVLDL cholesterol was estimated as one fifth the plasma triglyceride level. Subjects with triglyceride levels
above 500 mg/dl were excluded.
*Models for cardiovascular disease mortality are presented because nonfatal coronary heart disease cases were
not ascertained.

were similar to those seen in the corresponding
models for MRFIT and FHS. Thus, covariance
adjustment does not consistently reduce the strength
of the inverse relation of HDLC and CHD, except
when NHDL is the covariate.
Discussion
When the BRHS results are viewed with the
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term. If the latter type of model were used as the
standard but (as in the BRHS, where blood speci-
mens were not drawn in the fasting state) separate
LDLC and VLDLC levels are unavailable, then the
model containing HDLC and TOTC or HDLC alone
will usually provide a "better" estimate of the
relation between HDLC and CHD incidence than
does the model containing HDLC and NHDLC.

results from the four American studies (Table 4),
there is no real disagreement except in the choice of
other cholesterol fractions to include in the statisti-
cal model. When LDLC (with or without VLDLC)
or TOTC is included as a covariate, the HDLC
coefficient does not deviate systematically from its
adjusted value; when NHDLC is included as a
covariate, the HDLC coefficient is systematically
suppressed. Table 4 provides no evidence to sup-
port a systematic difference between British and
American men in the nature of the relation between
HDLC and CHD.
The question remains of why NHDLC (which is,
after all, simply the sum of LDLC and VLDLC)
acts as a confounder of the HDLC-CHD relation,
whereas its individual components, included as
separate terms, do not. To act as a confounder, a
variable must be associated with both the presump-
tive risk factor (HDLC) and the outcome (CHD
incidence). In these data, LDLC meets only the
latter criterion, whereas VLDLC meets only the
former; thus, even when both terms are included
separately as covariates, there is no confounding,
and the HDLC coefficient is essentially unchanged.
However, the composite variable NHDLC is asso-
ciated both with CHD and (inversely) with HDLC,
and its inclusion in the model weakens the inverse
association of HDLC and CHD. Although this
model is not "wrong" in an absolute sense, it gives
a result that differs from models in which each
lipoprotein species is represented by a separate
We also considered the possible implications of
another methodological difference-the use of the
logistic model in BRHS and of the proportional
hazards model in the current analysis. In general,
these two models differ only when a substantial
proportion of a cohort has had the event of interest,
has died, or has been lost to follow-up.24 This was
not true in any of the cohorts discussed here.
Logistic models that we computed for LRCF and
CPPT gave essentially the same results as the
proportional hazards models.
Although the data relating HDLC and CVD mor-
tality are relatively sparse and are not statistically
compelling, they are generally consistent with the
data for CHD incidence (Figure 2). A 1-mg/dl
increment in HDLC is associated with a 2-3%
decrement in risk. Our analysis yielded no trends
relating HDLC to increased non-CVD mortality
rates as have been reported elsewhere.4,25,26 In the
Minneapolis study,4 in which 260 men were fol-
lowed for 25 years with a 52% cumulative mortality
rate, the trend in non-CVD mortality may be attrib-
uted (at least in part) to the opposing trend in CVD
mortality; that is, men with low HDLC tend to die
most often from CVD, and those with high HDLC
tend to die most often from other causes. Life-table
analyses that include the duration of survival, as
well as the cause of death, are needed to determine
whether there was any real benefit (or detriment)
associated with a high HDLC level in this study.
However, in the USSR study,25,26 the trend relating
 14 Circulation Vol 79, No 1, January 1989
high HDLC levels to high non-CVD mortality was
not offset by a trend toward fewer CVD deaths.
Although such a result may be explained by patterns
of alcohol consumption, it persisted after adjustment
for self-reported habitual alcohol intake and other
potential confounding variables.
In conclusion, the epidemiological data generally
support an independent inverse association of HDLC
levels and CHD event rates, in which CHD risk
decreases by 2-3% for a 1-mg/dl (0.026 mM) incre-
ment in HDLC levels. Several hypothesized under-
lying mechanisms for this association have been
advanced, most notably "reverse transport" of
cholesterol by the HDL particle, but as yet, none
has been clearly established.27 Although clinical
trials of cholesterol lowering in hypercholesterol-
emic men indicate that increases in HDLC may
enhance the benefit of decreasing LDLC,12,28-30 the
value of therapy aimed specifically at increasing
HDLC levels remains unproven. However, the adop-
tion of certain hygienic measures, such as exercise,
weight loss, and smoking cessation, which are ben-
eficial in their own right and may also raise HDLC
levels,31,32 appear prudent.
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KEY WORDS * high-density lipoprotein * coronary heart
disease * cardiovascular disease * Framingham Heart Study
* epidemiology * Lipid Research Clinics * Coronary Primary
Prevention Trial * Multiple Risk Factor Intervention Trial .
British Regional Heart Study