(Circulation. 1995;92:1430-1436.)
© 1995 American Heart Association, Inc.
Articles |
Combined Effects of HDL Cholesterol, Triglyceride, and Total Cholesterol Concentrations on 18-Year Risk of Atherosclerotic Disease
Presented in part at the 66th Scientific Sessions of the American Heart Association, November 10, 1993, Atlanta, Ga.
From the Honolulu Epidemiology Research Unit (C.M.B., D.S.S.), Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Honolulu, Hawaii; Division of Endocrinology, Gerontology and Metabolism (A.L.), Department of Medicine, Stanford University School of Medicine, Palo Alto, Calif; Honolulu Heart Program (R.B., D.C., B.L.R., J.D.C.), Kuakini Medical Center, Honolulu, Hawaii; Department of Medicine (B.L.R., J.D.C.), John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii; and Department of Medicine (R.J.G.), University of Massachusetts Medical School (Worcester).
Correspondence to Dr Cecil Burchfiel, Honolulu Heart Program, 347 N Kuakini St, Honolulu, HI 96817. E-mail buzz@hhs.cba.hawaii.edu.
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Abstract |
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Background Whether the combination of a low level of HDL cholesterol (HDL-C) and high level of triglyceride (TG) confers increased risk of cardiovascular disease and whether risk varies across levels of total cholesterol (TC) are not well established. Combined effects of HDL-C, TG, and TC on the incidence of atherosclerotic disease were examined prospectively in Japanese-American men from the Honolulu Heart Program.
Methods and Results Among 1646 men aged 51 to 72 years who were
free of coronary heart disease (CHD), stroke, and cancer and
were not taking lipid-lowering medication, 318 developed
atherosclerotic events (angina, coronary insufficiency, aortic
aneurysm, definite CHD, or thromboembolic stroke) and 170
developed definite CHD between 1970 and 1988. Subjects were stratified
by TC level (desirable, <200 mg/dL; borderline high, 200 to 239 mg/dL;
high, 
240 mg/dL), HDL-C level (<35 and 35 mg/dL), and TG level
(<200 and 200 mg/dL). With Cox regression with high HDL-C and low TG
as reference, age-adjusted relative risks (RR) of atherosclerotic
events were significantly elevated in men with low HDL-C and high TG at
borderline-high (RR, 2.46; 95% CI, 1.48 to 4.09) and high (RR,
2.21; 95% CI, 1.34 to 3.66) TC levels but not in men with desirable TC
levels (RR, 0.89; 95% CI, 0.38 to 2.09). Elevated risks were
independent of blood pressure, obesity, fat distribution, diabetes,
smoking, and alcohol. Results were not materially altered by exclusion
of subjects with angina alone and were similar but somewhat weaker
for CHD.
Conclusions Risk of atherosclerotic disease appears elevated in subjects with low HDL-C and high TG levels when TC is borderline high or high, independent of other cardiovascular risk factors. These findings support recent cholesterol screening recommendations and suggest that joint effects of HDL-C and TG may be important to consider.
Key Words: Asian Americans • cardiovascular diseases • incidence • lipoproteins • longitudinal studies
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Important roles for individual lipids and lipoproteins in the development of atherosclerotic disease have been clearly established. However, relatively few studies have assessed the combined effects of HDL cholesterol (HDL-C), triglyceride (TG), and total cholesterol (TC) levels on risk of coronary heart disease (CHD). Several studies have examined the joint effects of HDL-C and TG,1 2 3 4 5 6 of HDL-C and TC,7 8 9 10 and of TC and TG.1 4 6 In one study, the joint effects of all three variables (HDL-C, TG, and TC) on CHD were evaluated cross sectionally.6 In most of these studies, adjustment for a number of variables that might confound the observed associations has not been feasible, and the length of follow-up for the prospective studies has been limited.
Although a direct association between TG and cardiovascular disease has been reported,11 12 adjustment for HDL-C may render the association no longer significant. This may be due to greater measurement variability in TG relative to HDL values11 or to the fact that TG and HDL-C metabolism are closely interrelated1 and therefore both variables, to a certain degree, measure the same metabolic abnormality.13 Associations between TG and CHD may also be confined to particular subgroups of the population. For example, one study found TG to be significantly associated with CHD mortality among men who had HDL-C levels of <35 mg/dL.14 Thus, assessment of independent effects of HDL-C and TG is difficult.
One of the features of individuals with syndrome X,15 or insulin-resistance syndrome,16 which is characterized by non–insulin-dependent diabetes, obesity, and hypertension, is the combination of low HDL-C and high TG levels. Given the recent National Cholesterol Education Panel (NCEP) recommendations regarding cholesterol screening,17 18 19 it is important to determine whether subsets of the population with low HDL-C and high TG levels but desirable (<200 mg/dL) or borderline-high (200 to 239 mg/dL) levels of TC are at increased risk of cardiovascular disease. Results of such an investigation could contribute to future population-based screening recommendations.
The Honolulu Heart Program provided an opportunity to examine the joint effects of HDL-C and TG on atherosclerotic disease at normal, borderline-high, and high TC levels, while controlling for the influence of a number of other cardiovascular risk factors. The potential independent contributions of low HDL-C and high TG to the risk of atherosclerotic disease as a whole and to CHD specifically were evaluated prospectively in a cohort of 1646 Japanese-American men aged 51 to 72 years who have been followed for a maximum of 18 years.
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Methods |
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Study Population
The Honolulu Heart Program is an ongoing prospective epidemiologic investigation of heart disease and stroke in a population-based cohort of Japanese-American men who were living on the island of Oahu in 1965. After the population was identified and recruited from selective service records, 8006 subjects aged 45 to 68 years completed a baseline examination between 1965 and 1968. The second and third examinations of the entire cohort were conducted an average of 2 (1968 to 1970) and 6 (1971 to 1975) years later, respectively. A 30% random sample of the subjects who completed the second examination was invited to participate in a series of three additional examinations (1970 to 1972, 1975 to 1978, and 1980 to 1982) targeted specifically to examine the role of lipids and lipoproteins in cardiovascular disease.20 A total of 1859 men (84% of those invited) completed the initial lipoprotein examination (1970 to 1972). Of these men, 213 had prevalent coronary heart disease, stroke, or cancer or were taking lipid-lowering medication and therefore were excluded, leaving 1646 subjects, who constitute the study population.
Data Collection
Lipid and lipoprotein measurements were
determined after the
subjects fasted overnight (for at least 12 hours) with the use of a
common protocol for participating sites of the Cooperative Lipoprotein
Phenotyping Study, as described in detail
previously.20 21 22
Alcohol consumption was determined by recording the usual
monthly intake of beer, wine, or liquor and was converted to
milliliters of ethanol consumed per day. Data for other
cardiovascular risk factors were obtained from the
second examination in 1968 through 1970. Standardized measurements of
blood pressure, body mass index, and subscapular and triceps skinfold
thicknesses were made, and cigarette smoking prevalence was determined.
A ratio of subscapular to triceps skinfold thickness was created as an
indicator of upper body obesity. Subjects were defined as hypertensive
if their systolic or diastolic blood pressure was 140/90
mm Hg or they were taking antihypertensive medication. Diabetes was
considered present if subjects were taking oral hypoglycemic
medication or insulin or were on a diabetic diet.
Cases of cardiovascular disease were identified from the date of the initial lipoprotein examination (1970 to 1972) through 1988 using comprehensive hospital surveillance on the island of Oahu and periodic examinations (1975 to 1978 and 1980 to 1982). A physician committee reviewed all available information, which included hospital discharge summaries, laboratory data, ECGs, and death certificates, and used standard criteria for the classification of cardiovascular end points, as described in detail previously.23 24 25 The two primary outcomes examined in this investigation were definite CHD and any atherosclerotic event, the former having possibly greater diagnostic certainty but fewer incident events and the latter representing events that may have a common pathogenesis and occur more frequently. Definite CHD included nonfatal myocardial infarction, fatal CHD, and sudden death within 1 hour due to an unknown cause. Atherosclerotic events included definite CHD, angina or coronary insufficiency,24 aortic aneurysm, and thromboembolic stroke (excluding transient ischemic attacks).25 In the case of multiple types of events, follow-up time to the initial atherosclerotic event was used.
The average duration of follow-up for the study population was 15.9 years (range, 0.5 to 18.1 years; SD, 3.5 years) with mortality taken into account, with 90% of the cohort being followed for at least 10.5 years. Duration of follow-up was slightly shorter when CHD (mean, 15.6 years; SD, 4.0 years) and atherosclerotic events (mean, 14.9 years; SD, 4.5 years) were considered. Determination of vital status and cardiovascular events is continuing, with only 4 of the original 8006 men lost to follow-up as of 1993. Migration from the island of Oahu has been low, averaging less than 1 per 1000 annually.
Statistical Analysis
Subjects were first categorized into
three groups by level of TC
(<200 mg/dL [desirable], 200 to 239 mg/dL [borderline
high], and
240 mg/dL [high]) using NCEP
guidelines.17 19 Subjects
were then categorized jointly by both HDL-C (<35 and 35 mg/dL) and
TG (<200 and 200 mg/dL) levels. These cutoff points were selected to
be consistent with recent national guidelines for
HDL-C,19 as well as with national,19
European,26 and international27 guidelines
for TG.
Age-adjusted incidence rates of CHD and any atherosclerotic event per 1000 person-years of observation were calculated by joint TC, HDL-C, and TG levels with the entire study population used as the standard. Age-adjusted cardiovascular risk factor levels were compared across HDL-C and TG categories separately for each level of TC with the use of a general linear model procedure and logistic regression (SAS Institute)28 29 ; subjects with high HDL-C and low TG levels served as the reference group. The Cox proportional hazards model was used to calculate relative risks, with adjustments for age and other risk factors to determine whether risk of these outcomes was elevated in subjects with the combination of low HDL-C and high TG levels independent of other established cardiovascular risk factors. Two-way interaction terms involving TC, HDL-C, and TG were considered, but because they were not statistically significant, the simpler models without interaction terms were used.
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Results |
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The prevalence of specific combinations of TC, HDL-C, and TG levels along with the numbers of events, person-years of observation, and age-adjusted incidence rates of CHD and atherosclerotic events are presented in Table 1
(incidence rates are also displayed in Figs 1 and
2). Overall, TC levels were desirable
(<200 mg/dL) in approximately 30% of the study population,
borderline-high (200 to 239 mg/dL) in 40%, and high (240 mg/dL)
in 30%. Although 17% of all subjects had low HDL-C levels (<35
mg/dL) and 23% had high TG levels (200 mg/dL), only 9% had the
joint combination of low HDL-C and high TG levels. The proportion of
subjects who had low HDL-C and high TG levels was relatively constant
across TC categories, ranging from 3% to 4%. The optimal combination
of desirable TC, HDL-C 35 mg/dL, and TG <200 mg/dL was present
in 20% of the population.
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Between 1970 and 1988, 170 definite CHD events and 318 atherosclerotic
events (18.9% of which were based on angina alone) occurred during
approximately 25 000 person-years of follow-up.
Age-adjusted incident rates of atherosclerotic and CHD events are
presented by HDL-C and TG levels separately for the three TC
levels in Figs 1
and 2, respectively. Compared
with the most desirable
subgroup (high HDL and low TG), incidence rates of atherosclerotic
events were not elevated in subjects with low HDL-C and high TG levels
when TC level was in the desirable range (9.0 versus 9.6 per 1000
person-years, respectively) but were elevated in subjects with TC
levels between 200 to 239 mg/dL and 240 mg/dL (9.4 versus 21.7 and
15.9 versus 34.3 per 1000 person-years, respectively). Similarly,
incidence rates of CHD comparing the most desirable with the least
desirable subgroup were 4.3 versus 6.1, 4.9 versus 9.9, and 8.8 versus
14.1 per 1000 person-years, respectively (Fig 2). In general,
these
patterns were more evident for atherosclerotic events than for CHD. For
atherosclerotic events, the gradient in incidence rates increased
3.8-fold when subjects with the optimal profile of desirable TC, high
HDL-C, and low TG levels were compared with those having the worst
profile of high TC, low HDL-C, and high TG levels. For CHD, comparable
incidence rates increased 3.3-fold.
When age-adjusted incident rates of atherosclerotic events were compared across the three TC levels for subjects with low and high HDL-C (without taking into account TG), those with low HDL-C exhibited a threefold increase in rates (9.7, 20.0, and 30.2 per 1000 person-years, respectively), whereas those with high HDL-C experienced only a 1.5-fold increase (9.9, 10.3, and 15.8 per 1000 person-years, respectively). These comparisons are consistent with a protective effect of HDL-C at borderline-high and high TC levels. A test for interaction involving HDL-C and TC was of borderline significance (P=.054). The contrast in incidence rates across TC levels by TG category (without taking into account HDL-C) was less in magnitude (9.3, 10.1, and 16.5, and 11.8, 17.2, and 20.7 per 1000 person-years for low and high TG level, respectively). Similar comparisons for CHD showed a twofold increase in rates across TC levels for subjects with low HDL-C and a 1.7-fold increase for those with high HDL-C; approximate twofold and 1.3-fold increases in rates of CHD were observed for subjects with a low and a high TG level, respectively.
To determine whether other cardiovascular risk factors
might account for the increased incidence of CHD and atherosclerotic
events in subjects with low HDL-C, high TG, and either
borderline-high or high TC levels, age-adjusted risk factor
levels were first compared across the four HDL-TG combinations
separately for each TC level (Table 2). In general,
individuals with the optimal combination of high HDL-C and low TG
levels tended to have a more favorable risk factor profile for all
three TC levels. This profile was characterized by lower blood pressure
and prevalence of hypertension, lower levels of generalized obesity,
and a more favorable body fat distribution, although prevalence of
diabetes and smoking, as well as alcohol intake, tended to be
intermediate for this group relative to the other three combinations.
Estimates of diabetes prevalence were based on small numbers in all
except one of the subgroups (high HDL-C and low TG levels). The group
with high HDL-C and high TG levels had the highest alcohol intake. It
is possible that some of the differences in a specific risk factor
level across the HDL-C and TG subgroups were due to differences in
other risk factor levels. For example, differences in blood pressure
and prevalence of hypertension in the group with high HDL-C and high TG
levels relative to the group with low HDL-C and high TG levels were not
statistically significant but were reduced when adjustment for alcohol
intake was performed (data not shown). Among subjects with
borderline-high TC levels, age-adjusted levels of body mass
index, skinfold measurements and their ratio, and prevalence of smoking
were highest in subjects with the adverse combination of low HDL-C and
high TG levels. Most of the differences in these risk factor levels
were statistically significant using the group with high HDL-C and low
TG levels as reference. Among subjects with a high TC level, the
subgroup with low HDL-C and high TG levels had the highest prevalence
of hypertension and smoking, both significantly elevated relative to
the optimal reference group.
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Age- and risk factor–adjusted relative risks of CHD and
atherosclerotic events are presented in Table 3
by level of HDL-C and TG, separately for the three TC levels with the
optimal subgroup as reference. Relative risks for CHD were elevated
slightly but not significantly, although several of the subgroup
comparisons reached borderline statistical significance.
Age-adjusted relative risks of an atherosclerotic event were
significantly elevated for three subgroups: low HDL-C, low TG, and
borderline-high TC levels; low HDL-C, high TG, and
borderline-high TC levels; and low HDL-C, high TG, and high TC
levels. When further adjustment for other risk factors was performed,
relative risks were reduced slightly in magnitude but remained
significantly elevated in subjects with low HDL-C and high TG levels
and either borderline-high or high TC level. Specifically among
subjects with a borderline-high TC level, the relative risk of an
atherosclerotic event, in a comparison of individuals with low HDL-C
and high TG levels with those with high HDL-C and low TG levels, was
2.5 with adjustment for age only and 2.1 with adjustment for age and
other cardiovascular risk factors. Similarly, in
subjects with a high TC level, the relative risk was reduced slightly
from 2.2 to 1.7, respectively, but remained statistically significant
with adjustment for other risk factors. Relative risks of CHD and
atherosclerotic events were slightly higher in the borderline-high
than in the high TC level group. In addition, when subjects with angina
alone (n=60) were excluded from analyses of atherosclerotic
events, the results were not materially affected.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In the present study of Japanese-American men living in Hawaii, the proportion of the population with specific lipid and lipoprotein combinations was examined, and associated risks of CHD and atherosclerotic events were determined. A protective role for HDL-C was found to be especially apparent at high TC levels. In addition, an elevated risk of atherosclerotic disease was observed among subjects with the joint combination of low HDL-C and high TG levels when TC was borderline-high or high but not when TC was in the desirable range. Although some attenuation in relative risks occurred, the excess risk was found to be independent of other cardiovascular risk factors.
The proportion of men in the present study who had TC levels of
<200 mg/dL (29%) was considerably lower than the proportion of men in
the Cardiovascular Health Study (CHS) (51%) who were
older (65 to 100 years) and were examined more recently (1989 to
1990).30 These proportions were also higher for men aged
20 to 74 years from the second (44%) and third (48%) National Health
and Nutrition Examination Surveys (NHANES II and III) conducted from
1976 through 1980 and 1988 through 1991,
respectively.31 32 The proportion of men with TC
levels of
240 mg/dL were highest in the present cohort (30%), intermediate
for men from NHANES II (25%) and III (19%), and lowest for men from
CHS (13%). The proportion of men with HDL-C levels of <35 mg/dL was
slightly higher in the present cohort (17%) than in men from CHS
(13%) and was comparable for men aged 40 to 59 (21%) and 60 to 79
(14%) years from the Lipid Research Clinics Program.33
Differences in these proportions could be due to differences in age of
the subjects, laboratory methods, and the point in time when
measurements were made since TC levels have clearly declined over the
past 30 years among US adults.34
Results from the present study provide support for a protective role of HDL-C in the clinical manifestations of atherosclerosis. The protective effect of HDL-C, apparent when evaluating HDL-C without taking TG into account and more evident at higher levels of TC, is consistent with the role of HDL-C in reverse cholesterol transport35 36 or in impeding oxidative modification of LDL cholesterol.37 Although the test for statistical interaction involving HDL-C and TC was not quite statistically significant, these incidence patterns suggest that the impact of TC on atherosclerotic disease may depend to some extent on the level of HDL-C. Such a protective role for HDL-C is consistent with the results of other epidemiologic studies.2 38 39 Although an elevated risk associated with low HDL-C in subjects with desirable TC levels was not observed in our study, such a finding has been demonstrated using myocardial infarction,7 10 CHD incidence,9 and arteriographically documented coronary disease8 as outcomes. A somewhat stronger influence was observed for HDL-C than for TG in the present study and in the study reported by Freedman et al.6 TG was significantly associated with an increased risk of CHD death in subjects who had TC levels of <220 mg/dL from the Paris Prospective Study40 but was not identified in another study as a predictor of cardiovascular disease mortality in men who had TC levels of <240 mg/dL.41 In general, results from the present study support the more recent NCEP guidelines,19 in which a greater emphasis was placed on the potential role of HDL-C in cardiovascular disease.
The combination of low HDL-C and high TG levels appears to confer an increased risk of atherosclerotic disease among individuals with a borderline-high or high TC level. A number of studies have focused on identification of independent effects of specific lipids and lipoproteins by using various multivariate techniques. However, as indicated in a recent review,42 relatively few studies have examined the joint influences of risk factors such as HDL-C and TG levels on cardiovascular end points. Consistent with our findings, an increased risk of CHD has been demonstrated among subjects with the combination of low HDL-C and high TG levels compared with those who had high HDL-C and low TG levels.1 2 3 4 5 6 This approach may be useful in identifying specific subgroups of the population who are at increased risk of cardiovascular disease and who may benefit from large-scale screening programs.
The elevated risk of atherosclerotic disease observed in the present study among men with low HDL-C and high TG levels was independent of a number of traditional cardiovascular risk factors (eg, blood pressure, measures of obesity and body fat distribution, smoking, alcohol, and diabetes). This finding is consistent with the increased risk of cardiovascular disease associated with the insulin-resistance syndrome,16 or syndrome X,15 since the joint combination of low HDL-C and high TG levels is one of the characteristics of this syndrome. Because hypertension, obesity, and glucose intolerance are also characteristics of this syndrome, some attenuation in the magnitude of risk would be expected, and it was observed, with adjustment for these variables. The occurrence of a cluster of abnormalities involving insulin, HDL-C, and TG may contribute to increased risk of cardiovascular disease, with insulin resistance being the underlying defect.43 In one metabolic study that examined the four possible combinations of low and high HDL-C and TG levels, only the group with low HDL-C and high TG levels showed increased insulin responses to an oral glucose load consistent with insulin resistance.44 It is possible that an insulin-resistant state, perhaps present for a number of years, could lead to both alterations in lipid metabolism and manifestations of atherosclerotic disease. It is also possible that insulin resistance leads to abnormally low levels of HDL-C and high levels of TG, which subsequently enhance the risk of atherosclerotic disease.45
A relatively small number of events occurring in certain subgroups of the study may have limited the power to detect an increased or decreased risk, particularly for CHD. The infrequent occurrence of certain combinations of lipid and lipoprotein values is due in part to the strong correlations between these variables, particularly between HDL-C and TG. Separate effects of HDL-C and TG may be difficult to demonstrate especially in a multivariate model with both of these variables entered as continuous measures.12 The stratification approach used in the present study may provide a more appropriate assessment of the influence of both HDL-C and TG, given the high degree of correlation between them, although this approach requires large samples. Even after stratification, it is possible that some differences in mean levels of HDL-C and TG may persist within respective HDL-C and TG combinations. In addition, the focus on joint influences of risk factors may more accurately reflect the actual patterns found within individuals and populations.
Some misclassification of subjects by TC, HDL-C, and TG category could have occurred. The imprecision associated with measurement of triglyceride levels (being much greater than that seen with HDL-C and TC), along with the strong correlation between HDL-C and TG, may have an impact on relative risk estimates.46 Lipid and lipoprotein levels may have changed somewhat during follow-up; however, cross-sectional assessment of these levels by age suggests that such changes would be relatively small in this cohort.47 It is likely that existence of such factors would lead to relative risk estimates closer to unity. It is also possible that the impact of this misclassification may have been somewhat greater on associations with CHD than atherosclerotic events given the smaller number of incident CHD events. Alternatively, other mechanisms such as thrombosis, in addition to atherosclerosis, may be operative to a slightly greater extent in the case of CHD relative to other clinical manifestations included in the atherosclerotic event category.
Caution should be used in generalizing these results to other populations. This study was limited to men between the ages of 51 and 72 years who were of Japanese-American ancestry and who have been characterized as having somewhat lower incidence rates of CHD relative to other caucasian populations.24 However, it appears that findings from this cohort are in general agreement with those of several other prospective epidemiologic studies. The long prospective follow-up, comprehensive surveillance for atherosclerotic disease, ability to adjust for multiple risk factors, and assessment of joint effects of all three lipids and lipoproteins simultaneously are strengths of this study. The similar patterns of risk for CHD and atherosclerotic events, although slightly weaker for CHD, as well as results that were unaffected by excluding subjects with angina alone, contribute to the consistency of the findings.
At desirable levels of TC, risks of atherosclerotic disease, and CHD in particular, were not elevated in subjects with the combination of low HDL-C and high TG levels. The conclusions reached by the recent National Institutes of Health Consensus Conference were based on US and European populations, and it was recognized that they might not be applicable to populations with a low incidence of CHD.48 Although a limited number of end points occurred in several of the subgroups with TC in the desirable range, evidence from the present study suggests that current screening recommendations from the NCEP are appropriate in this population of Japanese-American men. Additional prospective follow-up of this cohort and others may be useful in expanding the evidence on which these guidelines are based.
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Acknowledgments |
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This work was supported by National Heart, Lung, and Blood Institute contract NO1-HC-05102.
Received January 18, 1995; accepted March 10, 1995.
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