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Low Triglycerides–High High-Density Lipoprotein Cholesterol and Risk of Ischemic Heart Disease
Jørgen Jeppesen, MD;
Hans Ole Hein, MD;
Poul Suadicani, DD;
Finn Gyntelberg, MD
Arch Intern Med. 2001;161:361-366.
ABSTRACT
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Background A high triglyceride (TG)–low high-density lipoprotein cholesterol
(HDL-C) level (TG  1.60 mmol/L [142 mg/dL] and HDL-C  1.18 mmol/L
[46 mg/dL]) is associated with a high risk of ischemic heart disease (IHD),
whereas a low TG–high HDL-C level (TG 1.09 [97 mg/dL] and HDL-C 1.48
mmol/L [57 mg/dL]) is associated with a low risk. Conventional risk factors
tend to coexist with high TG–low HDL-C levels. We tested the hypothesis
that subjects with conventional risk factors would still have a low risk of
IHD if they had low TG–high HDL-C levels.
Methods Observational cohort study of 2906 men aged 53 to 74 years free of IHD
at baseline.
Results During 8 years, 229 subjects developed IHD. Stratified by conventional
risk factors—low-density lipoprotein cholesterol level (4.40 mmol/L
or >4.40 mmol/L [170 mg/dL or >170 mg/dL] [median value]), hypertensive
status (blood pressure >150/100 mm Hg or taking medication), level of physical
activity (>4 h/wk or 4 h/wk), and smoking status (nonsmokers vs smokers)—the
incidence in men with high TG–low HDL-C levels was 9.8% to 12.2% in
the low-risk and 12.2% to 16.4% in the high-risk strata; the corresponding
values in men with low TG–high HDL-C concentrations were 4.0% to 5.1%
and 3.7% to 5.3%, respectively. Based on an estimate of attributable risk,
35% of IHD might have been prevented if all subjects had had low TG–high
HDL-C levels.
Conclusion Men with conventional risk factors for IHD have a low risk of IHD if
they have low TG–high HDL-C levels.
INTRODUCTION
IN THE Copenhagen Male Study (CMS), the combined lipid profile of a
high fasting plasma triglyceride (TG) concentration and a low high-density
lipoprotein cholesterol (HDL-C) concentration is associated with a high risk
of ischemic heart disease (IHD), whereas the combined lipid profile of a low
fasting plasma TG concentration and a high HDL-C concentration is associated
with a low risk of IHD.1
In the early part of cardiovascular epidemiology, the role of major
risk factors of IHD such as a high low-density lipoprotein cholesterol (LDL-C)
concentration, hypertension, low physical activity, and smoking was established.2, 3 These major risk factors tend to coexist
with high TG–low HDL-C concentrations.1
The present study was initiated to test the hypothesis that subjects with
the major classic risk factors listed previously would still have a low risk
of IHD if they had low TG–high HDL-C concentrations.
SUBJECTS AND METHODS
We describe the methods in the CMS in greater detail elsewhere.1 The CMS was started in 1970 as a cardiovascular study
of 5249 men.4, 5 In 1985 and 1986,
a new baseline was established and was used for the present study. All survivors
from the 1970 study were traced by means of the Danish Central Population
Register. Between June 1, 1985, and June 1, 1986, all survivors (except 34
emigrants) from the original cohort were invited to take part in this study;
3387 men (75%) agreed and gave informed consent. Their mean age was 63 years
(range, 53-74 years). Each subject was interviewed by a physician (H.O.H.)
about a previously completed questionnaire and examined with measurements
of height, weight, and blood pressure. A venous blood sample was taken for
lipid measurements after subjects had fasted for at least 12 hours.
Men who had a history of acute myocardial infarction, angina pectoris,
stroke, or intermittent claudication were excluded from the follow-up study.
For all who reported admission to the hospital because of acute myocardial
infarction before the start of the study, hospital records were checked. Information
on angina pectoris, stroke, and intermittent claudication was established
from the questionnaire. Three hundred forty-two men (10.1%) were excluded
because of cardiovascular disease and 139 men (4.1%) were excluded because
of missing data. Thus, 2906 men were eligible for the prospective study.
Serum concentrations of total cholesterol, TGs, and HDL-C were analyzed
by standard methods.6, 7, 8, 9
The concentration of LDL-C was determined according to the Friedewald formula.10 Approximately 1.5% of the study population had a
TG level greater than 4.50 mmol/L [>399 mg/dL], where the indirect LDL-C calculation
becomes unreliable. However, excluding subjects with TG levels greater than
4.50 mmol/L [>399 mg/dL] from the study did not materially affect any of the
results, so we continued to use the formula of Friedewald 10
in subjects with TG levels greater than 4.50 mmol/L [>399 mg/dL] and did not
measure LDL-C level directly.
Men were subdivided into 3 groups based on serum concentrations of fasting
TGs and HDL-C. A high TG–low HDL-C concentration was defined as belonging
to the highest third of TG (cutoff point, 1.60 mmol/L [142 mg/dL])
and the lowest third of HDL-C (cutoff point, 1.18 mmol/L [46 mg/dL]).
A low TG–high HDL-C concentration was defined as belonging to the lowest
third of TG (cutoff point, 1.09 mmol/L [97 mg/dL]) and the highest
third of HDL-C (cutoff point, 1.48 mmol/L [57 mg/dL]). An intermediate
group was defined as not belonging to either of these 2 groups.
Self-reported type 2 diabetes mellitus was accepted, provided the diagnosis
had been verified previously by a physician. In the CMS, no measurements of
plasma insulin or glucose levels were performed. Blood pressure was measured
on the right arm with the subject seated by means of the manometer developed
by the London School of Hygiene.11 The definition
of hypertension was based on questionnaire information and blood pressure
measurements; the criteria were self-reported use of antihypertensive medication
or systolic blood pressure of at least 150 mm Hg and diastolic blood pressure
of at least 100 mm Hg. Body mass index (BMI) was calculated as weight in kilograms
divided by the square of height in meters.
Total weekly consumption of alcohol was calculated from questionnaire
items about average alcohol consumption on weekdays and weekends. Intakes
of beer, wine, and spirits were reported separately. One drink corresponded
to 10 to 12 g of ethanol. Men classified themselves as never smokers, previous
smokers, or current smokers. As estimated by serum cotinine levels, the validity
of tobacco reporting was high.12
With respect to leisure time physical activity, men classified themselves
as sedentary or slightly active less than 4 hours per week or physically more
active based on questions in the questionnaire. According to the system of
Svalastoga,13 men were divided into 5 social
classes based on level of education and job profile.
In 1995, a register follow-up was carried out on morbidity and mortality
between 1985-1986 and December 31, 1993. All men who had taken part in the
1985-1986 examination were traced from registers. Information on hospital
admissions and death certificate diagnoses during follow-up was obtained.
We used the diagnoses from official national registers. Ischemic heart disease
diagnoses accepted were International Classification of
Diseases, Eighth Revision,14 codes 410-414.
Previous studies15, 16 have demonstrated
a high validity of Danish national registers.
Variables of interest were expressed as mean (SD) or frequency percentage.
Differences between groups were tested using analysis of variance or the Kendall 
B test for trend or  2 analysis. The simultaneous contributions
of several factors to the risk of IHD were analyzed using multiple logistic
regression models and the maximum likelihood ratio method. All calculations
were performed using statistical software.17, 18
Unless otherwise stated, P.05 was taken as statistically
significant.
The study was approved by The Ethics Committee for Medical Research
in the County of Copenhagen, Denmark.
RESULTS
Lipid and nonlipid characteristics of the 3 groups are summarized in Table 1. During 8-year follow-up, 229 men
had a first IHD event; about a quarter of the events were fatal. In total,
426 men died of all causes. Crude cumulative incidences of IHD were 4.5% in
the low TG–high HDL-C group and 12.2% in the high TG–low HDL-C
group (P<.001). Table 2 shows the characteristics of the men who had a first IHD
event during follow-up compared with those who remained free of IHD.
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Table 1. Characteristics of 2906 Men According to Category of Dyslipidemia*
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Table 2. Characteristics of Men With First Ischemic Heart Disease (IHD)
Event During 8 Years of Follow-up Compared With Men Free of an IHD Event*
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The relative strength of association with risk of IHD of a high TG–low
HDL-C concentration and a low TG–high HDL-C concentration after adjustment
for potentially confounding factors or covariates is shown in Table 3 and Table 4,
respectively. Variables are ordered according to strength of association with
risk after multivariate adjustment in a logistic regression model with backward
elimination of variables. Table 3
shows that a high TG–low HDL-C concentration was entered as the strongest
risk factor of IHD, and Table 4
shows that a low TG–high HDL-C concentration was associated with a significantly
decreased risk of IHD.
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Table 3. Relative Effect of High TG-Low HDL-C and of Other Risk
Factors on Risk of IHD During 8 Years of Follow-up*
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Table 4. Relative Effect of Low TG–High HDL-C and of Other Risk
Factors on Risk of IHD During 8 Years of Follow-up*
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To study the interplay of high TG–low HDL-C and low TG–high
HDL-C concentrations with conventional risk factors of IHD,2, 3
we calculated the crude cumulative incidence in the 3 groups stratified by
LDL-C level (4.40 mmol/L or >4.40 mmol/L [170 mg/dL or >170 mg/dL]
[median value]) (Figure 1), hypertensive
status (blood pressure >150/100 mm Hg or taking antihypertensive medication)
(Figure 2), level of physical activity
(>4 h/wk or 4 h/wk) (Figure 3),
and smoking status (nonsmokers vs smokers) (Figure 4). In all 4 figures, a clear gradient of risk was seen across
the 3 groups within each stratum of conventional risk factors, with an approximately
2 to 3 times higher risk of IHD in the high TG–low HDL-C group compared
with the low TG–high HDL-C group (P<.001).
It is also seen that when a low TG–high HDL-C concentration was present
with conventional risk factors of IHD, risk was approximately 5% or less.
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Figure 1. Incidence of ischemic heart disease
(IHD) according to lipid categories and level of low-density lipoprotein cholesterol
(LDL-C). P value represents statistical significance between
the 2 groups. TG indicates triglycerides; HDL-C, high-density lipoprotein
cholesterol.
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Figure 2. Incidence of ischemic heart disease
(IHD) according to lipid categories and hypertensive status. P
value represents statistical significance between the 2 groups. TG indicates
triglycerides; HDL-C, high-density lipoprotein cholesterol.
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Figure 3. Incidence of ischemic heart disease
(IHD) according to lipid categories and level of physical activity. P value represents statistical significance between the 2 groups. TG
indicates triglycerides; HDL-C, high-density lipoprotein cholesterol.
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Figure 4. Incidence of ischemic heart disease
(IHD) according to lipid categories and smoking status. P value
represents statistical significance between the 2 groups. TG indicates triglycerides;
HDL-C, high-density lipoprotein cholesterol.
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In all 4 figures, IHD incidence for those with the risk factor in question
but with low TG–high HDL-C concentrations was compared with that for
those without the risk factor but with high TG–low HDL-C concentrations,
and it is seen (Figure 1) that those
with a high LDL-C level and a low TG–high HDL-C concentration had a
significantly lower risk of IHD than those with a low LDL-C level and a high
TG–low HDL-C concentration. The same was the case for the other conventional
risk factors, although the difference reached statistical significance with
respect to physical activity only (Figure
3).
Finally, we calculated the attributable risk of IHD associated with
not being in the low TG–high HDL-C group. In a logistic regression analysis
adjusted for the potentially confounding factors or covariates shown in Table 4, the odds ratio associated with
belonging to the intermediate and high TG–low HDL-C groups was 1.7 (95%
confidence interval, 1.02-2.5). Based on the estimated relative risk and information
about how large a proportion of the study population had this increased risk,
approximately 80%, the attributable risk could be calculated to 35% (95% confidence
interval, 2%-55%).
COMMENT
MAIN RESULTS
The major new finding from this study was that men with major classic
risk factors of IHD such as a high LDL-C level, hypertension, low physical
activity, and smoking2, 3 still
had a low risk of IHD if they had low TG–high HDL-C concentrations.
In addition, our results showed that a high TG–low HDL-C concentration
was a stronger risk factor than several major conventional risk factors of
IHD.
BIOLOGICAL PLAUSIBILITY
There seems to be substantial biological support for our finding that
a low TG–high HDL-C concentration is associated with a very low risk
of IHD, whereas a high TG–low HDL-C concentration is a central risk
factor of IHD. We think that our results should be considered with special
reference to the absence or presence of the metabolic syndrome.19, 20, 21
The metabolic syndrome describes the frequent aggregation in a single person
of multiple interrelated abnormalities in glucose and lipid metabolism, including
insulin resistance, glucose intolerance, an atherogenic dyslipidemia, and
hypertension,19, 20, 21
and the metabolic syndrome is believed to play a major role in the pathogenesis
and clinical course of what are often referred to as diseases of Western civilization.21 The characteristic lipid abnormality seen in people
with the metabolic syndrome is a lipid profile with high TG–low HDL-C
levels,19, 20, 21 whereas
a lipid profile with low TG–high HDL-C levels is the characteristic
finding in people without this syndrome.19
The metabolic syndrome with high TG–low HDL-C concentrations has an
effect on LDL particle size, density distribution, and composition, leading
to a smaller and denser LDL particle22, 23
that is more easily oxidized24 and thus much
more atherogenic.25, 26 The metabolic
syndrome with high TG–low HDL-C concentrations includes an increased
amount of TG-rich lipoproteins, some of which are very atherogenic, leading
to progression of coronary artery lesions.27, 28
The metabolic syndrome with high TG–low HDL-C concentrations is closely
associated with deficient fibrinolysis through higher levels of plasminogen
activator inhibitor-121, 29 and
is closely associated with hyperinsulinemia and hyperglycemia, 2 other changes
known to be important risk factors of IHD.30, 31
Thus, it is clear that when a high TG–low HDL-C concentration is present,
several other important, well-established risk factors of IHD will also frequently
be present to enhance the risk of IHD.20, 21
In contrast, when a low TG–high HDL-C concentration is present, people
will be without this cluster of risk factors and thus tend to have a much
lower risk. A high level of LDL-C is not associated with the metabolic syndrome
per se,32 and when a high LDL-C level is present
with a low TG–high HDL-C level, the LDL particle is larger, more buoyant,22, 33 and less easily oxidized24 and thus much less atherogenic.25
This, together with the absence of the other risk factors in the metabolic
syndrome, might explain why isolated hypercholesterolemia is not necessarily
associated with a high risk of IHD. Thus, in accordance with our findings,
in the West of Scotland Coronary Prevention Study,34
middle-aged men with isolated hypercholesterolemia had a 5-year risk of IHD
of only 5.3%, whereas middle-aged men with evidence of the metabolic syndrome
had a 5-year event rate of 14.1%. Finally, the results from 3 other recently
published prospective cardiovascular studies35, 36, 37
also suggest that the metabolic syndrome plays an important role in IHD.
In the CMS, we have no measurements of plasma insulin or glucose, and
simply basing the metabolic syndrome on lipid criteria might not be adequate
for some readers. However, although most readers probably would consider fasting
insulin to be a better surrogate for insulin resistance, in large-scale cohort
studies, carefully conducted metabolic ward studies have found a similar relation
between fasting TG levels and insulin resistance (r
= 0.65) as that between fasting insulin levels and insulin resistance (r = 0.47),22, 38
so we believe it is justified to discuss the metabolic syndrome on the basis
of TG and HDL-C levels, 2 lipid measurements readily available for most physicians,
making our observations easy to apply in clinical medicine. In addition, in
our study population, presence of other risk factors belonging to the metabolic
syndrome,19 such as low physical activity,
higher BMI, higher systolic and diastolic blood pressure, and higher prevalence
of hypertension and type 2 diabetes mellitus, tended to cluster in persons
with high TG–low HDL-C levels, whereas persons with low TG–high
HDL-C levels tended to have a higher level of physical activity, lower BMI,
lower systolic and diastolic blood pressure, and lower prevalence of hypertension
and type 2 diabetes mellitus (Table 1); so by focusing on high TG–low HDL-C and low TG–high HDL-C concentrations,
it was possible to identify persons who seemed to have or not have the metabolic
syndrome, respectively.
PUBLIC HEALTH IMPLICATIONS
Our results suggest that measurement of TG and HDL-C levels should always
be included in screening tests, and professionals working in preventive medicine
should have the metabolic syndrome in mind, not just high cholesterol. Our
results also underscore the importance of not having the metabolic syndrome
at the population level. Based on our point estimate of attributable risk,
35% of the IHD events in our study population might have been prevented if
all of the 2906 men had had low TG–high HDL-C levels. In this context,
the corresponding estimate of attributable risk for not being in the lowest
fifth of LDL-C levels (3.6 mmol/L [139 mg/dL]) was 18%. So, only 18%
of the IHD events in our study population would be expected to be prevented
if all of the 2906 men had had LDL-C levels of 3.6 mmol/L or less (139
mg/dL).
CLINICAL IMPLICATIONS
Because the presence of a high TG–low HDL-C concentration is associated
with such a high risk of IHD, individuals with this lipid profile should be
encouraged to make lifestyle changes, and even treatment with drugs should
be considered. However, it should be noted that so far no primary prevention
trials have been designed to specifically evaluate treatment strategies in
people with high TG–low HDL-C levels. Lifestyle changes such as weight
loss39 and moderate physical exercise40 will lower TG levels and increase the level of HDL-C,
and it might also be beneficial in a weight-controlling diet to replace saturated
fats by unsaturated fats that in addition to a positive effect on LDL-C levels
also will lower TG levels and increase HDL-C levels.41
Concerning drug treatment, results of post hoc subgroup analyses have suggested
that fibric acid derivatives might be useful in people with high LDL-C levels
and high TG–low HDL-C levels42 and that
statins might be useful in lowering the risk of IHD inpeople with high TG–low
HDL-C levels.34, 43 In addition,
our results suggest that persons with hypercholesterolemia and low TG–high
HDL-C levels probably do not require drug treatment of hypercholesterolemia
but only dietary advice because their absolute risk of IHD is low, a finding
in accordance with the West of Scotland Coronary Prevention Study,34 and although smokers and hypertensive persons with
low TG–high HDL-C levels have a low risk of IHD, they should be encouraged
to modify their lifestyle by not smoking and controlling their blood pressure
to lower their risk of cancer and stroke.
AUTHOR INFORMATION
Accepted for publication August 15, 2000.
This study received grants from King Christian X's Foundation, The Danish
Medical Research Counsil, The Danish Heart Foundation, and Else and Mogens
Wedell-Wedellsborg Foundation, Copenhagen, Denmark.
From The Copenhagen Male Study, Epidemiological Research Unit, Copenhagen
University Hospital, Bispebjerg (Drs Jeppesen, Hein, Suadicani, and Gyntelberg),
and The Glostrup Population Studies, Department of Internal Medicine C, Glostrup
University Hospital, Glostrup (Dr Hein), Denmark.
Corresponding author and reprints: Jørgen Jeppesen, MD, The
Copenhagen Male Study, Epidemiological Research Unit, Copenhagen University
Hospital, Bispebjerg, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark.
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