Turkish Journal of Endocrinology and Metabolism, (2002) 1 : 1-12
REVIEW
The Turkish Lipid Problem: Low Levels of High
Density Lipoproteins
Robert W. Mahley*
Guy M. Pépin**
Linda L. Mahley**
Thomas P. Bersot***
K. Erhan Palao¤lu****
* Gladstone Institute of Cardiovascular Disease, Departments of Pathology and Medicine, University of California,
San Francisco, CA, United States
** Gladstone Research Laboratory, Koç American Hospital, Istanbul, Turkey
*** Gladstone Institute of Cardiovascular Disease, Department of Medicine, University of California, San Francisco, CA,
United States
**** Lipid Diagnostic Laboratory, Koç American Hospital, Istanbul, Turkey
The unique lipid and li poprotein p rofile of Turks is characterized primarily by very
low plasma levels of high density lipoprotein cholesterol (HDL-C), specifically low
levels of the protective subclasses of HDL, HDL 2 and LpAI. The low HDL-C levels are
associated with a 25–30% elevation of hepatic lipase activity that would be predicted
to lower HDL levels. Low HDL-C levels occur in Turks living in Germany and the
United States, suggesting that the reduced HDL-C levels are at least partly of genetic
origin. Turkish girls and boys exhibit a marked 10–20 mg/dl drop in HDL-C levels
associated with puberty, suggesting that the low HDL-C levels in Turks may reflect
an ethnic difference in hormonal balance.
Data generated in the early 1990s in the original Turkish Heart Study and recently
updated by a study of Turkish men and women living in Istanbul indicate that the
lipid profile and other risk factors for coronary heart disease have not improved in
this decade. Despite their relatively low plasma total cholesterol levels, Turks have
extremely low HDL-C (<40 mg/dl in 70% of men and ~50% of women) resulting in very
high total cholesterol/HDL-C ratios that predict increased coronary heart disease in
other populations. The 2001 National Cholesterol Education Program guidelines
continue to focus on low density lipoprotein cholesterol levels and underestimate the
importance of low HDL-C levels, which undoubtedly are a powerful risk factor in
Turks. We suggest that guidelines for Turkey consider both low density lipoprotein
cholesterol levels and total cholesterol/HDL-C ratio as thresholds for initiating
lifestyle changes or drug treatment for patients with coronary heart disease risk.
Key words:
Coronary heart disease, hypercholesterolemia, high density
lipo proteins, cholesterol metabolism, total cholesterol/HDL-C ratio
Introduction
Correspondence address:
Robert W. Mahley, M.D., Ph.D.
Gladstone Institute of Cardiovascular Disease
P.O. Box 419100
San Francisco, CA 94141-9100
Tel: (1)(415) 826-7500
Fax: (1)(415) 285-5632
email: [email protected]
Coronary heart disease (CHD) and other atherosclerosis-related vascular diseases account for the
majority of deaths in most industrialized and
developing countries. However, the major risk
factors are well known, and most premature CHD
(morbidity and mortality before 65 years of age)
could be prevented if patients at risk were properly
managed.
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The major known risk factors are elevated levels of
low density lipoprotein cholesterol (LDL-C), reduced
levels of high density lipoprotein cholesterol
(HDL-C), cigarette smoking, hypertension, type 2
diabetes mellitus, obesity, and a family history of
premature (men <55 years; women <65 years) CHD
events in a first-degree relative (1). Observational
studies suggest that modifiable risk factors account
for 85% of excess risk for premature CHD (2,3).
When total cholesterol levels are below 160 mg/dl,
CHD risk is markedly reduced even in the presence
of additional risk factors suggesting that morbidity
and mortality from atherosclerotic vascular disease
largely result from hyperlipidemia or dyslipidemia
(4). The major cause of increased atherogenic risk
is hypercholesterolemia, and both genetic disorders
and diets enriched in saturated fat and cholesterol
contribute to the elevated lipid levels characteristic
of patients with premature CHD. There is now
universal acceptance of the cholesterol-diet-CHD
hypothesis (5).
Hypercholesterolemia, especially elevated plasma
LDL-C levels, has been the focus of much attention
because cholesterol levels can be effectively reduced
by drug therapy. In extensive, well-controlled studies
of patients with elevated LDL-C levels, CHD
mortality has been reduced by as much as 30-40%
over a relatively short period (~5 years) (6-8).
There is every reason to believe that far better
results can be achieved with more aggressive lipid
lowering over longer periods of time.
In 2002, we realize that dyslipidemic treatment
guidelines must not be based on absolute values of
LDL-C alone. Management of risk demands that
we also consider the impact of low plasma HDL-C
levels. Clinical trial data demonstrate that high risk
is associated with reduced levels of HDL-C even if
the LDL-C levels are low. Patients with low
HDL-C and so-called normal LDL-C levels benefit
from initiating hypolipidemic drug therapy (9).
Appropriate drug therapy reduced CHD endpoints
in low HDL-C patients by 20-35% (10,11). Since
low HDL-C is present in 40% of patients with CHD
in the United States (12) and is widely prevalent in
Turkey (13), it is obvious that treatment guidelines
should reflect the risk associated with low HDL-C
even if LDL-C levels are considered to be in the
"normal" range.
2
The importance of hypertriglyceridemia as an
independent CHD risk factor may be debatable,
but moderately elevated levels of triglycerides
(typically, 250-500 mg/dl) are often associated
with the atherogenic dyslipidemia that occurs as
part of the metabolic syndrome (1). The metabolic
syndrome is characterized by low HDL-C levels and
lipid-depleted small, dense LDL and is associated
with insulin resistance, obesity, hypertension, and
a hypercoagulable state (14,15). The metabolic
syndrome is common in CHD patients; therefore,
the identification of moderate hypertriglyceridemia,
even if the total cholesterol level is normal, should
trigger a careful evaluation and treatment of this
potentially atherogenic disorder (1). The age-adjusted
prevalence of the metabolic syndrome, as defined
by the National Cholesterol Education Program
(NCEP) (1), is 23.7% in the United States.
Although controlling other CHD risk factors (i.e.,
smoking, hypertension, obesity, and diabetes) is
very important, treatment of dyslipidemia can
markedly reduce CHD risk. In this review we
focus on dyslipidemia and on the unique lipid and
lipoprotein profile in the Turkish population.
The Turkish Lipid Problem
The Turkish population has a unique lipoprotein
profile that would be predicted to be associated
with an increase in CHD risk (13). Several studies
have now confirmed that HDL-C levels in Turks
are among the lowest in the world and are 10-15
mg/dl lower than those in western European or
U.S. populations (13, 16-20). Low HDL-C levels
are proatherogenic and are associated with a high
incidence of CHD (21-25).
The Turkish Heart Study:
The Turkish Heart
Study, which began in 1990, has evaluated plasma
lipids and lipoproteins in Turks in various regions
of Turkey (13), Germany (26), and the U.S. (27,
28). In the initial population survey conducted in
1990-1993, Turks in six regions of Turkey were
found to have relatively low total cholesterol
(~160-190 mg/dl) and LDL-C (~100-130 mg/dl)
levels (13), in agreement with results from other
studies (18,29). The variability in plasma total
cholesterol and LDL-C levels correlated primarily
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with the predominant type of fat being consumed
in the various regions. The lowest total cholesterol
levels were seen in individuals living in and
around Ayval›k, where olive oil, which is rich in
the cholesterol-lowering monounsaturated fats, is
widely consumed. Cholesterol levels were higher in
the regions where meat and dairy products, which
are rich in saturated fats, are widely consumed.
Interestingly, the more affluent men and women
had the highest total cholesterol and LDL-C levels,
which were associated with the higher consumption
of saturated fats (13). The highest cholesterol
levels were likewise seen in urban populations, as
opposed to rural populations. Importantly, Istanbul
men and women had mean cholesterol levels
similar to those seen in high-risk western populations.
On the other hand, HDL-C levels were low in all
regions of the country, were not significantly affected
by the dietary differences, and did not correlate with
affluence or socioeconomic status (SES) (13). The
HDL-C levels were extremely low (mean, 36 mg/dl
in men and 42 mg/dl in women) by comparison
with other populations and were not explained by
any metabolic or environmental factors, suggesting
a genetic origin.
Istanbul Participants — Original and Updated
Turkish Heart Study: We have continued to
monitor the plasma lipids and lipoproteins of the
high-risk Istanbul men and women. Table 1
summarizes the data from the original study
(1990-1993) (13) and a recent updated study (30).
In the Istanbul men, the average total cholesterol
and LDL-C levels were similar in both studies
(~200 and 130 mg/dl, respectively). The HDL-C
levels were also essentially identical in both
studies (36-38 mg/dl), and the total cholesterol/
HDL-C ratio reflected high risk (~5.5). The recent
data suggested a trend toward higher fasting
triglyceride levels in the men. The Istanbul women
appeared to have a similar trend toward slightly
higher total cholesterol and LDL-C levels in the
recent survey (Table 1). The mean HDL-C levels
for the women were ~46 mg/dl in the original
study and 42 mg/dl in the recent study. The total
cholesterol/HDL-C ratio in the original survey was
3.9; now it is 4.8, which reflects the lower HDL-C
levels in the Istanbul women.
The effects of age and body mass index (BMI) on
lipid values in the Istanbul men and women in both
studies are shown in Table 1. Total cholesterol and
LDL-C levels increased markedly with age, but
HDL-C levels were unchanged. A high BMI has
negative effects on plasma lipids, and recent data
demonstrate that increasing BMI is a problem both
in the United States (31) and in Turkey (32). In the
updated Turkish Heart Study, 66% of the men and
49% of the women were overweight (BMI >25
kg/m 2 ). In the United States, more than 50% of the
population is overweight, and 20% of the men and
25% of the women are obese (BMI >30 kg/m2 )
(31). Onat et al. (32) reported a similar prevalence
of obesity in Turkish men (~19%), but found an
alarmingly high prevalence of obesity in Turkish
women (~39%). An elevated BMI has many
detrimental effects on health, but especially an
increased risk of CHD (33-36). As BMI increased in
the Turkish men and women (Table 1), total cholesterol,
LDL-C, and triglyceride levels increased markedly,
whereas HDL-C levels decreased. Remarkably, the
total cholesterol/HDL-C ratio in the most recent
data rose from 5.4 in men with normal BMI to 6.8
in obese men and from 4.2 in women with normal
BMI to 5.8 in obese women. Thus, in the low
HDL-C Turkish population, BMI appears to have a
major effect on risk, suggesting that overweight and
obesity should be considered as CHD risk factors.
Table 2 illustrates the extent of low HDL-C and
elevated total cholesterol/HDL-C ratio in the Turkish
population. Low HDL-C levels were previously
defined as <35 mg/dl; more recently, low HDL-C
levels have been defined as <40 mg/dl (1). In the
update study of the Istanbul population, 53% of
men and 20% of women had HDL-C levels <35
mg/dl. In comparison, only about 15% of U.S. men
and 5% of U.S. women have such low HDL-C
levels. The impact of changing the definition of
low HDL-C to <40 mg/dl is astounding (1). Under
the new U.S. guidelines, 77% of Turkish men and
48% of Turkish women living in Istanbul have low
HDL-C levels. Analysis of the original Turkish
Heart Study data revealed very similar data for
Turks throughout the country (74% of the men and
53% of the women had HDL-C levels <40 mg/dl).
Because of their very low HDL-C levels, Turks
tend to have very high total cholesterol/HDL-C
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Table 1. Plasma lipids and lipoproteins in the original and updated Turkish Heart Study (THS): Effects of age and BMIa
n
M
F
All ages
2119
527
20–40 years
1210
Total Cholesterol
LDL-C
HDL-C
(mg/dl)
(mg/dl)
(mg/dl)
M
Triglycerides Total Cholesterol/
(mg/dl)
F
M
F
M
F
201 ± 45
173 ± 40
136 ± 40
111 ± 36
38.3 ± 8.0
45.5 ± 9.3
439
189 ± 44
165 ± 33
127 ± 39
105 ± 31
38.0 ± 7.6
909
88
216 ± 41
210 ± 47
148 ± 37
142 ± 42
All ages
196
209
197 ± 46
191 ± 50
126 ± 38
20–40 years
102
116
186 ± 44
169 ± 39
94
93
209 ± 46
BMI <25 kg/m2 912
356
25–29 kg/m 2
912
>30 kg/m2
M
BMI
(kg/m 2 )
HDL-C Ratio
F
M
F
M
F
131 ± 81
84 ± 61
5.4
3.9 25.6 ± 3.3
23.7 ± 4.0
45.5 ± 9.3
119 ± 74
76 ± 55
5.2
3.8 24.9 ± 3.1
23.3 ± 3.7
38.7 ± 8.5
45.5 ± 9.3
146 ± 86 121 ± 75
5.8
4.8 26.5 ± 3.2
25.8 ± 4.5
127 ± 42
35.8 ± 7.9
41.7 ± 8.7 174 ± 106 118 ± 68
5.7
4.8 26.4 ± 3.6
25.7 ± 5.1
120 ± 37
109 ± 32
36.1 ± 8.2
42.4 ± 8.3 152 ± 91
92 ± 51
5.4
4.1 25.8 ± 3.1
23.6 ± 4.4
219 ± 49
133 ± 38
148 ± 43
35.5 ± 7.5
40.8 ± 9.1 197 ± 115 150 ± 74
6.1
5.6 27.2 ± 4.0
28.5 ± 4.6
189 ± 42
167 ± 38
128 ± 38
106 ± 35
39.6 ± 8.3
46.6 ± 9.5 108 ± 64
71 ± 36
5.0
3.7 22.9 ± 1.6
21.7 ± 2.0
121
208 ± 44
183 ± 40
141 ± 40
119 ± 36
37.4 ± 7.7
43.4 ± 8.9 145 ± 83 108 ± 95
5.7
4.4 27.0 ± 1.3
26.8 ± 1.3
170
38
215 ± 46
184 ± 40
146 ± 40
124 ± 28
35.8 ± 6.4
41.4 ± 7.4 166 ± 109 111 ± 54
6.2
4.6 32.5 ± 2.6
33.1 ± 3.6
BMI <25 kg/m2 68
106
193 ± 51
174 ± 47
127 ± 42
114 ± 39
37.3 ± 8.1
43.7 ± 9.0 151 ± 102
89 ± 50
5.4
4.2 22.9 ± 1.9
21.7 ± 1.9
101
60
192 ± 40
203 ± 49
122 ± 34
135 ± 40
35.2 ± 8.1
40.1 ± 6.3 175 ± 101 140 ± 75
5.7
5.1 27.2 ± 1.3
27.4 ± 1.5
27
42
224 ± 45
214 ± 47
143 ± 35
145 ± 43
34.0 ± 6.0
38.3 ± 8.7 227 ± 117 158 ± 69
6.8
5.8 32.7 ± 2.6
33.5 ± 3.4
Original THS
>40 years
Update THS
>40 years
Original THS
Update THS
25–29 kg/m 2
>30 kg/m2
aValues for lipid levels and BMI are mean ± SD.
Table 2. Percentage of participants in the Updated Turkish Heart Study
with different levels of HDL-C and total cholesterol/HDL-C
ratio
HDL-C (mg/dl)
<30
<40
<4.5
4.5–5.9
≥6.0
16% 53% 77%
28%
34%
39%
Women (n = 209) 3% 20% 48%
53%
28%
19%
Men (n = 196)
<35
Total Cholesterol/HDL-C Ratio
ratios. Framingham data (37,38) indicate that a
ratio <3.5 is ideal and that CHD risk increased at a
ratio >4.5. PROCAM data demonstrate that CHD
risk increased significantly at a ratio >5.0 (24). Only
about 25% of the Istanbul men and 50% of the
Istanbul women have ratios <4.5 (Table 2). Moreover,
39% of Istanbul men and 19% of Istanbul women
have a ratio ≥6.0, which clearly indicates a high
risk of CHD. Data from the Turkish population
(n = ~9000) from the original study are quite similar.
Mechanism Responsible for Low HDL-C in the
Turkish Population: The possibility that the low
HDL-C levels in Turks reflect underlying genetic
4
factors is suggested by the observation that HDL-C
levels were low in all regions of Turkey despite
very different dietary habits (13). Furthermore,
low HDL-C levels were observed in Turks living
in Germany, some of whom had been living in
Germany for many years (Table 3) (26). The most
compelling data come from studies of Turks living
in San Francisco, California, who also had low
HDL-C levels (27) (Table 3). In addition, wives of
Turkish men living in San Francisco, who were of
western European ancestry, did not have low
HDL-C, but had values typical of other U.S. women.
Evaluation of common environmental factors did
not explain the 10-15 mg/dl lower HDL-C levels
seen in the Turks (13,27,28). Nevertheless, it is well
known that various factors, such as smoking, lack
of physical activity, obesity, and diets that elevate
triglyceride levels, can lower HDL-C levels (1,25).
All these factors are prominent in Turkey and could
be acting in concert to exacerbate the genetically
determined low HDL-C problem.
Elevated plasma triglyceride levels are associated
with low HDL-C levels (21). This inverse relationship
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Table 3. Mean HDL-C levels (mg/dl)
Americans
in U.S.A
Germans
in Germany
Turks
in Turkey
Turks
in Germany
Turks
in San Francisco
Men
47
47
37
38
37
Women
56
60
43
45
46
between triglyceride and HDL-C levels is also
present in the Turkish population; however, the
low HDL-C levels in Turks are not explained by
elevated triglyceride levels. For example, Danish
men in the Copenhagen Male Study (39) who had
triglyceride levels <100 mg/dl had mean HDL-C
levels of 61 mg/dl whereas Turkish men from the
Turkish Heart Study (13,27,28) and the Turkish Adult
Risk Factor Study (40) with the same triglyceride
levels had HDL-C levels of 40-41 mg/dl. Similarly,
triglyceride levels of 100-139 mg/dl in Turks and
Danes are associated with HDL-C levels of 37-38
mg/dl and 52 mg/dl, respectively. Furthermore,
Framingham data describing the relationship between
triglyceride and HDL-C in U.S. men and women
(21) demonstrate that Turks have HDL-C levels that
are typically 10-15 mg/dl lower over a triglyceride
range of 50-200 mg/dl.
Metabolism of HDL: Epidemiological and clinical
studies have demonstrated that higher levels of
HDL-C are protective against atherosclerotic vascular
disease, whereas low HDL-C levels represent a
powerful risk factor (21-25,41). HDL participate in
a process known as reverse cholesterol transport in
which HDL transport excess cholesterol from cells,
including cholesterol-loaded macrophages in the
artery wall, to the liver for excretion from the body.
Various enzymes and transfer proteins acting upon
HDL are involved, and an abnormality at any step
can cause a defect in the process and alter the levels
of HDL and the subclasses of HDL (for review,
see references 41-45).
Pre-β HDL are lipid-poor precursors of mature HDL
particles (Figure 1). As the pre-β HDL acquire free
cholesterol from cells, they are converted to the
small, spherical particles called HDL 3. The free
cholesterol is converted by the enzyme lecithin:
cholesterol acyltransferase to cholesterol esters
that form the core of the HDL particle. As more
free cholesterol is acquired and becomes esterified,
the particles increase in size and are converted to
HDL2 particles. The excess cholesterol esters are
Figure 1. HDL levels in the plasma are controlled by numerous enzymes and transfer proteins that act on the different subclasses of HDL.
CE, cholesterol ester; VLDL, very low density lipoproteins; IDL, intermediate density lipoproteins.
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transferred to very low density lipoproteins (VLDL)
and LDL by the cholesterol ester transfer protein.
The VLDL and LDL are ultimately removed from
the plasma by the liver, and in this indirect way the
excess cholesterol acquired from cells by the HDL
is delivered to lipoproteins taken up by the liver
and is excreted in the bile and eliminated from the
body. As the cholesterol ester transfer protein transfers
cholesterol esters from HDL to VLDL and LDL, it
also transfers triglycerides to the HDL2 particles to
replace the cholesterol esters. The HDL2 particles
are then acted upon by hepatic lipase to hydrolyze
the excess triglycerides and in the process are converted
to HDL3 (Figure 1). The newly regenerated HDL3
can acquire more cholesterol from cells and repeat
the transport cycle.
As discussed, high levels of some factors can
cause low HDL-C levels, whereas low levels of
others can also have this effect (41-44). Examination
of the activities of the various factors controlling
HDL metabolism demonstrated that Turks have
25-30% greater hepatic lipase activity than U.S.
(white American) men and women (27). Increased
hepatic lipase activity lowers HDL-C levels (25,
45,46).
Isolation and characterization of the HDL subclasses
in Turks revealed lower levels of HDL2 , lower
levels of LpAI (a subclass resembling HDL2), and
higher levels of a subclass known as LpAI/AII
than in western European or U.S. populations (28).
These changes would be predicted to be proatherogenic.
Because they are better acceptors of cholesterol,
HDL 2 and LpAI are more protective subclasses
than HDL3 or LpAI/AII (22,47-49). In addition,
particles with apolipoprotein AII, such as LpAI/AII,
are associated with an increased risk of atherosclerosis
(50,51). Thus, low levels of the protective HDL 2
and LpAI subclasses characterize the HDL-C of
Turks associated with elevated hepatic lipase
activity.
The cause of the increased hepatic lipase activity
has not been elucidated. We hypothesized that a
unique promoter polymorphism in the hepatic
lipase gene in Turks might enhance the synthesis
of the enzyme. To date, we have not identified a
polymorphism that could account for the increased
activity. However, testosterone is a major regulator
6
of hepatic lipase (52-54). Hergenç and associates
showed that Turks have lower levels of sex hormone
binding globulin than Germans and hypothesized
that the lower levels of this protein could be
associated with increased levels of free bioactive
testosterone in Turks (20). High levels of free
testosterone could upregulate hepatic lipase activity.
We believe the dynamic balance in levels of
hormones such as androgens, estrogens, leptin, and
insulin may be altered in Turks.
Impact of Puberty, Socioeconomic Status, and
Nutrition on Plasma Cholesterol and HDL-C
Levels in Turks: In western European and U.S.
populations, plasma lipids change markedly with
age and at puberty (55-63). At birth, plasma total
cholesterol and HDL-C levels are low (<100 and
~30 mg/dl, respectively), and there are no gender
differences. By ~8-10 years of age, total cholesterol
and HDL-C levels have increased, typically to
140-160 mg/dl and ~55-60 mg/dl, respectively, in
both males and females. After puberty, total
cholesterol levels continue to increase, more in
males than in females, but HDL-C levels decrease
by 8-10 mg/dl in males (to adult levels of 46-48
mg/dl) and by only ~2 mg/dl in females (to ~56-58
mg/dl).
To determine whether HDL-C levels in Turks are
low from birth to adulthood and to assess the
effects of puberty on HDL-C levels, we recently
studied Turkish newborns and prepubescent school
children (16). Healthy Turkish newborns had
plasma total cholesterol and HDL-C levels very
similar to those in other populations (~60 and ~30
mg/dl, respectively). Likewise, prepubescent Turkish
boys and girls also had cholesterol levels (130-150
mg/dl) and HDL-C levels (50-60 mg/dl) similar to
those in other populations. However, there were
two surprising findings. First, SES significantly
affected plasma lipid and lipoprotein levels in
prepubescent children. Second, after puberty, HDL-C
levels decreased dramatically; and to a much greater
extent than in other populations; to the typical low
levels of adult Turks.
The impact of SES on the plasma lipid and
lipoprotein levels was explained by dietary
differences (16). The plasma cholesterol levels
were ~20 mg/dl higher in upper SES boys and girls
than in lower SES children (Table 4). This difference
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Table 4. Mean plasma lipid levels (mg/dl ± SD): Upper and lower
socioeconomic status (SES) children 8–10 years of age
Total Cholesterol
HDL-C
Boys
Girls
Boys
Girls
Total
138 ± 26
143 ± 26
50 ± 13
49 ± 12
Upper SES
154 ± 20
158 ± 25
58 ± 14
55 ± 12
Lower SES
129 ± 25
134 ± 22
45 ± 10
45 ± 10
was explained by a 10% greater consumption of
fat, primarily animal (saturated) fat, in the diets of
the upper SES children. Diets rich in saturated fat
are known to increase plasma cholesterol levels
(64,65). The HDL-C levels were 10-13 mg/dl lower
in lower SES boys and girls than in upper SES
children (Table 4). This difference was explained
by the higher consumption of carbohydrates by the
lower SES children (~60% versus 50% of total
calories). High-carbohydrate diets are known to
cause low HDL-C levels (61,65-67).
The upper SES children consumed diets very
similar to those of western European and U.S.
children and had virtually identical lipid levels
(total cholesterol, ~155 mg/dl; HDL-C, 55-58 mg/dl)
(Figure 2). After puberty, the HDL-C levels decreased
by ~20 mg/dl in the upper SES boys and by ~13 mg/dl
in the upper SES girls (16). These puberty-associated
decreases in HDL-C are much greater than those in
other populations (Figure 2), suggesting that hormonal
changes at puberty affect HDL metabolism
differently in Turks than in populations with
higher HDL-C levels. SES was associated with
HDL-C differences in prepubescent Turkish children,
but had no effect on HDL-C after puberty or
throughout adulthood in Turkish men and women
(13,16). It remains to be determined if the modulation
of HDL-C at puberty involves androgens, estrogens,
leptin, insulin, or other hormones.
Treatment Guidelines for Turkish Patients
The uniqueness of the Turkish lipid profile raises
the question of whether the NCEP (1) or European
(68) guidelines are appropriate for Turks with low
HDL-C. These guidelines were developed for
populations in which >70% of the individuals have
HDL-C levels >40 mg/dl. However, at least 70%
of the men and 50% of the women in Turkey have
HDL-C levels <40 mg/dl. In our opinion, these
guidelines do not take into account the widespread
Figure 2. Changes in plasma HDL-C levels with age in western European and U.S. populations versus the upper SES Turkish population. A
profound decrease in HDL-C levels in Turkish men and women is observed (see reference 16 for more detail).
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prevalence of low HDL-C or the increased risk
associated with a progressive decrease in HDL-C
levels. Thus guidelines that are unique for populations
with low HDL-C need to be developed.
Since low HDL-C is a powerful risk factor for
CHD (21-25,69) and since low HDL-C is so
widespread in Turks (13,27,28), we must ask what
parameters are most appropriate to guide treatment
of hyperlipidemia in this population. Clearly,
elevated levels of total cholesterol and LDL-C
levels are predictive of increased risk, and lowering
the levels confers great benefit (6-11,70-74). However,
what about the majority of Turkish patients who
have "normal" total cholesterol (<200 mg/dl) and
LDL-C (<130 mg/dl) levels but also may have
extraordinarily low HDL-C levels (<40 mg/dl)?
The typical Turkish man with a total cholesterol of
180 mg/dl would be considered to have an ideal
level, but if he has an HDL-C of 30 mg/dl, is he at
risk of CHD? It is likely that his LDL-C is ~120
mg/dl (a desirable level). The preponderance of
evidence indicates that he is at risk despite a
normal total cholesterol and a normal or low LDL-C.
Data from the Framingham study (37) indicate that
the incidence of CHD is higher in patients with a
total cholesterol <200 mg/dl and an HDL-C <40
mg/dl than in patients with a total cholesterol of
>260 mg/dl and an HDL-C of 50-59 mg/dl (11.2%
versus 9.0%). Individuals with total cholesterol
>260 mg/dl but with HDL-C >60 mg/dl have a
CHD incidence of 3.8%. Thus, we suggest that
both total cholesterol and HDL-C must be taken
into account, especially in patients with low HDL-C
levels. Therefore, the best parameter for monitoring
CHD risk in Turkish patients is likely to be the
total cholesterol/HDL-C ratio. This suggestion is
consistent with results presented by Onat (19). The
Framingham study demonstrated that a total
cholesterol/HDL-C ratio of 5 to 5.5 predicts a 10%
CHD risk and therefore necessitates therapy (37,
38). In the PROCAM study, the incidence of
myocardial infarction over a 10-year period was
10.7% at a ratio >5.0, but was only 3.1% at a ratio
≤5.0 (75). In Turkish patients with low HDL-C, we
would suggest that a total cholesterol/HDL-C ratio
>5 to 7 should be used to indicate increased risk
even if they have a normal LDL-C. If multiple risk
factors are present, treatment should be considered
at even lower ratios.
Simplified Guidelines for Low HDL-C
Populations: As outlined in Table 5 (modified
from reference 30), the risk categories include
CHD or the equivalent (defined as any vascular
disease problem or diabetes), 2+ risk factors, or
0-1 risk factor. The risk factors are defined by the
2001 NCEP guidelines, but in addition we would
include overweight, defined as a BMI >25 kg/m2
and a waist circumference of 102 cm (men) or 88
cm (women) (1). We do not believe that most
physicians will use the Framingham risk tables;
therefore, we do not include the risk calculations.
We suggest that the total cholesterol/HDL-C ratio
be used in concert with LDL-C to determine how
to manage patients with low HDL-C. Because of
their relatively low LDL-C levels, many Turkish
patients simply do not meet the LDL-C criteria for
treatment by the NCEP guidelines. However,
several recent clinical trials have demonstrated that
low HDL-C patients with low or normal LDL-C
benefit from lipid-lowering therapy (10,11,71-76).
CHD or equivalent patients need to have a target
LDL-C <100 mg/dl. The recent Heart Protection
Study suggests that CHD patients with LDL-C
<100 mg/dl at baseline benefited from drug
treatment to the same extent as those with LDL-C
>100 mg/dl at baseline (73,74,77). Therefore, a
target of 100 mg/dl is probably still too high. In
CHD or equivalent patients with very low HDL-C
Table 5. Proposed treatment guidelines based on total cholesterol/HDL-C ratio for low HDL-C populations
Goals
TC/HDL-C
Lifestyle Change Initiated for
Drug Therapy Initiated for
LDL-C
LDL-C
Risk Category
LDL-C
TC/HDL-C
TC/HDL-C
CHD or equivalent
<100
and
<3.5
≥100
or
>3.5
≥100
or
≥3.5
2+ risk factors
<130
and
<4.5
≥130
or
≥4.5–5.9
≥130
or
≥6.0*
0–1 risk factor
<160
and
<5.5
≥160
or
≥5.5–6.9
≥160
or
≥7.0*
aTo decrease the number of individuals requiring drug treatment, these risk categories could be further restricted to men ≥45 years of age and to
women ≥55 years of age. TC, total cholesterol.
8
REVIEW
it is probably important to attain a total cholesterol/
HDL-C ratio <3.5 for maximum benefit.
These simplified treatment guidelines use the same
LDL-C target for initiating treatment as the NCEP,
but also use the total cholesterol/HDL-C ratio to
determine if lifestyle change or drug therapy
should be recommended (Table 5). The initiation
of drug therapy can be further restricted by age
(≥45 years for men; ≥55 years for women). This
restriction limits the number of individuals requiring
drug treatment to the higher-risk age group. These
are suggestions, but as always, clinical judgment
concerning the magnitude of overall risk, as well
as other considerations unique to the individual
patient, will contribute to the therapeutic decision.
Acknowledgments
We are indebted to our associates at the American
Hospital, Istanbul, especially Sibel Tan›r in the
Gladstone Research Laboratory (Istanbul). We
thank Sylvia Richmond and Catharine Evans for
manuscript preparation, Stephen Ordway and Gary
Howard for editorial assistance, and John C.W.
Carroll and Jack Hull for graphics. We acknowledge
the generous support of the American Hospital,
especially Mr. George Rountree, and the J. David
Gladstone Institutes.
References
1. National Cholesterol Education Program Expert Panel.
Executive summary of the third report of the National
Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III). J Am
Med Assoc 285: 2486-2497, 2001.
2. Stamler J, Wentworth D, Neaton JD. Is relationship
between serum cholesterol and risk of premature death
from coronary heart disease continuous and graded?
Findings in 356 222 primary screenees of the Multiple
Risk Factor Intervention Trial (MRFIT). J Am Med Assoc
256: 2823-2828, 1986.
3. Wilson PWF, D’Agostino RB, Levy D, Belanger AM,
Silbershatz H, Kannel WB. Prediction of coronary heart
disease using risk factor categories. Circulation 97:
1837-1847, 1998.
4. Grundy SM, Balady GJ, Criqui MH, Fletcher G,
Greenland P, Hiratzka LF, Houston-Miller N, KrisEtherton P, Krumholz HM, LaRosa J, Ockene IS, Pearson
TA, Reed J, Washington R, Smith SC Jr. Primary
prevention of coronary heart disease: Guidance from
Framingham. A statement for healthcare professionals
from the AHA Task Force on Risk Reduction. Circulatio n
97: 1876-1887, 1998.
5. Thompson GR, Barter PJ. Clinical lipidology at the end
of the millennium. Curr Opin Lipidol 10: 521-526, 1999.
6. Scandinavian Simvastatin Survival Study Group.
Randomised trial of cholesterol lowering in 4444 patients
with coronary heart disease: The Scandinavian Simvastatin
Survival Study (4S). Lancet 344: 1383-1389, 1994.
7. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR,
Macfarlane PW, McKillop JH, Packard CJ. Prevention of
coronary heart disease with pravastatin in men with
hypercholesterolemia. N Engl J Med333: 1301-1307, 1995.
8. The Long-Term Intervention with Pravastatin in Ischaemic
Disease (LIPID) Study Group. Prevention of cardiovascular
events and death with pravastatin in patients with coronary
heart disease and a broad range of initial cholesterol
levels. N Engl J Med 339: 1349-1357, 1998.
9. The Expert Panel. Summary of the second report of the
National Cholesterol Education Program (NCEP) Expert
Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (Adult Treatment Panel II).
J Am Med Assoc269: 3015-3023, 1993.
10. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro
DR, Beere PA, Langendorfer A, Stein EA, Kruyer W,
Gotto AM Jr. Primary prevention of acute coronary
events with lovastatin in men and women with average
cholesterol levels. Results of AFCAPS/TexCAPS. J Am
Med Assoc 279: 1615-1622, 1998.
11. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW,
Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman
G, Wilt TJ, Wittes J. Gemfibrozil for the secondary
prevention of coronary heart disease in men with low
levels of high-density lipoprotein cholesterol. N Engl J
Med 341: 410-418, 1999.
12. Rubins HB, Robins SJ, Collins D, Iranmanesh A, Wilt
TJ, Mann D, Mayo-Smith M, Faas FH, Elam MB, Rutan
GH, Anderson JW, Kashyap ML, Schectman G. Distribution
of lipids in 8,500 men with coronary artery disease. Am J
Cardiol 75: 1196-1201, 1995.
13. Mahley RW, Palao¤lu KE, Atak Z, Dawson-Pepin J,
Langlois A-M, Cheung V, Onat H, Fulks P, Mahley LL,
Vakar F, Özbayrakç› S, Gökdemir O, Winkler W. Turkish
Heart Study: Lipids, lipoproteins, and apolipoproteins.
J Lipid Res 36: 839-859, 1995.
14. Reaven GM. Pathophysiology of insulin resistance in
human disease. Physiol Rev 75: 473-486, 1995.
15. Grundy SM. Hypertriglyceridemia, atherogenic dyslipidemia,
and the metabolic syndrome. Am J Cardiol 81: 18B-25B,
1998.
16. Mahley RW, Arslan P, Pekcan G, Pépin GM, A¤açdiken
A, Karaa¤ao¤lu N, Rak›c›o¤lu N, Nursal B, Dayan›kl› P,
Palao¤lu KE, Bersot TP. Plasma lipids in Turkish children:
Impact of puberty, socioeconomic status, and nutrition on
plasma cholesterol and HDL. J Lipid Res 42: 1996-2006,
2001.
17. Onat A, Büyükbese MA, Ural E, Kelefl I, Ural D, ‹nce E,
Kurban B, Sansoy V. HDL-cholesterol and fibrinogen
9
REVIEW
levels and associations with some risk factors in the
population of the Marmara region (in Turkish). Arch Turk Soc
Cardiol 25: 520-525, 1997.
18. Onat A, Y›ld›r›m B, Uslu N, Gürbüz N, Kelefl I, Çetinkaya
A, Aksu H, Uysal Ö, Sansoy V. Plasma lipoproteins and
apolipoproteins in Turkish adults: Overall levels,
associations with other risk parameters and HDL’s role as
a marker of coronary risk in women (in Turkish). Arch
Turk Soc Cardiol 27: 72-79, 1999.
19. Onat A. Risk factors and cardiovascular disease in
Turkey. Atherosclerosis 156: 1-10, 2001.
20. Hergenç G, Schulte H, Assmann G, von Eckardstein A.
Associations of obesity markers, insulin, and sex
hormones with HDL-cholesterol levels in Turkish and
German individuals. Atherosclerosis 145: 147-156, 1999.
21. Schaefer EJ, Lamon-Fava S, Ordovas JM, Cohn SD,
Schaefer MM, Castelli WP, Wilson PWF. Factors
associated with low and elevated plasma high density
lipoprotein cholesterol and apolipoprotein A-I levels in
the Framingham Offspring Study. J Lipid Res 35: 871882, 1994.
22. Miller NE. Associations of high-density lipoprotein
subclasses and apolipoproteins with ischemic heart
disease and coronary atherosclerosis. Am Heart J 113:
589-597, 1987.
23. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD,
Castelli WP, Knoke JD, Jacobs DR Jr, Bangdiwala S,
Tyroler HA. High-density lipoprotein cholesterol and
cardiovascular disease. Four prospective American
studies. Circulation 79: 8-15, 1989.
24. Assmann G, Schulte H. Relation of high-density
lipoprotein cholesterol and triglycerides to incidence of
atherosclerotic coronary artery disease (the PROCAM
experience). Am J Cardiol 70: 733-737, 1992.
25. Vega GL, Grundy SM. Hypoalphalipoproteinemia (low
high density lipoprotein) as a risk factor for coronary
heart disease. Curr Opin Lipidol 7: 209-216, 1996.
26. Lüttmann S, von Eckardstein A, Wei W, Funke H,
Köhler E, Mahley RW, Assmann G. Electrophoretic
screening for genetic variation in apolipoprotein C-III:
Identification of a novel apoC-III variant, apoC-III
(Asp45→Asn), in a Turkish patient. J Lipid Res 35:
1431-1440, 1994.
27. Bersot TP, Vega GL, Grundy SM, Palao¤lu KE,
Atagündüz P, Özbayrakç› S, Gökdemir O, Mahley RW.
Elevated hepatic lipase activity and low levels of high
density lipoprotein in a normotriglyceridemic, nonobese
Turkish population. J Lipid Res 40: 432-438, 1999.
28. Mahley RW, Pépin J, Palao¤lu KE, Malloy MJ, Kane JP,
Bersot TP. Low levels of high density lipoproteins in
Turks, a population with elevated hepatic lipase: High
density lipoprotein characterization and gender-specific
effects of apolipoprotein E genotype. J Lipid Res 41:
1290-1301, 2000.
29. Onat A, Surdum-Avc› G, fienocak M, Örnek E, Gözükara
Y. Plasma lipids and their interrelationship in Turkish
adults. J Epidemiol Community Health46: 470-476, 1992.
10
30. Mahley RW, Pépin GM,
K. New findings of the
treatment suggestions for
HDL (in Turkish). Arch
2002.
Bersot TP, Palao¤lu KE, Özer
Turkish Heart Study: Guiding
levels of plasma lipids and low
Turk Soc Cardiol 30: 93-103,
31. Mokdad AH, Serdula MK, Dietz WH, Bowman BA,
Marks JS, Koplan JP. The spread of the obesity epidemic
in the United States, 1991-1998. J Am Med Assoc282:
1519-1522, 1999.
32. Onat A, Y›ld›r›m B, Çetinkaya A, Aksu H, Kelefl I, Uslu
N, Gürbüz N, Sansoy V. Indices of obesity and central
obesity in Turkish adults: Distinct rise in obesity in
1990-98 more pronounced among men (in Turkish). Arch
Turk Soc Cardiol 27: 209-217, 1999.
33. Pi-Sunyer FX, Becker DM, Bouchard C, Carleton RA,
Colditz GA, Dietz WH, Foreyt JP, Garrison RJ, Grundy
SM, Hansen BC, Higgins M, Hill JO, Howard BV,
Klesges RC, Kuczmarski RJ, Kumanyika S, Legako RD,
Prewitt TE, Rocchini AP, Smith PL, Snetselaar LG,
Sowers JR, Weintraub M, Williamson DF, Wilson GT.
Clinical Guidelines on the Identification, Evaluation, and
Treatment of Overweight and Obesity in Adults. The
Evidence Report. Bethesda, MD, U.S. Department of
Health and Human Services, Public Health Service,
National Institutes of Health (NIH Publ. No. 98-4083),
1998, 58-59.
34. WHO Consultation on Obesity. Obesity: Preventing and
Managing the Global Epidemic. Geneva, Switzerland,
1998.
35. National Institutes of Health Consensus Development
Panel. Health implications of obesity. National Institutes
of Health Consensus Development Conference Statement.
Ann Intern Med 103: 1073-1077, 1985.
36. Wolf AM, Colditz GA. Social and economic effects of
body weight in the United States. Am J Clin Nutr 63
(Suppl.): 466S-469S, 1996.
37. Castelli WP, Garrison RJ, Wilson PWF, Abbott RD,
Kalousdian S, Kannel WB. Incidence of coronary heart
disease and lipoprotein cholesterol levels. The Framingham
Study. J Am Med Assoc256: 2835-2838, 1986.
38. Castelli WP. The folly of questioning the benefits of
cholesterol reduction. Am Fam Physician 49: 567-574,
1994.
39. Jeppesen J, Hein HO, Suadicani P, Gyntelberg F.
Triglyceride concentration and ischemic heart disease.
An eight-year follow-up in the Copenhagen Male Study.
Circulation 97: 1029-1036, 1998.
40. Onat A, Sansoy V, Yildirim B. Which fasting triglyceride
levels best reflect coronary risk? Evidence from the
Turkish Adult Risk Factor Study. Clin Cardiol 24: 9-14,
2001.
41. Mahley RW, Weisgraber KH, Farese RV Jr. Disorders of
lipid metabolism. In Williams Textbook of Endocrinology,
9th Edition (Eds: Wilson JD, Foster DW, Kronenberg
HM, Larsen PR). Philadelphia, W.B. Saunders, 1998,
1099-1153.
42. Mahley RW, Bersot TP. Drug therapy for hypercholesterolemia and dyslipidemia. In Goodman & Gilman’s
REVIEW
The Pharmacological Basis of Therapeutics, 10th Edition
(Eds: Hardman JG, Limbird LE). New York, McGraw-Hill,
2001, 971-1002.
43. Breslow JL. Insights into lipoprotein metabolism from
studies in transgenic mice. Annu Rev Physiol56: 797810, 1994.
44. Tall AR, Jiang X-C, Luo Y, Silver D. 1999 George
Lyman Duff Memorial Lecture. Lipid transfer proteins,
HDL metabolism, and atherogenesis. Arterioscler Thromb
Vasc Biol 20: 1185-1188, 2000.
45. Cohen JC, Wang Z, Grundy SM, Stoesz MR, Guerra R.
Variation at the hepatic lipase and apolipoprotein AI/
CIII/AIV loci is a major cause of genetically determined
variation in plasma HDL cholesterol levels. J Clin Invest
94: 2377-2384, 1994.
56. Hardell LI. Serum lipids and lipoproteins at birth based
on a study of 2815 newborn infants. I. Concentrations
and distributions of triglycerides and cholesterol. Acta
Pædiatr Scand Suppl 285: 5-10, 1981.
57. Viikari J, Åkerblom HK, Nikkari T, Seppänen A, Uhari
M, Pesonen E, Dahl M, Lähde P-L, Pietikäinen M,
Suoninen P. Atherosclerosis precursors in Finnish
children and adolescents. IV. Serum lipids in newborns,
children and adolescents. Acta Pædiatr Scand Suppl 318:
103-109, 1985.
58. Loughrey CM, Rimm E, Heiss G, Rifai N. Race and
gender differences in cord blood lipoproteins. Atherosclerosis 148: 57-65, 2000.
46. Schaefer EJ. Clinical, biochemical, and genetic features
in familial disorders of high density lipoprotein deficiency.
Arteriosclerosis 4: 303-322, 1984.
59. Webber LS, Osganian V, Luepker RV, Feldman HA,
Stone EJ, Elder JP, Perry CL, Nader PR, Parcel GS,
Broyles SL, McKinlay SM. Cardiovascular risk factors
among third grade children in four regions of the United
States. The CATCH study. Am J Epidemiol 141: 428439, 1995.
47. Luc G, Bard J-M, Poulain P, Arveiler D, Evans AE,
Cambien F, Fruchart J-C, Ducimetière P. Relationship
between low-density lipoprotein size and apolipoprotein
A-I-containing particles: The ECTIM study. Eur J Clin
Invest 27: 242-247, 1997.
60. Dwyer T, Iwane H, Dean K, Odagiri Y, Shimomitsu T,
Blizzard L, Srinivasan S, Nicklas T, Wattigney W, Riley M,
Berenson G. Differences in HDL cholesterol concentrations
in Japanese, American, and Australian children. Circulation
96: 2830-2836, 1997.
48. Parra HJ, Arveiler D, Evans AE, Cambou JP, Amouyel P,
Bingham A, McMaster D, Schaffer P, Douste-Blazy P,
Luc G, Richard JL, Ducimetière P, Fruchart JC, Cambien
F. A case-control study of lipoprotein particles in two
populations at contrasting risk for coronary heart disease.
The ECTIM study. Arterioscler Thromb 12: 701-707, 1992.
49. O’Brien T, Nguyen TT, Hallaway BJ, Hodge D, Bailey
K, Holmes D, Kottke BA. The role of lipoprotein A-I and
lipoprotein A-I/A-II in predicting coronary artery disease.
Arterioscler Thromb Vasc Biol 15: 228-231, 1995.
50. Warden CH, Hedrick CC, Qiao J-H, Castellani LW, Lusis
AJ. Atherosclerosis in transgenic mice overexpressing
apolipoprotein A-II. Science 261: 469-472, 1993.
51. Schultz JR, Verstuyft JG, Gong EL, Nichols AV, Rubin
EM. Protein composition determines the anti-atherogenic
properties of HDL in transgenic mice. Nature 365: 762764, 1993.
52. Boberg J, Boberg M, Gross R, Turner JD, Augustin J,
Brown WV. Hepatic triglyceride and lipoprotein lipase
activities of post-heparin plasma in normals and hypertriglyceridemics. Upsala J Med Sci 84: 215-227, 1979.
53. Kantor MA, Bianchini A, Bernier D, Sady SP, Thompson
PD. Androgens reduce HDL2 -cholesterol and increase
hepatic triglyceride lipase activity. Med Sci Sports Exerc
17: 462-465, 1985.
54. Applebaum-Bowden D, Haffner SM, Hazzard WR. The
dyslipoproteinemia of anabolic steroid therapy: Increase
in hepatic triglyceride lipase precedes the decrease in
high density lipoprotein2 cholesterol. Metabolism 36:
949-952, 1987.
55. Winkler L, Schlag B, Goetze E. Concentration and
composition of the lipoprotein classes in human umbilical
cord serum. Clin Chim Acta 76: 187-191, 1977.
61. Knuiman JT, Hermus RJJ, Hautvast JGAJ. Serum total
and high density lipoprotein (HDL) cholesterol concentrations
in rural and urban boys from 16 countries. Atherosclerosis
36: 529-537, 1980.
62. Freedman DS, Srinivasan SR, Webber LS, Berenson GS.
Divergent levels of high density lipoprotein cholesterol
and apolipoprotein A-I in children. The Bogalusa Heart
Study. Arteriosclerosis 7: 347-353, 1987.
63. Webber LS, Harsha DW, Phillips GT, Srinivasan SR,
Simpson JW, Berenson GS. Cardiovascular risk factors in
Hispanic, white, and black children: The Brooks County
and Bogalusa Heart Studies. Am J Epidemiol 133: 704714, 1991.
64. Keys A, Anderson JT, Grande F. Serum cholesterol
response to changes in the diet. IV. Particular saturated
fatty acids in the diet. Metabolism 14: 776-787, 1965.
65. Mensink RP, Katan MB. Effect of dietary fatty acids on
serum lipids and lipoproteins. A meta-analysis of 27 trials.
Arterioscler Thromb 12: 911-919, 1992.
66. Knuiman JT, West CE, Katan MB, Hautvast JGAJ. Total
cholesterol and high density lipoprotein cholesterol levels
in populations differing in fat and carbohydrate intake.
Arteriosclerosis 7: 612-619, 1987.
67. Mensink RP, Katan MB. Effect of monounsaturated fatty
acids versus complex carbohydrates on high-density
lipoproteins in healthy men and women. Lancet 1: 122125, 1987.
68. Wood D, De Backer G, Faergeman O, Graham I, Mancia
G, Pyörälä K. Prevention of coronary heart disease in
clinical practice. Recommendations of the Second Joint
Task Force of European and other Societies on Coronary
Prevention. Summary of recommendations. Eur Heart J
11
REVIEW
69. Genest JJ, McNamara JR, Salem DN, Schaefer EJ.
Prevalence of risk factors in men with premature coronary
artery disease. Am J Cardiol 67: 1185-1189, 1991.
70. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL,
Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold
JMO, Wun C-C, Davis BR, Braunwald E. The effect of
pravastatin on coronary events after myocardial infarction
in patients with average cholesterol levels. N Engl J Med
335: 1001-1009, 1996.
71. Gotto AM Jr, Whitney E, Stein EA, Shapiro DR,
Clearfield M, Weis S, Jou JY, Langendörfer A, Beere
PA, Watson DJ, Downs JR, de Cani JS. Relation between
baseline and on-treatment lipid parameters and first acute
major coronary events in the Air Force/Texas Coronary
Atherosclerosis Prevention Study (AFCAPS/TexCAPS).
Circulation 101: 477-484, 2000.
72. Gotto AM Jr, Whitney E, Stein EA, Shapiro DR,
Clearfield M, Weis S, Jou JY, Langendörfer A, Beere
PA, Watson DJ, Downs JR, de Cani JS. Application of
the National Cholesterol Education Program and joint
European treatment criteria and clinical benefit in the Air
Force/Texas Coronary Atherosclerosis Prevention Study
(AFCAPS/TexCAPS). Eur Heart J 21: 1627-1633, 2000.
12
73. MRC/BHF Heart Protection Study Collaborative Group.
MRC/BHF Heart Protection Study of cholesterol-lowering
therapy and of antioxidant vitamin supplementation in a
wide range of patients at increased risk of coronary heart
disease death: Early safety and efficacy experience. Eur
Heart J 20: 725-741, 1999.
74. MRC/BHF Heart Protection Study Collaborative Group.
Randomised trial of cholesterol-lowering therapy and of
antioxidant vitamins in 20,536 people at increased risk of
coronary heart disease death. Circulation 104: 2B-3B,
2001 (Abstr).
75. Assmann G. Pro and con: High-density lipoprotein,
triglycerides, and other lipid subfractions are the future of
lipid management. Am J Cardiol 87 (Suppl.): 2B-7B, 2001.
76. Robins SJ, Collins D, Wittes JT, Papademetriou V,
Deedwania PC, Schaefer EJ, McNamara JR, Kashyap
ML, Hershman JM, Wexler LF, Rubins HB. Relation of
gemfibrozil treatment and lipid levels with major
coronary events. VA-HIT: A randomized controlled trial.
J Am Med Assoc285: 1585-1591, 2001.
77. MRC/BHF Heart Protection Study Collaborative Group.
Eligibility: MRC/BHF Heart Protection Study. Available
at: http://www.ctsu.ox.ac.uk/~hps/slides/results/sld002.htm.
Accessed January 16, 2002.