Journal of Internal Medicine 1999; 246: 331±340
FRONTIERS IN MEDICINE
The effects of light to moderate drinking on cardiovascular
diseases
1
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2
3
4
5
6
B. FAGRELL , U. DE FAIRE , S. BONDY , M. CRIQUI , M. GAZIANO , M. GRONBAEK , R. JACKSON ,
A. KLATSKY , J. SALONEN & A. G. SHAPER
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From the Department of Medicine, Karolinska Hospital, Stockholm, Sweden; Institute for Clinical Evaluative Sciences, Toronto, Ontario Canada;
Department of Family Preventive Medicine, UCSD, La Jolla, CA, USA; Brigham and Womens Hospital, Boston, MA, USA; Danish Epidemiology
Science Center, Institute of Preventive Medicine, Kommunehospitalet, Copenhagen, Denmark; Department of Community Health, University of Aukland,
NZ; Kaiser Permanente Medical Center, Oakland, CA, USA; University of Kuopio, Kuopio, Finland; and Royal Free and University College Medical
School, London, UK
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4
5
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Keywords: alcohol, cardiovascular diseases.
Introduction
Alcohol is used throughout the world and it has
long been known that heavy alcohol consumption is
hazardous to various body organs including the
cardiovascular system. In several countries it is also
a major social problem, and alcohol is the second
leading cause of preventable deaths after smoking in
most industrialized countries [1]. However, there is
now also substantial evidence that the intake of light
to moderate amounts of alcohol is associated with
reduced morbidity and mortality from several
cardiovascular conditions, particularly coronary
heart disease (CHD) [2]. The interpretation of these
beneficial effects has been vigorously discussed and
it has been suggested that the effects on cardiovascular disorders might not be due to alcohol per se but
to other so called confounding factors [3]. The topic
has been extensively covered during the last decades
and in 1997, the National Institute of Health
published a huge monograph on alcohol and the
# 1999 Blackwell Science Ltd
cardiovascular system [4]. In order to examine the
scientific evidence relating to the effects of a low to
moderate intake of alcohol a group of experts in the
field gathered in April 1998 in San Diego, California.
The present article summarizes the conclusions
agreed upon at that meeting.
Objectives
It is well established that heavy alcohol consumption exerts deleterious effects on the human body
with increased risk to most organs, but primarily to
the liver, central nervous and cardiovascular systems [5]. However, light to moderate intake of
alcohol does not seem to have these untoward effects
and the evidence now suggests that individuals
consuming up to and including 2 drinks per day
have a reduced risk of some major cardiovascular
events [6±9]. However, it is still under debate
whether this `protective' effect is due to alcohol per
se or is in some way, or to some extent, due to the
331
332
B . F A G R E L L et al.
characteristics of those who drink lightly or moderately.
The purpose of the present workshop was to
review the scientific data accumulated on alcohol
consumption and cardiovascular effects and to try to
evaluate whether alcohol in itself could be responsible for the beneficial effects noted in those
individuals consuming low to moderate amounts.
Definitions
disregard these findings and focus on the effects of
light or moderate drinking as defined above.
The epidemiological evidence
Several factors have to be taken into consideration
when the results of the different epidemiological
studies on the effect of alcohol on cardiovascular
events are evaluated. Some of the more important
factors are discussed here.
Factors influencing the results
Amount of alcohol
It was decided to look in particular at data for low to
moderate drinkers, which was defined as individuals
consuming 1±2 (3) drinks/day (<10±20 (30) g of
ethanol), and not to discuss the effects of heavier
drinking (Fig. 1).
The definition of a `drink' varies considerably from
country to country, but it is usually agreed to be a
can/glass of beer (250±350 cc), a glass of wine
(150 cc) or a tot/measure (30±50 cc) of spirits.
Thus, a `drink' may contain anywhere between 10
and 15 g of alcohol and it is important that all
alcohol studies should be explicit about the methods
used to estimate intake in grams of alcohol per unit
time (day, week, months).
The group is aware that several studies have
shown that three drinks/per day or more may also
be associated with beneficial effects [2, 10, 11], for
example a reduction in risk of CHD events [12, 13],
but the risk of multiple adverse effects are increased
at this level of intake. It was therefore decided to
Fig. 1 Risk reduction from low to moderate intake of alcohol ± the
`J-curve'. In the present document we will only discuss the effect
of 1±2 units of alcohol per day on different cardiovascular events,
and disregard effects of larger quantities.
Reference group. It is essential to choose an
appropriate reference (baseline) group. In most
earlier studies, and even in some recent reports,
the nondrinkers forming the reference group includes ex-drinkers [9, 10], a group which may
include people of increased risk of major cardiovascular events and total mortality compared with
regular light or moderate drinkers, and their risks
may even exceed those of heavy drinkers [11]. The
use of a reference group containing a significant
proportion of ex-drinkers will considerably exaggerate the apparent benefits of light or moderate
drinking. However, in most of the recent studies the
ex-drinkers are analysed separately [2, 12, 13].
Life long teetotallers would appear to be a more
appropriate group, but their proportion in any study
sample varies considerably and is often very small.
For this reason, and because life long teetotallers in
some studies have shown increased risk of total
mortality [12, 14], it has been proposed that the
large and relatively stable group of occasional, i.e.
nonregular drinkers, could be used as the reference
group [11]. However, the use of life long teetotallers
or occasional drinkers would appear to provide the
most appropriate, and least biased reference category.
Changes in drinking habits (Table 1). Available
data show that there is a continuing tendency for
alcohol intake to be reduced with increasing age
[15]. In particular heavy and moderate drinkers
show the largest reductions in intake over time,
moving towards lighter drinking and nondrinking.
This process is affected to a considerable extent by
the accumulation of ill health and regular medication. This has to be taken into account when
subjects are followed up for prolonged periods but
# 1999 Blackwell Science Ltd Journal of Internal Medicine 246: 331±340
FRONTIERS IN MEDICINE: DRINKING AND CARDIOVASCULAR DISEASES
333
Table 1 Change in alcohol intake over time
Intake 12±14 years later
Number of subjects at screening
Intake at screening (%)
None (%)
Occasional (%)
Light (%)
Moderate (%)
Heavy (%)
306
1378
1929
1381
564
None (6)
Occasional (25)
Light (35)
Moderate (25)
Heavy (10)
79
30
9
7
4
14
45
23
14
7
5
23
57
48
29
2
1
10
26
40
0
0.4
0.8
4
20
Alcohol intake at screening and 12±14 years later in 5549 middle-aged British men. The table illustrates changes in drinking habits during
the observation period [16].
are classified by their alcohol intake at one
particular point in time. The trend towards reduction of intake or giving up drinking is associated
with higher rates of new diagnoses than in those
remaining stable in their alcohol intake, and also
with higher rates of both cardiovascular and
noncardiovascular mortality [16]. Thus the increased cardiovascular risk and other mortality in
exdrinkers, and those who have considerably
reduced their alcohol intake, may be explained by
the reasons for their having given up drinking.
Most prospective studies in cardiovascular disease
start in middle age, with subjects aged 40±60 years
or more, by which time many will have passed
through their period of heavy drinking in their
earlier decades. Consequently, many individuals
may have reduced their intake or given up drinking,
often for health reasons, but not necessarily for
alcohol-related illness. The use of nondrinkers as a
baseline, and the failure or inability to adequately
take into account the characteristics of subjects in
the different alcohol intake categories, may exaggerate the risk of cardiovascular events and all cause
mortality in nondrinkers and the benefits of light
drinking. Only a very small group of subjects
increased their alcohol intake with age, but this is
unlikely to affect the interpretations of relative risks
made in this report.
Confounding factors. It has been argued that the
effects of light/moderate alcohol intake on the
cardiovascular system are not entirely due to the
direct effects of alcohol, but are at least in part due to
confounding factors associated with alcohol consumption, e.g. social class, smoking, physical
activity, personality type. As exemplified in the
Copenhagen City Heart Study (Table 2) there are
differences in various life style characteristics and
cardiovascular risk factors with relation to the
amount of alcohol consumed. This is particularly
apparent in the extreme groups of nondrinkers and
excessive consumers [17]. In many studies in recent
years attempts have been made to adjust for these
factors, or to take them into account by stratification
[9, 11, 17±21]. In the present overview, we have
tried to keep this consideration in mind and to build
our statements mainly on those studies which
include adjustments for these factors in their
analyses. However, few studies provide information
on the characteristics of the subjects in the alcohol
intake categories used. This makes it difficult to
assess the likelihood of these associated characteristics having affected the outcome of the analysis.
Thus, when it is seen that both exdrinkers and
lifelong teetotallers have characteristics which are
likely to increase their risk of cardiovascular events
or total mortality in comparison with light regular
drinkers, then the ability of statistical analysis to
adequately take account of the differences between
alcohol intake groups could be difficult. Such
differences in characteristics between nondrinkers
and light to moderate drinkers might contribute to
an enhanced difference in cardiovascular risks
between the two groups. However, when such
confounding factors have been specifically adjusted
for in the analyses, it has not resulted in a marked
reduction in or elimination of benefits found from
low to moderate alcohol intake on CHD risk
[9, 11, 17±21].
Other inherent problems. Several other problems
also have to be taken into account when the effects
of alcohol on humans are considered. Some of these
are listed here:
# 1999 Blackwell Science Ltd Journal of Internal Medicine 246: 331±340
334
B . F A G R E L L et al.
Table 2 Distribution of potential confounders in the Copenhagen City Heart Study
Alcohol intake in drinks per week
0
1±6
7±13
14±27
28±41
42±69
>69
Amongst 6.051 men
Age
Smoking
Body mass index
Physical activity, leisure
Physical activity, work
Income
Education
Cholesterol
High density lipoprotein
Blood pressure, systolic
Blood pressure, diastolic
mean, year
% smokers
mean, kg m22
% inactive
% sitting
% lowest
% lowest
mean, mmol L21
mean, mol L21
mean, mmHg
mean, mmHg
55.5
63.3
25.9
26.2
31.4
35.0
59.5
5.97
1.16
140
86
54.4
66.8
25.8
17.5
30.6
21.0
48.8
6.02
1.17
139
84
53.4
68.2
25.7
16.9
31.5
17.9
44.2
6.00
1.27
140
86
54.3
72.4
25.8
19.4
28.6
19.2
48.3
6.04
1.34
140
86
51.7
76.6
26.3
21.7
22.7
16.8
50.6
5.96
1.41
143
89
52.6
79.2
26.9
27.8
18.2
20.5
54.7
5.95
1.43
143
90
49.8
85.9
26.7
34.2
14.7
27.1
54.4
5.92
1.43
140
91
Amongst 7.234 women
Age
Smoking
Body mass index
Physical activty, leisure
Physical activity, work
Income
Education
Cholesterol
High density lipoprotein
Blood pressure, systolic
Blood pressure, diastolic
mean, year
% yes
mean, kg m22
% of inactive
% of sitting
% of low
% of low
mean, mmol L21
mean, mol L21
mean, mmHg
mean, mmHg
56.5
52.7
25.5
25.7
23.2
46.4
65.5
6.48
1.53
139
83
51.7
59.5
24.6
15.7
25.9
25.5
46.1
6.23
1.60
134
82
52.6
59.6
24.1
17.1
29.6
23.5
36.0
6.25
1.62
135
84
51.4
67.6
23.8
20.11
31.2
23.2
37.6
6.17
1.79
138
83
51.1
69.9
23.9
34.3
26.5
26.1
34.3
6.42
1.95
133
82
51.6
77.4
24.5
38.7
48.2
24.1
58.1
6.07
1.59
135
83
44.2
94.4
26.4
38.9
46.7
55.6
27.8
5.97
1.38
134
85
Mean age, body mass index, cholesterol, high density lipoprotein and blood pressure by alcohol intake group. Smoking is percentage
current smokers by alcohol intake group. Physical activity is percentage inactive by alcohol intake group. Income is percentage low income
level by alcohol intake group. Education is percentage low educational level by alcohol intake group.
Because neither drinkers, nor nondrinkers, are
likely to agree to being randomised to drinking or
abstinence for periods of years, and because of a
variety of other problems (social, ethical and
logistic), it is highly unlikely that any interventional
study on the long-term effects of alcohol consumption will ever be seriously contemplated, let alone
undertaken. We therefore have to rely on information from well designed prospective epidemiological
observational studies in representative populations.
It has been postulated that inaccurate data on
alcohol use will be given by some individuals, and
most probably there will be an underestimation,
especially in heavy drinkers. However, as we in this
paper are only dealing with light to moderate
drinkers this will most probably not influence the
conclusions drawn [21±23].
The drinking process is very dynamic and, as has
been stated earlier, there is a change in alcohol
intake (or stated alcohol intake) over time (Table 1),
and this needs to be kept in mind when evaluating
the results of different studies [15, 16]. The majority
of heavy and moderate drinkers will reduce their
intake when growing older. There are also occasional drinkers who will become nondrinkers, and
many light drinkers will reduce the intake to
occasional or nondrinkers. Very few individuals will
increase their intake of alcohol during the years in
the age groups we are dealing with here. Consequently, the changes in drinking habits with time
would most probably increase the apparent strength
of a protective association between lighter drinking
and a reduction in cardiovascular events.
Another problem is the lack of standardization of
the amount of type of alcohol consumed Fortunately, however, a standard `unit' of beer, wine and
distilled spirits contains approximately the same
amount of alcohol (10±15 g) [24].
The diagnoses of different cardiovascular disorders
can sometimes be rather difficult. The symptoms of
# 1999 Blackwell Science Ltd Journal of Internal Medicine 246: 331±340
FRONTIERS IN MEDICINE: DRINKING AND CARDIOVASCULAR DISEASES
angina pectoris for example, are subjective, and to
reach a diagnosis with accuracy is time consuming
and often requires expensive investigations. In
addition, many studies have combined all cardiovascular conditions to obtain sufficiently large
numbers in the different groups. This might result
in a cancellation of positive or negative associations.
Heavy drinking has clear harmful effects on the
cardiovascular system which is not the case with
light to moderate drinking [4, 5, 24].
Alcohol and cardiovascular diseases
Mortality. Almost all large-scale studies consistently show that lighter drinkers far better than
nondrinkers, and that heavy drinkers are subjected
to more cardiovascular deaths than lighter drinkers
[2±10]. This is the well-known J-shaped curve
[21, 24]. Some of the `cardiovascular' deaths related
to heavy drinkers are most probably not due to
atherosclerotic coronary disease, but to other
causes, e.g. cardiomyopathy, hypertension or haemorrhagic stroke [23, 25]. This fact has certainly
influenced the difference between light and heavy
drinkers found in some studies [24, 26]
In almost all studies performed on adult populations (30±80 years) there is an overall reduction in
cardiovascular deaths from 10 to 50% in individuals
consuming #2 units per day, compared to nondrinkers. The most apparent effects can be seen in
subjects with one or more risk factors for cardiovascular diseases [26, 27].
Coronary heart disease (CHD). There is strong
evidence supporting the hypothesis that small to
moderate amounts of alcohol protects against CHD.
In some of the largest prospective cohort studies
alcohol lowers CHD mortality substantially, usually
compared with nondrinkers [2±8, 10, 11, 17, 24±
28]. The lowest risk seems to be amongst subjects
reporting an average intake of 1±4 drinks daily. This
effect can also be seen in women, and in the Nurses'
Health Study of women consuming 3±9 units per
week there was a 40% reduction of CHD in
comparison to nondrinkers [29, 30].
Stroke. Several epidemiological studies have suggested that light to moderate drinking may be
protective against ischemic stroke and that abstainers are at increased risk [31±35]. However, there
335
may be a risk of overestimating the beneficial effects
because of inaccurate comparison groups in some
studies [32].
Peripheral arterial disease. The role of alcohol in
peripheral vascular disease has received far less
attention than the effects of alcohol on other
cardiovascular diseases. In one study, the odds of
intermittent claudication for a one standard deviation increase in alcohol intake was 1.0, suggesting
that alcohol had no influence on the disease [36].
However, in the Edinburgh Artery Study (Scotland),
a cross sectional analysis of alcohol intake and
relationship with ankle brachial pressure index, a
greater alcohol intake in males was related to a
higher index, i.e. less severe peripheral arterial
disease. In this study the protective effect was more
related to wine consumption than to beer or spirits
[37]. Also in a large study on approximately.
22 000 US male physicians the results showed that
alcohol consumption (regardless of type of alcohol)
decreased the risk of peripheral arterial disease in
apparently healthy men [38].
Sex and age
Sex. Most of the studies have been performed in
men and it can be concluded that the most apparent
beneficial effects of light to moderate drinking are
found in men over the age of 40 years. In the
relatively few studies performed in women on
alcohol consumption and cardiovascular disease
[20, 29±31], it has been found that women who
consume #2 drinks a day also benefit. This is
particularly noted in postmenopausal women over
the age of 50 [30, 31].
Age. There is no hard evidence for a reduction in
cardiovascular mortality in light to moderate
drinkers at an age below 40 years, neither for men
nor for women. However, given the very low
incidence of cardiovascular disease in young people,
it would be very difficult to detect a real protective
effect of alcohol in this population, except in very
large studies. There is also some evidence that there
is a minor increase in the risk of breast cancer in
younger women consuming even small amounts of
alcohol on a regular basis [39, 40].
# 1999 Blackwell Science Ltd Journal of Internal Medicine 246: 331±340
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B . F A G R E L L et al.
Type of alcohol
Based upon ecological studies on the correlation
between wine intake per capita in different countries, and incidence of cardiovascular diseases, it has
been postulated that wine has a more beneficial
effect than beer or spirits. St Leger et al. [41],
Renaud et al. [6], and later Criqui et al. [18] found
inverse relations between incidence rates of cardiovascular disease and wine consumption in different
countries, but no such relation for the other types of
beverages. A number of clinical and experimental
studies support the hypothesis that there may be
additional beneficial factors present in wine, but not
in beer and spirits [41±47]. Several prospective
cohort studies of the effects of alcohol on cardiovascular disease morbidity and mortality have addressed the question of different effects of the
different beverages types. The conclusions have
been diverse, but some studies specifically addressing
this question, including studies able to distinguish
between the effects of the different types of alcohol
and beverages, have concluded that there may be an
additional beneficial effect of wine [17, 44±47]. In
one study it was concluded that beer drinking men
and wine drinking women were at a lower risk of
hospitalization than others [45]. However, Rimm
et al. concluded that since an even number of studies
found beer, wine, and spirits to be equally protective,
the differences may be due to specific cohort effects,
and that ethanol in itself could be responsible for the
reduced risk of CHD [7]. A large part, but not all, of
the greater benefit for CHD and total mortality seen
in wine drinkers can be attributed to their advantageous life style characteristics, suggesting that these
factors are largely responsible for the apparent
benefits of being a wine drinker [46, 47]. Consequently, in view of the literature available today it
must be concluded that there is no strong evidence
for a better protective effect on cardiovascular events
of wine than of other type of liqueurs, but that
confounding factors such as diet and life-style factors
may play a role [45±47].
Mechanisms
Protective effects. The protective effect of low to
moderate consumption of alcohol on cardiovascular
diseases could mainly be the result of the following
factors:
. Blood lipids: The protective association observed
between moderate alcohol consumption and risk
of CHD is likely to be mediated primarily through
the effects of alcohol on blood lipids [48±50] and
on haemostasis [51±53]. It has furthermore been
estimated that the protective effect could be
explained by the favourable effects of alcohol on
high density lipoprotein cholesterol (HDL) and
particularly its subfractions HDL2 and HDL3
[48, 49]. The effects on HDL may account for
about 50% of the beneficial effect found [50].
The effects of moderate alcohol consumption
are, however, small on other lipids and lipoprotein
levels such as LDL cholesterol, triglycerides, and
lipoprotein(a), although marked effects have been
noted in high consumers (reductions in LDL
cholesterol and Lp(a) and increase of triglycerides)
[48].
. Coagulation system: Moderate alcohol consumption is known to acutely inhibit platelet aggregation, particularly after a fatty meal, and influences
the coagulation system by reducing the circulating level of plasma fibrinogen [51]. There is both
prospective cohort study evidence that platelet
activity influences CHD risk and randomized trial
evidence that aspirin, which like alcohol decreases
the secondary aggregation of platelets, reduces
CHD risk [52]. Moreover, the alcohol induced
increase in fibrinolytic activity is independent of
the lipid effects [53], and it is therefore likely that
the effects on haemostasis partly explain the
protective effect of drinking on CHD risk
[13, 53]. This is also supported by several studies
suggesting that there is also an acute protective
effect of alcohol on the risk of CHD [54±56].
. Antioxidant properties and effects on vascular smooth
muscles: Experimental data imply that moderate
alcohol consumption may induce antioxidant
effects [57], although the exact mechanisms and
its contribution to protection is yet not known.
Alcohol consumption may also affect vascular
smooth muscles and vascular tone by interactions
with nitric oxide. Acute effects of small amounts of
alcohol causes vascular relaxation, whereas higher amounts may induce contraction [58]. Further
research is needed to establish both the complex
mechanisms and the long-term effects on the
vasculature.
. Insulin resistance: Regular intake of low to
moderate amounts of alcohol seems to enhance
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FRONTIERS IN MEDICINE: DRINKING AND CARDIOVASCULAR DISEASES
insulin sensitivity with lower fasting insulin
values and lower estimates of insulin resistance
[59±61].
. Psychological effects: Whether psychological mechanisms may account for part of the beneficial
effects on cardiovascular events is still unclear.
However, it has been proposed that low to
moderate levels of alcohol consumption may
reduce stress, and decrease tension and anxiety
[62, 63]. Also, in elderly people moderate drinking has been reported to stimulate appetite and
improve mood [64].
Adverse effects. The adverse effects of a regular
light to moderate intake of alcohol are modest and
socially related in terms of increased risks for various
traumas, accidents, etc. With regard to biologically
related adverse effects the following should be
mentioned:
. High blood pressure: The blood pressure is not
significantly affected if intake is light to moderate
[65].
. Cancer: There may be a modest increase in
incidence of colorectal cancer [66], and breast
cancer [39, 40, 67].
. Alcohol dependency: There is always a risk of
regular to moderate drinkers becoming alcohol
dependent, but in the age groups we are discussing here (men .40 and women .50 years) this
risk seems to be marginal (,1%) [15, 16]
. Interaction with medication: The risk of interactions
between therapeutic medication and alcohol has
also to be born in mind as a large proportion of
the population most likely to benefit from light
alcohol intake are on regular medication [68].
Our opinion
In consideration of the data presented in this article
it is our opinion that the following can be stated.
. There are specific groups of individuals in whom
the benefits of light to moderate drinking of
alcohol for atherothrombotic cardiovascular diseases appear to outweigh the negative effects of
alcohol. Those most likely to benefit are those at
higher risk of atherothrombotic cardiovascular
diseases, such as middle aged men and postmenopausal women, especially those with cardiovascular risk factors.
. It is yet unknown whether the benefit of different
337
types of alcohol and beverages (beer, wine, and
spirits) is equal in regard to the risk of atherothrombotic cardiovascular diseases.
. In light of the evidence it is not necessary to
advise established light to moderate drinkers at
above average risk for atherothrombotic disease to
abstain from drinking.
. There is concern about the data which suggest
that even low levels (1±2 drinks/day) of alcohol
intake are associated with increased risk of breast
cancer and injuries
Caveats
There is still uncertainty about the magnitude of the
association between light-to-moderate drinking and
the overall benefits because of study limitations and
methodological difficulties. These difficulties arise
from: (i) the unresolved issue of which alcohol
intake category is the most appropriate to use as a
baseline, i.e. nondrinkers in general, lifelong teetotallers or occasional drinkers; (ii) the problem of
adequately taking into account the characteristics of
subjects in the various alcohol intake categories; (iii)
the failure to take into account the changing nature
of alcohol intake over time; and (iv) the problems
with adjustments for the confounding influence of
ill-defined life style factors and psychosocial factors.
However, where control for some social factors
has been included in the analysis, this has not
resulted in an elimination, nor a marked reduction,
of apparent benefit of alcohol intake and CHD
[61, 62].
Preventive implications
Based on the data available today we think that the
following statements can be made.
. There are no scientific reasons to propose general
recommendations to increase alcohol consumption in the population.
. Recommendations to individuals on alcohol consumption should be based on the balance of risks
and benefits to that particular individual.
. All heavy drinkers should be encouraged to
reduce their consumption.
. Most light to moderate drinkers need no specific
advice.
. Nondrinkers should not generally be encouraged
to start drinking.
# 1999 Blackwell Science Ltd Journal of Internal Medicine 246: 331±340
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B . F A G R E L L et al.
. There is no overall evidence that there is any
difference in protective effects between beer, wine
or spirits on atherothrombotic cardiovascular
events.
Conclusion
In conclusion, although we recognize the benefits
associated with light to moderate drinking in special
groups (especially individuals with risk factors for
atherothrombotic cardiovascular events), the major
preventive measures to be taken in the control of
established atherothrombotic cardiovascular disease
remain the well-known risk factors such as cigarette
smoking, dyslipoproteinemia, physical inactivity and
hypertension.
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Received 15 June 1999; accepted 18 June 1999.
Correspondence: Dr Bengt Fagrell, Department of Medicine,
Karolinska Hospital, s-171 76 Stockholm, Sweden (fax:. + 46±
8-31 82 64; e-mail: [email protected]).
# 1999 Blackwell Science Ltd Journal of Internal Medicine 246: 331±340