Cardiovascular benefits and risks of moderate alcohol consumption

Authors:
Christine C Tangney, PhD
Robert S Rosenson, MD
Section Editor:
Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC
Deputy Editor:
Daniel J Sullivan, MD, MPH

EFFECT OF ALCOHOL ON CARDIOVASCULAR RISK — Several prospective cohort studies

suggest that light to moderate alcohol consumption decreases the risk of coronary heart
disease (CHD) by 40 to 70 percent, compared with drinking no alcohol or to heavy alcohol
intake [3]. A 2011 meta-analysis of 84 observational studies found that, relative to nondrinkers,
alcohol drinkers had a relative risk (RR) of 0.75 (95% CI 0.70-0.80) for cardiovascular disease
mortality, 0.75 (0.68-0.81) for CHD mortality, and 0.71 (0.66-0.77) for incident CHD [4]. Different
results showing no net benefit on all-cause mortality have also been reported [5].

This protective effect has been found in multiple groups, including individuals without CHD at
baseline [6-8], those with risk factors for CHD [9], and adults over age 65 [10,11].

A population-based cohort study from the United Kingdom followed close to two million adults
≥30 years old who were free from cardiovascular disease [12]. At a median follow-up of six
years, 5.9 percent of these individuals had received a cardiovascular diagnosis. Non-drinking
compared with moderate drinking was associated with an increased risk of unstable angina
(hazard ratio [HR] 1.33, 95% CI 1.21-1.45), myocardial infarction (MI; HR 1.32, 95% CI 1.24-
1.41), coronary death (HR 1.56, 95% CI 1.38-1.76), heart failure (HR 1.24, 95% CI 1.11-1.38),
ischemic stroke (HR 1.12, 95% CI 1.01-1.24), peripheral arterial disease (HR 1.22, 95% CI
1.13-1.32), and abdominal aortic aneurysm (HR 1.32, 95% CI 1.17-1.49). By contrast, heavy
drinking was generally associated with worse cardiovascular outcomes.

Cardiovascular mortality — Most studies have found that moderate alcohol consumption is
associated with a specific reduction in cardiovascular mortality [4,9,11,13-17]. A 2006 meta-
analysis of 34 studies (over one million subjects and 94,000 deaths) found that total mortality
was reduced by 18 percent in women who consumed one drink daily and men who had
one to two drinks daily, compared with nondrinkers [18].

More than two drinks a day in women and three drinks a day in men, however, were
associated with increased mortality. Heavy alcohol consumption (six or more drinks per day)
or binge drinking increases the risk for sudden death [19]. (See "Overview of sudden cardiac
arrest and sudden cardiac death".)

Stroke. 1998 May;29(5):900-7.

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Alcohol consumption and atherosclerosis: what is the
relation? Prospective results from the Bruneck Study.
Kiechl S1, Willeit J, Rungger G, Egger G, Oberhollenzer F, Bonora E.
Author information
Abstract
BACKGROUND AND PURPOSE:
Potential effects of regular alcohol consumption on atherogenesis are still controversial mainly due
to the lack of prospective population-based studies.

METHODS:
The Bruneck Study is a prospective population-based survey of atherosclerosis and its risk factors.
The study population comprises a sex- and age-stratified random sample of men and women aged
40 to 79 years. Participation and follow-up were more than 90% complete. Changes in carotid
atherosclerosis between the 1990 baseline and the first follow-up in 1995 were monitored by high-
resolution duplex ultrasonography. Alcohol intake was quantified with a standardized questionnaire
and prospective diet records.

RESULTS:
Alcohol consumption less than once a week (occasional drinking) had no effect on atherogenesis.
The association between regular alcohol intake and incident carotid atherosclerosis (early
atherogenesis) was J-shaped, with light drinkers facing a lower risk than either heavy drinkers or
abstainers. Protection offered by alcohol consumption of <50 g/d appeared to act through
inhibition of the injurious action of high levels of low-density lipoprotein (LDL) cholesterol.
Excess risk of incident atherosclerosis observed among heavy alcohol consumers (> or =100 g/d)
clearly surpassed the risk burden afforded by heavy smoking. The association between regular
alcohol intake and incident carotid stenosis (advanced atherogenesis) was U-shaped. Odds ratios
were generally shifted toward protection and did not rely on LDL cholesterol levels. We failed to find
any differential effects of alcohol from various sources. All associations remained independently
significant when we adjusted for lifestyle, coincidental smoking, and the metabolic complex
associated with drinking.

CONCLUSIONS:
Our findings support the view that adverse and beneficial effects of alcohol on arterial disease are
mediated in part by a dose-dependent promotion or deceleration of atherogenesis. The protection
afforded by light drinking may possibly be attributed to antithrombotic effects and inhibition of the
atherogenic action of high levels of LDL cholesterol.
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Alcohol Clin Exp Res. 2001 Jul;25(7):1046-50.

Influence of alcohol intake on risk for increased low-

density lipoprotein cholesterol in middle-aged Japanese
men.
Nakanishi N1, Yoshida H, Nakamura K, Kawashimo And H, Tatara K.
Author information
Abstract
BACKGROUND:
Decreased low-density lipoprotein (LDL) cholesterol in chronic alcoholics is well known. However,
the importance of light to moderate alcohol consumption is less certain.

METHODS:
We investigated the association of alcohol intake with risk for increased LDL cholesterol over 5 years
in a cohort of 933 Japanese male office workers aged 35 to 54 years who had LDL cholesterol levels
less than 140 mg/dl and were not taking medication for dyslipidemia, hypertension, diabetes, liver
disease, or hyperuricemia at study entry. Incident-increased LDL cholesterol was defined by an LDL
cholesterol level of 140 mg/dl or more or use of medication for dyslipidemia. Each individual's slope
for LDL cholesterol was also calculated with a simple linear regression model.

RESULTS:
Three hundred twenty-one men developed increased LDL cholesterol during 3785 person-years of
follow-up. After controlling for potential predictors of increased LDL cholesterol, the relative risk for
increased LDL cholesterol compared with nondrinkers was 0.89 for those who drank 0.1 to 22.9
g/day of ethanol, 0.74 for those who drank 23.0 to 45.9 g/day of ethanol, 0.64 for those who drank
46.0 to 59.9 g/day of ethanol, and 0.54 for those who drank 69.0 g/day or more of ethanol (p <
0.001). Slopes of LDL cholesterol level decreased significantly as alcohol intake increased. From
multiple linear regression analyses, alcohol intake remained as an independent negative factor for
slopes of LDL cholesterol level.

CONCLUSIONS:
Alcohol intake is negatively associated with development of increased LDL cholesterol in middle-
aged Japanese men.
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Atherosclerosis. 1984 Nov;53(2):185-93.

Accelerated turnover of very low density lipoprotein

triglycerides in chronic alcohol users. A possible
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mechanism for the up-regulation of high density
lipoprotein by ethanol.
Sane T, Nikkilä EA, Taskinen MR, Välimäki M, Ylikahri R.
Abstract
The concentration of high density lipoproteins (HDL) is related to the catabolism of triglyceride-rich
lipoproteins. In order to elucidate the mechanisms by which alcohol increases plasma HDL levels we
measured the turnover kinetics of very low density lipoprotein (VLDL) triglycerides in 10 alcoholic
men without liver disease and in nonalcoholic control men matched for age, weight and plasma
VLDL triglyceride level. The study was repeated in the alcoholics after a 2-week abstinence period.

The alcoholic men had elevated HDL cholesterol but reduced low density lipoprotein (LDL)
cholesterol as compared to the controls. The fractional catabolic rate and the total turnover
(production) rate of VLDL triglycerides were both significantly increased (P less than 0.05) in the
alcoholic men before abstinence. After withdrawal of alcohol both the synthetic rate and the catabolic
rate of VLDL triglycerides returned to normal and the HDL (HDL2 and HDL3) cholesterol fell. The per
cent decrease in HDL2 cholesterol during abstinence was positively correlated to the respective fall
of VLDL triglyceride fractional catabolic rate (r = +0.51). The results suggest that the absence of
hypertriglyceridemia and the elevated levels of HDL in regular alcohol users may be partly based on
increased metabolic clearance of VLDL particles and on subsequent accelerated transfer of the
VLDL surface components to HDL.

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Clin Chim Acta. 2009 Jun 27;404(2):154-9. doi: 10.1016/j.cca.2009.03.047. Epub 2009 Mar 29.

Modification of the association between alcohol drinking

and non-HDL cholesterol by gender.
Wakabayashi I1, Groschner K.
Author information
Abstract
BACKGROUND:
Serum non-HDL cholesterol is a strong predictor of cardiovascular diseases. We studied the
relationship between habitual alcohol drinking and non-HDL cholesterol.

METHODS:

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Healthy male subjects (n = 27,005) and female subjects (n = 16,805) were divided into 5 groups by
average daily ethanol intake. Serum non-HDL cholesterol level and prevalence of serum high non-
HDL cholesterol (> or = 170 mg/dl) were compared among the groups.

RESULTS:
Non-HDL cholesterol level and prevalence of high non-HDL cholesterol became lower as alcohol
intake increased. The threshold alcohol intake in the drinker groups showing significantly lower
non-HDL cholesterol level and significantly lower prevalence of high non-HDL cholesterol, compared
with those in non-drinkers, was lower in women (<10 g/d) than in men (> or = 10 and <20 g/d). Odds
ratios of each drinker group vs. the non-drinker group for high non-HDL cholesterol became lower as
alcohol intake increased. The odds ratio of each drinker group vs. the non-drinker group for high
non-HDL cholesterol tended to be lower in women than in men.

CONCLUSIONS:
The results suggest that even light drinking is sufficient to significantly lower serum non-HDL
cholesterol and that this effect of alcohol drinking on non-HDL cholesterol is more pronounced in
women than in men.

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Effect of moderate alcohol consumption on Lp(a) lipoprotein

concentrations
Reduction is supported by other studies
Peter C Sharpe, Senior registrar in clinical biochemistry

Ian S Young, Consultant in clinical biochemistry

Alun E Evans, Professor of epidemiology

Copyright and License information ►

EDITOR —We agree with Paassilta et al that there may be a relation between moderate alcohol
consumption and lower Lp(a) lipoprotein concentrations.1 The relation between alcohol
consumption and cardiovascular mortality is U shaped, with the lowest mortality at an alcohol
consumption of 2-4 units (16-32 g) a day.2Several mechanisms contribute to this cardioprotective
effect including beneficial increases in high density lipoprotein cholesterol3 and inhibition of
platelet aggregation.4 However, other factors may be involved. Lp(a) lipoprotein is a recognised
independent risk factor for the development of atherosclerosis and, as stated by Paassilta et al,
little attention has been directed to the effects of alcohol on Lp(a) lipoprotein.
In 1995 we reported a significant reduction in Lp(a) lipoprotein concentration in a prospective
study of 20 healthy volunteers (men and women) given 21 g of alcohol daily for 10 days in the
form of red wine (median (range) 186 (15-1420) mg/l v 132 (10-1210) mg/l, P<0.001).5 This
reduction was not repeated when the same subjects were given white wine, raising the issue of

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potential differences between various alcoholic drinks. Interestingly, we found no changes in
high density lipoprotein cholesterol concentrations.
We have conducted a larger unpublished crossover trial in 50 men comparing the effects of 3
units (24 g) of alcohol a day as red wine or vodka for 14 days on Lp(a) lipoprotein
concentrations. Each period of alcohol consumption was preceded by two weeks’ abstinence.
Both drinks produced a 10-12% decrease in Lp(a) concentration (geometric mean 153
mg/100 ml v 135 mg/l after vodka, P<0.001; 151 mg/l v 136 mg/l after red wine, P<0.01). These
results suggest that moderate alcohol consumption results in changes in Lp(a) lipoprotein which
are independent of the type of alcoholic drink consumed. In conclusion, we agree with Paassilta
et al that lower Lp(a) concentrations may be one factor conferring lower mortality and
cardiovascular benefit in social drinkers.

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Ann Epidemiol. Author manuscript; available in PMC 2010 Feb 10.
Published in final edited form as:
Ann Epidemiol. 2008 Feb; 18(2): 101.
Published online 2007 Sep 14. doi: 10.1016/j.annepidem.2007.07.103
PMCID: PMC2819069
NIHMSID: NIHMS169726
Relationship of Alcohol Consumption and Type of Alcoholic
Beverage Consumed With Plasma Lipid Levels: Differences
Between Whites and African Americans of the ARIC Study
KELLY A. VOLCIK, PhD, CHRISTIE M. BALLANTYNE, MD, FLAVIO D. FUCHS, MD, A. RICHEY SHARRETT,
MD, andERIC BOERWINKLE, PhD
Author information ► Copyright and License information ►

The publisher's final edited version of this article is available at Ann Epidemiol

See other articles in PMC that cite the published article.

Abstract

PURPOSE:
Alcohol consumption has been shown to contribute to a favorable lipid profile, and most studies
have reported a reduction in coronary heart disease risk with low-to-moderate consumption of
alcohol that is generally attributed to the beneficial effects of alcohol on lipids. The influence of
different types of alcoholic beverages on plasma lipid levels has been investigated to a lesser
extent and in limited populations.

METHODS:
We investigated the effect of overall alcohol consumption, as well as the type of alcoholic
beverage consumed, on multiple lipid measures in the large bi-ethnic population of the
Atherosclerosis Risk in Communities study.

RESULTS:

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We found both low-to-moderate and heavy alcohol consumption, regardless of the type of
alcoholic beverage consumed, to result in significantly greater levels of high-density lipoprotein
(HDL) cholesterol, HDL3 cholesterol, and apolipoprotein A-I in both white and African-
American males and females. Associations with other lipid measures contrasted between whites
and African Americans, with greater levels of alcohol consumption resulting in significantly
greater triglyceride levels in African Americans.

CONCLUSIONS:
Our results confirm previous studies associating alcohol consumption, regardless of beverage
type, with greater HDL cholesterol levels, with additional consistent associations detected for the
major HDL cholesterol density subfraction, HDL3 cholesterol, and the major HDL cholesterol
structural apolipoprotein, apolipoprotein A-I.

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8
DISCUSSION
In the current study, we demonstrated both low-to-moderate and heavy alcohol consumption,
regardless of the type of alcoholic beverage consumed, to result in significantly greater levels of
HDL cholesterol, HDL3cholesterol, and apolipo-protein A-I in both white and African-American
males and females of the large ARIC study. Associations with other lipid measures contrasted
between whites and African Americans, as well as between males and females. HDL2 cholesterol
levels were significantly associated with low-moderate and heavy drinking in both white males
and females, but not in African Americans. Significantly lower levels of LDL cholesterol,
apolipoprotein B, and triglycerides were observed only in white females, whereas significantly
higher triglyceride levels were observed only in African-Americans. The small number of
African-American wine drinkers precluded any conclusions about the association between lipid
measures and wine consumption for this racial group. Overall, our results confirm previous
studies associating alcohol consumption, regardless of beverage type, with higher HDL
cholesterol levels, with additional consistent associations detected for the major HDL cholesterol
density subfraction, HDL3cholesterol, and the major HDL cholesterol structural apolipoprotein,
apolipoprotein A-I.
The effects of alcohol consumption on lipid profiles have been primarily investigated in men, or
when women have been included, the data were generally not analyzed by sex. The few studies
evaluating this relationship in separate populations of men and women have indicated that the
association of alcohol consumption with higher levels of HDL cholesterol occurs at lower
intakes of alcohol in women than in men (23, 37-39). Results from the current study corroborate
these previous findings. When comparing never drinkers to low-to-moderate drinkers, as well as
never drinkers to heavy drinkers, the percent raise in HDL cholesterol levels was similar in both
white and African-American men and women. However, these findings were observed for
consuming ≤105 grams of alcohol per week for women (low-moderate; >105 grams/week for
heavy) and for consuming ≤210 grams of alcohol per week for men (low-moderate; >210
grams/week for heavy). Women have been shown to be more sensitive to the effects of alcohol
than men, especially with respect to liver function (37, 40, 41). Greater blood alcohol
concentrations have also been observed in women compared with men after ingestion of the
same amount of alcohol, with this difference attributed to decreased gastric metabolism of
alcohol by women (42). Thus, the question has been raised as to whether alcohol consumption
also affects lipid metabolism differently in men and women, but biochemical studies of lipid and
alcohol metabolism have not addressed this issue (37). In the current study, we observed similar
changes in lipid levels at lower intakes of alcohol in women compared to men, but a mechanistic
interpretation of these findings is difficult because of the lack of detailed metabolic and
biochemical measures on these same individuals.

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Long-term ethanol consumption impairs reverse cholesterol

transport function of high-density lipoproteins by depleting high-
density lipoprotein sphingomyelin both in rats and in humans
Philippe Marmillot,a,b,c Jennifer Munoz,a,b,c Sanket Patel,a,b,c Mamatha Garige,a,b,c Richard B. Rosse,d and M. Raj
Lakshmana,b,c,*

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Abstract
Moderate alcohol consumption has been linked to lower incidence of coronary artery disease due
to increased plasma high-density lipoprotein (HDL), whereas heavy drinking has the opposite
effect. Because of the crucial role of HDL in reverse cholesterol transport and positive
correlation of HDL sphingomyelin (SM) content with cholesterol efflux, we have compared
HDL SM content with its reverse cholesterol transport capacity both in rats fed ethanol on long-
term basis and alcoholic individuals. In rats, SM HDL content was decreased in the ethanol
group (−15.4%, P < .01) with a concomitant efflux decrease (−21.0%, P < .01) compared to that
in controls. Similarly, HDL from the ethanol group, when compared with HDL from the control
group, exhibited 13.8% (P < .05) less cholesterol uptake with control-group hepatocytes and
35.0% (P < .05) less cholesterol uptake with ethanol-group hepatocytes. Conversely, hepatocytes
from the ethanol group, when compared with hepatocytes from the control group, exhibited
31.0% (P < .01) less cholesterol uptake with control-group HDL and 48.0% (P < .01) less with
ethanol-group HDL. In humans, SM content in plasma HDL was also decreased in chronically
alcoholic individuals without liver disease (−51.5%, P < .01) and in chronically alcoholic
individuals with liver disease (−51.3%, P < .01), compared with nondrinkers. Concomitantly, in
alcoholic individuals without liver disease, both efflux and uptake were decreased by 83.0% and
54.0% (P < .01), respectively, and in chronically alcoholic individuals with liver disease by
84.0% and 61.0% (P < .01), respectively, compared with nondrinkers. Based on these findings,
we conclude that long-term ethanol consumption significantly impairs not only cholesterol efflux
function of HDL by decreasing its SM content but also cholesterol uptake by affecting
presumably hepatocyte receptors for HDL.

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Management of Low Levels of High-Density Lipoprotein-

Cholesterol
Amit V. Khera, MD and Jorge Plutzky, MD

Author information ► Copyright and License information ►

The publisher's final edited version of this article is available free at Circulation

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Case 1
A 61-year-old healthy man presents for a routine outpatient clinic visit. He was diagnosed with
hypertension 6 years ago with blood pressure well controlled on amlodipine 5 mg daily. He is a
lifelong nonsmoker and has no family history of premature coronary disease. He is employed as
a business executive. Exercise is limited to 15 minutes of walking daily in transit to work. Diet
includes frequent dining out with clients and occasional moderate alcohol consumption.
Examination is notable for a blood pressure of 125/70 mm Hg and a body mass index of 32
kg/m2. A fasting lipid panel is notable for total cholesterol of 188 mg/dL, high-density

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lipoprotein-cholesterol (HDL-C) of 31 mg/dL, calculated low-density lipoprotein-cholesterol
(LDL-C) of 125 mg/dL, and triglycerides of 160 mg/dL.
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Case 2
A 58-year-old man with coronary artery disease presents for follow-up. When he was 50 years of
age, chest discomfort led to diagnosis of a non–ST-segment elevation myocardial infarction.
Cardiac catheterization revealed a 90% left anterior descending lesion, which was stented, and
40% left circumflex artery stenosis. A lipid profile was returned with total cholesterol of 180
mg/dL, LDL-C of 130 mg/dL, HDL-C of 28 mg/dL, and triglycerides of 150 mg/dL. In addition
to other cardiovascular medications, the patient was treated with atorvastatin 80 mg. The follow-
up LDL-C was 72 mg/dL, and HDL-C was 26 mg/dL; vital signs were well controlled. Four
years ago, at 54 years of age, he re-presented with exertional chest discomfort. Stress testing led
to repeat catheterization and stenting of a 90% left circumflex lesion and a 90% left anterior
descending lesion distal to the previous intervention. Lipoprotein(a), checked because of a family
history of premature coronary artery disease, was 110 mg/dL (upper limit of normal, 40 mg/dL).
A trial of niacin was started, and titrated, which the patient tolerated. On 2 g of niacin and
atorvastatin 80 mg daily, his most recent lipid profile was returned with a total cholesterol of 132
mg/dL, HDL-C of 44 mg/dL, LDL-C of 64 mg/dL, triglycerides of 120 mg/dL, and
lipoprotein(a) of 44 mg/dL.
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The Clinical Problem

A low level of circulating HDL-C represents a problem that is both common and clinically
challenging, with a difficult-to-reconcile current database. National Cholesterol Treatment Panel
guidelines suggest that a HDL-C level of <40 mg/dL be considered low.1 National Health and
Nutrition Examination Survey data indicate that 31% of men and 12% of women in the
community currently meet this criterion.2 The National Cholesterol Treatment Panel, in their
more detailed text regarding metabolic syndrome, recognize sex-specific cutoffs of HDL-C <40
mg/dL for men and <50 mg/dL for women as undesirable. Low HDL, linked to premature
coronary artery disease, is being identified with increasing frequency as lipid screening
recommendations are increased.
The inverse association between plasma HDL-C and cardiovascular disease remains one of the
most robust epidemiological observations ever made (Figure 1A). First described in 1977 in
Framingham Heart Study data, the relationship has been replicated in multiple
cohorts.3 Epidemiological data link a 1 mg/dL increase in HDL to a 2% to 3% reduction in
cardiovascular events, an impact greater than that noted for LDL-C. However, pharmacological
interventions that raise HDL-C have not been clearly shown to reduce adverse cardiovascular
outcomes. This conundrum has forced clinicians to reconsider existing and emerging data on
HDL biology and therapeutic strategies to optimize clinical outcomes in the statin era.

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Figure 1

The HDL conundrum in 4 representative datasets. A, A strong epidemiological risk association. Total
HDL-C levels exhibit a wellvalidated, robust inverse relationship with cardiovascular risk, even among
patients with the same (including lower) LDL levels, ...

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The Biology
The epidemiological association between HDL-C and cardiovascular disease has stimulated
research to clarify its mechanistic underpinnings and provide biological plausibility for
causation. Numerous models have been proposed, based mainly on animal or in vitro models.
HDL-C promotes reverse cholesterol transport, which facilitates cholesterol transport from
peripheral lipid-laden macrophages to the liver for biliary excretion. In this construct, HDL is
atheroprotective by removing cholesterol from pathological sites, like the vasculature, and
depositing it in the liver and gastrointestinal tract. Considerable preclinical research also suggests
other HDL properties that might decrease atherosclerotic complications, including anti-
inflammatory effects, decreased low-density lipoprotein (LDL) oxidation, increased nitric oxide
production, decreased endothelial adhesion molecule expression, decreased thrombogenicity, and
decreased inflammatory-induced apoptosis (Figure 2).

Figure 2

HDL-cholesterol: levels vs function? HDL, like other lipoproteins, includes a range of complex
macromolecules with diverse functional effects and distinct characteristics. HDL, in part, through its
major apolipoprotein, apolipoprotein A-I, promotes cholesterol ...

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The Controversy
Recently, the HDL hypothesis—the notion that HDL-mediated atheroprotection can be
modulated for therapeutic benefit—has faced multiple challenges (Figure 1). Analyses seeking to
isolate the impact of HDL-C via observational epidemiology are limited by extensive
confounding; multiple cardiovascular risk factors, including male sex, smoking, visceral
adiposity, insulin resistance, and systemic inflammation alter HDL-C levels. Furthermore,
intensive statin therapy may attenuate responses that might have otherwise been significant; null

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associations between on-treatment HDL-C and cardiovascular outcomes were noted in several
recent clinical trials, although a risk relationship with HDL-C despite statin therapy persisted in
other studies.
Although human genetics analyses have further solidified the causal relationship between LDL-
C and atherosclerosis, analogous studies of patients with genetic mutations that alter HDL-C
levels have yielded inconsistent results. Markedly decreased HDL concentrations in patients with
monogenic disorders involving apolipoprotein A-I (ie, apolipoprotein A-IMilano), ABCA1 (Tangier
disease), and LCAT (familial lecithin cholesterol acyltransferase deficiency) have not been
clearly associated with increased or premature cardiovascular disease. Mendelian randomization
analyses use high-throughput genotyping to try to overcome confounding in assessing causality.
For example, if HDL-C is directly atheroprotective, inherited variations in HDL-C levels should
change cardiovascular risk by a magnitude predicted by known epidemiology. In 1 recent
analysis, a genetic score that combined 14 common polymorphisms that influence HDL-C levels
had no association with cardiovascular events. However, some specific polymorphisms did
correlate with reduced risk.4 This study suggests that HDL-C levels as a predictor of
cardiovascular benefit may depend on how a given intervention alters HDL function (Figure 2).
With regard to therapeutics, evidence that pharmacological agents that increase HDL-C improve
cardiovascular outcomes has been limited. Despite early smaller clinical trials and long-term
follow-up studies of HDL-C interventions suggesting significant cardiovascular benefit, 4 recent
high-profile clinical trials of HDL-raising therapies have argued otherwise: Atherothrombosis
Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global
Health Outcomes (AIM-HIGH; secondary prevention trial adding niacin to LDL-lowering
therapy)5; Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular
Events (HPS-2 THRIVE; secondary prevention of adding niacin/laropiprant to statin therapy)6; a
Study Examining Torcetrapib/Atorvastatin And Atorvastatin Effects on Clinical CV Events in
Patients With Heart Disease (ILLUMINATE, primary prevention trial in high-risk patients
adding the cholesteryl ester transfer protein [CETP] inhibitor torcetrapib to atorvastatin)7; and
Dalcetrapib Outcomes Study (Dal-OUTCOMES, secondary prevention trial in acute coronary
syndrome patients adding the CETP inhibitor dalcetrapib to optimal therapy; Figure 1D).8 Each
of these studies has complicating features that preclude definitive conclusions about the impact
of the HDL changes seen. However, these negative results reinforce the need for caution and
reexamination of HDL-centric therapies.
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Nonpharmacological Interventions

Aerobic Exercise
A high level of exercise was previously thought necessary in order to increase HDL-C levels.
However, sustained and regular moderate-intensity activity can increase HDL-C levels by 5% to
10%. Individuals with low HDL-C and elevated triglycerides and abdominal obesity, as in case 1
above, may have particularly robust HDL-C responses to exercise, potentially mediated through
increased insulin sensitivity independent of diet. Observational data and randomized trials with
surrogate cardiovascular end points support the potential for cardiovascular risk reduction with
exercise. Therefore, adherence to current American Heart Association guidelines for physical

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activity in adults (at least 30 minutes most days of the week and at least 60 minutes for weight
loss) remains advisable.8a

Weight Loss
Overweight and obesity are strongly associated with both low HDL-C and elevated
circulating triglycerides. Acute changes in weight loss may modestly decrease HDL-C levels,
likely via decreased lipoprotein lipase activity. However, on weight stabilization, HDL-C levels
generally increase by 0.35 mg/dL per kilogram.9 This increase in HDL-C occurs regardless of
weight loss strategy: diet, physical activity, pharmacological therapies, or surgical approaches.

Nutrition
Patients who consume very low fat diets often have lower HDL-C levels, although LDL-C is also
reduced, confounding the assignment of potential risk reduction. Meanwhile, diets high in
saturated or trans fats tend to increase HDL-C levels at the possible expense of impaired HDL
functionality and increased LDL-C. Processed carbohydrates that rapidly increase glucose levels
(ie, high glycemic index) may lower HDL-C levels, increase inflammation, and increase
cardiovascular risk. An emphasis on modest portion sizes and a diet high in fresh fruits and
vegetables, low in processed carbohydrates and meats, and high in polyunsaturated fatty acids
remains advisable.

Smoking Cessation
The oxidant stress and inflammation induced by cigarette smoking have been linked to both
decreased HDL levels and function. Smokers tend to have an HDL-C level that is 5% to 10%
lower than matched controls. Importantly, smoking cessation leads to an increase in HDL-C of
≈4 mg/dL with minimal impact on other lipid parameters.10

Alcohol Intake
Alcohol consumption can increase HDL-C ≈2 mg/dL per daily alcoholic beverage.11 Moderate
alcohol intake (1–2 drinks/d in men, 1 drink/d in women) has been associated with improved
cardiovascular outcomes in observational studies, although via unclear mechanisms.
Recommending that nondrinkers with low HDL-C initiate moderate alcohol consumption for
cardiovascular risk reduction remains speculative and difficult to endorse given the adverse
outcomes associated with alcohol intake. In select patients at low risk for alcohol-related
problems, providing the relevant information regarding modest, responsible alcohol intake and
cardiovascular risk might be considered.

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