Critique 061: The reduction in risk of coronary heart disease from alcohol consumption may involve mechanisms other than an increase in HDL-cholesterol. — 10 November 2011

Magnus P,  Bakke E,  Hoff DA,  Høiseth G,  Graff-Iversen S,  Knudsen GP,  Myhre R,  Normann PT,  Næss Ø,  Tambs K,  Thelle DS, Mørland J. 

Controlling for High-Density Lipoprotein Cholesterol Does Not Affect the Magnitude of the Relationship Between Alcohol and Coronary Heart Disease.  Circulation 2011;124: DOI: 10.1161/CIRCULATIONAHA.111.036491

Authors’ Abstract

Background—This study tested the hypothesis that moderate alcohol intake exerts its cardioprotective effect mainly through an increase in the serum level of high-density lipoprotein cholesterol.

Methods and Results—In the Cohort of Norway (CONOR) study, 149,729 adult participants, recruited from 1994 to 2003, were followed by linkage to the Cause of Death Registry until 2006.  At recruitment, questionnaire data on alcohol intake were collected, and the concentration of high-density lipoprotein cholesterol in serum was measured.  Using Cox regression, we found that the adjusted hazard ratio for men for dying from coronary heart disease was 0.52 (95% confidence interval, 0.39–0.69) when consuming alcohol more than once a week compared with never or rarely. The ratio changed only slightly, to 0.55 (0.41– 0.73), after the regression model included the serum level of high-density cholesterol.  For women, the corresponding hazard ratios were 0.62 (0.32–1.23) and 0.68 (0.34 –1.34), respectively.

Conclusions—Alcohol intake is related to a reduced risk of death from coronary heart disease in the follow-up of a large, population-based Norwegian cohort study with extensive control for confounding factors.  Our findings suggest that the serum level of high-density cholesterol is not an important intermediate variable in the possible causal pathway between moderate alcohol intake and coronary heart disease.

Forum Comments

Background:  Most epidemiologic studies have shown that higher levels of high-density lipoprotein cholesterol (HDL) are strongly associated with a lower risk of coronary heart disease.1,2  Alcohol consumption has been shown to be a key lifestyle factor associated with HDL levels in the general population.3  The present study is unusual in finding that while alcohol consumption was associated with a markedly lower risk of death from coronary heart disease, changes in HDL appeared to not be an important explanation for the lower risk.

 Comments on the present paper:  As stated by the authors, very low levels of alcohol consumption were reported by the subjects in this study.  Whether this represents a gross under-estimation of intake or actually reflects very low intake is unclear.  It is noteworthy that the never or rarely drinking group had the highest level of systolic blood pressure, further suggesting that even subjects in the highest category of drinking were not consuming much alcohol (as most studies show an increase in blood pressure with greater intake of alcohol).  One reviewer wished that we had more information provided on the pattern of alcohol consumption and the type of beverage consumed. 

A Forum reviewer pointed out that in this population the low-level drinkers had higher levels of physical activity and lower BMI, blood pressure, triglycerides, and cholesterol in comparison with rare or never drinkers; these, as well as higher educational levels may have resulted in over-adjustment in the analyses and thus lower estimated effects of HDL.  Accounting for them in the model when there is potential for a high level of inter-correlation may well have precluded the isolation of any additive effect of alcohol on HDL as an explanation for the reduction of coronary mortality with increasing alcohol consumption.  For example, it would have been interesting to see the contribution of HDL without having triglycerides in the model because of the strong inverse association between HDL and triglycerides that is usually found. 

It is suggested that the extensive data included in the meta-analysis by Brien et al4 dealing with the effect of alcohol consumption on biological markers may provide a better measure of the role that changes in HDL associated with alcohol intake may play in affecting coronary disease risk.

Do changes in HDL-cholesterol relate to changes in cardiovascular risk?  It is unclear the extent to which changes in HDL levels affect the subsequent risk of cardiovascular disease.  A Forum reviewer pointed out a meta-analysis by Briel et al5 that investigated the association between treatment-induced change in HDL and total death, coronary heart disease death, and coronary heart disease events in trials of lipid modifying interventions.  The meta-regression analysis included 108 randomized trials involving 299,310 participants at risk of cardiovascular events.  All analyses that adjusted for changes in low density lipoprotein (LDL) cholesterol showed no association between treatment-induced change in HDL and risk ratios for coronary heart disease deaths, coronary heart disease events, or total deaths.  With all trials included, change in HDL explained almost none of the variability (<1%) in any of the outcomes.

On the other hand, Nichols et al6 recently reported that among 30,000 subjects with diabetes among whom two measures of HDL were measured 6 months to 24 months apart, subjects showing an increase in HDL subsequently showed fewer hospitalizations for cardiovascular disease (over a mean follow-up period of 55 months).  In contrast, those subjects whose HDL decreased showed a 11% increased risk of hospitalizations. 

Further, using data from the Framingham Heart Study, Grover et al7 evaluated the risk of a cardiovascular event associated with changes in blood lipid levels among individuals who started lipid therapy.  The independent effect of HDL levels on future cardiovascular risk (average follow-up, 8 years) was estimated after adjustment for changes in low-density lipoprotein cholesterol, plasma triglycerides, and pretreatment blood lipid levels.  Potential confounders (e.g., smoking status, weight, and the use of beta-blockers) were then added to the model.  These investigators found that the change in HDL level was a strong independent risk factor for cardiovascular events (hazard ratio, 0.79 per 5-mg/dL increase; 95% CI, 0.67-0.93) after adjustment for the other lipid changes associated with treatment

As there is not yet a widely used drug that specifically increases HDL, there have not been controlled trials to determine the effects of changes in HDL on cardiovascular risk.  Further, while observational studies have shown that subjects who begin to consume alcohol tend to have lower subsequent risk of cardiovascular disease, there have not been clinical trials to evaluate the role that an increase in HDL from alcohol may play in the effects on cardiovascular disease outcomes.


1.  Gaziano JM, Buring JE, Breslow JL, Goldhaber SZ, Rosner B, Van-Denburgh M, Willett W, Hennekens CH. Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, and decreased risk of myocardial infarction.  N Engl J Med. 1993;329:1829–1834.

2. Mukamal KJ, Jensen MK, Grønbæk M, Stampfer MJ, Manson JE, Pischon T, Rimm EB. Drinking frequency, mediating biomarkers, and risk of myocardial infarction in women and men.  Circulation 2005;112:1406–1413.

3.  Ellison RC, Zhang Y, Qureshi MM, Knox S, Arnett DK, Province MA.  Lifestyle determinants of HDL-cholesterol: the NHLBI Family Heart Study.  Am Heart J 2004;147:529-535.

4.  Brien SE, Ronksley PE,Turner BJ, Mukamal KJ, Ghali WA.  Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies.  BMJ 2011;342:d636; doi:10.1136/bmj.d636.

5.  Briel M, Ferreira-Gonzalez I, et al.  Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ. 2009;338:b92

6.  Nichols GA, Vupputuri S, Rosales AG.  Change in high-density lipoprotein cholesterol and risk of subsequent hospitalizations for coronary artery disease or stroke among patients with type 2 diabetes mellitus.  Am J Cardiol 2011;108:1124-1128.

7.  Grover SA, Kaouache M, Joseph L, Barter P, Davignon J.  Evaluating the incremental benefits of raising high-density lipoprotein cholesterol levels during lipid therapy after adjustment fort the reductions in other blood lipid levels.  Arch Intern Med 2009;169:1775-1780.

Forum Summary

In a prospective, observational study of approximately 150,000 Norwegians, the investigators found that alcohol consumption was associated with a large decrease in the risk of death from coronary artery disease.  For men, the fully adjusted hazard ratio for cardiac death was 0.52 (95% CI 0.39 – 0.69) when comparing subjects reporting more than one drink/week in comparison with those reporting never or rarely drinking; for women, it was 0.62 (0.32–1.23).  There was little change in the hazard ratio when HDL-cholesterol (HDL) was added to the model, suggesting that very little of the lower risk of heart disease was due to an increase in HDL from alcohol consumption.

Forum members considered this a well-done analysis.  They were surprised at the very low amounts of alcohol intake reported by the subjects, with only 16% of males and about 8% of females reporting more than one drink/week.  It is possible that the low levels of drinking, or perhaps over-adjustment in the multivariable analysis, led to the lack of effect of HDL.  Most other studies have shown a much larger proportion of the effect of alcohol on heart disease risk to be associated with an increase in HDL.

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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:

Ian Puddey, MD, Dean, Faculty of Medicine, Dentistry & Health Sciences, University of Western Australia, Nedlands, Australia

Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA

Ulrich Keil, MD, PhD, Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany

R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

Giovanni de Gaetano, MD, PhD, Research Laboratories, Catholic University, Campobasso, Italy

Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy

David Vauzour, PhD, Senior Research Associate, Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark