Critique 034: A review of interventional studies in humans showing effects of alcohol on risk factors for cardiovascular disease – – – 5 March 2011

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.

Authors’ Abstract

Objective To systematically review interventional studies of the effects of alcohol consumption on 21 biological markers associated with risk of coronary heart disease in adults without known cardiovascular disease.

Design Systematic review and meta-analysis.

Data sources Medline (1950 to October 2009) and Embase (1980 to October 2009) without limits.

Study selection Two reviewers independently selected studies that examined adults without known cardiovascular disease and that compared fasting levels of specific biological markers associated with coronary heart disease after alcohol use with those after a period of no alcohol use (controls).  A total of 4,690 articles were screened for eligibility, the full texts of 124 studies reviewed, and 63 relevant articles selected.

Results Of 63 eligible studies, 44 on 13 biomarkers were meta-analysed in fixed or random effects models.  Quality was assessed by sensitivity analysis of studies grouped by design.  Analyses were stratified by type of beverage (wine, beer, spirits).  Alcohol significantly increased levels of high density lipoprotein cholesterol (pooled mean difference 0.094 mmol/L, 95% confidence interval 0.064 to 0.123), apolipoprotein A1 (0.101 g/L, 0.073 to 0.129), and adiponectin (0.56 mg/L, 0.39 to 0.72).  Alcohol showed a dose-response relation with high density lipoprotein cholesterol (test for trend P=0.013).  Alcohol decreased fibrinogen levels (−0.20 g/L, −0.29 to −0.11) but did not affect triglyceride levels.  Results were similar for crossover and before and after studies, and across beverage types.

Authors’ Conclusions Favourable changes in several cardiovascular biomarkers (higher levels of high density lipoprotein cholesterol and adiponectin and lower levels of fibrinogen) provide indirect pathophysiological support for a protective effect of moderate alcohol use on coronary heart disease.

Forum Comments

Background:  There have not yet been randomized clinical trials to evaluate the effects of alcohol administration on cardiovascular outcomes such as myocardial infarction, cardiac death, or other cardiovascular diseases (CVD) in humans.  It is unlikely that such studies will be done because of the long time of follow up required, the huge cost, and the difficulties in getting a very large number of people randomly assigned to agree to consume a specified amount of alcohol, or agree to avoid all alcohol, for many years.  (Similarly, there will never be a human trial to prove that smoking has a causal role in the development of lung cancer.)  For these lifestyle habits, we must use our best judgment based on carefully done observational studies, research into potential mechanisms of effect, and studies of intermediate outcomes that are in pathways and processes in the development of the disease.

There have been thousands of basic science studies showing that administering alcohol or wine to laboratory animals results in beneficial effects on the risk of atherosclerosis and heart disease.  The present excellent paper summarizes what are now a large number of human trials testing whether wine and/or alcohol have the same effects on reducing risk factors for CVD.

Comments on the paper:  This review and meta-analysis deals with the effects of wine/alcohol on key biomarkers for the development of CVD: lipids, inflammatory markers, hemostatic factors, endothelial function, and adipocyte hormones that affect risk.  It concludes that favorable effects on levels of high density lipoprotein cholesterol, apolipoprotein A1, adiponectin, and fibrinogen strengthen the case for a causal link between alcohol intake and reduced risk of coronary heart disease.

The Forum members were unanimous in praising the quality and usefulness of this paper (along with a companion paper by the same authors in the same issue of the BMJ, which is reviewed as Critique 035¹).  They felt that “the authors had gathered and handled data and discussed the implications thereof admirably and presented a particularly comprehensive and thorough review.”  The paper is a useful source of information.  It was stated that it is “satisfying to see epidemiological relationships causally supported by physiological data.”  One Forum member wrote: “These two studies are absolutely excellent!  Once in a while having confirmatory data does not limit the relevance of the message.”

Another Forum member believed that “the findings of this paper extend previous evidence supporting an apparent causal role for alcohol consumption in preventing coronary heart disease through favorable effects on levels of HDL-C, fibrinogen, and adiponectin and limited adverse effects on triglycerides at levels of alcohol consumption that are considered ‘not risky.’  The limited adverse effects on triglycerides are worth mentioning because a number of lipidologists have paid a lot of attention to an increase in triglycerides after drinking seen in some studies and argued that this mechanism would partly undo the other beneficial effects associated with drinking.”  A Forum member commented that he expected that alcohol consumption would increase the HDL-cholesterol to a greater degree.  However, a mean increment of almost 0.1 mmol/l is important and better than most currently available lipid lowering drugs, except for nicotinic acid.

One Forum member stated that “It is also important to note that the different kinds of alcoholic beverages had similar effects on the different biomarkers, suggesting that it is the alcohol which does the job, and not other ingredients contained in alcoholic beverages.”  On the other hand, a number of Forum members believed that the authors failed to discuss a huge scientific literature that has demonstrated, both in epidemiologic studies and in intervention studies, that the polyphenols in wine and other alcoholic beverages can make a large contribution to cardiovascular health.  While it is clear that alcohol itself is the key factor in increasing HDL-cholesterol, strong independent effects of many polyphenols have been shown for coagulation, fibrinolysis, endothelial function, and many other mechanisms, as summarized well by Collins et al.² In addition, while several of the large American epidemiologic studies have shown little difference in effect according to type of beverage, most European studies suggest clear advantages in risk factors, and CVD and many other diseases, when the predominant beverage is wine.  For example, this has been shown repeatedly since 1990 by investigators in Copenhagen.^3-5

References from Forum review

1.  Ronksley PE, Brien SE, Turner BJ, Mukamal KJ, Ghali WA.  Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis.  BMJ 2011;342:d671; doi:10.1136/bmj.d671

2.  Collins MA, Neafsey EJ, Mukamal KJ et al. Alcohol in moderation, cardioprotection, and neuroprotection: epidemiological considerations and mechanistic studies. Alcohol Clin Exp Res 2009;33:206-219.

3.  Grønbaek M, Deis A, Sørensen TI, Becker U, Schnohr P, Jensen G.  Mortality associated with moderate intakes of wine, beer, or spirits. BMJ 1995;310:1165-1169.

4.  Truelsen T, Gronbaek M, Schnohr P, Boysen G.  Intake of beer, wine, and spirits and risk of stroke : the copenhagen city heart study.  Stroke 1998;29:2467-2472.

5.  Grønbaek M, Becker U, Johansen D, Gottschau A, Schnohr P, Hein HO, Jensen G, Sørensen TI.  Type of alcohol consumed and mortality from all causes, coronary heart disease, and cancer. Ann Intern Med 2000; 133:411-419.

Forum Summary:  A summary paper on the effects of alcohol consumption on biologic mechanisms associated with coronary heart disease provides an excellent review of a large number of intervention studies in humans.  Appropriate analyses were done and the results are presented in a very clear fashion, although there was little discussion of the separate, independent effects of alcohol and polyphenols on risk factors.  The trials the authors reviewed have demonstrated that the moderate intake of alcoholic beverages leads to increases in HDL-cholesterol, apolipoprotein A1, and adiponectin and decreases in fibrinogen, all factors associated with a lower risk of heart disease.  The findings described in this paper strengthen the case for a causal link between alcohol intake and a reduced risk of coronary heart disease.

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Contributions to this critique by the International Scientific Forum on Alcohol Research were made by the following members:

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

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

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

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

Gordon Troup, MSc, DSc, School of Physics, Monash University, Victoria, Australia

Dominique Lanzmann-Petithory,MD, PhD, Nutrition/Cardiology, Praticien Hospitalier Hôpital Emile Roux, Paris, France

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

Andrew L. Waterhouse, PhD, Department of Viticulture and Enology, University of California, Davis