Critique 177: A clinical trial testing the effects of alcohol on inflammatory markers — 21 December 2015
Stote KS, Tracy RP, Taylor PR, Baer DJ. The effect of moderate alcohol consumption on biomarkers of inflammation and hemostatic factors in postmenopausal women. European J Clin Nutrition 2015;advance online publication. doi:10.1038/ejcn.2015.182
BACKGROUND/OBJECTIVES: Inflammation and hemostasis contribute to the etiology of cardiovascular disease. We previously demonstrated that moderate alcohol consumption (1–2 drinks/day) may decrease risk for cardiovascular disease because of an improved lipid profile. In addition to these beneficial changes, the alcohol-mediated reduction in risk may be through its effect on inflammation and hemostasis. The objective of the study was to evaluate the effect of moderate alcohol consumption on biomarkers of inflammation and hemostasis in postmenopausal women.
SUBJECTS/METHODS: As part of a controlled diet study, 53 postmenopausal women each consumed a weight-maintaining diet plus 0, 15 and 30 g/day of alcohol for 8 weeks, in a randomized crossover design. The controlled diet contained 15%, 53% and 32% of energy from protein, carbohydrate and fat, respectively.
RESULTS: Soluble intercellular adhesion molecule-1 decreased by 5% (P<0.05) with consumption of both 15 and 30 g of alcohol. Fibrinogen concentrations decreased by 4% and 6% (P<0.05) after consumption of 15 and 30 g alcohol, respectively. Fibrin D-dimer decreased by 24% (P<0.05) after consumption of 30 g of alcohol. Plasminogen activator inhibitor-1 (PAI-1) concentrations were increased 27 and 54% (P<0.05) after consumption of 15 and 30 g of alcohol. Plasma high-sensitivity C-reactive protein, interleukin-6 and factor VII coagulant activity did not change with alcohol consumption.
CONCLUSIONS: These data suggest that moderate alcohol consumption may have beneficial effects on inflammation and hemostasis in postmenopausal women, and this may be somewhat mitigated by an increase in PAI-1.
While there have been hundreds of observational studies of the relation of alcohol consumption to health risks and benefits, the number of clinical trials of alcohol administration for its health effects are limited. The present paper is based on a controlled diet cross-over trial among 53 postmenopausal women who consumed a weight-maintaining diet plus 0, 15 (a little over one typical drink) and 30 g/day (about 2 to 2 ½ drinks) of alcohol for 8 weeks each during the trial. The investigators evaluated the effects of no alcohol versus two levels of alcohol on a number of measures of inflammation.
A standard diet was provided for a period of 6 months; two meals each weekday were consumed at the study facility and food was provided for other meals. To the standard meal, during three 8-week interventions, either 0, 15 g, of 30 g of alcohol were added to the daily diet. Weight remained stable and no adverse effects were reported.
The key results of the trial were that, during periods when alcohol (ethanol) was consumed, there were small but significant decreases in markers of cellular adhesion molecules and components in the hemostatic pathway; these are indices of inflammation and the effects are consistent with a decreased risk of cardiovascular disease (CVD). Specifically, reductions were seen when alcohol was administered for s-ICAM, fibrinogen, and D-dimer, all of which would be expected to lower CVD risk. PAI-1 increased with alcohol, and there were no effects on CRP, Factor VIIc or IL-6.
Forum members considered that, overall, this was a very well-done, difficult-to-carry-out study that shows alcohol’s beneficial effects on a number of inflammatory and hemostatic factors. They appreciated that the investigators had to persuade the subjects to eat only what was provided for them for a period of six months. The trial supports such effects on inflammation as seen in many observational studies. It indicates that alcohol consumption may have its beneficial effects on CVD by inflammatory and hemostatic changes, in addition to well-described lipid changes (especially an increase in HDL-cholesterol).
A detailed critical overview of the methodology of this study by Forum member Puddey; “This study was initially designed to address alcohol effects on lipid profiles (Baer et al) and insulin and glucose concentrations (Davies et al) in post-menopausal women. In this further analysis, the effects of alcohol on a variety of inflammatory and hemostatic biomarkers have now been assessed. There were potentially beneficial changes demonstrated in some but not all inflammatory markers, but baseline levels of each of the inflammatory and hemostatic biomarkers prior to the controlled diets are not provided. Further, the subjects either received 340 ml orange juice or the same volume of orange juice with either 15 or 30g/alcohol added in 3 separate dietary periods. This raises the question as to whether there could have been additional antioxidant or anti-inflammatory effects of either citrus flavonoids (typically hesperetin or naringenin) or vitamin C that influenced the negative outcomes with respect to hs-CRP, interleukin-6 and factor VII coagulant activity.”
Puddey continued: “The authors report an estimated 90% power to detect a minimum effect size from alcohol on fibrinogen. However, the power and possible effect sizes for other variables in the current analysis are not provided, raising the further question as to whether another reason for the absence of any effect on hs-CRP, interleukin-6 and factor VII coagulant activity could be related to power. We are also not given any indication as to whether all the variables were normally distributed, and if not, how this was handled. In this regard a subject with high triglyceride levels was excluded in their previous reports from this study (Baer et al, Davies et al), but appears to have been included on this occasion. Triglyceride levels can be strongly correlated to PAI-I levels.
“The volunteers had their breakfast and evening meals in a research facility but then took the orange juice (with or without alcohol) 1-2 hr before bedtime. Consuming alcohol with a standard meal has previously been reported to increase PAI-I but with lower levels in the early morning (Hendriks et al). Taking the alcohol post-prandial in the current study may have been relevant to the 54% increase seen in PAI-I levels. The authors downplay this substantial and potentially detrimental and dose-related increase in PAI-I with alcohol. However, it has been a consistent finding in previous interventions (Hendriks et al, Dimmit et al). This increase in PAI-I needs to be interpreted in the light of reports that have shown not just an increase in PAI-I after alcohol but a simultaneous increase in tissue plasminogen activator (tPA) antigen levels (Hendriks et al, Dimmit et al). The net in vivo effect of these oppositely acting fibrinolytic factors may therefore be neutral or even beneficial with respect to fibrinolysis.”
Puddey added: “There is a very wide range of BMI, with some of the volunteers morbidly obese (range 17.3- 41.8 kgm-2). This raises the question of a potential impact of pre-existing obesity and insulin resistance on the response of both the inflammatory and hemostatic makers to alcohol. In one of the initial reports from this study (Davies et al), when analysing the effects of alcohol on fasting insulin and glucose levels, the authors checked for a potential influence of a BMI x alcohol interaction, stratifying subjects according their baseline BMI (17 subjects <25 kgm-2, 21 subjects 25-30 kgm-2, 13 subjects >30 kgm-2). This would have been a worthwhile addition to the present report.”
Specific comments by other Forum members: Forum member Finkel wondered how firm the results are considering that there were only 53 subjects. Reviewer Ellison pointed out that dietary intervention trials are especially difficult to carry out, and getting this many subjects to accept only provided food for 6 months is quite an accomplishment. As it was a cross-over trial, so that each subject had an 8-week period of no alcohol and two levels of alcohol intake, this makes it much easier for the investigators to control for confounding factors, as the effects from each intervention were measured in the same subjects.
Reviewer De Gaetano considered this to be a very well performed experimental study. He commented: “Some time ago, Ramon Estruch’s group and our group jointly performed similar studies and observed anti-inflammatory and anti-hemostatic effects of 30 g alcohol in healthy men, administered during 30 days as red wine (in comparison with the same amount of alcohol given as gin) (Estruch et al, Sacanella et al). In that study, we could only find the above mentioned effects with wine but not with gin, while both beverages had, in contrast, a comparable beneficial effect on the lipid profile. We suggested that the observed anti-inflammatory effect was linked to non–alcoholic components (polyphenols?), while alcohol by itself was able to improve the lipid profile. The present study suggests that alcohol also has anti-inflammatory effects.”
Forum member Stockley considered this to be “A nicely designed and executed study of the relatively short-term effects of alcoholic beverages on biomarkers for CVD. It adds to the accumulating evidence of multiple mechansims by which moderate alcohol intake may lead to lower risk of CVD. The provision of food was a neat way to reduce dietary confounding.” Reviewer Skovenborg agreed: “The results are more or less expected; however, as the authors admit, the biological significance of these relatively modest changes are not fully understood.” Forum member Thelle agreed, stating that more studies on mechanisms are warranted.
Forum member Van Velden commented that “This was a well-controlled study, and confirms our results from 2002 (Van Velden et al 1; Mansveldt et al 1). However, we found these potentially protective effects occurred only with red wine (Van Velden 2). Further, in our studies, persons with the metabolic syndrome did not react as favourably because of genetic differences, such as APOE polymorphism and familial hypercholesterolemia (Mansveldt et al 2). Overall, this article supports our results and strengthens the argument that moderate ethanol consumption, itself, has beneficial effects on the cardiovascular system.”
References from Forum critique
Baer DJ, Judd JT, Clevidence BA, Muesing RA, Campbell WS, Brown ED, et al. Moderate alcohol consumption lowers risk factors for cardiovascular disease in postmenopausal women fed a controlled diet. Am J Clin Nutr 2002; 75:593-599.
Davies MJ, Baer DJ, Judd JT, Brown ED, Campbell WS, Taylor PR. Effects of moderate alcohol intake on fasting insulin and glucose concentrations and insulin sensitivity in postmenopausal women: a randomized controlled trial. JAMA 2002; 287:2559-2562.
Dimmitt SB, Rakic V, Puddey IB, Baker R, Oostryck R, Adams MJ, et al. The effects of alcohol on coagulation and fibrinolytic factors -a controlled trial. Blood Coagul Fibrinolysis 1998; 9:39-45.
Estruch R, Sacanella E, Badia E, Antunez E, Nicolas JM, Fernandez-Sola J et al. Different effects of red wine and gin consumption on inflammatory biomarkers of atherosclerosis: a prospective randomized crossover trial. Effects of wine on inflammatory markers. Atherosclerosis 2004; 175: 117–123.
Hendriks HFJ, Veenstra J, Velthuistewierik EJM, Schaafsma G, Kluft C. Effect of moderate dose of alcohol with evening meal on fibrinolytic factors. Br Med J 1994; 308:1003-1006.
Mansvelt EPG (1), van Velden DP, Fourie E, Rossouw M, van Rensburg SJ, Smuts M. The in vivo antithrombotic effect of moderate and regular wine consumption on human blood platelets and haemostatic factors. Ann NY Acad Sci 2002;957:329-332.
Mansvelt EPG (2), Fourie E, Blackhurst D, Kotze T, Stofberg H, van der Merwe S. Kotze MJ, van Velden DP. The influence of a Mediterranean Diet with and without red wine on the haemostatic and inflammatory parameters of subjects with the metabolic syndrome. S Afr J Enol Vitic 2007;28:37-43.
Sacanella E, Vazquez-Agell M, Mena MP, Antunez E, Fernandez-Sola J, Nicolas JM et al. Down-regulation of adhesion molecules and other inflammatory biomarkers after moderate wine consumption in healthy women: a randomized trial. Am J Clin Nutr 2007; 86: 1463–1469.
Van Velden DP (1), Mansvelt EPG, Fourie E, Rossouw M, van Rensburg SJ. The Cardioprotective effect of Wine on Human Blood Chemistry Ann NY Acad Sci 2002;957:337-340.
Van Velden DP (2), Mansvelt EPG, Troup GJ. Red wines good, white wines bad? Redox Report 2002;7:1-2.
While there have been many observational studies of the relation of alcohol consumption to health risks and benefits, the number of clinical trials of alcohol administration for its health effects are limited. The present paper is based on a controlled diet cross-over trial among 53 postmenopausal women. A standard diet was provided for a period of 6 months; two meals each weekday were consumed at the study facility and food was provided for other meals. To the standard meal, during three 8-week interventions, either 0, 15 g, of 30 g of alcohol (ethanol) were added to the daily diet, with the two doses of alcohol the equivalent of a little over one typical drink and 2 ½ typical drinks. Weight remained stable and no adverse effects were reported.
The key results of the trial were that, during periods when alcohol was consumed, there were small but significant decreases in markers of cellular adhesion molecules and components in the hemostatic pathway; these are indices of inflammation and the effects are consistent with a decreased risk of cardiovascular disease (CVD). Specifically, reductions were seen when alcohol was administered for s-ICAM, fibrinogen, and D-dimer, all of which would be expected to lower CVD risk. PAI-1 increased with alcohol, and there were no effects on CRP, Factor VIIc or IL-6.
While there were a number of question about the study, Forum members considered that, overall, this was a very well-done, difficult-to-carry-out study that shows alcohol’s beneficial effects on a number of inflammatory and hemostatic factors. The results are in line with many observational studies, although some previous intervention studies have found such effects only after the administration wine (but not of gin), suggesting a key effect of the polyphenols in wine. This study indicates that ethanol itself may have similar beneficial effects on mechanisms that relate to the development of cardiovascular disease.
Reference: Stote KS, Tracy RP, Taylor PR, Baer DJ. The effect of moderate alcohol consumption on biomarkers of inflammation and hemostatic factors in postmenopausal women. European J Clin Nutrition 2015; advance online publication. doi:10.1038/ejcn.2015.182
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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:
David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa
Dag S. Thelle, MD, PhD, Senior Professor of Cardiovascular Epidemiology and Prevention, University of Gothenburg, Sweden; Senior Professor of Quantitative Medicine at the University of Oslo, Norway
Pierre-Louis Teissedre, PhD, Faculty of Oenology–ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway
Creina Stockley, PhD, MSc Clinical Pharmacology, MBA; Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia
Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board, Aarhus, Denmark
Ian Puddey, MD, Dean, Faculty of Medicine, Dentistry & Health Sciences, University of Western Australia, Nedlands, Australia
Dominique Lanzmann-Petithory,MD, PhD, Nutrition/Cardiology, Praticien Hospitalier Hôpital Emile Roux, Paris, France
Giovanni de Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
R. Curtis Ellison, MD, Professor of Medicine & Public Health, Boston University School of Medicine, Boston, MA, USA