Critique 106: A clinical trial shows that glucose metabolism is improved more by red wine than by gin — 14 March 2013

Chiva-Blanch G,  Urpi-Sarda M, Ros E, Valderas-Martinez P, Casas R, Arranz S, Guillén M, Lamuela-Raventós RM, Llorach R, Andres-Lacueva C, Estruch R.  Effects of red wine polyphenols and alcohol on glucose metabolism and the lipid profile: A randomized clinical trial.  Clinical Nutrition 2013.  Pre-publication.

Authors’ Abstract

Background & aims: Epidemiological data suggest that moderate red wine consumption reduces cardiovascular mortality and the incidence of diabetes.  However, whether these effects are due to ethanol or to non-alcoholic components of red wine still remains unknown.  The aim of the present study was to compare the effects of moderate consumption of red wine, dealcoholized red wine, and gin on glucose metabolism and the lipid profile.

Methods: Sixty-seven men at high cardiovascular risk were randomized in a crossover trial.  After a run-in period, all received each of red wine (30 g alcohol/d), the equivalent amount of dealcoholized red wine, and gin (30 g alcohol/d) for 4 week periods, in a randomized order.  Fasting plasma glucose and insulin, homeostasis model assessment of insulin resistance (HOMA-IR), plasma lipoproteins, apolipoproteins and adipokines were determined at baseline and after each intervention.

Results: Fasting glucose remained constant throughout the study, while mean adjusted plasma insulin and HOMA-IR decreased after red wine and dealcoholized red wine. HDL cholesterol, Apolipoprotein A-I and A-II increased after red wine and gin. Lipoprotein(a) decreased after the red wine intervention.

Conclusions: These results support a beneficial effect of the non-alcoholic fraction of red wine (mainly polyphenols) on insulin resistance, conferring greater protective effects on cardiovascular disease to red wine than other alcoholic beverages.

Forum Comments

For many decades, epidemiologic studies have shown a strong inverse association between moderate alcohol intake and both cardiovascular disease and diabetes.  In earlier meta-analyses of the association between alcohol intake and diabetes, Howard et al (1) and Koppes et al (2) showed a 30% or greater reduction in risk of diabetes among moderate drinkers, in comparison with non-drinkers.

Forum member Lanzmann-Petithory pointed out the results of a large international European case-cohort study with 12,403 incident cases of diabetes, where an inverse association between alcohol and diabetes was found.(3)  Those investigators concluded: “The inverse association between alcohol consumption and diabetes was more pronounced amongst overweight than normal-weight men and women; wine consumption for men and fortified wine consumption for women were most strongly associated with a reduced risk of diabetes.”(3)  Further, in a meta-analysis of prospective cohort studies, Koppes et al have shown that, among diabetics, the development of coronary artery disease and death are much lower among moderate drinkers than among abstainers.(4) 

Results from previous randomized clinical trials:  There have been a limited number of randomized clinical trials comparing the effects of alcohol alone and the effects of the polyphenols (that are especially present in red wine) on glucose metabolism and lipids.  The present paper is from an excellent Spanish research group that has been working for many years on the comparison of the effects of red wine and alcohol on health.  Their first contributions on this topic derived from a project on Wine and Health supported by the European Commission in the 1990s;(5)  Forum member De Gaetano contributed to that paper, which concluded: “After either gin or wine consumption, plasma fibrinogen decreased by 5 and 9%, respectively, and cytokine IL-1alpha by 23 and 21%.  The expression of LFA-1 (-27%), Mac-1 (-27%), VLA-4 (-32%) and MCP-1 (-46%) decreased significantly after wine, but not after gin. Wine reduced the serum concentrations of hs-CRP (-21%), VCAM-1 (-17%) and ICAM-1 (-9%).”  Subsequent studies by Badia et al have shown other differences between the effects of wine and alcohol, as the authors reported: “TNF-alpha-induced adhesion of monocytes to endothelial cells was virtually abolished after red wine consumption but was only partially reduced after gin consumption.”(6) 

Shai et al randomly assigned 109 patients (41–74 years old) with established type 2 diabetes who had previously abstained from alcohol to receive 150 ml wine (13 g alcohol) or nonalcoholic diet beer (control) each day during a 3-month multicenter trial.(7)  They reported that the “initiation of moderate daily alcohol consumption reduced fasting plasma glucose but not postprandial glucose, with more favorable benefits among patients with higher A1C levels.”  Joosten et al carried out a clinical trial comparing white wine and grape juice and found that “moderate alcohol consumption for 6 weeks improves insulin sensitivity, adiponectin levels, and lipid profile in postmenopausal women.”(8)  More recently, another study by Eustruch and colleagues comparing the effects of different beverages on health reported: “Compared to gin, red wine intake has greater antioxidant effects, probably due to its high polyphenolic content.”(9)

Chiva-Blanch et al recently reported on an earlier trial among 67 high-risk, male volunteers, where wine versus gin were compared for effects on other mechanisms of cardiovascular disease.(10)  They concluded from that study: “The results suggest that the phenolic content of red wine may modulate leukocyte adhesion molecules, whereas both ethanol and polyphenols of red wine may modulate soluble inflammatory mediators in high-risk patients.” 

Specific comments on the present study: The present trial was carried out among subjects at high risk of cardiovascular disease (from family history, diabetes, hypertension, dyslipidemia, or obesity) and involved cross-over interventions with red wine (RW), largely de-alcoholized RW (DRW), and gin.  The RW and gin were given in a dosage that was the equivalent of approximately 30 grams/alcohol per day; the DRW contained almost exactly the same polyphenol content as the RW.   Each intervention was administered for 4 weeks, with the order of administration assigned randomly.

Forum members were unanimous in agreeing that this appeared to be a very well-conducted randomized trial.  Of necessity, the beverages being consumed were not blinded.  However, dietary records, blood tests, and repeated 24-hour urine collections confirmed excellent compliance with the beverages administered. 

The key findings are that both RW and gin raised HDL-cholesterol and apolipoprotein A levels, indicating that the alcohol contained in the beverages is the main determinant of the changes in these lipids.   However, the decrease in insulin levels and HOMA-insulin resistance related most strongly to RW, with less effect from DRW and even less of an effect from gin.  This suggests that while there is some effect from alcohol, polyphenols may be even more important in improving glucose metabolism.  None of the interventions affected fasting glucose levels.  In addition, the RW intervention was associated with improved levels of lipoprotein(a).      

Reviewer Van Velden commented: “This is a very interesting study, and there are similarities in it to our own study on the comparison of red wine vs brandy consumption in relation to genetic risk factors for cardiovascular disease correlated with the lipoprotein profile, oxidative stress and inflammation.  Both the wine and brandy interventions resulted in a significant increase in HDL-cholesterol.  These levels increased with alcohol intake in both the presence and absence of the E4 allele of the Apolipoprotein E polymorphism.  An increase of triglyceride levels with alcohol intake was only seen in HFE mutation-positive individuals.  The level of total glutathione as an indicator of redox status was significantly decreased only after the brandy intervention when compared to the baseline.  It was concluded that alcohol has a protective effect against cardiovascular risk factors, while red wine has an additional benefit that may be ascribed to the presence of polyphenolic antioxidants in red wine.”

Forum member Waterhouse agreed that this was a very well done clinical trial on disease markers for both cardiovascular disease and diabetes. “The only comment I have is that these are markers and not endpoints of disease or mortality. This is done because it is so difficult to undertake such a study with chronic disease due to the very long time such a trial would need to be conducted.  However, these results and Estruch’s success with the Mediterranean diet (11) suggest that a controlled trial of wine and alcohol for disease outcomes should be attempted.”

Reviewer Klatsky agreed that this was an interesting study, especially because of the insulin resistance data.  “It joins the substantial number of reports presenting data suggesting that drinkers of red wine have more favorable levels of various markers of potential risk of atherothrombotic disease, compared with drinkers of other alcoholic beverages.  However, without clinical endpoints, these reports indicate only hypothetical or potential benefit for disease.” 

Klatsky added: “It would have been more interesting yet if the study had white wine and beer arms.  There are epidemiologic data indicating lower risk of events in drinkers of both of these, with quite compelling data in several beer-drinking populations.  It seems likely that most of the subjects who are described as ‘moderate consumers’ were wine drinkers before the study.  (I wonder whether they drank the dealcoholized wine and gin slowly with dinner, as wine is usually ingested.)  In any case, the data in this report do support possible benefit from alcohol, with possible additional benefit from red wine phenolics.  The relative magnitude of these two areas of benefit remains unclear, but the preponderance of evidence favors the idea that alcohol has the major role.”

Forum reviewer Ursini stated: “Obviously I must rate this study as well conducted and convincing.  The issue of what is good or bad for your health can best be addressed by intervention studies with carefully done statistics.”  He added: “What is needed now is more understanding of the biological and nutritional nature of non-essential phytochemicals.”

References from Forum critique

1.    Howard AA, Arnsten JH, Gourevitch MN:  Effect of alcohol consumption on diabetes mellitus: a systematic review.  Ann Intern Med 2004;140:211-219.

2.   Koppes LL, Dekker JM, Hendriks HF, et al:  Moderate alcohol consumption lowers the risk of type 2 diabetes: a meta-analysis of prospective observational studies.  Diabetes Care 2005;28:719-725.

3.   Beulens JW, van der Schouw YT, Bergmann MM, Rohrmann S, Schulze MB, Buijsse B. et al.  Alcohol consumption and risk of type 2 diabetes in European men and women: influence of beverage type and body size.  The EPIC-InterAct study.  J Intern Med 2012;272:358-370.

4.   Koppes LLJ, Dekker JM, Hendriks HFJ, Bouter LM, Heine RJ.  Meta – analysis of the relationship between alcohol consumption and coronary heart disease and mortality in type 2 diabetic patients.  Diabetologia 2006;49:648–652.

5.   Estruch R, Sacanella E, Badia E, Antúnez E, Nicolás JM, Fernández-Solá J, Rotilio D, de Gaetano G, Rubin E, Urbano-Márquez A.  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.

6.   Badía E, Sacanella E, Fernández-Solá J, Nicolás JM, Antúnez E, Rotilio D, de Gaetano G, Urbano-Márquez A, Estruch R.  Decreased tumor necrosis factor-induced adhesion of human monocytes to endothelial cells after moderate alcohol consumption..  Am J Clin Nutr 2004;80:225-230.

7.   Shai I, Wainstein J, Harman-Boehm I, Raz I, Fraser D, Rudich A, Stampfer MJ.  Glycemic effects of moderate alcohol intake among patients with type 2 diabetes: A multicenter, randomized, clinical intervention trial. Diabetes Care 2007;30:3011–3016.

8.   Joosten MM, Beulens JW, Kersten S, Hendriks HF. Moderate alcohol consumption increases insulin sensitivity and ADIPOQ expression in postmenopausal women: a randomised, crossover trial.  Diabetologia 2008;51:1375-1381.

9.   Estruch R, Sacanella E, Mota F, Chiva-Blanch G, Antúnez E, Casals E, Deulofeu R, Rotilio D, Andres-Lacueva C, Lamuela-Raventos RM, de Gaetano G, Urbano-Marquez A.  Moderate consumption of red wine, but not gin, decreases erythrocyte superoxide dismutase activity: a randomised cross-over trial.  Nutr Metab Cardiovasc Dis 2011;21:46-53.

10.  Chiva-Blanch G, Urpi-Sarda M, Llorach R, Rotches-Ribalta M, Guillèn M, Casas R, Arranz S, Valderas-Martinez P, Portoles O, Corella D, Tinahones F, Lamuela-Raventos RM, Andres-Lacueva C, Estruch R.  Differential effects of polyphenols and alcohol of red wine on the expression of adhesion molecules and inflammatory cytokines related to atherosclerosis: a randomized clinical trial.  Am J Clin Nutr 2012. doi: 10.3945/ajcn.111.022889.

11.   Estruch R, Ros E, Salas-Salvadó J, Covas M-I, Corella D, Arós F, et al, for the PREDIMED Study Investigators.  Primary prevention of cardiovascular disease with a Mediterranean diet.  N Engl J Med 2013. DOI: 10.1056/NEJMoa1200303

Forum Summary

To compare the effects of moderate consumption of red wine, dealcoholized red wine, and gin on glucose metabolism and the lipid profile, a group of Spanish investigators carried out a randomized control trial among 67 men at high cardiovascular risk.  All received each of red wine (30 g alcohol/d), the equivalent amount of dealcoholized red wine, and gin (30 g alcohol/d) for 4 week periods, in a randomized order.  While fasting glucose levels were not affected, mean adjusted plasma insulin and HOMA-IR decreased after red wine and dealcoholized red wine, but not after gin.  HDL cholesterol, Apolipoprotein A-I and A-II increased after red wine and gin. Lipoprotein(a) decreased after the red wine intervention.  The authors conclude that their results support a beneficial effect of the non-alcoholic fraction of red wine (mainly polyphenols) on insulin resistance, thus greater protective effects on cardiovascular disease from red wine than from other alcoholic beverages.

Forum members were unanimous in considering this to be a very well-done and important trial.  It supports a huge amount of observational data from epidemiologic cohort studies that have shown that subjects who consume moderate amounts of alcohol tend to have much lower risk of developing diabetes.  Further, patients with diabetes who drink moderately have much lower risk of subsequent cardiovascular disease and lower mortality.  Studies such as this one help scientists understand the mechanisms by which moderate drinking, especially of wine, can reduce the risk of metabolic and vascular diseases.

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

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

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

David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa

Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis; Davis, CA, USA

Pierre-Louis Teissedre, PhD, Faculty of Oenology – ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France

Creina Stockley, PhD, MBA, Clinical Pharmacology, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia

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

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

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

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

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

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

Arthur Klatsky, MD, Dept. of Cardiology, Kaiser Permanente Medical Center, Oakland, CA, USA