“Should We Recommend Alcohol for its Health Benefits?”

1. “Should We Recommend Alcohol for its Health Benefits?” R. Curtis Ellison, MD Professor of Medicine & Public Health Section of Preventive Medicine & Epidemiology Boston University School of Medicine

2. YES!

3. NO!

4. IT DEPENDS!

5. The International Scientific Forum on Alcohol Research I serve as the Scientific Co-Director of a Forum made up of an international group of 40 scientists doing research on alcohol and health and committed to balanced and well-researched data on the subject. The Forum publishes critiques of emerging reports on alcohol & health through its Boston University web-site (www.bu.edu/alcohol-forum).

6. Members, International Scientific Forum on Alcohol Research USA Luc Djoussé, MD, DSc, Dept. of Medicine, Division of Aging, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA  R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA Tedd Goldfinger, DO, FACC, Desert Cardiology of Tucson Heart Center, Dept. of Cardiology, University of Arizona School of Medicine, Tucson, Arizona Lynn Gretkowski, MD, Obstetrics/Gynecology, Mountainview, CA, Stanford University, Stanford, CA, USA  Dwight Heath, PhD, Dept. of Anthropology, Brown University, Providence, RI, USA Imke Janssen, PhD, Department of Preventive Medicine, Rush University Medical Centre, Chicago, IL Arthur Klatsky, MD, Dept. of Cardiology, Kaiser Permanente Medical Center, Oakland, CA Lynda Powell, MEd, PhD, Chair, Dept of Preventive Medicine, Rush University Medical School, Chicago, IL Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis; Davis, CA Yuqing Zhang, MD, DSc, Epidemiology, Boston University School of Medicine, Boston, MA

7. Members, International Scientific Forum on Alcohol Research Europe Alberto Bertelli, MD, PhD, Institute of Human Anatomy, University of Milan, Italy Giorgio Calabrese, MD, Docente di Dietetica e Nutrizione, Umana Università Cattolica del S. Cuore, Piacenza, Italy Maria Isabel Covas, DPharm, PhD, Cardiovascular Risk and Nutrition Research Group, Institut Municipal d´Investigació Mèdica, Barcelona, Spain Alan Crozier, PhD, Plant Biochemistry and Human Nutrition, University of Glasgow, Scotland, UK Giovanni de Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy Alun Evans, MD, Centre for Public Health, The Queen's University of Belfast, Belfast, UK Oliver James, MD, Head of Medicine, University of Newcastle, UK Ulrich Keil, MD, PhD, Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany Rosa M. Lamuela-Raventos, PhD, Department of Nutrition and Food Science, University of Barcelona, Spain Dominique Lanzmann-Petithory,MD, PhD, Nutrition/Cardiology, Praticien Hospitalier Hôpital Emile Roux, Paris, France Rosa M. Lamuela-Raventos, PhD, Department of Nutrition and Food Science, University of Barcelona, Spain Fulvio Mattivi, PhD, Head of the Department Good Quality and Nutrition, Research and Innovation Centre, Foundazione Edmund Mach, in San Michele all’Adige, Italy Jean-Marc Orgogozo, MD, Professor of Neurology and Head of the Neurology Divisions, the University Hospital of Bordeaux, Pessac, France Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark  Jan Snel, PhD, Social and Behavioral Sciences, University of Amsterdam, Amsterdam, Holland Jeremy P E Spencer, Reader in Biochemistry, The University of Reading, UK Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo,Norway Pierre-Louis Teissedre, PhD, Faculty of Oenology - ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France 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 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

8. Members, International Scientific Forum on Alcohol Research Australia, New Zealand, South Africa Dee Blackhurst, PhD, Lipid Laboratory, University of Cape Town Health Sciences Faculty, Cape Town, South Africa Maritha J. Kotze, PhD,Human Genetics, Dept of Pathology, University of Stellenbosch, Tygerberg, South Africa Arduino A. Mangoni, PhD, Strategic Professor of Clinical Pharmacology and Senior Consultant in Clinical Pharmacology and Internal Medicine, Department of Clinical Pharmacology, Flinders University, Bedford Park, SA; Australia Ross McCormick PhD, MSC, MBChB, Associate Dean, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand Ian Puddey, MD, Dean, Faculty of Medicine, Dentistry & Health Sciences, University of Western Australia, Nedlands, Australia CreinaStockley, PhD, MBA, Clinical Pharmacology, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia Gordon Troup, MSc, DSc, School of Physics, Monash University, Victoria, Australia David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa

9. Potential Conflict of Interest Partial expenses for operating the Forum are from unrestricted donations to Boston University from associations and companies in the beverage industry (including NY Wine & Grape Foundation, Diageo, Brown-Forman) As donors have no input into the papers reviewed by the Forum or the opinions published, the IRB at Boston University has deemed that these do not constitute a conflict of interest.

10. “Should We Recommend Alcohol for its Health Benefits?” Among the factors that we must consider: 1. Is excessive alcohol intake associated with adverse health effects? 2. Is light-to-moderate alcohol intake associated with beneficial health effects? Is it the cause? 3. Does the pattern of drinking affect the net health effects? (speed of intake, with food, regular vs binge) 4. Does the type of beverage affect the net health effects? 5. Is the public often faced with biased, exaggerated statements about alcohol? What are proper guidelines?

11. Types of Scientific Evidence Case reports Ecologic data (comparing populations without individual data) Case-control studies Prospective cohort studies (may be population-based, must deal with confounders) Experimental data Human clinical trials (for intermediary outcomes, for disease outcomes)

12. Potential Confounding in Observational Studies • There is often clustering of healthy lifestyle factors • We must deal with such potentially confounding variables: • Age • Sex • Cigarette smoking • Education, occupation, and income • Diet, physical activity, level of obesity • Previous alcohol use • Adjust for many of these factors through stratification and multivariable analysis techniques. 

13. Research on Alcohol and Cardiovascular Disease Prospective epidemiologic studies for many decades, even when fully controlled for known confounding, have been amazingly consistent: moderate drinkers are at lower risk of CHD than are abstainers.

14. Alcohol & CHD: Meta-analysis Corrao et al, 2000

15. Alcohol Consumption and CHD Mortality: Review & Meta-analysis. Ronksley et al. BMJ 2011 • Reviewed 84 well-done prospective epidemiologic studies; > 1 million subjects. • Estimated effects of alcohol intake on mortality from coronary heart disease

17. Effects of Alcohol on Cardiovascular Disease(Ronksleyet al, 2011) ■ This meta-analysis showed risk reductions for moderate alcohol drinkers of 25% for CHD mortality 29% for incident coronary heart disease 25% for cardiovascular disease mortality 13 % for all-cause mortality.

18. Alcohol & Mortality, adjusting for SES and a Propensity Score (Lee et al, 2009) • 12,519 subjects, Health & Retirement Study • With demographic adjustments, moderate drinkers ( ≤ 1 drink/day vs non-drinkers) had a RR for mortality of 0.50. • With full adjustments for SES, RF, behavioral factors and a propensity score for moderate drinking, RR was 0.62 (CI 0.48-0.80).

19. Net Effect of Moderate Alcohol Intake on Mortality (Konnopka et al, 2009) • Considered "moderate" up to 40 grams/day (more than 3 drinks/day) for men and up to 20 g/day (about 1 1/2 drinks/day) for women; included binge drinkers. • Deaths "avoided" by moderate alcohol use were about twice as high (n=29,818) as the number "caused" by moderate drinking (n=14,457)

20. Deaths Attributable to “Moderate” Alcohol Intake (weekly mean <40 g/d for men, < 20 g/day for women)(Rehm et al, Ann Epidem, 2007)

21. Deaths Attributable to “Moderate” Alcohol Intake (when “binge drinkers” excluded)(Rehm et al, Ann Epidem, 2007)

22. Mechanisms of Effect of Alcohol/Polyphenols on CVD Blood lipids (esp. HDL-cholesterol) Coagulation, fibrinolysis Arterial endothelium Genes (alcohol and/or polyphenols) Ventricular function Inflammation Glucose metabolism

23. Mechanisms of Effect of Alcohol on Cardiovascular Disease (Collins et al, Alcoholism: ClinExp Res, 2009)

24. “Healthy Lifestyle” for Preventionof Diseases of Ageing Don’t smoke Stay lean (avoid becoming obese) Exercise regularly Eat a diet low in animal fat, with lots of fiber (fruits & vegetables) and whole grains Unless contraindicated, consume ½ - 2 drinks of an alcoholic beverage daily from Stampfer, Hu, Chiuve, et al

25. Effects of Alcohol on Risk of MI by Other Lifestyle Factors (1. non-smoking, 2. not obese, 3. active, 4. good diet) Least healthy (0-1 factors)=▲; Moderate (2-3 factors)=□; Healthy (4 factors)=◊ (Mukamal et al, Arch Intern Med 2006;166:21

26. Risk of Diabetes by Alcohol & Lifestyle Factors Joosten et al, Am J ClinNutr 2010 Healthy lifestyle factors: (1) BMI <25, (2) physically active, (3) non-smoker, (4) high adherence to Dash diet __________Hazard Ratio, adjusted______ Moderate No. of Healthy FactorsAbstainerDrinker* p-trend None or 1 3.90 1.98 < 0.001 2 to 3 2.68 1.21 0.002 3 or 4 1.00 0.56 0.02 *“Moderate drinker” = 5 - 14.9 g/d for women, 5 - 29.9 g/d for men

27. But what about experiments and human clinical trials on alcohol & health?

28. Daily-moderate versus weekend-binge alcohol in mice. Liu et al. Atherosclerosis 2011

29. Daily-moderate versus weekend-binge alcohol in mice. Liu et al. Atherosclerosis 2011

30. Meta-analysis of Interventional Studies of Alcohol and Coronary Heart Disease Brien SE, Ronksley PE, Turner BJ, Mukamal KJ. Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta- analysis of interventional studies. Published in BMJ 2011;342:d636

31. Human Interventional Studies on Mechanisms of Effects of Alcohol on CV Risk (Brien et al, 2011)

32. Wine Increases the Number and Functional Capacity of Circulating Endothelial Progenitor Cells by Enhancing Nitric Oxide Bioavailability A Clinical Trial of 80 Healthy Adults Huang et al, Arteriosclerosis Thrombis & VascBiol, 2010 “The intake of red wine significantly enhanced circulating endothelial progenitor cell levels and improved their functions by modifying nitric oxide bioavailability.”

33. Omega-3 Fatty Acids: An Untapped Resource for Improving Health R. Curtis Ellison, MD Professor of Medicine & Public Health Director, Institute on Lifestyle & Health Boston University School of Medicine Boston, MA,

34. Molecular Mechanisms for Increased Fibrinolysis (Booyse et al, 2007)

35. Effects of Moderate Drinking on All-cause Mortality

36. All-Cause Mortality, by Alcohol Consumption

37. Alcohol and Mortality(With repeated assessments of ETOH) The Zutphen Study (Streppel et al , 2009) • Men followed for up to 40 years, until death in the vast majority, with repeated assessments of alcohol intake • Up to 20 g/day of alcohol (vs none) was associated with 25-30% lower rates of cardiovascular and all-cause mortality

38. Total Mortality, by Alcohol ConsumptionDi Castelnuovo et al, Arch Int Med, 2006

39. Effects of Alcohol on All-cause Mortality by Type of Beverage

41. Survival after Age 50, by Long-TermAlcohol Consumption (Streppel et al, 2009)

42. Alcoholic Beverages and Incidence of Dementia: 34-Year Follow-upMehlig et al, 2008 HR 95% CI Wine drinkers 0.6 0.4, 0.8 Wine only 0.3 0.1, 0.8 Spirits drinkers 1.5 1.0, 2.2 Conclusion: wine and spirits displayed opposing associations with dementia.

43. Effects of Pattern of Drinking on Cardiovascular & All-cause Mortality

44. Does drinking pattern modify the effect of alcohol on risk of CHD? A meta-analysis.Bagnardi et al, 2008

45. Effects of Changes in Alcohol Consumption and Health Outcomes

46. Changes in Alcohol Intake & Subsequent Risk of Diabetes Health Professionals Study, n = 38,031 subjects Joosten et al¸ Diabetes 2011 For initial non-drinkers, a 7.5 g/d increase = 22% decrease in risk Intake 4 yrs Later_____ Baseline>0-4.9 g/d5-29.9g/d≥30g/dp-trend >0-4.9 g/d 1.00 0.75 0.35 < 0.001 5-29.9 g/d 1.09 0.74 0.59 < 0.001 ≥ 30 g/d 0.78 0.67 0.50 0.08

47. Klatsky has clearly stated that advice regarding alcohol depends on the individual’s age, sex, past alcohol use experience, cardiovascular risk, and other factors. We can apply similar approaches in giving population advice, as well. He added that most people know very well what the difference is between light to moderate drinking and binge or excessive drinking. While some patients may rationalize their heavy drinking because of its purported health effects, he has yet to find someone who had developed alcohol abuse because of messages about the health effects of moderate drinking. Medical practitioners, in his view, have a ‘‘solemn duty’’ to tell the truth about alcohol consumption, as they understand it, to all of their patients. Changes in Alcohol Intake & All-Cause Mortality Among Women with Invasive Breast Cancer Newcomb et al, J Clin Oncology, 2013   (7, 780 deaths in 23,000 women with breast cancer)  Changes in All-Cause Mortality Change in alcohol HR 95% CI Never drinker 1.0 -- Drinker No change 0.86 0.71-1.03 Decreased 1.03 0.85-1.25 Increased 0.76 0.60-0.97

48. Effects of Moderate Drinking on The Diseases of Ageing CV Diseases(↓ heart disease, stroke, CHF, vascular dis.) Metabolic Diseases(↓ diabetes, MS, osteoporosis) Cognitive Disorders (↓ Alzheimer’s, dementia) Obesity (emerging data suggest ↓ weight gain) Cancer (Abuse ↑ UADT cancers; moderate alcohol ↓ kidney cancer & lymphoma, slight↑breast & colon cancer risk) Total mortality(↓ among moderate drinkers)

49. Conclusion Data over many decades (observational studies, animal experiments, & human intervention trials) have consistently shown that Moderate drinking, especially of wine, is associated with a lower risk of CVD and most of the other diseases of ageing.

50. Klatsky has clearly stated that advice regarding alcohol depends on the individual’s age, sex, past alcohol use experience, cardiovascular risk, and other factors. We can apply similar approaches in giving population advice, as well. He added that most people know very well what the difference is between light to moderate drinking and binge or excessive drinking. While some patients may rationalize their heavy drinking because of its purported health effects, he has yet to find someone who had developed alcohol abuse because of messages about the health effects of moderate drinking. Medical practitioners, in his view, have a ‘‘solemn duty’’ to tell the truth about alcohol consumption, as they understand it, to all of their patients.