Critique 224: A brief summary of the association between wine/alcohol consumption and health in diabetics 12 March 2019
Golan R, Gepner Y, Shai I. Wine and Health–New Evidence. Mini Review. European Journal of Clinical Nutrition. https://doi.org/10.1038/s41430-018-0309-5; 2019: in press.
Authors’ Abstract
Health benefits of moderate wine consumption have been studied during the past decades, first in observational studies and more recently, in experimental settings and randomized controlled studies. Suggested biological pathways include antioxidant, lipid regulating, and anti-inflammatory effects. Both the alcoholic and polyphenolic components of wine are believed to contribute to these beneficial effects. Although several of these studies demonstrated protective associations between moderate drinking and cardiovascular disease, atherosclerosis, hypertension, certain types of cancer, type 2 diabetes, neurological disorders, and the metabolic syndrome, no conclusive recommendations exist regarding moderate wine consumption. Yet, it is suggested that the physician and patient should discuss alcohol use.
In the CASCADE (CArdiovaSCulAr Diabetes & Ethanol) trial, 224 abstainers with type 2 diabetes were randomized to consume red wine, white wine or mineral water for two years. Here, we summarize our previous findings, offer new evidence concerning the differential effects of wine consumption among men and women, and further suggest that initiating moderate alcohol consumption among well-controlled persons with type 2 diabetes is apparently safe, in regard to changes in heart rate variability and carotid plaque formation.
Forum Comments
An inverse association of moderate alcohol consumption with the risk of diabetes mellitus has been demonstrated consistently in epidemiologic studies for many decades (e.g., Stampfer et al). Lando et al reported a meta-analysis based on 15 prospective cohort studies that included 11,959 incident cases of type 2 diabetes in 369,862 individuals who, on average, were followed for 12 years. They report: “Compared with nonconsumers, the relative risk (RR) for type 2 diabetes in those who consumed ≤6 g/day alcohol was 0.87 (95% CI 0.79–0.95). For the moderate consumption ranges of 6–12, 12–24, and 24–48 g/day, RRs of 0.70 (0.61–0.79), 0.69 (0.58–0.81), and 0.72 (0.62–0.84) were found, respectively. The risk of type 2 diabetes in heavy drinkers (≥48 g/day) was equal to that in nonconsumers (1.04 [0.84–1.29]).” These authors concluded: “The present evidence from observational studies suggests an ∼30% reduced risk of type 2 diabetes in moderate alcohol consumers, whereas no risk reduction is observed in consumers of ≥48 g/day.”
Further, for subjects who have diabetes, most studies have shown a marked reduction in the risk of cardiovascular morbidity and mortality for moderate drinkers, in comparison with abstainers (e.g., Solomon et al; Koppes et al; Lando et al).
Specific comments by Forum members
Alcohol consumption and the risk of developing diabetes: Cardiovascular disease is a leading cause of death among diabetics, and most previous cohort studies have shown that moderate alcohol intake may reduce the risk of cardiovascular disease among diabetics. As reviewed by Forum member Stockley: “Earlier studies show that the consumption of large amounts of alcohol is associated with an increased risk of developing type 2 diabetes mellitus (Carlsson et al; Kao et al), and likely related to a dose dependent elevation of blood glucose levels (Gerard et al). The increased risk with the heavy consumption of alcoholic beverages may also reflect increases in body weight and changes to the plasma concentration of certain fats such as triglycerides, as well as increases in blood pressure (Wannamethee & Shaper; Wannamethee, Lowe, et al; Wannamethee, Camargo et al).
“On the other hand, moderate alcohol intake tends to reduce the risk of diabetes. A meta-analysis of 20 cohort studies by Baliunas et al suggested that for women, the risk of developing type 2 diabetes mellitus was observed to be most reduced at 24 g alcohol/day, with a risk reduction of 40% compared with lifetime abstainers. Alcohol consumption remained protective until approximately 50 g/day. For men, the protective effect of alcohol consumption was greatest at 22 g/day, with the risk of diabetes being 0.87 times that of lifetime abstainers, and remained protective until consumption of 60 g/day. Similarly, for both men and women, higher amounts of consumption (above 50 g/day for women and 60 g/day for men) were no longer protective and increased the risk for diabetes.”
A relatively recent meta-analysis by Li et al suggested that “Compared to abstainers, both light and moderate alcohol consumption reduced the risk of developing type 2 diabetes. Also compared to abstainers, however, heavier consumption did not increase or decrease significantly the risk of developing type 2 diabetes.” The authors added: “An ‘optimal’ amount to reduce risk in men was approximately 40 g alcohol/day and in women 20 g alcohol/day. Risk of developing type 2 diabetes was reduced by approximately 30% in both men and women with this moderate alcohol consumption.”
Effects of changes in alcohol intake on the risk of developing diabetes: An interesting study by Joosten et al reported not only on risk of diabetes associated with baseline alcohol intake but also on the effects of changes in alcohol intake over time. They found the following: “We prospectively examined 38,031 men from the Health Professionals Follow-Up Study who were free of diagnosed diabetes or cancer in 1990. Alcohol consumption was reported on food frequency questionnaires and updated every 4 years. A total of 1,905 cases of type 2 diabetes occurred during 428,497 person-years of follow-up. A 7.5 g/day (approximately half a glass) increase in alcohol consumption over 4 years was associated with lower diabetes risk among initial nondrinkers (multivariable hazard ratio [HR] 0.78; 95% CI: 0.60–1.00) and drinkers initially consuming <15 g/day (HR 0.89; 95% CI: 0.83–0.96), but not among men initially drinking ≥15 g/day (HR 0.99; 95% CI: 0.95–1.02; P-interaction < 0.01).” They concluded: “Increases in alcohol consumption over time were associated with lower risk of type 2 diabetes among initially rare and light drinkers. This lower risk was evident within a 4-year period following increased alcohol intake.”
Alcohol’s effects on cardiovascular disease among diabetics: In addition to lowering the risk of developing diabetes among healthy people, moderate alcohol may lower the risk of cardiovascular disease among people who already have diabetes. Stockley comments: “As in the general population, a decrease is also observed in cardiovascular risk with moderate alcohol consumption in type 2 diabetics (Ajani et al; Hu et al; Scognamiglio et al, Beulens et al). For example, from the SMART study, Beulens et al observed that ‘Moderate alcohol consumption (1-2 drinks/day) was not only associated with a reduced risk of vascular and all-cause death in high-risk patients with clinical manifestations of vascular disease, but also with reduced risks of non-fatal events like coronary heart disease (CHD), stroke and possibly amputations.’
“Many other observational studies have confirmed the association of moderate alcohol consumption with a reduced risk of CHD and vascular mortality. In an early report from a prospective cohort study with 12.3 years of follow up, Valmadrid et al found that, compared with never drinkers and controlling for age, sex, cigarette smoking, glycosylated hemoglobin level, insulin use, plasma C-peptide level, history of angina or myocardial infarction, digoxin use, and the presence and severity of diabetic retinopathy, former drinkers had a relative risk (RR) of 0.69 (95% confidence interval [CI], 0.43-1.12); for those who drank less than 2 g/d (less frequent than 1 drink a week), the RR was 0.54 (95% CI, 0.33-0.90); for 2 to 13 g/d, it was 0.44 (95% CI, 0.23-0.84); and for 14 or more g/d (about 1 drink or more a day), it was 0.21 (95% CI, 0.09-0.48). These authors concluded: ’Our results suggest an overall beneficial effect of alcohol consumption, decreasing the risk of death due to coronary heart disease in people with older-onset diabetes.’”
Rajpathak et al, in a prospective cohort study of 3,198 women with diabetes from the Women’s Health Initiative, concluded: “Moderate alcohol consumption of postmenopausal women with type 2 diabetes may have a benefit on CHD, with a similar risk to that seen in postmenopausal women who are not diabetics. The potential risks of alcohol on noncardiac outcomes may need consideration when recommending alcohol to women with diabetes.”
In an analysis of 2,419 men who reported a diagnosis of diabetes at age 30 or older in the Health Professionals’ Follow-up study (HPFS), Tenasescu et al documented 150 new cases of CHD (81 nonfatal myocardial infarction [MI] and 69 fatal CHD). They found that alcohol use was inversely associated with risk of CHD in men with type 2 diabetes. The age-adjusted RRs corresponding to intakes of 0.5 drinks/day, 0.5 to 2 drinks/day and 2 drinks/day were 0.76 (95% confidence interval: [CI]: 0.52 to 1.12), 0.64 (95% CI: 0.40 to 1.02) and 0.59 (95% CI: 0.32 to 1.09), respectively, as compared with nondrinkers.
Forum member de Gaetano added that it is also important to consider diet when one seeks to prevent cardiovascular disease in diabetics: “In our studies, the traditional Mediterranean diet was associated with reduced risk of both total and cardiovascular mortality in diabetic subjects, independent of the severity of the disease. Major contributions were offered by moderate alcohol intake, high consumption of cereals, fruits. and nuts, and a reduced intake of dairy and meat products (Bonaccio et al).”
Randomized clinical trials of alcohol in diabetics. There have been few randomized clinical trials among humans of the effects of wine or alcohol administration among diabetics. An early trial by Joosten et al showed that “Moderate alcohol consumption for 6 weeks improves insulin sensitivity, adiponectin levels and lipid profile in postmenopausal women.” More recently, an important long-term trial was reported from Israel where the investigators carried out an intervention study in which non-drinking diabetic patients were randomly assigned to begin to consume 150 mL of mineral water, white wine, or red wine with dinner each day for 2 years (Gepner, Golan, et al). These authors report: “Red wine significantly increased high-density lipoprotein cholesterol (HDL-C) level by 0.05 mmol/L (2.0 mg/dL) and apolipoprotein(a)1 level by 0.03 g/L Only slow ethanol metabolizers (alcohol dehydrogenase alleles [ADH1B*1] carriers) significantly benefited from the effect of both wines on glycemic control (fasting plasma glucose, homeostatic model assessment of insulin resistance, and hemoglobin A1c) compared with fast ethanol metabolizers (persons homozygous for ADH1B*2). Overall, compared with the changes in the water group, red wine further reduced the number of components of the metabolic syndrome by 0.34 (CI, -0.68 to -0.001; P = 0.049).” They conclude: “This long-term RCT suggests that initiating moderate wine intake, especially red wine, among well-controlled diabetics as part of a healthy diet is apparently safe and modestly decreases cardiometabolic risk.” In the present paper, these authors comment further on the association of wine and health outcomes among diabetics.
Are there dangers from moderate alcohol intake among diabetics? Reviewer Goldfinger commented: “The paper makes the case for safety and benefit in diabetics who choose to consume wine, particularly red wine, and that clinicians can safely speak of the positive health effects for those who chose to consume wine and alcohol in moderation. It clearly does not, however, solidify the recommendation that diabetics who do not drink at present be encouraged to drink. However, one must remember that diabetics, harboring diffuse microvascular pathology, succumb not from excessive sweetness but from cardiovascular disease and its consequences, such as myocardial infarction, cardiomyopathy, and sudden death.”
Goldfinger continued: “Interestingly this paper looked at heart rate variability (HRV) as a marker for atherosclerosis. More so, HRV is a marker for sudden cardiac death, and whereas their finding of exposure to one glass of red wine had no effect on HRV parameters, it appears to me to be a soft and marginally significant finding. One glass of red wine may not increase the risk of sudden death in this small population. Would we otherwise have expected the contrary?
“These authors also looked at carotid plaque volume, but I am unclear how this was measured. Carotid intimal medial thickening, a surrogate for atherosclerotic burden mentioned in their paper, is a technically difficult sonographic tool, hard to reproduce (at least it was in our lab), and, in my opinion, of limited value. Their comment of ‘a possible trend among those with the highest plaque burden at baseline’ is also a soft finding. In summary, diabetics die from cardiovascular disease, particularly complications of atherosclerosis. They stand to benefit the most, of all groups, from the salutary effects of moderate regular wine consumption. This paper, softly, restates this point.”
Wine as part of a healthy diet: Reviewer de Gaetano noted that it is also important to consider diet when one seeks to prevent cardiovascular disease in diabetics: “It may be useful to recall some recent data from the Moli-sani Study cohort, showing the role of alcohol in moderation within the context of a Mediterranean diet. Briefly, in a sample of about 2,000 subjects with type 2 diabetes in whom high adherence to Mediterranean diet was associated with significantly improved survival, removal of moderate alcohol intake from the Mediterranean diet score reduced by 15% the overall beneficial effect of the Mediterranean diet. The traditional Mediterranean diet was associated with reduced risk of both total and cardiovascular mortality in diabetic subjects, independent of the severity of the disease. Major contributions were offered not only by moderate alcohol intake but by a high consumption of cereals, fruits and nuts and reduced intake of dairy and meat products. The majority of the people enrolled were wine consumers (Bonaccio et al).”
Reviewer Van Velden commented: “The present study confirms our results of the influence of moderate consumption of red wine, compared with brandy, on cardiovascular risk factors. It must, however, also be noted that wine drinkers on average have a healthier lifestyle than brandy drinkers, and they have a more vegetarian-like diet that adds to the health benefits of wine drinkers. Scientists tend to focus on mono-interventions, and we have to take confounders into consideration in our analyses.”
Should diabetics be encouraged by their physicians to consume wine for its health effects? Reviewer Skovenborg noted: “The issue of discussion is whether doctors should recommend light to moderate use of alcohol to their patients with diabetes. Indeed, a greater absolute benefit would actually be expected in older patients with diabetes, compared with unselected populations, because they are at higher baseline risk of CHD, comparable to subjects with known cardiac disease.”
Forum member Waterhouse wrote: “A concern about recommending that someone begin drinking is the fear that this will lead to abusive consumption. I am sure the dataset is confounded by some inaccurate reporting, as alcohol abusers often have periods when they abstain from drinking, or report that they do, but it appears that the risk of abuse from individuals who mainly consume wine is lower than with the consumption of other beverages (Flensborg-Madsen et al).” Forum member Finkel agreed: “I would note that physicians need not feel constrained in suggesting modest drinking when they deem the evidence of benefit suffices and when they know their patient well enough.”
Forum member de Gaetano and his colleagues, along with reviewers Puddey and Ursini, were more cautious about encouraging alcohol consumption. Stated de Gaetano: “We agree with your general conclusions, in the sense that it is correct and ethical for a MD to inform his/her diabetic patients about the results of many observational studies suggesting a beneficial effect of moderate alcohol (especially red wine) consumption in type 2 diabetes. We believe however that a doctor should simply inform but not formally advise (nor, of course, ‘prescribe’) nondrinking diabetic patients to start to consume alcohol (wine) in moderation for health reasons only. Our opinion mainly relates to the fact that little data are presently available from randomized controlled trials to show that nondrinking diabetics who start drinking alcohol/wine have health benefits. We rather prefer to say that regular moderate drinkers should not be encouraged by their doctor to stop drinking (especially if they drink during healthy meal consumption), in marked contrast with the conclusions from WHO, some recent Lancet articles, and the Italian Istituto Superiore di Sanità that all strongly recommend no alcohol consumption at all, at any dose, for any healthy or diseased people: zero tolerance!”
Forum member Puddey noted: “This is quite a brief review of the previously reported outcomes from the CASCADE trial and fails to convey the complexity in interpreting the results from those reports. The first report related to the effects of alcohol on lipids, glycaemic control and parameters constituting the metabolic syndrome (Gepner, Golan, et al). Improvements in HDL-C levels were seen only with red wine, not white wine consumption, while improvements in glycaemic control were seen only with white wine and not red wine. Only red wine, not white wine, improved the number of components of the metabolic syndrome, but at the same time had no effects on visceral adiposity or abdominal fat distribution (Golan, Shelef, et al). The divergent results for red vs white wine (with nearly identical doses of alcohol from the red vs white wine – 16.9g vs 15.8g) do not argue for a consistently favourable effect of alcohol on cardiovascular risk factors in type 2 diabetic patients and would be a relatively weak basis on which to recommend the commencement of a daily glass of wine in patients who had previously been largely non-drinkers.
“This is reinforced further in the current report where we are informed that any benefits of alcohol as red wine on HDL-C and apolipoprotein (a) were only confined to female participants (who comprised only 31% of the study participants), with no changes seen in the males. The authors raise the possibility of a moderating influence of gender on alcohol metabolism and suggest this would need consideration before any recommendation for diabetic patients to commence a daily glass of alcohol. The authors have also previously reported on the potential impact of genetic variants of alcohol dehydrogenase in their participants further modifying any favourable responses seen (Gepner, Golan, et al: Gepner, Henkin et al), with improvements in glycaemic control seen only in slow metabolisers of alcohol (35.6% of the study participants). In contrast, although no overall changes in blood pressure were seen, early falls in night time blood pressure were observed only in fast metabolisers of alcohol (21.3% of the study participants).
“Type 2 diabetic patients are not uncommonly on a large number of medications with several co-morbid conditions and again this would need serious consideration before a general recommendation for non-drinkers to commence a glass of wine a day. In this regard, the authors reported that falls in blood pressure after alcohol ingestion were seen only in those already taking antihypertensive medication. Our group has also previously reported falls in night time systolic BP after 4 weeks ingestion of 24-31g alcohol per day as red wine in type 2 diabetic patients, but this was followed by increases in daytime systolic BP and accompanied by a 24 hr increase in heart rate (Mori et al). As we commented at the time, such an increase in HR could ultimately be detrimental, higher HR being predictive of increased microvascular complications and increased cardiovascular mortality in type 2 diabetic patients. In addition, in contrast to all our previous alcohol intervention trials, our study in type 2 diabetics found no effect of alcohol to favourably increase HDL-C or decrease fibrinogen levels, despite a higher daily alcohol intake than that used in CASCADE (albeit for a much shorter period). The CASCADE trial found no effect of 2 years of alcohol ingestion on carotid atherosclerosis (Golan, Shai, et al). Until further long term trials are carried out, especially those with hard cardiovascular or total mortality endpoints, I think an evidence base for recommending a daily glass of wine to non-drinking type 2 diabetic patients has not been established.”
Reviewer Ellison noted that studies by his own colleagues also failed to support an association between alcohol intake and calcified carotid atherosclerosis (Ellison et al). Those authors stated: “Despite its frequently demonstrated beneficial effects on coronary artery disease risk, alcohol consumption in this study was not associated with calcified atherosclerotic plaque in the coronary arteries or in the aorta. This suggests that alcohol’s effects on cardiovascular risk may occur through mechanisms other than those associated with the development of calcified plaque. On the other hand, many studies (e.g., Freiberg et al) have shown a beneficial effect of moderate alcohol consumption on most components of the metabolic syndrome. In any case, I believe that it is much more important to relate alcohol consumption to direct measurements of disease end-points, such as myocardial infarction and cardiac death; focusing on only one indirect measure is not sufficient to judge the net effects of alcohol intake on disease.”
Physicians should discuss alcohol consumption with all patients: Forum members believe that it is important that physicians discuss alcohol consumption with all of their patients. Forum member Ellison stated: “While I can agree with Dean Puddey that general advice to the public should not state that everyone should consume alcohol, at the same time I think that it is not ethical if physicians withhold valid scientific data about light-to-moderate alcohol consumption from patients. The large majority of patients in most areas of the USA and most European countries have had some exposure to alcohol in the past; there appear to be few ‘never drinkers’ in these populations. Obviously, if someone has religious prohibitions against alcohol, has had a previous problem with alcohol, has severe liver disease or other condition that may be aggravated by alcohol, or does not wish to consider drinking, he/she should not be encouraged to consume alcohol.
“Otherwise, for middle-aged or older patients with no prohibitions against alcohol use, especially those at high risk of cardiovascular disease, the physician should be prepared to describe current scientific data on the topic. (Given the wild exaggerations about alcohol use that frequently appear in the media, the latter is not a reliable source for learning the truth about drinking.) For people who drink only occasionally and have no concerns about drinking, the emphasis could be on favorable effects of small amounts with food on a regular basis. For those whose alcohol experience is bouts of heavy drinking, they should be told not only that such habits are harmful both to themselves and others, but that any health benefits are lost with such drinking. If they decide that they would desire to continue drinking, the physician could advise that they consume small amounts on a regular basis, and preferably with food. The risk that such information about moderate drinking would lead to alcohol abuse is considered to be extremely small, while the potential health benefits could be considerable.”
In a Panel Discussion at an international conference in 2007, Arthur Klatsky, MD, a noted cardiologist and one of the leaders in this field for decades, summarized extremely well the situation of physicians advising alcohol consumption to individuals: “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” (Panel Discussion V: The message on moderate drinking, Annals of Epidemiology).
References from Forum Critique
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Forum Summary
Diabetes mellitus is an increasingly common condition throughout the world, related closely to increases in obesity and ageing of populations. There are many, serious health conditions associated with diabetes, especially a marked increase in the risk of morbidity and mortality from cardiovascular disease. Scientific data from well-done cohort studies have demonstrated for decades that people who are moderate consumers of alcohol tend to have a considerably lower risk of developing diabetes in the first place, and diabetics who consume moderate amounts of alcohol are, in comparison with abstainers, at much lower risk of developing cardiovascular disease.
The present “mini-review” by scientists who have previously carried out the first large randomized clinical trial of wine and health outcomes among diabetics provides an interesting overview of the association of alcohol, particularly of wine, with health. The authors expand the implications of their research and conclude that “Initiating moderate alcohol consumption among well controlled persons with type 2 diabetes is apparently safe, in regard to changes in heart rate variability and carotid plaque formation.” Their findings have stimulated this critique by our Forum to also consider if available data now suggest that physicians should encourage the modest consumption of wine with food for selected patients with diabetes.
Our critique describes a number of risk factors (lipid levels, glucose, insulin, etc.) and intermediate conditions (such as endothelial function and arterial calcification) that have been shown to relate to the consumption of alcohol. Some Forum members believe that while all of these associations are important, the key information needed is the effect of alcohol consumption on disease outcomes themselves (coronary heart disease, stroke, dementia, etc.) and on mortality. At present, any recommendations regarding alcohol consumption must be based primarily on observational data from long-term cohort studies.
The key question we discuss in this critique is “Should physicians advise their older diabetic patients who are non-drinkers to begin to consume small amounts of an alcoholic beverage?” The consensus of Forum members is that current data suggest that, at a minimum, we should not advise such patients who currently consume alcohol moderately to stop their consumption. On the other hand, most members emphasize that we should discuss alcohol consumption with all patients. If they are at least occasional consumers of alcohol (the large majority of patients in most Western countries), our only advice might relate to the pattern of drinking. At present, the pattern commonly shown to be associated with the lowest risk of the usual diseases of ageing and mortality appears to be small amounts of alcohol, especially wine, with meals on a regular basis. For patients who indicate that they are drinking only in binges, we should emphasize the adverse health effects (for them as well as for society), and encourage a healthier pattern of drinking.
But what about current non-drinkers? For middle-aged or older non-drinkers who avoid alcohol because of religious prohibitions, previous misuse of alcohol, certain medical conditions, or a stated dislike of alcohol, our advice on prevention of disease should focus on not smoking, getting exercise, eating a healthy diet, and trying to avoid obesity. But for patients without such conditions that would indicate that they should avoid alcohol, many Forum members believe that they should at least be told of the current scientific evidence of possible beneficial health effects of regular, moderate intake. However, until considerably more data on its effects are available, we are not encouraging physicians to prescribe alcohol consumption for their diabetic patients.
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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, Emeritus, Faculty of Medicine, Dentistry & Health Sciences, University of Western Australia, Nedlands, Australia
Creina Stockley, PhD, MSc Clinical Pharmacology, MBA; Adjunct Senior Lecturer at the University of Adelaide, Australia
David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa
Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board, Aarhus, Denmark
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway
Harvey Finkel, MD, Hematology/Oncology, Retired (Formerly, Clinical Professor of Medicine, Boston University Medical Center, Boston, MA, USA)
Andrew L. Waterhouse, PhD, Department of Viticulture and Enology, University of California, Davis, USA
Susan J van Rensburg, PhD, Department of Pathology, Stellenbosch University, Tygerberg, South Africa
R. Curtis Ellison, MD, Professor of Medicine, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA
Giovanni de Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy
Fulvio Ursini, PhD, Dept. of Chimica Biologica, Universit a di Padova, Padova, Italy
Pierre-Louis Teissedre, PhD, Faculty of Oenology–ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France
Tedd Goldfinger, DO, FACC, Desert Cardiology of Tucson Heart Center, University of Arizona School of Medicine, Tucson, AZ, USA