Gender

Women are known to show decreased tolerance to alcohol, which is thought to relate to lower levels of alcohol-clearing enzymes (especially alcohol dehydrogenase), their generally smaller body size, and the greater proportion of their body consisting of fat, which metabolizes alcohol less well than muscle does. Both the beneficial and adverse effects of alcohol appear at lower dosages for women. Hence, guidelines generally suggest that moderate drinking for women should be only about half the amount of alcohol for men. From a meta-analysis, Di Castelnuovo and coworkers found that women drinkers showed an increase in mortality over that of nondrinkers above about 2 drinks/day, whereas the increase among men was at about drinks/day. In the Australia Longitudinal Study on Women’s Health, with approximately 12,000 subjects aged 70 years and older, Byles and colleagues found that nondrinkers and women who rarely drink had a significantly higher risk of dying (HR = 1.94; 95% CI, 1.4-2.6) during the survey period than did women who consumed alcoholic beverages at a level of one or two drinks per day; the best general health status and highest levels of physical functioning were among those drinking at this level for 3 to 6 days per week.

Age

Alcohol has been shown to be associated with CHD in the elderly as well as in middle-aged people. In the Cardiovascular Health Study, subjects older than 65 years who consumed 14 or more drinks per week had a risk of incident myocardial infarction or cardiac death about 40% lower than that of abstainers. People tend to drink less as they age, and most current recommendations state that individuals older than 65 years should drink less than what is considered moderate for younger people. On the other hand, two analyses comparing the health effects among elderly subjects consuming one or two drinks per day, in comparison with those consuming only one drink per day or less, have not shown higher morbidity or mortality among those consuming more alcohol.

Tolvanen and colleagues evaluated 10-year mortality according to alcohol intake among subjects initially aged 60 to 99 years, of whom 50% of men and 40% of women died during follow-up. After adjustment for age, sex, educational level, marital status, chronic diseases, functional ability, and smoking, the relative risk for mortality of frequent drinkers (versus nondrinkers) was 0.6 (95% CI, 0.4, 0.8); for occasional drinkers, 0.7 (0.5, 1.0); and for ex-drinkers, 1.1 (0.8, 1.7).

Ethnicity

Whereas most of the original studies relating alcohol intake to CHD were in Europeans and European Americans, a large number of studies have found essentially the same effects among Asians. Data on African Americans are limited, and Sempos and colleagues found no inverse association between alcohol and CVD risk among African Americans. Klatsky and associates, however, found similar inverse associations between alcohol and heart failure in the Kaiser Permanente cohort among whites, Asians, and African Americans. Using data from the Women’s Health Initiative, Freiberg and coworkers reported lower total mortality among African American hypertensives who consumed alcohol than among those who did not drink, but a similar relation was not seen among nonhypertensive African Americans.

Lipids

The first recognized mechanism by which alcohol may prevent CVD relates to induced changes in plasma lipid profile, especially increases in high-density lipoprotein cholesterol (HDL-C) and its subtypes (HDL ₂ , HDL ₃ ). Numerous observational and experimental studies have confirmed a strong, direct association between alcohol intake and HDL. Although it was initially believed that only certain HDL subtypes were increased by alcohol (and that those had little effect on CVD risk), alcohol intake has been shown to increase both HDL ₂ and HDL ₃ , and both play a role in CVD prevention. In addition, most studies also show slightly lower LDL concentrations, especially small-particle LDL, and non-HDL lipoprotein levels among moderate drinkers. Oxidation of lipids has been shown to be decreased by alcohol or polyphenols in many studies but not in all.

Platelet Aggregation and Thrombosis

As described by Booyse and colleagues, other changes in vascular, myocardial, hemostatic, and endothelial cell functions may be equally important in collectively contributing to the reduction of the risk of CVD. These factors appear to result from alcohol, from polyphenols present in some beverages (especially wine), or from a combination of both, resulting in reduced thrombosis.

The early studies of Serge Renaud and his colleagues pointed out the importance of platelet function in the development of atherosclerosis, thrombosis, and CHD. In an intervention study in humans, Zhang and coworkers showed that alcohol, at physiologically relevant doses, has a dose-dependent inhibitory effect on platelet aggregation. These authors concluded that their findings are consistent with the view that alcohol reduces platelet sensitivity to thrombotic stimuli by inhibition of arachidonic acid release and therefore subsequent thromboxane synthesis. Inhibition of platelet aggregation or function has also been shown by others. Ruf suggested that wine has a greater effect on platelet function than alcohol alone does, stating that the polyphenols in wine provide further reduction in prostanoid synthesis from arachidonate and also decrease platelet activity mediated by nitric oxide. Demrow and colleagues demonstrated that polyphenols from both red wine and grape juice favorably affect platelet aggregation.

Many of the effects of alcohol and polyphenols on coagulation are transient effects, and the beneficial effects may last only 24 to 36 hours after someone has consumed alcohol. Furthermore, after heavy alcohol intake, there may be a rebound with increased platelet aggregation if further alcohol is not consumed, although such rebound may be less after drinking wine than after consuming other beverages. One explanation for the much lower CHD rates in France than in most other countries is that the French have traditionally consumed some alcohol (primarily red wine) with their evening meal every day. Thus, their clotting mechanisms remain in a favorable state all of the time. Unfortunately, many Americans and northern Europeans tend to drink only on the weekend, often consuming a large number of drinks rapidly, a very unhealthy way to drink.

Other Mechanisms

Additional mechanisms for protection of alcohol and polyphenols against CHD and myocardial infarction include decreased myocardial ischemia-reperfusion injury, increased endothelial cell–dependent vasorelaxation, simultaneous activation of endothelial cell antiapoptotic and proapoptotic pathways, decreased plasma levels of factor VII and fibrinogen, increased fibrinolysis and upregulation of fibrinolytic protein gene transcription in cultured human endothelial cells, and increased levels of atrial natriuretic peptide.

There is also strong experimental evidence for additional mechanisms by which alcohol and wine polyphenols affect the initiation or progression of atherosclerotic lesions. These include reduced LDL oxidation and aggregation, foam cell formation, and lesion progression ; inhibition of endothelin 1 synthesis ; downregulation of tissue factor gene transcription in cultured human endothelial cells and monocytes ; and inhibition of smooth muscle cell proliferation. Research studies increasingly show a strong protective effect from alcohol and polyphenols against various indices of inflammation. Wang and colleagues have shown a U-shaped association between alcohol and high-sensitivity C-reactive protein (hsCRP) levels; a proportional odds model analysis showed an odds ratio for increased hsCRP of 0.32 (95% CI, 0.14-0.74) for consumers of 20 to 70 g/day (about to almost 6 drinks) in comparison with nondrinkers. Alpert and coworkers found that CRP was lowest in consumers of 5 to 7 drinks/week.

Booyse and coworkers have demonstrated the sequence of molecular events by which endothelial cell expression of tissue plasminogen activator is increased through common activation of p38 MAPK signaling by alcohol as well as by certain wine polyphenols. Gorelik and associates have shown that red wine polyphenols lower levels of postprandial cytotoxic lipid peroxidation products (malondialdehyde) in humans, another possible mechanism for the benefits of the consumption of wine on risk of disease.

In some epidemiologic studies, the combined beneficial effect of alcohol on HDL-C, fibrinogen, and hemoglobin A1c (the last a marker of glycemic control and insulin resistance) can almost entirely explain the reduced CHD risk among moderate drinkers.

Hypertension

One cardiovascular risk factor that is generally not associated favorably with alcohol consumption is hypertension, and most studies show an elevation of blood pressure with increasing alcohol intake. Some studies show that the effect is mainly from heavier drinking and that light alcohol intake has no effect or even a slight lowering of blood pressure. For example, Klatsky and associates found increases in blood pressure only among subjects reporting three or more drinks per day, a finding similar to the association in all groups except African American men in an ARIC report. In the Luebeck Blood Pressure Study in Germany, Keil and associates reported increases in blood pressure for men consuming more than 40 g of alcohol per day (more than three typical drinks) or women reporting more than 20 g/day. Klatsky and associates have shown that hypertension remains a strong risk factor for CVD regardless of alcohol intake, and hypertensives who are heavy drinkers show a substantial decrease in blood pressure when they decrease their intake. Whereas a direct association between alcohol and blood pressure has been confirmed in most studies, important sequelae of hypertension (notably CHD and ischemic stroke) show an inverse association with moderate drinking.

Genetic Risk Factors

There is no question that individuals differ markedly in their response to alcohol consumption, for its beneficial and adverse health effects. Davey Smith has described how “mendelian randomization—the random assortment of genes from parents to offspring that occurs during gamete formation and conception—provides one method for assessing the causal nature of some environmental exposures.” Such an approach avoids many of the problems of confounding in observational studies. He concluded that “mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.”

At present, however, the association of genes with CHD is poorly understood. The most studied individual genes are those that relate to the metabolism of alcohol, especially those that control alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). Hines and coworkers showed that moderate drinkers who are homozygous for the slow-oxidizing ADH3 allele had higher HDL levels and a substantially decreased risk of myocardial infarction. However, other studies have failed to show such an association. Jensen and coworkers have found conflicting results across different cohorts in their study relating lipoprotein lipase to CHD.

Current data suggest that there are many genes contributing to the effects of alcohol on the risk of CHD; each tends to play only a small role by itself but a potentially large role in combination with other genes and environmental factors. Furthermore, certain genes seem much more important in certain ethnic groups and cultures than in others. The large number of collaborative genome-wide association studies now being done, with huge numbers of subjects, should help clarify the role that genetic factors play in the potential protection against cardiovascular and other diseases from alcohol use.

Similarly, for cancer, data on genetic factors modifying alcohol’s effects are unclear. Druesne-Pecollo and coworkers published an overview of studies on the combined effects of alcohol drinking and polymorphisms in genes for ADH, ALDH, cytochrome P-450 2E1, and methylenetetrahydrofolate reductase on the risk of alcohol-related cancer. They concluded that current data lend support to a role of polymorphisms ADH1B and ALDH2 combined with alcohol consumption in cancer, but other available data are insufficient or inconclusive.

Summary of Mechanisms

Collins and associates have provided a summary of epidemiologic and mechanistic studies demonstrating how alcohol and polyphenols may be cardioprotective (as well as neuroprotective). In Figure 18-2 , mechanisms of cardioprotection by both alcohol and resveratrol, one of the polyphenols in red wine that has been studied extensively, are illustrated.

Cardioprotection from alcohol and from resveratrol. A, Cardioprotective and molecular targets of alcohol. Cardioprotective targets are shown on the right; the molecular targets are shown on the left. B, Cardioprotective and molecular targets of resveratrol. Cardioprotective targets are shown on the right; the molecular targets are shown on the left.

(From Collins MA, Neafsey EJ, Mukamal KJ, et al: Alcohol in moderation, cardioprotection, and neuroprotection: epidemiological considerations and mechanistic studies. Alcohol Clin Exp Res 33:206, 2009. Reprinted with permission.)

Clinical trials in humans are limited, but Leighton and colleagues have carried out a number of intervention studies looking at the effects of wine on CVD risk factors. Their results show that moderate wine consumption may result in an increase in HDL-C, a decrease in the omega-6/omega-3 ratio, and in some cases a slight increase in triglyceride levels. Observed changes in hemostasis include reduced coagulation and increased fibrinolysis; effects on blood pressure have been inconsistent. They have found a reduction in inflammatory markers and an improvement in endothelial function. These investigators concluded that limitation of consumption to below 30 g of alcohol daily (about typical U.S. drinks) for men and half that dose for women is necessary to prevent negative changes in cardiovascular risk factors such as hypertension, hypertriglyceridemia, and hyperhomocysteinemia. Other clinical trials have demonstrated improvements in glucose metabolism from the administration of alcohol. In the future, more such trials as well as genetic studies will help determine the extent to which the beneficial effects of alcohol consumption on CVD risk seen in most observational studies are caused by the alcoholic beverage itself.

Development of Diabetes

Stampfer and colleagues reported in 1988 that moderate drinkers in the Nurses’ Health Study had a lower risk for development of diabetes than did abstainers; compared with nondrinkers, women consuming 5 to 14.9 g of alcohol per day had an age-adjusted relative risk of diabetes of 0.4 (95% CI, 0.3-0.6); for 15 g or more per day, the relative risk was 0.3 (95% CI, 0.2-0.4). The authors reported that a strong inverse association between alcohol drinking and body weight explained much of the apparent protective effect of alcohol. After simultaneous adjustment for Quetelet index (weight [kg]/height [m] ² ), family history of diabetes, total calorie intake, and age, the relative risk of diabetes for consumers of 5 to 14.9 g/day was 0.8 (95% CI, 0.6-1.2), and for women who drank 15+ g/day, the relative risk was 0.6 (95% CI, 0.3-0.9). Reports in the British Medical Journal in 1995 from two large prospective studies similarly showed a lower risk of diabetes among moderate drinkers. Since then, many epidemiologic studies have presented data supporting such an inverse association. Howard and coworkers have provided a good summary of the research on alcohol and diabetes, giving an estimate of 33% to 56% lower incidence of diabetes for consumers of one to three drinks per day. A meta-analysis by Koppes and associates indicated that for a wide range of alcohol intake (from about to more than 3 drinks/day), the relative risk of diabetes for drinkers is about 30% lower than it is for abstainers.

Mechanisms are unclear for the effects of alcohol intake on diabetes. Some studies have shown lower glucose levels and HbA1c. In an intervention trial, Davies and coworkers found among nondiabetic postmenopausal women that the consumption of 30 g/day of alcohol reduced fasting insulin concentration by 19.2%, reduced triglyceride concentration by 10.3%, and increased insulin sensitivity by 7.2% but did not affect plasma glucose levels. Kroenke and associates found that HbA1c was inversely associated with alcohol intake; among overweight women, there was also an inverse association with insulin. Specifically, these investigators found that insulin levels were lowest for drinkers consuming no more than two drinks per day up to three days per week. In a large heterogeneous group of nondiabetic subjects, insulin sensitivity was lower among abstainers than in all categories of drinkers. Adiponectin serum levels were higher in men consuming alcohol on 2+ days/week than in nondrinkers or occasional drinkers; among women, those consuming all levels of alcohol had higher adiponectin concentrations than nondrinkers did.

There have also been a number of clinical trials relating alcohol intake to diabetic mechanisms. Sierksma and coworkers carried out a randomized crossover study of 23 healthy middle-aged men who were given 40 g of ethanol (four glasses of whiskey, versus no alcohol) on a daily basis for 17 days. They found that alcohol increased plasma adiponectin levels by 11% and increased the insulin sensitivity index in an insulin-resistant subgroup by 21%. A randomized crossover trial by Joosten and coworkers showed that moderate alcohol consumption increased insulin sensitivity and ADIPOQ expression in postmenopausal women.

Shai and colleagues carried out a randomized trial among 91 formerly abstaining diabetics who were randomly assigned to consume 5 ounces of either sauvignon blanc or merlot at dinner every evening or advised to continue to avoid alcohol. Significantly lower levels of fasting blood glucose concentration during a 3-month intervention period were seen among subjects consuming wine than were seen for abstainers. The effect of the wine was variable, with beneficial effects primarily among those with more severe disease.

Effects of Alcohol Intake on Cardiovascular Disease Among Diabetics

Valmadrid and coworkers reported that among persons with older-onset diabetes, the relative risk for death from CHD was 0.44 for subjects consuming 2 to 13 g/day and 0.21 for those consuming 14+ g/day, in comparison with nondrinkers. Solomon and colleagues reported from the Nurses’ Health Study that the risk for development of CHD among type 2 diabetics who were moderate drinkers was much lower than that for nondrinking diabetic subjects: for < drink daily, the relative risk was 0.72, and for ≥ drink daily, the relative risk was 0.45. In the Physicians’ Health Study, increasing levels of alcohol intake were associated with even greater reduction in deaths from CHD among diabetics than among nondiabetic subjects.

A meta-analysis by Koppes and associates indicates that the risk of CHD is 34% to 55% lower among diabetics who are moderate drinkers than in those who consume no alcohol. Among more than 38,000 diabetics observed by the Kaiser Permanente group in California, those who consumed alcohol had evidence of considerably better control of their diabetes than did nondrinkers ; the authors concluded that this finding “supports current clinical guidelines for moderate levels of alcohol consumption among diabetes patients.”

Alcohol has been shown to affect not only the macrovascular sequelae of diabetes but also the microvascular complications of diabetes. In a report from the EURODIAB Prospective Complications Study, involving the follow-up of 3250 type 1 diabetic patients from 16 different European countries, Beulens and colleagues found a lower occurrence of retinopathy, neuropathy, and nephropathy among those individuals who consumed alcohol moderately in comparison with nondrinkers. The association was strongest among wine drinkers, and to some extent among beer drinkers, but was not seen among those consuming spirits.

In summary, evidence from a large number of prospective epidemiologic studies and limited clinical trials strongly suggests that moderate drinkers are less likely to develop diabetes and its sequelae, especially CHD. Although not all of the mechanisms are known, many studies suggest improved insulin resistance or increased adiponectin levels.

Development of Metabolic Syndrome

The findings relating alcohol to metabolic syndrome show associations with alcohol similar to those for diabetes. In the NHLBI Family Heart Study and in NHANES III, we found evidence that moderate drinking is associated with lower risk of most components of the metabolic syndrome (all components except for hypertension). Fan and coworkers evaluated the association between estimates of lifetime alcohol intake and the metabolic syndrome. They found that subjects who averaged more than one drink per day for women or two drinks per day for men had an increase in their prevalence ratio for metabolic syndrome in comparison with drinkers who did not exceed these limits; nondrinkers were not included in these analyses. In a meta-analysis on alcohol intake and metabolic syndrome, based on data from seven previous studies with a total of 22,000 subjects, Alkerwi and coworkers found that the moderate intake of alcohol (defined as ≤40 g of alcohol per day for men and ≤20 g of alcohol per day for women) was associated with 16% lower risk of metabolic syndrome for men and 25% lower risk for women; no significant effects were seen for heavier drinking.

Obesity

An unexpected finding in epidemiologic studies is that obesity is often found to be less common among moderate drinkers than among abstainers. In the prospective Nurses’ Health Study, it was found that light to moderate drinking was not associated with weight gain in women (overall, a 16% lower risk for those reporting 15.0 to 29.9 g of alcohol per day versus abstainers). This potentially beneficial effect on weight gain was not seen in African American women or in heavier drinkers. Arif and Rohrer evaluated alcohol intake and BMI among 8236 nonsmoking respondents who participated in the Third National Health and Nutrition Examination Survey. Current drinkers who reported drinking one drink or two drinks per day had 0.46 (95% CI, 0.34-0.62) and 0.59 (95% CI, 0.41-0.86) the odds of obesity, respectively, than did abstainers.

Tolstrup and colleagues found that among men, the odds ratios for having a high BMI among subjects drinking 1 to 3 days/month, 1 day/week, 2 to 4 days/week, 5 or 6 days/week, and 7 days/week were 1.39 (95% CI, 1.36-1.64), 1.17 (1.02-1.34), 1.00 (reference), 0.87 (0.77-0.98), and 0.73 (0.65-0.82), respectively. Similar associations were found for waist circumference, and corresponding results were found for women. These authors concluded that for a given level of total alcohol intake, obesity was inversely associated with drinking frequency, whereas the amount of alcohol intake was positively associated with obesity. Such an association was supported by Breslow and Smothers among 45,896 never-smoking adults in the 1997-2001 National Health Interview Surveys in the United States. As shown in Figure 18-3 , from that study, more frequent drinking was associated with lower BMI. On the other hand, given drinking of a certain frequency, the number of drinks per drinking day was directly associated with BMI.

Alcohol consumption and BMI by frequency of drinking quintiles and quantity of alcohol. Association between alcohol consumption and BMI in stratified analyses of frequency quintiles within quantity categories, National Health Interview Surveys, 1997-2001. Q, quintile.

(From Breslow RA, Smothers BA: Drinking patterns and body mass index in never smokers: National Health Interview Survey, 1997-2001. Am J Epidemiol 161:368, 2005. Reprinted with permission.)

These results suggest that the frequent consumption of small amounts of alcohol is the optimal drinking pattern associated with a lower risk of obesity.

Bone Mineral Density and Hip Fracture

A number of epidemiologic studies have shown that moderate drinkers have less osteoporosis and a lower risk of hip fractures than do abstainers. (This goes against “conventional wisdom,” which has always assumed that elderly who drink alcohol may be more unsteady on their feet and at increased risk of falling and sustaining fractures.) Mukamal and colleagues found that among older adults, moderate alcohol consumption had a U-shaped relationship with risk of hip fracture but a graded positive relationship with bone mineral density at the hip. A meta-analysis by Berg and coworkers involving the review of 33 previous studies supports a reduced risk of hip fracture and higher bone density among men and women who consume small to moderate amounts of alcohol (in comparison with nondrinkers). There is probably a J-shaped curve, with increased risk of fractures among heavier drinkers.

Dementia

Among the most exciting recent scientific findings are that moderate drinkers tend to be less likely to develop Alzheimer disease and other types of dementia. This was reported for wine drinkers in Bordeaux by Orgogozo and colleagues in 1997, and Truelsen and coworkers reported similar protection from wine in Denmark, as did Panza and coworkers in a summary paper.

Britton and coworkers reported from the Whitehall Study in the United Kingdom that there was less cognitive impairment in drinkers for tests of memory (borderline significant), verbal and mathematical reasoning, verbal meaning, and verbal fluency. For men, the risk of dysfunction was lower by about 40% to 50% for drinkers, with the lowest risk at >241 g/week of alcohol, the equivalent of about three drinks per day by U.S. standards. Women drinkers had lower point estimates for most measures, but statistically significant results were seen for verbal and mathematical reasoning (OR = 0.3; CI, 0.2 -0.6) and for verbal fluency (OR = 0.5; CI, 0.3-0.9), both at 49 to 80 g of alcohol per week (the equivalent of about four to seven drinks per week). Lifetime abstaining men and women generally had much greater risk of cognitive dysfunction than did occasional drinkers.

Espeland and colleagues reported from the Women’s Health Initiative Memory Study that compared with no intake, intake of one drink or more per day was associated with higher baseline Modified Mini-Mental State Examination scores ( P < 0.001) and an odds ratio of 0.41 (95% CI, 0.23-0.74) for significant declines in cognitive function. Stampfer and coworkers reported that among women who were moderate drinkers, compared with nondrinkers, the relative risk of impairment was 0.77 for general cognition (95% CI, 0.67-0.88) and 0.81 on the global cognitive score (95% CI, 0.70-0.93). Zhang and coworkers reported that education modifies the putative effects of alcohol on memory, with better results among those with higher education, probably because of more moderate drinking patterns.

Ganguli and colleagues studied men and women aged 74.4 years at baseline who were observed during 7 years with repeated assessments of cognitive functioning; abstainers showed lower baseline scores and a tendency for more rapid deterioration in cognitive functioning than did drinkers. Solfrizzi and colleagues also found less progression from mild cognitive impairment to dementia for light drinkers in comparison with nondrinkers.

Mehlig and coworkers, in a well-done analysis from a long-term prospective study of women in Sweden, reported that the lifetime risk of dementia was associated differently with wine consumption (a decrease in risk of dementia of 70%) and spirits consumption (an increase in dementia risk of about 50%). The authors concluded that the different associations by type of beverage suggest that the nonalcohol components in wine may be an important factor in lowering the risk of dementia. Whereas the investigators adjusted for the usual risk factors for dementia, including education and social class, there is always the possibility that other lifestyle factors that are different between wine drinkers and spirits drinkers may have influenced the results.

Peters and associates carried out a meta-analysis on alcohol and dementia and concluded that moderate drinkers, especially wine drinkers, were at lower risk than abstainers for development of Alzheimer disease or other dementia. The mechanism for such protection is not known but may relate, among other factors, to prevention of cerebral atherosclerosis or decreased inflammation in brain tissue. Collins and associates have reported additional mechanisms for neuroprotection, as described earlier (under mechanisms of alcohol’s effects on CVD).