Moderate Consumption of Beer and Its Effects on Cardiovascular and Metabolic Health: An Updated Review of Recent Scientific Evidence

There is growing interest in the potential health-related effects of moderate alcohol consumption and, specifically, of beer. This review provides an assessment of beer-associated effects on cardiovascular and metabolic risk factors to identify a consumption level that can be considered “moderate”. We identified all prospective clinical studies and systematic reviews that evaluated the health effects of beer published between January 2007 and April 2020. Five of six selected studies found a protective effect of moderate alcohol drinking on cardiovascular disease (beer up to 385 g/week) vs. abstainers or occasional drinkers. Four out of five papers showed an association between moderate alcohol consumption (beer intake of 84 g alcohol/week) and decreased mortality risk. We concluded that moderate beer consumption of up to 16 g alcohol/day (1 drink/day) for women and 28 g/day (1–2 drinks/day) for men is associated with decreased incidence of cardiovascular disease and overall mortality, among other metabolic health benefits.


Introduction
In recent years, there has been an increasing interest in the potential health-related effects of moderate alcohol consumption. Although the harmful effects of excessive alcohol use are well established, the association of low-to-moderate alcohol consumption with health-related benefits is still controversial, since the results of available studies are not homogeneous and reaching clear conclusions is challenging. This lack of consensus is observed in alcohol consumption guidelines published in the last five years, which use different terminology ("risky drinking", "moderate consumption", or "low-risk drinking") as well as different drinking thresholds [1][2][3][4][5][6] (Table 1). Furthermore, other variables, such as differences in concentrations of non-alcoholic components (i.e., polyphenols), may confound the beneficial effects of specific alcoholic drinks [7,8]. Beer is an alcoholic beverage frequently consumed in Europe. In 2018, the average yearly beer consumption in Europe was 72 L per capita, with a few countries (Czech Republic, Austria, and Germany) consuming more than 100 L per capita per year [9]. However, patterns of consumption differ across the region varying from predominantly meal-associated drinking in Mediterranean countries, to high rates of heavy episodic drinking in Central and Eastern Europe, and relatively frequent consumption both with and outside of meals in Central Western Europe [10].
Beer is mainly composed of water, but it is also rich in nutrients-carbohydrates, amino acids, minerals, vitamins, and polyphenols-resulting from a multi-step brewing and fermentation process [7,[11][12][13]. Hop flowers, used as a bittering and flavoring agent [14], contain phenolic compounds, including prenylated flavonoids [15,16], which have been shown in vitro to have different antioxidant, anticarcinogenic, anti-inflammatory, oestrogenic, and antiviral biological activities [7,17]. Xanthohumol is the most abundant of these compounds and, in addition to potential bioactivity [7,18], it also inhibits platelet activation without increasing the bleeding risk [19]. Thus, brewing processes have been optimized to achieve the highest possible content of xanthohumol [20]. Regarding antioxidant content, ale beers have been reported to display a higher antioxidant activity than lager beers due to the higher fermentation temperature in the brewing process. However, despite these enrichment processes, controversy remains as to the bioavailability of the phenolic compounds in beer [21][22][23].
Alcohol content in regular beers varies between 3% and 6% alcohol by volume [11]. There is vast scientific literature on excessive alcohol consumption. Indeed, chronically high alcohol intake acts as a toxin to the heart and vascular system and may also exacerbate pre-existing heart disorders. However, low-to-moderate amounts of alcohol intake might have beneficial effects on the cardiovascular (CV) system, since it increases high-density lipoprotein cholesterol (HDL) and reduces arterial stiffness (both effects shown specifically with beer) [21,22,24,25], and also decreases fibrinogen, platelet activation and aggregation, as well as blood oxidative stress and inflammatory parameters [26][27][28]. The alcohol content of beer might also have an effect on glucose homeostasis [29]. Alcohol contributes to total calorie intake and may increase weight when consumed in excess [30,31]. Non-alcoholic components also contribute to the energy content of beer. Thus, Public Health England lists the mean energy content of alcohol-free beers at seven kilocalories/100 g [32]. Overall, 28% of the total monthly kilocalories contributed by beer among regular drinkers derive from its non-alcoholic ingredients [33].
We conducted an analysis of all reviews, meta-analyses, and longitudinal, prospective, cohort studies published from January 2007 to April 2020 regarding beer consumption and its relationship with CVD and mortality risk, with the objective of evaluating the average intake of beer that could be considered "moderate" based on the reported consumption. Furthermore, we aimed to identify several differences shown in specific population subgroups in the selected studies.

Materials and Methods
In April 2020, a literature search of papers published after January 2007 was conducted using PubMed EMBASE, and through reference list cross-checking of previous meta-analyses, prospective clinical studies, and systematic reviews in humans, evaluating beer effects on health. The search strategy retrieved citations from databases containing the subject heading "beer" in combination with "health", "cardiovascular", "mortality", "obesity", "diabetes", "young", "women", or "alcoholism". The search terms were adapted for use with both bibliographic databases (Table 2). Original eligible papers, based on their title/abstract, were obtained and reviewed to select those meeting the inclusion criteria: clinical studies in humans with prospective cohort design, plus systematic reviews and meta-analyses evaluating beer effects on health since 2007, and publications that authors considered could provide additional information on the subject. A total of 13 reviews (narrative or systematic reviews and/or meta-analysis), 9 prospective cohort studies, and 1 open-label, randomized, cross-over study were selected (Table 3).

Results
A summary of related studies is shown in Table 4. Two reviews referring specifically to beer, reported that moderate consumption (up to 55 g alcohol/day; i.e., 385 g/week) showed a beneficial effect on non-fatal CV events [34,57]. Both reviews found that the highest effect was associated with moderate beer or wine consumption, suggesting that the polyphenolic content of these beverages probably contributes to the observed CV benefits [34,57]. Threshold for lowest risk of all-cause mortality was 100 g/week. Association between alcohol consumption and total CVD risk showed higher HR for beer and spirits than for wine.   These data are in agreement with most findings from reviews/meta-analyses and cohort studies, which report a protective effect of moderate alcohol drinking for CVD compared to abstention, former drinking, or occasional drinking [22,34,47,49,56,57,60]. Only the review by Toma et al. does not support these conclusions; the authors suggest that this protective effect may be a confounder due to the inclusion of former drinkers in the non-drinkers group [48]. However, the prospective cohort study by Bell et al., conducted in almost 2 million people, took these potential confounders into consideration, and also found a positive effect of moderate drinking (112 g/week in women and 168 g/week in men) on CV risk [49]. Costanzo et al. found a negative (although not significant) association between spirits and vascular events, suggesting alcohol content, and not solely polyphenols, may also play a role in cardiovascular events [57]. Moreover, as Roerecke et al. [54] noted that distinctions between former drinkers and lifetime abstainers might not be sufficient for an accurate analysis, based on the heterogeneity of reasons underlying non-drinkers' decision not to drink, which might further confound the results. Finally, drinking patterns may also play a key role in outcomes [54], since self-reported weekly intakes might include alcohol consumed during the weekend during a binge, which would be associated with worse CV results.

Gender Differences
Due to the paucity of separate data for men and women, none of the beer-specific CVD studies stratified their conclusions by gender. The meta-analysis by Roerecke et al. [54] noted that women are more sensitive to the protective effect of moderate alcohol consumption, based on a previous meta-analysis [56], which showed a steeper J-curve for ischemic heart disease (IHD), mortality and morbidity in women than in men. The detrimental effect on CV risk of binge drinking seems to be lower in women than in men [49,60], and an increased risk of heart failure has been observed in abstemious women compared with moderate drinkers [49]. In addition, Snow et al. [60] observed that the beneficial effects of low and/or moderate usual consumption on CV risk were only evident in younger women (aged 18-34), whereas cardio-protection became evident at middle (aged [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] or older age (aged 50-64) in men. Overall, these gender differences may be due to hormonal changes over the life course or to a lower lifetime consumption of total alcohol.

Moderate Beer Consumption and Mortality
A summary of related studies is shown in Table 5. The systematic review by de Gaetano et al. [34] suggested that a J-shaped relationship also exists between beer consumption and all-cause mortality. The lowest mortality risk was observed in subjects with low to moderate alcohol consumption compared to abstainers or heavy drinkers, with the lowest risk at beer consumption of 84 g alcohol/week [34]. For beer: Never. Light: 0.1-2.9 g/day, 3-9.9 g/day, 10-19.9 g/day, 20-39.9 g/day (only for men). ≥20 g/day (extreme for women) ≥40 g/day (extreme for men) / Wine and beer All-cause mortality Light consumers (0.1-2.9 g/day) In women: Compared to low-level consumers, lifetime non-drinkers (HR: 1.06; 1.02 to 1.12), and consumers of beer at amounts ≥3 g/day displayed significantly higher overall mortality risk.
In men: Lifetime non-drinkers (HR: 1.07; 0.98 to 1.16) and consumers of 3-9.9 g/day (HR: 1.04; 0.98 to 1.10) showed no significant differences compared to light consumers. Consumers of beer amounts ≥10 g/day displayed a significantly higher overall mortality risk. Studies on general alcohol consumption have similar conclusions. A prospective cohort study by Suadicani et al. found an association between wine consumption and all-cause mortality, with a consistent effect at 84 g alcohol/week, and a larger effect seen with higher consumption in men with non-O blood type [34,61]. However, a meta-analysis by Stockwell et al. [53] suggested that, when the necessary adjustments for study design characteristics are implemented, no association of moderate alcohol consumption with mortality is observed. Two later prospective studies, with well-adjusted variables, confirmed the association between lower risk of total and CV mortality [49,51] and moderate alcohol consumption defined by 168 g/week, 24 g/day for men and 112 g/week, 16 g/day for women in the Bell et al. study [49] or by 43-196 g/week for men and 43-98 g/week for women in the Xi et al. study [51].

Gender Differences
In the EPIC study, beer consumption in women was more strongly related than wine consumption to overall mortality for amounts >21 g/week compared with the reference category (0.7-20.3 g/week) [69]. On the other hand, in the study by Xi et al., the protective effect of low and moderate alcohol consumption against all-cause and CV disease (CVD) mortality was more pronounced in women [51]. Thus, it seems that women may be both more sensitive to the protective effects against mortality of moderate beer intake and to the risk effects of higher amounts. Table 6 details the studies on this subject. Although beer seems to have a direct effect on weight gain [52], and on waist circumference in men [59], there is not enough evidence to confirm whether moderate intake (<500 mL/day) is associated with general or abdominal obesity [55], although daily amounts ≥500 mL increase the risk of not losing weight [59]. In this regard, Padro et al., have reported that the moderate consumption of either alcoholic (30 g/day for men; 15 g/day for women) or non-alcoholic beer for four weeks did not increase the body weight of obese individuals [46]. Furthermore, moderate beer consumption was associated with increases in the anti-oxidative properties of high-density lipoprotein, which facilitate the efflux of cholesterol [46].   Total alcohol intake in men positively predicted change in BMD at the lumbar spine and hip (beta = 0.008% and 0.006%

Moderate Beer Consumption and Obesity, Diabetes, and Osteoporosis
per year per gram of alcohol intake, p < 0.05). The frequency of drinking red wine was positively associated with percentage change in BMD at the lumbar spine in men (beta= 0.08% per year per class, p= 0.048).
At baseline, lumbar spine BMD was positively associated with frequency of low-alcohol beer drinking in women (beta = 0.034 g/cm(2) per category, p = 0.002).

Mukamal et al., 2007 [62]
The National Heart, Lung, and Blood Institute. The National Institute on Ageing.
Prospective population-based cohort study (12 y  Based on the reviewed diabetes studies [43,50], moderate alcohol consumption may decrease diabetes risk in men. A meta-analysis of 13 prospective studies, with 397,296 participants, showed that wine consumption was associated with a significant reduction of the risk for type 2 diabetes mellitus (T2DM), with a pooled relative risk of 0.85, whereas beer or spirits consumption led to a slight trend towards a decreasing risk for T2DM (relative risk 0.96 and 0.95, respectively) [70]. Chronic alcohol consumption, however, is considered a risk factor for T2DM, which may be triggered by a deterioration in glucose tolerance, alterations in signalling of peptides involved in appetite regulation, and dysfunction and apoptosis of pancreatic β-cells [71,72].
Data on bone mineral density (BMD) and fracture risk have been less conclusive, probably due to the few studies available, and both relatively high and low levels of alcohol consumption have shown benefits for bone health. Thus, the consumption of both beer and wine at doses up to 60 g/day in men alone in the study by Yin et al. [58], and up to 13 drinks/week (182 g/week) in the study by Mukamal et al. [62], were shown to increase BMD and/or decrease risk of fracture in the elderly. Even very low levels of consumption were associated with a decreased fracture risk. Considering beer specifically, consumption of <1 beer/week (<14 g/week) in men and women was significantly associated with a lower risk of hip fracture (HR 0.66, 95%CI 0.44-0.99) [62]. Notably, low-alcohol beer consumption in women was associated with increased lumbar BMD [58], suggesting that, beyond the putative positive effect of alcohol on BMD, the non-alcoholic components of beer may also be involved. Other compounds present in beer (e.g., phytoestrogens such as 8-prenylnaringenin) act synergically with silicon to stimulate osteoblast cells, improve bone structure, and help remineralize bone and teeth [44]. The polyphenolic fraction, flavonoids, and the silicon content in beer may contribute to the positive effects on bone metabolism [45]. The protective effect of polyphenols has also been proven in human studies, where they reduced systolic and diastolic pressure and reduced lipoprotein cholesterol serum levels, among others [73]. The cardioprotective role of polyphenols in beer (traditional or alcohol-free) in particular has been reported in individuals with high cardiovascular risk [8,74].

Gender Differences
With regard to obesity, the study by Schütze et al. [59] suggested that only men observe a risk for an increase in waist circumference (WC) with beer consumption of >500 mL/day. In women, beer-abstainers showed lower relative odds for WC gain compared with their very low-level drinking counterparts (1 to <125 mL/day), which was close to significance. Similar gender differences were seen in the diabetes studies. Cullman et al. found that alcohol effect on glucose metabolism was different between men and women [43], depending on amounts of consumption and alcohol type; overall, in individuals with normal glucose tolerance, a decrease in T2DM risk was observed in occasional consumers of beer and wine vs abstainers among men, and in high consumers (≥192 g/week) of wine vs occasional consumers among women. This cohort study showed that men who were high consumers of beer and had baseline normal glucose tolerance had a significantly increased risk of developing abnormal glucose regulation (OR 1.63, CI 1.07-2.48 for pre-diabetes plus T2DM and OR 1.84, CI 1.13-3.01 for pre-diabetes) compared to occasional drinkers [43]. Men abstainers had a significantly higher risk of developing abnormal glucose regulation (OR 2.13, CI 1.03-4.39) than occasional beer drinkers, suggesting occasional beer consumption may be protective in men. Data for beer consumption in women were not provided in the Cullman et al. study. When considering individuals with normal glucose tolerance or pre-diabetes at baseline, the only significant difference found when using occasional drinking as a reference was the case of women with low consumption of total alcohol, who showed a decreased risk of T2DM (OR 0.41, CI 0. 22-0.79). Most studies reviewed by Polsky et al. [50] also showed differences between men and women. In one study, a lower risk for T2DM was only observed in women who consumed alcohol (any quantity; no dose-relationship observed) compared to lifetime abstainers, but this was not found in men [75]. Another study showed that in men alone, a moderate alcohol consumption (10-14.9 g/day) was associated with a reduced risk of T2DM with respect to very low consumption (0.01-4.9 g/day), linked to wine consumption [76].
Regarding BMD, the study by Yin et al. [58] found that alcohol intake was positively associated only in men with an increase in the percentage of spinal and hip BMD after two years, whereas in women, lumbar spine BMD at baseline was positively associated with frequency of low-alcohol beer consumption (beta = 0.034 g/cm 2 per category, p = 0.002).

Discussion
Despite the paucity of studies specifically exploring beer-related health effects, available data suggest that moderate beer consumption is associated with a decreased risk for non-fatal CV events and total mortality. For other health effects, such as those on general or abdominal obesity, study data have generally been inconclusive, although a recent small study suggests that moderate consumption of either alcoholic or non-alcoholic beer does not increase body weight in obese individuals [46]. Furthermore, moderate beer consumption has been associated with decreased diabetes risk (only in men), and with an increase in BMD, which lowers the risk of fracture in the elderly.
Although the available evidence supports the health benefits of moderate beer consumption in adults (aged ≥ 18 years), study heterogeneity makes it difficult to establish the precise quantity of beer needed to obtain these benefits. Different units of measurement (i.e., grams of alcohol or non-standardized drinks per day vs. standard drink units), and different definitions of consumption levels limit the direct comparison of these studies. Nevertheless, given the ranges of alcohol consumption associated with observed benefits in CVD (40-252 g/week for men; 21-210 g/week for women), mortality (75-196 g/week for men; 75-112 g/week for women), and diabetes, obesity, and osteoporosis (12-350 g/week for men; 12-210 g/week for women), a conservative upper limit of moderate beer drinking in men could be ≤196 g/week (approximately 1-2 beers per day). Available studies suggest that women may present a higher sensitivity to beer effects and, therefore, their upper limit of moderate consumption may be slightly lower at ≤112 g/week (approximately 1 beer per day). Notably, these values are similar to the low-risk drinking guidelines established by many countries (Table 1) [1][2][3][4][5][6]. Importantly, evaluating the overall effect of alcohol consumption on health is challenging, given it can be linked to improved benefits in CVD, as shown in this study, but it can also be associated with an increased risk of cancer [77]. Notably, moderate alcohol consumption varies between reports, and large-scale studies are warranted to adequately evaluate the role that specific ranges of alcohol consumption play in health.
Aside from gender differences, alcohol-associated health benefits might be modulated by intrinsic characteristics of populations, including their socioeconomic status [68] and/or diet and general lifestyle. In a well-established example, the Mediterranean diethistorically associated with high life expectancy and low CVD rates-is characterized by its high consumption of fresh foods, low consumption of animal fats, and low-to-moderate consumption of wine, generally with meals [78]. Indeed, the food pyramid recommended by the Spanish Society of Community Nutrition reflects the Mediterranean diet and includes fermented alcoholic beverages (wine, beer, and cider) among foods and drinks advised for an optional, occasional, and moderate consumption [3]. Importantly, this inclusion of alcoholic beverages in the food pyramid regards its consumption with meals, not alone. The inclusion of optional alcohol in the food pyramid is in agreement with data that shows that daily moderate beer consumption in the context of a Mediterranean diet is associated with favourable changes in the blood lipid profile [24].
The moderate consumption of alcohol ≤196 g/week (≤28 g/day or 1-2 beers daily) or ≤112 g/week (≤16 g/day or 1 beer daily) for men and women, respectively, has been associated with a variety of health benefits. However, it must be noted that weekly recommended amounts of alcohol should be spread across several days and not include episodes of heavy alcohol use or "binge drinking", as irregular heavy drinking is associated with a higher risk of ischemic heart disease [79]. This episodic heavy drinking is defined by the World Health Organization as consumption of ≥60 g (approximately ≥6 drinks) per occasion [80] and by the United States National Institute on Alcohol Abuse and Alcoholism [81] as consumption of ≥5 drinks (male) or ≥4 drinks (female) in less than 2 h. While moderate regular drinking is associated with a lower risk of ischemic heart disease compared with abstention [54,82], excessive or binge drinking not only increases the risk of CV events, but also the risk of all-cause mortality [51,83]. Therefore, consumption of moderate amounts of alcohol should be always considered in the context of the Mediterranean lifestyle (moderate quantities of alcohol consumed as part of a meal), as a strategy to promote a more socially responsible consumption, avoiding excessive alcohol intake, often associated with Nordic European, as well as Central and Eastern Europeans and Anglo-Saxon alcohol consumers [10,84]. In a recent study using data from 123,219 men and women who were followed up to 34 years of age, the authors reported that the adherence of the participants to five low-risk lifestyle-related factors (never smoking, normal weight, regular physical activity, healthy diet, and moderate alcohol consumption) could prolong life expectancy at age 50 years by 14.0 and 12.2 years for female and male US adults, respectively, compared with individuals who adopted no low-risk lifestyle factors [85].
In developing this review, we considered the possibility that study sponsors might bias published results. Reported funding sources and conflict of interests (COIs) were assessed for every study selected for this review. Out of the selected studies, only three were directly funded by alcohol-related foundations [34,55,57], and COIs were reported by some of their authors. In addition, the sponsors of these three studies declared no intervention in the study execution and writing, and no differences in study results were observed regardless of funding source.
In conclusion, we consider that an approximate intake of 10-16 g alcohol/day (1 beer/day) for women and 20-28 g alcohol/day (1-2 beers/day) for men could be defined as moderate beer drinking, providing that the consumption is distributed throughout the week with no heavy episodic or "binge drinking" on a single occasion, especially during weekends. Moderate beer drinking decreases CV risk and overall mortality. In addition, moderate consumption decreases diabetes risk in men, increases BMD, lowering the risk of fracture in the elderly, and does not seem to be associated with general or abdominal obesity. Furthermore, moderate beer drinking should be considered within the context of mealtime consumption, as the custom in Mediterranean countries. Future studies should refine the quantity of beer considered as low-to-moderate consumption, which is the lowest risk level, and further determine the possible health benefits associated with moderate beer drinking.
Although research in this field is acquiring great interest and possible benefits are being found, the authors of this article insist on not recommending the consumption of alcohol in children, adolescents, pregnant women, adults under medication, or at work when using machinery (or driving). In addition, the consumption of alcohol must be always accompanied by meals and excess must be avoided. Funding: This study was partially supported by the "Centro de Información Cerveza y Salud". The funding organization has not had any role in the data collection, their analysis and interpretation, nor in the right to approve or disapprove publication of the finished manuscript.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
No new data were created or analyzed in this study. Data sharing is not applicable to this article.