Critique 271 – Moderate alcohol consumption, types of beverages and drinking pattern with cardiometabolic biomarkers in three cohorts of US men and women
Li X; Hur J; Cao Y; Song M; Smith-Warner SA; Liang L; Mukamal KJ; Rimm EB; Giovannucci EL
European Journal of Epidemiology (2023) https://doi.org/10.1007/s10654-023-01053-w
Background Underlying mechanisms of the inverse relationship between moderate alcohol consumption and cardiometabolic disorders are unclear. Modification by types of alcoholic beverages consumed and drinking pattern remains understudied. We aimed to provide insight into the mechanisms by examining 14 insulinemic/glycaemic, inflammatory and lipid markers.
Methods We used cross-sectional data from 15,436 women in the Nurses’ Health Study, 19,318 women in the Nurses’ Health Study II, and 6872 men in the Health Professionals Follow-up Study. Multivariable linear regression was used to estimate the percentage differences in biomarker concentrations according to alcohol intakes.
Results The average alcohol intake in the combined cohort was 3.3 servings/week. We found a 1 serving/d increment in alcohol intake (14 g ethanol, 44 ml liquor or 355 ml beer or 118 ml wine per day) was associated with a 0.6% lower level of HbA1c, 1.7–3.6% lower proinflammatory markers and 4.2% higher adiponectin, as well as 7.1% higher HDL-cholesterol and 2.1% lower triglyceride with a significant linear trend. Wine, especially red wine, was associated with lower inflammation in particular. Beer had weaker favourable to null associations with blood lipids and adiponectin. Liquor was associated with higher C-peptide and interleukin-6, yet equally associated with lower HbA1c and higher HDL-cholesterol as other beverages. Drinking 3 days or more per week was related to a better biomarker profile than nonregular drinking independent of intake levels. Drinking appeared to have similar associations irrespective whether done with meals or not.
Conclusions Our data indicated moderate alcohol intake, especially if consumed from wine and done regularly, was associated with favourable profiles of insulinemic/glycaemic and inflammatory markers and blood lipids.
Background including previous results
Cardiovascular diseases (CVDs) are the leading cause of death globally, taking an estimated 17.9 million lives each year (World Health Organization, 2021). CVDs are a group of disorders of the heart and blood vessels and include coronary heart disease (CHD), cerebrovascular disease, rheumatic heart disease and other conditions. More than four out of five CVD deaths are due to myocardial infarctions or heart attacks and strokes, and one third of these deaths occur prematurely in people under 70 years of age. Leading risk factors for CHD and stroke are high blood pressure, high low-density lipoprotein (LDL) cholesterol, diabetes, smoking and second-hand smoke exposure, obesity, unhealthy diet, and physical inactivity.
Previous observational studies have consistently shown an inverse association between moderate alcohol consumption and a lower risk of CVDs, such as heart attacks (Hu et al., 2022, Ronksley et al., 2011). The effect of moderate alcohol consumption as cardiovascular protector is considerable and is the main contributor to the beneficial association of moderate alcohol consumption to overall mortality (Di Castelnuovo et al., 2006, 2022). However, the protective effect of moderate alcohol consumption has been previously challenged by a hypothesis that the inclusion of former heavy drinkers who quit drinking due to sickness would confound the association. This ´sick quitters´ hypothesis has, however, been regularly debunked over the past 20 years (Klatsky and Udaltsova 2007, Klatsky, 2010). Although researchers have used various other control groups, such as non-drinkers without sick quitters, non-drinkers without previous alcohol abusers, rarely drinkers or very light drinkers, a J-shaped curve showing a protective CVD effect could always be observed (Harriss et al. 2007, Rimm and Moats 2007, Athyros et al. 2008, Djoussé et al. 2009a, Streppel et al. 2009, Holahan et al. 2010, Fuller et al. 2011, Howie et al. 2011, Rostron 2012).
Epidemiological studies that investigate associations may be sensitive to confounding, some confounders may be corrected for, others may be unknown. Therefore, randomized controlled trials may better able to study cause and effect relations since the intervention allows control for potentially confounding factors. Randomized controlled trials, however, are usually short-term interventions which make use of biomarkers that may or may not be representative indicators for the health outcome of interest such as CVDs. The combination of the two types of research is optimal: epidemiological research providing associations; and randomized trials providing mechanistic explanations.
Various randomized controlled trials have previously identified biomarkers that change with moderate alcohol consumption and which may explain its beneficial effects on CVDs. These biomarkers include, as mentioned by the authors of this study, HDL cholesterol, glycaemic control as HbA1c and adiponectin and inflammatory markers. Other relevant biomarkers changing with moderate alcohol consumption are fibrinogen (Sierksma et al., 2002), fibrinolysis (Hendriks et al., 1994), platelet aggregation (ISFAR critique 268), other lipoproteins, such as LDL cholesterol (Van Der Gaag, Sierksma, et al., 2000), HDL functionality (Trius-Soler et al., 2023), oxidative markers and triglycerides.
Some previous epidemiological studies even calculated the contribution of several biomarker change to the cardioprotective effect (Rimm et al. 1999, Mukamal et al., 2005). The latter authors concluded that, ”Levels of HDL-C, HbA1c, and fibrinogen, which have been causally linked to frequent alcohol use in randomized trials, appeared to mediate the bulk of the alcohol-myocardial infarction relation. The present results provide support for the hypothesis that the observed relationship of alcohol intake and risk of myocardial infarction is causal, although definitive confirmation of this will require long-term, randomized outcome trials.” It has been further suggested that alcohol-induced changes in HDL, fibrinogen and adiponectin are pharmacologically relevant and comparable, if not greater than that induced by traditional US Food and Drug Administration-approved drug therapy (Brien et al. 2011).
Compared to studies examining amount of an alcoholic beverage and CVD risk, there have been relatively few prospective studies also examining associations between CVD risk and drinking frequency or patten (McElduff and Dobson 1997, Mukamal et al. 2003, Britton and Marmot 2004, Tolstrup et al. 2006). Drinking pattern is important for both the beneficial and adverse effects of alcohol consumption. Binge drinking, per se and in combination with regular moderate alcohol consumption, negatively affects short-term behaviour and health as well as long-term health (Bagnardi et al., 2008).
Li et al. (2023) in addition to evaluating mediating biomarkers, also analysed drinking pattern and beverage types using three cohorts consisting of primarily women. Drinking pattern considered frequency with, and without, a concurrent meal. Previous studies suggested that more frequent or regular drinking is more cardioprotective than irregular moderate alcohol consumption (Mukamal et al., 2005), with the lowest risks among those who drank three to seven days per week. Drinking with meals is usually advised since considerably lower blood alcohol concentrations are achieved when drinking with meals. Blood alcohol concentrations are probably lower with a meal because the liver is metabolically active and metabolizes a considerable portion of the absorbed alcohol during the first pass and subsequent passes through the liver (Cederbaum, 2012).
Beverage type analyses are interesting since alcoholic beverages such as beer, wine and spirits, not only contain alcohol but also varying quantities of water and other bioactive substances such as polyphenols and xanthohumols. It has been long debated whether the three main alcoholic beverages themselves contribute to a different disease profile or that the consumers of beer, wine and spirits may differ in their behaviour other than their drinking behaviour, for instance in their dietary habits (Tjønneland et al., 1999, Klatsky et al. 20003) or other healthy lifestyle factors. Wine consumers, for example, are often considered to generally have ‘healthier’ traits, such as a healthier diet and lifestyle, and an optimal amount and pattern of consumption (Klatsky et al. 1990, Grønbaek et al, 1999, Mortensen et al. 2001, Barefoot et al. 2002, Hansel et al. 2013).
An additional complicating factor in epidemiological studies is that most people do not restrict themselves to one specific alcoholic beverage type, most people drink various beverage types depending on the occasion. Indeed, in the long-term, however, the moderate consumption of only one specific alcoholic beverage does not seem to be significantly better or best associated with disease outcome (Estruch & Hendriks, 2021).
Direct comparison of alcoholic beverages types in their effect on CVD risk biomarkers has not been extensively investigated in clinical trials. Those nutrition interventions that did compare beverage types, however, did not show major differences. HDL cholesterol and associated reverse cholesterol transport (Van Der Gaag et al., 2001), LDL cholesterol and antioxidative capacity (Van der Gaag et al., 1999), overall serum antioxidant capacity (Van Der Gaag, Van Den Berg, et al., 2000) and the majority of liver enzymes (Sillanaukee et al., 2003) were not essentially different after drinking either beer, water, wine or spirits.
Design and main outcomes
This epidemiological study used cross-sectional data from three cohorts mainly consisting of women (34,754 women and 6,872 men) evaluating 14 biomarkers. Overall, moderate alcohol consumption was associated with a reduced HbA1c, lower proinflammatory markers, lower triglycerides, higher adiponectin and higher HDL cholesterol. All these changes are consistent with a reduced CVD risk. Some beverage types affected some biomarkers differently; wine and specifically red wine was associated with lower inflammation particularly. Drinking in moderation on three or more days per week was associated with a better biomarker profile than irregular drinking, while drinking with meals seemed to have no affect.
Comments on outcomes and methodology
This interesting study provided further mechanistic insight in the beneficial association between moderate alcohol drinking and CVD risk reduction. The study confirmed that HDL cholesterol, glycaemic control and inflammation are beneficially affected by moderate alcohol consumption. These outcomes were shown in a cross-sectional analysis of three similar American cohorts but also in a follow-up increase in alcohol consumption by calculating the effect of a one serving/day increment to the average alcohol consumption. Interesting to see that some but not all inflammatory markers and HbA1c did not change with a serving per day increment, whereas HDL cholesterol, some other inflammatory markers, triglycerides and adiponectin increased further with such an increment. This may be due, as the authors discuss, to the relatively older population of women that are exposed to moderate alcohol consumption for a longer period of time.
HDL cholesterol and HDL/triglyceride ratio are important biomarkers for CVD risk. However, the biomarker HDL cholesterol has been criticized. Main reason being that some nutrition and pharmacological interventions have shown an increase in HDL cholesterol, whereas the incidence of CVDs was not beneficially affected (Rosenson, 2016, Tariq et al., 2014). It was suggested that whereas HDL cholesterol may be increased, its functions residing in the proteins associated with the HDL particle may be compromised (Femlak et al., 2017). In a study using the functionality of HDL, viz HDL mediated reverse cholesterol transport capacity, it was shown that reverse cholesterol transport, was indeed inversely associated with the incidence of cardiovascular events, whereas baseline HDL cholesterol level was not in fully adjusted analysis (Rohatgi et al., 2014). So, HDL cholesterol levels may be an oversimplification and may not provide a comprehensive understanding (Trius-Soler et al., 2023). It would have been interesting to know if HDL functionality, be it reverse cholesterol transport or HDL anti-oxidative capacity or HDL anti-inflammatory activity, was stimulated by moderate alcohol consumption and if this functionality would differ between the various alcoholic beverage types.
Some biomarkers changes did not differ between the various alcoholic beverages whereas other biomarkers changes did differ. The type of drinkers was defined in this study based on the beverage they consumed with the highest frequency as an average of the two last food frequency questionnaires. This implies that at least some portion of the beer drinkers, for example, were also drinking wine. In these three cohorts, the women primarily drank white wine and liquor, whereas the men primarily drank liquor (Supplemental Figure 1). The authors discuss the beverage differences and state that variation by beverages remained when socio-economic status (SES) and lifestyle were adjusted in these quite homogeneous cohorts, as such minimizing the potential for residual confounding. Although confounding has been minimized in this study, differentiation of the effects of the various alcoholic beverages may be too difficult to assess in an epidemiological setting. Also, HDL cholesterol and HbA1c increase did not show a clear beverage type effect, whereas these biomarkers in combination with fibrinogen may be responsible for the majority of the beneficial CVD outcomes (Mukamal et al., 2005).
It is surprising that drinking with meals did not affect the biomarker outcomes of this study. Drinking with meals does yield lower blood alcohol concentrations, which is considered beneficial. Supplementary Table 5 describes the changes in all biomarkers compared to those that drink less than 25% of their alcohol with meals. Those drinking between 25 and 75% of their alcohol with meals did show tendencies in the direction that corresponds to an improved biomarker profile, but none of the changes were significant. No trend analysis over the three categories of drinking with meals was performed. Possibly, the study had insufficient power to detect differences induced by drinking with meals. Alternatively, the average drinking levels of alcohol consumption were relatively low. The highest alcohol consumption category was about 35 +/- 10 g alcohol/day. At these relatively low alcohol consumptions, very high blood alcohol concentrations may not be generated even in the case where alcohol was consumed without a meal.
Specific Comments from Forum Members
Forum member Skovenborg considers that “this is a much-needed study with an admirable quality. I also agree that the study did not have sufficient power to detect differences induced by drinking with meals. To compare drinkers of less than 25% of their alcohol with meals with people that drink 25-75% of their alcohol with meals is far away from the proper Mediterranean Alcohol Drinking Pattern where close to 100% of the alcohol intake takes place with a meal and where the reference group should have a clear pattern of drinking on an empty stomach.” He went on to say that “the condition to demonstrate a certain “safe level” without risk does not conform with the current scientific method – the principle of falsifiability, a deductive standard of evaluation of scientific theories and hypotheses, that was introduced by the philosopher of science Karl Popper.”
Forum member Ursini states that “the fundamentals of what is beneficial and detrimental to our well-being are well-established in basic science and he wholeheartedly supports the study’s conclusions. Nevertheless, politicians and the media insist on a statistical validation, an inherently impossible demand termed ‘evidence-based.’ Let’s continue engaging in substantive arguments, but I am uncertain how much longer we can sustain this discourse”
Forum member Ellison added: “This is a very important paper as it comes from the Harvard-based Nurses’ Health Studies and the Health Professionals Follow-up study. These are probably the most-balanced ongoing epidemiologic studies currently being carried out, as they are very well designed, implemented, and analyzed. These studies combine high levels of follow up from similarly educated subjects (which decreases potential confounding by lifestyle and other socio-economic factors) along with repeated assessments of potential confounders and reliable assessments of outcomes. Their results are key in estimating the net unbiased effects on health of beverages containing alcohol. These studies also provide valuable data for setting alcohol policy.
The results of this publication support that has been demonstrated regularly over many decades from experimental studies and clinical trials: moderate alcohol consumption leads to a variety of biologic/physiologic mechanisms that would be expected to reduce the risk of cardiovascular disease and total mortality. Thus, when cohort studies consistently show fewer heart attacks and strokes and lower risk of mortality among moderate drinkers, this is only what would be expected.”
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World Health Organisation (2021):
Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:
Henk Hendriks, PhD, Netherlands
Creina Stockley, PhD, MBA, Independent consultant and Adjunct Senior Lecturer in the School of Agriculture, Food and Wine at the University of Adelaide, Australia
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
Tedd Goldfinger, DO, FACC, Desert Cardiology of Tucson Heart Center, University of Arizona School of Medicine, Tucson, AZ, USA
Pierre-Louis Teissedre, PhD, Faculty of Oenology–ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France
Fulvio Mattivi, MSc, Head of the Department Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, in San Michele all’Adige, Italy
Andrew Waterhouse, PhD, Department of Viticulture and Enology, University of California, Davis
Giovanni Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy
Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy
R. Curtis Ellison, MD, Section of Preventive Medicine/Epidemiology, Boston University School of Medicine, Boston, MA, USA