Association Between Daily Alcohol Intake and Risk of All-Cause Mortality

This systematic review and meta-analysis evaluates the association between daily alcohol intake and risk of all-cause mortality.


Introduction
The proposition that low-dose alcohol use protects against all-cause mortality in general populations continues to be controversial. 1 Observational studies tend to show that people classified as "moderate drinkers" have longer life expectancy and are less likely to die from heart disease than those classified as abstainers. 2 Systematic reviews and meta-analyses of this literature 3 confirm J-shaped risk curves (protective associations at low doses with increasing risk at higher doses).
However, mounting evidence suggests these associations might be due to systematic biases that affect many studies.For example, light and moderate drinkers are systematically healthier than current abstainers on a range of health indicators unlikely to be associated with alcohol use eg, dental hygiene, exercise routines, diet, weight, income 4 ; lifetime abstainers may be systematically biased toward poorer health 5 ; studies fail to control for biases in the abstainer reference group, in particular failing to remove "sick quitters" or former drinkers, many of whom cut down or stop for health reasons 2 ; and most studies have nonrepresentative samples leading to an overrepresentation of older White men.Adjustment of cohort samples to make them more representative has been shown to eliminate apparent protective associations. 6Mendelian randomization studies that control for the confounding effects of sociodemographic and environmental factors find no evidence of cardioprotection. 7 published 2 previous systematic reviews and meta-analyses that investigated these hypotheses.The first of these focused on all-cause mortality, 8 finding negligible reductions in mortality risk with low-volume alcohol use when study-level controls were introduced for potential bias and confounding, such as the widespread practice of misclassifying former drinkers and/or current occasional drinkers as abstainers (ie, not restricting reference groups to lifetime abstainers). 8r alcohol and coronary heart disease (CHD) mortality meta-analysis of 45 cohort studies 9 found that CHD mortality risk differed widely by age ranges and sex of study populations.In particular, young cohorts followed up to old age did not show significant cardio-protection for low-volume use.
Cardio-protection was only apparent among older cohorts that are more exposed to lifetime selection biases (ie, increasing numbers of "sick-quitters" in the abstainer reference groups and the disproportionate elimination of drinkers from the study sample who had died or were unwell).
The present study updates our earlier systematic review and meta-analysis for all-cause mortality and alcohol use, 8 including studies published up to July 2021 (ie, 6.5 years of additional publications).The study also investigated the risk of all-cause mortality for alcohol consumption according to (1) median ages of the study populations (younger than 56 years or 56 years and older), replicating the methods of Zhao et al 9 ; (2) the sex distribution of the study populations, and (3) studies of cohorts recruited before a median age of 51 years of age and followed up in health records until a median age of at least 60 years (ie, with stricter rules to further minimize lifetime selection biases).Because younger cohorts followed up to an age at which they may experience heart disease are less likely to be affected by lifetime selection biases, 9 we hypothesized that such studies would be less likely to show reduced mortality risks for low-volume drinkers.Finally, we reran the analyses using occasional drinkers (<1 drink per week) as the reference, for whom physiological health benefits are unlikely.Occasional drinkers are a more appropriate reference group, given evidence demonstrating that lifetime abstainers may be biased toward ill health. 10

Methods
The present study updates the systematic reviews and meta-analyses described above 8 by including studies published up to July 2021 to investigate whether the risk differed for subgroups.The study protocol was preregistered on the Open Science Framework. 11Inclusion criteria, search strategy, study selection, data extraction, and statistical analytical methods of the study are summarized in later sections (see eAppendix in Supplement 1 for more details).

Statistical Analysis
6][37][38][39][40][41] Relative risk (RR), including hazard ratios or rate ratios, were converted to natural log-transformed formats to deal with skewness.Publication bias was assessed through visual inspection of the funnel plot of log-RR of all-cause mortality due to alcohol consumption against the inverse standard error of log-RR 42

and
Egger's linear regression method. 36We also plotted forest graphs of log-RR of all-cause mortality for any level of drinking to assess heterogeneity among studies. 42The between-study heterogeneity of RRs were assessed using Cochran Q 37 and the I 2 statistic. 38If heterogeneity was detected, mixedeffects models were used to obtain the summarized RR estimates.Mixed-effects regression analyses were performed in which drinking groups and control variables were treated as fixed-effects with a random study effect because of significant heterogeneity. 43l analyses were weighted by the inverse of the estimated variance of the natural log relative risk.Variance was estimated from reported standard errors, confidence intervals, or number of deaths.The weights for each individual study were created using the inverse variance weight scheme and used in mixed regression analysis to get maximum precision for the main results of the meta-analysis. 42In comparison with lifetime abstainers, the study estimated the mean RR of all-cause mortality for former drinkers (ie, now completely abstaining), current occasional (<9.1 g per week), low-volume (1.3-24.0g per day), medium-volume (25.0-44.0g per day), high-volume (45.0-64.0g) and highest-volume drinkers (Ն65.0 grams per day).The analyses adjusted for the potential confounding effects of study characteristics including the median age and sex distribution of study samples, drinker biases, country where a study was conducted, follow-up years and presence or absence of confounders.Analyses were also repeated using occasional drinkers as the reference group.We used t tests to calculate P values, and significance was set at .05.All statistical analyses were performed using SAS version 9.4 (SAS Institute) and the SAS MIXED procedure was used to model the log-transformed RR. 44 Data were analyzed from September 2021 to August 2022.

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Daily Alcohol Intake and Risk of All-Cause Mortality
Unadjusted mean RR estimates for most study subgroups categorized by methods/sample characteristics showed markedly or significantly higher RRs for alcohol consumers as a group vs abstainers.Exceptions were for studies with less than 10 years of follow-up and those with some form of abstainer bias (Table 1).Bivariable analyses showed that mortality risks for alcohol consumers varied considerably according to other study characteristics, such as quality of the alcohol consumption measure, whether unhealthy individuals were excluded at baseline, and whether socioeconomic status was controlled for (Table 1).
No evidence of publication bias was detected either by inspection of symmetry in the funnel plot of log-RR estimates and their inverse standard errors (eFigure 2 in Supplement 1) or by Egger linear regression analysis (eTable 2 in Supplement 1, all P > .05for each study group).Significant heterogeneity was observed across studies for all drinking categories confirmed by both the Q statistic (Q 723 = 5314.80;P < .001)and I 2 estimates (all >85.87%).(See eFigure 3 in Supplement 1 for forest plot of unadjusted risk estimates of mortality risks for the 20 newly identified studies).

All-Cause Mortality Risk on the Basis of Median Age of Study Cohorts at Baseline
As hypothesized, there was a significant interaction between cohort age and mortality risk (P = .02;d Median age at study enrollment.
e Control for heart disease and/or other illnesses.
f Lifetime abstention was strictly defined as 0 consumption or never drank 1 drink and did not include studies with any level of occasional lifetime or past year drinking (eg, less than 12 drinks or "rarely" or "hardly ever" drinking).
g Smoking confounding effect was adjusted for in multivariable regression analysis in original studies.
h Body mass index is calculated as weight in kilograms divided by height in meters squared.

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Daily Alcohol Intake and Risk of All-Cause Mortality the study populations at enrollment (Table 3).In unadjusted and partially adjusted analyses, older cohorts displayed larger reductions in mortality risk associated with low-volume consumption than younger cohorts.However, in fully adjusted analyses with multiple covariates included for study a Natural log of the RR estimated using the rate ratio or hazard ratio without weighting and adjusting for between-study variation or covariates.
b Weighted estimates adjusted for between-study variation.
c Weighted estimates adjusted for between-study variation, abstainer biases, median age, sex, country in which a study was conducted, study publication year, follow-up years of study samples, drinking pattern, and whether studies controlled for heart problem, social status, race, diet, exercise, body mass index, and smoking status.characteristics, these differences disappeared.Younger cohorts also displayed greater mortality risks than older cohorts at higher consumption levels.Among studies in which participants were recruited at age 50 years or younger and followed up to age 60 years (ie, there was likely reduced risk of lifetime selection bias) higher RR estimates were observed for all drinking groups vs lifetime abstainers.These differences were significant in all drinking groups except low-volume drinkers (eTable 3 in Supplement 1).

All-Cause Mortality Risk for Drinkers by Sex
Across all levels of alcohol consumption, female drinkers had a higher RR of all-cause mortality than males (P for interaction = .001).As can be seen in

Discussion
In fully adjusted, prespecified models that accounted for effects of sampling, between-study variation, and potential confounding from former drinker bias and other study-level covariates, our meta-analysis of 107 studies found (1) no significant protective associations of occasional or low-volume drinking (moderate drinking) with all-cause mortality; and (2) an increased risk of a Natural log of the RR estimated using the rate ratio or hazard ratio without weighting and adjusting for between-study variation or covariates.
b Weighted estimates adjusted for between-study variation.
c Weighted estimates adjusted for between-study variation, abstainer biases, sex, country in which a study was conducted, study publication year, follow-up years, drinking pattern, and whether studies controlled for heart problem, social status, race, diet, exercise, body mass index, and smoking status.

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Daily Alcohol Intake and Risk of All-Cause Mortality In addition to presenting our fully adjusted models, a strength of the study was the examination of the differences in relative risks according to unadjusted and partially adjusted models, including the effect of removing individual covariates from the fully adjusted model.We found evidence that abstainer biases and other study characteristics changed the shape of the risk relationship between mortality and rising alcohol consumption, and that most study-level controls increased the observed risks from alcohol, or attenuated protective associations at low levels of consumption such that they were no longer significant.The reduced RR estimates for occasional or moderate drinkers observed without adjustment may be due to the misclassification of former and occasional drinkers into the reference group, a possibility which is more likely to have occurred in studies of older cohorts which use current abstainers as the reference group.This study also demonstrates the degree to which observed associations between consumption and mortality are highly dependent on the modeling strategy used and the degree to which efforts are made to minimize confounding and other threats to validity.

P
< .001)and 65 or more grams (RR, 1.35; 95% CI, 1.23-1.47;P < .001).The Figure shows the changes in RR estimates for low-volume drinkers when removing each covariate from the fully adjusted model.In most cases, removing study-level covariates tended to yield lower risk estimates from alcohol use.

Figure
Figure.Relative Risk (RR) of All-Cause Mortality Due to Low-Volume Alcohol Consumption (1.3-24.0g Ethanol per Day) With and Without Adjustment for Potential Confounding by Each Covariate or Set of Covariates

Table 1 .
The Sample Characteristics of the Metadata on All-Cause Mortality and Alcohol Consumption From 1980 to 2022 a Number of relative risk estimates for any drinking from the included studies.bUnadjusted mean relative risk (RR) and 95% confidence interval (CI) due to any drinking from the included studies.c Reference category.

Table 2 .
Mean Relative Risk Estimates of All-Cause Mortality Due to Alcohol Consumption Up to 2022 According to 107 Studies With 724 Relative Risk Estimates

Table 3 .
Mean RR Estimates of All-Cause Mortality Due to Alcohol Consumption by Median Age at Enrollment of Studies (<56 or ≥56 y) Up to 2022

on 09/27/2023 all
2cause mortality for drinkers who drank 25 g or more and a significantly increased risk when drinking 45 g or more per day.Several meta-analytic strategies were used to explore the role of abstainer reference group biases caused by drinker misclassification errors and also the potential confounding effects of other study-level quality covariates in studies.2Drinkermisclassification errors were common.Of 107 studies identified, 86 included former drinkers and/or occasional drinkers in the abstainer reference group, and only 21 were free of both these abstainer biases.The importance of controlling for former JAMA Network Open.2023;6(3):e236185.doi:10.1001/jamanetworkopen.2023.6185(Reprinted) March 31, 2023 7/17 Downloaded From: https://jamanetwork.com/

Table 4 .
Mean RRs of All-Cause Mortality Due to Alcohol Consumption by Sex (Men or Women) Up to 2022 Stockwell T, Zhao J, Macdonald S. Who under-reports their alcohol consumption in telephone surveys and by how much?An application of the 'yesterday method' in a national Canadian substance use survey.Addiction.2014;109(10):1657-1666. doi:10.1111/add.12609135.Kerr WC, Fillmore KM, Bostrom A. Stability of alcohol consumption over time: evidence from three longitudinal surveys from the United States.J Stud Alcohol.2002;63(3):325-333.doi:10.15288/jsa.2002.63.325 136.Shaper AG, Wannamethee G, Walker M. Alcohol and mortality in British men: explaining the U-shaped curve.Lancet.1988;2(8623):1267-1273. doi:10.1016/S0140-6736(88)92890-5137.Justice AC, McGinnis KA, Tate JP, et al.Risk of mortality and physiologic injury evident with lower alcohol exposure among HIV infected compared with uninfected men.Drug Alcohol Depend.2016;161:95-103.doi:10.1016/j.drugalcdep.2016.01.017 138.Austin PC, Steyerberg EW.The number of subjects per variable required in linear regression analyses.J Clin Epidemiol.2015;68(6):627-636.doi:10.1016/j.jclinepi.2014.12.014 139.Roerecke M, Rehm J. Irregular heavy drinking occasions and risk of ischemic heart disease: a systematic review and meta-analysis.Am J Epidemiol.2010;171(6):633-644. doi:10.1093/aje/kwp451SUPPLEMENT 1. eAppendix.Methodology of Meta-analysis on All-Cause Mortality and Alcohol Consumption eReferences eFigure 1. Flowchart of Systematic Search Process for Studies of Alcohol Consumption and Risk of All-Cause Mortality eTable 1. Newly Included 20 Studies (194 Risk Estimates) of All-Cause Mortality and Consumption in 2015 to 2022 eFigure 2. Funnel Plot of Log-Relative Risk (In(RR)) of All-Cause Mortality Due to Alcohol Consumption Against Inverse of Standard Error of In(RR) eFigure 3. Relative Risk (95% CI) of All-Cause Mortality Due to Any Alcohol Consumption Without Any Adjustment for Characteristics of New Studies Published between 2015 and 2022 eFigure 4. Unadjusted, Partially Adjusted, and Fully Adjusted Relative Risk (RR) of All-Cause Mortality for Drinkers (vs Nondrinkers), 1980 to 2022 eTable 2. Statistical Analysis of Unadjusted Mean Relative Risk (RR) of All-Cause Mortality for Different Categories of Drinkers for Testing Publication Bias and Heterogeneity of RR Estimates From Included Studies eTable 3. Mean Relative Risk (RR) Estimates of All-Cause Mortality Due to Alcohol Consumption up to 2022 for Subgroups (Cohorts Recruited 50 Years of Age or Younger and Followed up to 60 Years of Age)