No Role for Alcohol in CV Health: UK Biobank Data

Small amounts of alcohol have been touted by some as cardioprotective, but it appears this positive influence stems largely from lighter drinkers having healthier lifestyles, data from the UK Biobank indicate. Importantly, however, the relationship between alcohol and outcomes wasn’t linear but J-shaped, with the heaviest consumers paying the highest penalty in terms of hypertension and CAD risk.

The study, which involved both Cox proportional hazards modeling as well as mendelian randomization, was published online recently in JAMA Network Open.  

Speaking with TCTMD, senior author Krishna G. Aragam, MD (Massachusetts General Hospital, Boston), noted that much research has been done on alcohol and cardiovascular disease. While early reports supported a “heart-healthy” role for lower levels of alcohol consumption, more recent work has established that extremely heavy drinking may damage the heart, while even lighter consumption has been associated with atrial fibrillation. Yet there are lingering questions over whether mild-to-moderate drinking might provide cardiovascular benefits that outweigh the risks.

What their study does, said Aragam, is get more granular. “We did see this trend toward a healthier overall lifestyle in people who happened to consume light-to-moderate amounts of alcohol,” he said. With adjustment for smoking, body mass index, red meat intake, vegetable intake, physical activity, and self-reported health, however, “those protective associations that had been seen for years with light-to-moderate alcohol consumption start to really dissipate, if not disappear altogether.”

Mendelian randomization, on the other hand, provided clarity on the dose-response relationship. “It’s not linear,” he said—any level of alcohol increased risk over abstinence. “Here we actually can see that those risk increases are not uniform. There are modest risk increases for what we would consider light alcohol consumption, maybe even up to like a drink a day or so. But then after that . . . you start to see there’s this inflection upwards.”

In other words, the risk increase between two to three drinks appears to be sharper than the increase from one to two. “That has a lot of implications for how much is ‘okay,’” Aragam pointed out, as a common threshold is fewer than 15 weekly drinks for men and fewer than eight weekly drinks for women.

Gregory Marcus, MD (University of California, San Francisco), who did not take part in the study, told TCTMD, “It’s interesting and it’s informative, but it’s not definitive because it’s not randomized—so you can’t exclude confounding as an explanation of the results.”

What it does show is that heavy alcohol consumption is consistently, and strongly, linked to worse outcomes, he said. It also shows “the idea that light, regular drinking may protect against coronary disease, for example, does not mean that drinking more means more protection. There does seem to be a nonlinear relationship there, and there may be quantitatively important differences between light regular drinking and heavier drinking.”

Drinking more than two drinks per day, Marcus said, “is most certainly harmful.” He’s less convinced, though, by the conclusion that low consumption can’t be protective.

Exponential Rise in Risk

Led by Kiran J. Biddinger (Broad Institute of MIT and Harvard, Cambridge, MA), the analysis included 371,463 participants (mean age 57 years; 46% men) in the UK Biobank database from 2006 to 2010, with follow-up obtained through 2016. One-third had hypertension, and 7.5% had CAD.

These individuals consumed a mean of 9.2 standard drinks per week. Low alcohol consumption was anywhere up to 8.4 weekly drinks, while moderate consumers drank between 8.4 and 15.4 drinks. Heavy drinkers reached up to 24.5 drinks, and abusive drinkers exceeded that amount.

Without adjustment, people whose intake was low to moderate seemed to benefit from alcohol, with lower risks of hypertension and CAD compared with nondrinkers. However, these people tended to have healthier lifestyles—for example, they were less apt to smoke, had lower body mass index, exercised more, and ate more vegetables.

Adjusting for these characteristics attenuated alcohol’s protective effects for low and moderate alcohol consumers, so much so that in the moderate group the benefit of alcohol was no longer significant. This suggests “that adjustments for yet unmeasured or unknown factors may further attenuate—if not, eliminate—the residual, cardioprotective associations observed among light drinkers,” the researchers say. For heavy and abusive drinkers, risks were elevated with or without adjustment.

Mendelian randomization analyses using genetically predicted alcohol consumption showed that each standard-deviation increase in drinks was associated with a 1.3-fold (95% CI 1.2-1.4) higher risk of hypertension and 1.4-fold (95% CI 1.1-1.8) rise in CAD. Analyzed differently, however, the association between alcohol and risk wasn’t linear, Biddinger and colleagues found. For both hypertension and CAD, “light alcohol intake was associated with minimal increases in cardiovascular risk, whereas heavier consumption was associated with exponential increases in risk of both clinical and subclinical cardiovascular disease.”

For the study authors, these data carry two key clinical takeaways. For one, they reemphasize the point that no level of alcohol consumption is truly protective against CVD. Also, “they newly demonstrate that the adverse effects of alcohol unduly affect those who consume heavily, implying that for an equivalent reduction in alcohol intake, the improvements to cardiovascular health may be significant for heavier drinkers but only slight for those who consume modestly,” the researchers explain.

Aragam suggested that clinicians counseling patients should realize the “bang for their buck” varies when it comes to lifestyle changes. Someone with multiple CV risk factors including three daily drinks will likely benefit more from cutting back than those who consume one daily.

The Strength of the Evidence

Marcus drew attention to a few details in the paper. For one thing, even after adjusting for a healthier lifestyle, the study’s epidemiologic analysis showed “evidence of a relationship between light or moderate drinking—about a drink a day—and a lower risk of coronary disease,” he said.

He also highlighted the specifics of the mendelian randomization analysis. “There is this hope that mendelian randomization might represent a method to allow appropriate inference of causal effects using observational data,” Marcus said. But the strength of this approach depends on which genetic variants are chosen.

To offer valid information, mendelian randomization must rely on genetic variants that are “only associated with the predictor and not at all with the outcome,” he said. Here, the variants were derived in part from self-reported alcohol use on the Alcohol Use Disorder Identification Test–Consumption (AUDIT-C) questionnaire and related to habitual heavy drinking, he said, rather than something more neutral like alcohol metabolism.

Only a randomized trial can definitively answer the question of whether light drinking might still offer benefits. Marcus said he and a colleague have submitted a grant to do just that. “We would give advice or instruction rather than giving alcohol,” much as it happens in clinical practice, he noted. “It’s not like doctors are handing out alcohol, they’re just recommending ‘a drink a night is okay’ versus ‘avoid all alcohol.’”

Aragam said that, based on their results, he suspects there’s no benefit to light alcohol consumption. For one thing, they only adjusted for lifestyle factors with available data, so further adjustment might have attenuated what little benefit there was. Moreover, the mendelian randomization analyses lend support to that message.

He agreed with Marcus’ point about the limitations posed by self-reported alcohol use, though he pointed out that ultimately their analysis rested on genetic variants. What this means is that the shape of the curves is more informative than the absolute risk estimates, Aragam said.

Another reassurance came by way of abstainers, he added. “Some people just don’t drink, and some people do.” Individuals with the genetic variants linked to alcohol who choose not to drink can serve as negative controls. If everything’s working as it should, then nondrinkers with those genetic traits wouldn’t be at higher risk of the cardiovascular outcomes than those without the traits, he said, and that’s what they found.