Causal or Casual?—The Association Between Consumptionof Artificially Sweetened Carbonated Beverages and VascularDisease

Shuchi Anand, MD and Wolfgang C. Winkelmayer, MD, ScD

Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, USA.

J Gen Intern Med 27(9):1100–1

DOI: 10.1007/s11606-012-2126-1

© Society of General Internal Medicine 2012

T he United States leads the world in per capitaconsumption of carbonated soft drinks. On average,

each American consumed 714 eight-ounce servings of“soda pop” in 2011.1 Given their widespread use, it is inthe public’s interest to understand any potential healthoutcomes from the consumption of these beverages, and asa result, an increasing number of studies have examined theassociation between the use of carbonated soft drinks and avariety of health outcomes.

In this issue of the Journal of General Internal Medicine,Gardener et al. report on the association between soft drinkconsumption and vascular events in the diverse, population-based cohort of the Northern Manhattan Study (NOMAS).2

Their surprising finding that regular consumption ofartificially-sweetened (diet) soft drinks, but not sugar-sweetened soft drinks, was associated with an increasedrisk of vascular events deserves further exploration.

A causal association between increased consumption ofsugar-sweetened soda beverages is biologically plausibleand supported by the literature. Several prospective cohortanalyses have demonstrated an increased risk for coronaryheart disease3,4 and diabetes5,6 among persons who regu-larly consume sugar-sweetened soft drinks. For example, inthe Nurses’ Health Study, the relative risk for fatal ornonfatal myocardial infarction increased by 35 % per twoserving increase in sweetened soft drinks consumption.3

Remarkably, women who began to consume one or moresoft drinks a day gained four kilograms over a four-yearperiod and experienced an 80 % increase in risk for type 2diabetes.6 Similar results were observed among men in theHealth Professionals Follow Up study.4,5

Given the observed weight gain in the Nurses’ HealthStudy and other studies demonstrating a higher total energyintake (i.e., indicating that the drinks are not being used ascalorie substitutes, but rather are calorie-additive) amongpersons regularly consuming sugar-sweetened soft drinks,7

we can easily grasp the biological plausibility of thisassociation. Another proposed causal mechanism points tothe high glycemic load of the soft drink which predisposesto insulin resistance.8

In light of this evidence, it is curious that Gardener’s etal. analysis did not demonstrate a significant increase invascular events among persons drinking daily sugar-sweetened beverage in their overall cohort. Statistical powermay have been an issue. The NOMAS study followed 2,564for 10 years, with 591 vascular events; in comparison, theNurses Health Study involved 88,520 women followed for24 years with 3,105 incident coronary events. An alternativeexplanation for the null finding may be due to the fact thatsoda consumption was only ascertained at baseline, with anuncertain but possibly large amount of person-time beingmisclassified with regard to the exposure of interest.However, consistent with other studies the authors do reporta 57 % increase in risk for vascular events among non-obese persons without metabolic syndrome or diabetes. Thenovel finding in this subgroup is the association with acomposite outcome that included stroke in addition tomyocardial infarction, indicating an even broader in-crease in risk of chronic diseases with consumption ofsugar-sweetened soft drinks than has been previouslyacknowledged.

But what about diet soft drinks? Can regular consumptionof this no-calorie substitute with presumably no directpathway to weight gain lead to adverse health outcomes?Some nutrition experts have suggested so, particularly dueto correlation in time of the obesity epidemic with risingconsumption of diet soft drinks.9,10 Putative mechanisms forthis include activation of intestinal “sweet taste” receptorsby the artificial sweeteners which in turn purportedlyincrease glucose uptake. Davidson et al. proposed that theartificial sweeteners inhibit the association between sweettaste and caloric intake, such that rats fed artificial sweet-eners are unable to put the brakes on intake of sweet foodbecause they do not associate the sweet food withcalories.11

Analysis from the Multi-Ethnic Study of Atheroscelorosiscohort demonstrated an increase in risk for incidentmetabolic syndrome and type 2 diabetes with consumptionof at least one diet soft drink daily.12 Upon adjustment forPublished online June 13, 2012

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baseline body mass index the associations attenuated,although remained significant for the increase in incidenttype 2 diabetes. In the larger Health Professionals Follow Upstudy, the crude association between regular consumption ofdiet soft drink and type 2 diabetes disappeared completely onmultivariate analyses adjusting for baseline body massindex.5 Similarly null results have been observed in analysesfor incident coronary heart disease in the Health Professio-nals Follow Up study and the Nurses’ Health Study.3,4

Thus although there is epidemiological and somebiologic suggestion for a link between diet soft drinkconsumption and adverse health outcomes, the preponder-ance of evidence from large cohort analyses has not beensupportive. Attenuation of the crude association on adjust-ment for body size in several of these analyses suggests thatdiet soft drink intake may be a marker for persons at higherrisk for adverse health outcomes, rather than a causal factor.

The current NOMAS analysis, though suggestive of amodest association, does not provide convincing evidencefor causation for several reasons. First, compared withpersons consuming less than one serving a month, personsconsuming diet soft drinks daily demonstrated evidence fora tendency toward an “unhealthy” lifestyle. They consumedmore total calories and sodium; their size as captured bybody mass index and waist circumference was generallylarger. Second, they carried a higher burden of co-morbid-ities such as hypertension, peripheral vascular disease, andprevious cardiac disease. Strikingly the prevalence ofmetabolic syndrome and diabetes was nearly 1.5-2 foldhigher in this group. Although the authors adjusted forseveral of these confounders, the relatively modest observedassociation between diet soft drink consumption andvascular events could reflect residual confounding. It wouldtake just a weak and common or a relatively rare, yetmoderately strong unobserved confounder to render thereported association null. Finally, intake of soft drinks wasevaluated at baseline, with no further ascertainment of this“exposure” during the 10-year follow up period. Both theNurses’ Health and Health Professionals Follow Up study—though significantly less diverse than the NOMAS cohort—likely captured “exposure” better because of repeatedmeasurements of beverage intake at regular intervals.

Whether regular diet soft drink consumption leads toweight gain and vascular events, via one of the putativemechanisms based of appetite stimulation, has not yet beendefinitely answered. It is hard to imagine a scenario whereresearchers could conduct a randomized, blinded, placebo-controlled trial of diet soft drink consumption. Thus thebest scientific evidence for causation is likely to comefrom observational studies—ones that enroll participantswho have similar dietary habits and co-morbidities, and

rigorously capture exposure and outcomes over follow uptime. The current NOMAS analysis does not satisfy all ofthese criteria.

In summary, the article by Gardener et al. differs from theexisting evidence on this topic in two ways. While theabsence of an association between sugared soda consump-tion and vascular events may be a result of relatively limitedstatistical power or exposure misclassification due to lack ofupdated information, we conclude that the surprisingassociation between diet soft drink consumption andvascular events may well be spurious and certainly notconclusive or indicative of cause and effect.

Acknowledgements: Dr. Anand is supported by F32 DK 084697.

Corresponding Author: Shuchi Anand, MD; Division of Nephrology,Department of Medicine, Stanford University School of Medicine,780 Welch Road, Suite 106, Palo Alto, CA 94304, USA(e-mail: Sanand2@stanford.edu).

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