Diet Soda vs Metabolic Syndrome

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Diet Soda Intake and Risk of IncidentMetabolic Syndrome and Type 2 Diabetesin the Multi-Ethnic Study of Atherosclerosis

(MESA)*JENNIFER A. NETTLETON, PHD1PAMELA L. LUTSEY, PHD2

YOUFA WANG, MD, PHD3

JOAO A. LIMA, PHD4

ERIN D. MICHOS, MD4

DAVID R. JACOBS, JR., PHD2,5

OBJECTIVE We determined associations between diet soda consumption and risk ofincident metabolic syndrome, its components, and type 2 diabetes in the Multi-Ethnic Study ofAtherosclerosis.

RESEARCH DESIGN AND METHODS Diet soda consumption was assessed by foodfrequency questionnaire at baseline (20002002). Incident type 2 diabetes was identified atthree follow-up examinations (20022003, 20042005, and 20052007) as fasting glucose

126 mg/dl, self-reported type 2 diabetes, or use of diabetes medication. Metabolic syndrome(and components) was defined by National Cholesterol Education Program Adult TreatmentPanel III criteria. Hazard ratios (HRs) with 95% CI for type 2 diabetes, metabolic syndrome, andmetabolic syndrome components were estimated, adjusting for demographic, lifestyle, anddietary confounders.

RESULTS At least daily consumption of diet soda wasassociatedwith a 36%greater relativerisk of incident metabolic syndrome and a 67% greater relative risk of incident type 2 diabetescompared with nonconsumption (HR 1.36 [95% CI 1.111.66] for metabolic syndrome and1.67 [1.272.20] for type 2 diabetes). Of metabolic syndrome components, only high waistcircumference (men102 cm andwomen88 cm)and high fasting glucose (100mg/dl) wereprospectively associated with diet soda consumption. Associations between diet soda consump-tion and type 2 diabetes were independent of baseline measures of adiposity or changes in thesemeasures, whereas associations between diet soda and metabolic syndrome were not indepen-dent of these factors.

CONCLUSIONS Although these observational data cannot establish causality, consump-tion of diet soda at least daily was associated with significantly greater risks of select incidentmetabolic syndrome components and type 2 diabetes.

Diabetes Care 32:688694, 2009

Two longitudinal cohort studies haveshown positive associations be-tween diet soda consumption and

incident metabolic syndrome indepen-dent of baseline measures of adiposity(1,2). Artificially sweetened beverages,

such as diet soda, are commonly consid-ered benign because they contribute noenergy and few nutrients to the diet. Con-sequently, the previously observed dietsodametabolic syndrome associationsare generally speculated to be the result of

residual confounding by other dietary be-haviors, lifestyle factors, or demographiccharacteristics (1,2). Biological mecha-nisms possibly explaining these associa-tions are few and largely focus on artificialsweeteners in beverages/foods increasingthe desire for (and consumption of)sugar-sweetened, energy-dense beverag-es/foods (3) or disrupting consumersability to accurately estimate energy in-take and remaining energy needs (4).Thus, diet soda consumption may resultin overconsumption, increased bodyweight, and consequent metabolic dys-function. If true, such relations haveimportant implications for dietary coun-seling, given the high frequency of dietbeverage consumption by those at highrisk for metabolic dysfunction (5).

Replication of previously observeddiet sodametabolic syndrome associa-tions in a distinct cohort would bolstertheir credibility and provide further in-sight into the nature of the relationship.Previous studies have not addressed asso-

ciations between diet soda and individualmetabolic syndrome components or riskof type 2 diabetes nor have they fully ad-dressed potential longitudinal mediatorsof these relationships, i.e., changes in ad-iposity status (body weight and or waistcircumference). Therefore, we evaluatedassociations between diet soda consump-tion and risk of incident metabolic syn-d r o m e ( a n d m e t a b o l i c s y n d r o m ecomponents) as well as incident type 2diabetes in the Multi-Ethnic Study of Ath-erosclerosis (MESA), while consideringthe influence of multiple lifestyle con-founders, including measures of baselineadiposity and changes in adiposity.

RESEARCH DESIGN AND

METHODS MESA is a population-based study of 6,814 Caucasian, African

American, Hispanic, and Chinese adults,aged 4584 years, initiated to investigatethe prevalence and progression of sub-clinical cardiovascular disease (CVD).Self-reported race/ethnicity, other demo-graphics, and lifestyle and clinical charac-teristics were collected in six field centers:

From the 1Division of Epidemiology, University of Texas Health Sciences Center, Houston, Texas; the2Division of Epidemiologyand Community Health, Universityof Minnesota,Minneapolis, Minnesota;the3Center for Human Nutrition, Department of International Health, The Johns Hopkins University, Bal-timore, Maryland; the 4Division of Cardiology, The Johns Hopkins University, Baltimore, Maryland; andthe 5Department of Nutrition, University of Oslo, Oslo, Norway.

Corresponding author: Jennifer A. Nettleton, [email protected] 1 October 2008 and accepted 30 December 2008.Published ahead of print at http://care.diabetesjournals.org on 16 January 2009. DOI: 10.2337/dc08-1799.*A full list of participating Multi-Ethnic Study of Atherosclerosis (MESA) investigators and institutions can

be found at http://www.mesa-nhlbi.org. 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

C a r d i o v a s c u l a r a n d M e t a b o l i c R i s k

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Baltimore County, Maryland; Chicago, Il-linois; Forsyth County, North Carolina;New York, New York; Los AngelesCounty, California; and St. Paul, Minne-sota (6). Each examination cycle spanned2 years, with baseline (20002002) andthree follow-up examinations con-ducted from 20022003, 20042005,

and 20052007. Institutional review boardapproval was obtained at all centers; all par-ticipants gave informed consent.

Type 2 diabetesFasting glucose was measured at each ex-amination by rate reflectance spectropho-tometry using thin-film adaptation of theglucose oxidase method on the Vitros an-alyzer (Johnson & Johnson Clinical Diag-nostics, Rochester, NY). Type 2 diabeteswas defined as self-reported type 2 diabe-tes, fasting glucose 126 mg/dl (for mil-

limoles per liter, multiply by 0.0555) atany examination, or use of hypoglycemicmedication. Incident cases comprise indi-viduals without type 2 diabetes at baselinewho met any one of the three criterialisted above at follow-up examinations.Consistency of the serum glucose assayover examinations was established by re-analyzing 200 samples from each of thefour examinations over a short time pe-riod and then recalibrating the originalobservations.

Metabolic syndrome

Metabolic syndrome was defined accord-ing to the modified National CholesterolEducation Program Adult TreatmentPanel III definition (7) as the presence ofthree or more of the following: 1) waist102 (men) or88 cm (women),2) trig-lycerides150 mg/dl (for millimoles perliter, multiply by 0.0113), 3) HDL choles-terol40 (men) or 50 mg/dl (women)(for millimoles per liter, multiply by0.0259), 4) blood pressure 130/85mmHg or antihypertensive treatment,and 5) fasting glucose100 mg/dl or an-

tihyperglycemic treatment. Participantscompleted standardized medical historyquestionnaires ascertaining medicationuse and previous diagnoses and providedsamples for quantification of fasting insu-lin and lipids (8). Waist circumferencewas measured at the umbilicus using astandard tape measure. BMI was calcu-lated from measured weight in kilogramsdivided by the square of height in meters.Resting seated blood pressure was mea-sured three times using a Dinamap modelPro 100 automated oscillometric sphyg-momanometer (Critikon, Tampa, FL).

The average of the last two measurementswas used in analysis.

Dietary intakeDiet was assessed at the baseline exami-nation via a food frequency questionnaire(8,9). Diet soda intake was quantifiedfrom an item listing Diet soft drinks, un-

sweetened mineral water (hereafter re-ferred to as diet soda). Sugar-sweetenedsoda intake was quantified from an itemlisting Regular soft drinks, soda, sweet-ened mineral water (not diet), nonalco-holic beer (hereafter referred to as sugar-sweetened soda). Frequency responseoptions for these items were the follow-ing: rare/never, 13/month, 1/week, 24/week, 56/week, 1/day, 23/day, 45/day, or 6 /day. Participants reportedserving size as small, medium, or large(weighted as intake frequency 0.5,

1.0, and

1.5 for small, medium, andlarge, respectively) (8). Intake of diet sodaor regular soda was characterized as rare/never,rare/never but1 serving/week,1 serving/week but 1 serving/day,and 1 serving/day. Participants whoprovided unreliable dietary informationwere excluded from analyses (n 630)(8).

Statistical analyses We used Cox proportional hazards re-gression to calculate hazard ratios (HRs)for metabolic syndrome and type 2 diabe-

tes (PROC tPHREG in SAS 9.2; SAS Insti-t ut e , C a ry, NC ). We a ssume d t heincidence date to be the date of the exam-ination at which type 2 diabetes or meta-bolic syndrome was first identified. Whenestimating HR for incident type 2 diabe-tes, we excluded participants with preva-lent type 2 diabetes (n 859) and thosewhose prevalent type 2 diabetes statuswas unknown or could not be updatedover follow-up (n 328). When estimat-ing HR for incident metabolic syndrome,we excluded individuals with prevalent

metabolic syndrome (n

2,241) andthose whose metabolic syndrome statuswas unknown at baseline or could not beupdated over follow-up (n 226). Whenestimating HR for a given metabolic syn-drome component, we excluded partici-pants meeting the criteria for thatcomponent at baseline. Sample sizes forthese analyses are shown in RESULTS.

Model 1 adjusted for baseline age,sex, race/ethnicity, examination site, andenergy intake. Model 2 added additionalpossible socioeconomic or lifestyle con-founders: attained education (less than,

equal to, or more than high school), timespent in inactive and active pursuits dur-ing leisure (MET-minutes per week),smoking status (current, former, or neversmoker), pack-years, and regular dietarysupplement use (weekly use or moreversus nonweekly use). We also exploredthe impact of adjustment for various di-

etary factors (specifically, those associ-ated with both diet soda consumptionand type 2 diabetes and/or metabolic syn-drome in ours or previous studies), suchas food intakes (servings per day of wholegrain bread/rice/cereal/pasta, nuts/seeds,fruit, vegetables, white potatoes, refinedgrain bread/rice/cereal/pasta, saltysnacks, desserts, red meat, processedmeat, high-fat dairy products, low-fatdairy products, sugar-sweetened soda,and coffee) or nutrient intakes (fiber, cal-cium, phosphorus, potassium, magne-

sium, and sodium). Finally, to assess thecontribution of adiposity, we adjusted for1) baseline waist circumference (continu-ous, in centimeters), baseline BMI (con-tinuous), or both (single model); 2)change in waist circumference or bodyweight (most recent measurement baseline measurement); and 3) stratifica-tion by BMI (25 and 25 kg/m2).

HRs and 95% CIs are presented rela-tive to the lowest consumption category.

We considered CIs excluding 1.00 statis-tically significant.

RESULTS

Approximately 14% of participants con-sumed 1 serving of diet soda daily(19.4% of whites, 8.6% of blacks, 11.9%of Hispanics, and 5.4% of Chinese),whereas 59% of participants reportednever consuming diet soda. Fourteen per-cent consumed 1 serving of sugar-sweetened soda daily (10.7% of whites,20.7% of blacks, 17.7% of Hispanics, and3.4% of Chinese), whereas 45% neverconsumed sugar-sweetened soda. Twen-ty-four percent did not consume either

beverage; only 2% reported consuming1 serving of both at least daily. Overfollow-up, 871 cases of incident meta-bolic syndrome (22.5%) and 413 cases ofincident type 2 diabetes (8.2%) wereidentified. Demographic and lifestylecharacteristics are shown in Table 1.

Diet soda and risk of metabolicsyndrome and type 2 diabetesCompared with nonconsumers, the riskof metabolic syndrome was 36% greaterin those consuming 1 serving of diet

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soda daily after adjustment for demo-graphic characteristics and energy intake(model 2, Table 2). Relative risk estimateschanged little after additional adjustmentfor other dietary factors (foods or nutri-

ents, data not shown). However, with adjustment for baseline measures ofadiposity (waist circumference and/orBMI), the association was no longer sig-nificant (Table 2). Similarly, the associa-

tion was strongly attenuated whenadjusted for change in waist circumfer-ence or change in body weight betweenbaseline and examination 4 (data notshown).

Table 1Characteristics of 5,011 participants free of prevalent type 2 diabetes according to diet soda consumption categories in MESA

Rare or never rare/never but 1

serving per week1 serving/week to 1

serving/day 1 serving/day P*

n 2,961 455 914 681

Median diet soda intake (serving/day) 0.0 0.1 0.4 2.5Sex (% male) 48.9 43.7 43.7 48.5 0.11

Age (years) 62.5 0.2 61.2 0.5 61.5 0.3 58.9 0.4 0.001Race/ethnicity 0.001

% white 34.0 46.6 58.6 62.11% African American 27.0 23.7 15.4 17.8

% Hispanic 22.7 18.0 21.1 15.3% Chinese 16.3 11.7 4.8 4.9

High school degree (%) 80.3 91.2 92.5 88.5 0.001 Active leisure (MET-min/week) 2,357 56 2,762 143 2,746 101 2,670 117 0.001

Inactive leisure (MET-min/week) 1,665 21 1,692 52 1,744 37 1,628 43 0.73Smoking (% current) 15.6 10.8 13.3 12.0 0.006

Cigarette pack-years 11.5 0.4 8.4 1.0 10.1 0.7 12.3 0.9 0.87 Weekly supplement use (% current) 58.5 54.5 58.9 57.9 0.42

Fasting insulin (mg/dl) 44 0.7 44 1.4 43 0.7 45 1.4 0.80Fasting glucose (mg/dl) 89.9 0.2 88.7 0.5 89.1 0.3 89.2 0.4 0.03

BMI (kg/m2) 27.3 0.1 28.3 0.2 28.5 0.2 29.3 0.2 0.001 Waist circumference (cm) 95.6 0.3 97.2 0.6 98.3 0.5 100.6 0.5 0.001

Dietary intakeEnergy (kcal/day) 1,673 14 1,608 36 1,631 25 1,871 29 0.001

Protein (g/day) 65.5 0.3 69.2 0.7 68.3 0.5 68.0 0.6 0.001Total fat (g/day) 65.4 0.2 63.5 0.6 64.0 0.4 63.4 0.5 0.001

Saturated fat (g/day) 20.7 0.1 20.3 0.3 20.5 0.2 20.3 0.2 0.11Monounsaturated fat (g/day) 23.9 0.1 23.1 0.3 23.5 0.2 23.2 0.2 0.001

Polyunsaturated fat (g/day) 14.9 0.1 14.0 0.2 13.9 0.2 13.9 0.2 0.001

Trans fat (g/day) 3.3 0.03 3.3 0.1 3.5 0.05 3.4 0.1 0.002Carbohydrate (g/day) 210 0.7 209 2 207 1 207 1 0.007

Fiber 17.6 0.1 18.7 0.3 18.2 0.2 17.8 0.2 0.07Calcium (mg/day) 746 7 799 18 794 13 769 15 0.006

Potassium (mg/day) 2,645 12 2,813 31 2,789 22 2,694 26 0.001Magnesium (mg/day) 258 1 273 3 274 2 269 35 0.001

Phosphorus (mg/day) 1,057 5 1,112 13 1,121 9 1,143 11 0.001Sodium (mg/day) 2,345 11 2,393 28 2,408 20 2,431 23 0.001

Whole grains (servings/day) 0.56 0.01 0.66 0.03 0.66 0.02 0.62 0.02 0.001Nuts/seeds 0.28 0.01 0.29 0.02 0.31 0.01 0.29 0.02 0.12

Fruit 1.8 0.03 2.0 0.1 1.9 0.1 1.9 0.1 0.04 Vegetables 2.3 0.02 2.4 0.1 2.3 0.04 2.3 0.1 0.57

White potatoes 0.20 0.004 0.18 0.01 0.20 0.01 0.20 0.01 0.66 White bread, rice, pasta, cereal 1.3 0.01 1.2 0.04 1.2 0.03 1.2 0.03 0.001

Salty snacks 0.21 0.01 0.22 0.01 0.24 0.01 0.22 0.01 0.05Desserts 0.31 0.01 0.29 0.02 0.34 0.01 0.36 0.02 0.006

Low-fat dairy products 0.71 0.02 0.91 0.05 0.89 0.04 0.81 0.04 0.001High-fat dairy products 0.53 0.01 0.50 0.03 0.46 0.02 0.47 0.02 0.001

Red meat 0.38 0.01 0.39 0.01 0.38 0.01 0.37 0.01 0.33Processed meat 0.18 0.004 0.15 0.01 0.16 0.01 0.15 0.01 0.004

Nondiet soda 0.45 0.02 0.31 0.04 0.28 0.03 0.39 0.03 0.001Coffee 1.1 0.03 1.2 0.1 1.5 0.1 1.4 0.1 0.001

Data are means SE or %. Characteristicsof participantsfree of prevalentmetabolicsyndrome (n 3,878)acrosscategories of diet soda consumption were similar.*P for linear trend calculated with the categorical variable modeled continuously. With the exception of energy intake, all dietary variables are adjusted forkilocalories per day.

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If we excluded from our analyses par-ticipants with any metabolic syndromecomponent at baseline (leaving a muchsmaller sample of 1,078 participants and46 incident cases of metabolic syn-drome), the HR comparing extreme dietsoda consumption categories was greater(1.54 [95% CI 0.653.65], model 2) butnot statistically significant.

Daily consumers of diet soda had a67% elevated risk of type 2 diabetes com-

pared with nonconsumers with adjust-ment for demographics and lifestylefactors (model 2, Table 2). Adjustment forother dietary factors did not markedlychange risk estimates (data not shown).

With adjustment for baseline differencesin waist circumference and/or BMI, HRsfor type 2 diabetes were slightly attenu-ated but remained statistically significant(Table 2). The association also remainedstatistically significant with adjustmentfor change in waist circumference (HR1.08 [95% CI 0.751.57], 1.45 [1.12

1.89], and 1.69 [1.282.22] across in-c r e a s i n g d i e t s o d a c o n s u m p t i o ncategories compared with nonconsump-tion, respectively). Results were similarwhen adjusted for change in body weight(data not shown).

With stratification for BMI (25 vs.25 kg/m2), HRs were similar in bothstrata for metabolic syndrome and type 2diabetes, although there were few inci-dent cases andmuch larger confidencein-tervals in the BMI 25 kg/m2 strata,comparing extreme intake categories formetabolic syndrome (HR 2.2 [95% CI

1.104.51] with BMI 25 kg/m2 and1.48 [1.072.05] with BMI 25 kg/m2)and for type 2 diabetes (1.94 [0.874.35]with BMI 25 kg/m2 and 1.54 [1.152.07] with BMI25 kg/m2).

Sugar-sweetened soda and risk ofmetabolic syndrome and type 2diabetes

Although our primary analyses focusedon diet soda intake, we also estimatedcor-responding risks for metabolic syndromeand type 2 diabetes according to con-sumption of sugar-sweetened soda. Datashowed no significant associations be-tween sugar-sweetened soda consump-t i o n a n d r i s k o f e i t h e r m e t a b o l i csyndrome or type 2 diabetes (data notshown).

If risk estimates for type 2 diabetesacross diet soda categories were calcu-lated in only the participants who did notconsume sugar-sweetened soda (n

2,245), the association with diet sodaconsumption remained significant, al-though CIs were wide (HR 1.43 [0.792.61], 1.76 [1.182.63], and 2.23 [1.493.34], across increasing diet sodaconsumption categories compared withnonconsumption, respectively). This re-sult was also true for metabolic syndrome(1.63 [1.132.36], 1.36 [1.021.81], and1.81 [1.36- 2.42] across increasing dietsoda consumption categories comparedwith nonconsumption, respectively, n 1,773).

Metabolic syndrome componentCompared with nonconsumers, individ-uals consuming 1 daily serving of dietsoda had a significantly greater risk of de-veloping high waist circumference (102cm if male and88 cm if female) or highfasting glucose (100 mg/dl) during fol-low-up (HR 1.59 [95% CI 1.232.07] and1.28 [1.081.52] for high waist circum-ference and high fasting glucose, respec-tively) (Table 3). Diet soda consumption

was not associated with the developmentof other metabolic syndrome components(Table 3). As an alternative approach toaddress the same question, we also eval-uated the amount of attenuation that oc-curred when metabolic syndrome HRswere adjusted for baseline measures of in-dividual metabolic syndrome compo-nents. Similarly, the largest amount ofattenuation occurred when HRs for inci-dent metabolic syndrome were adjustedfor baseline waist circumference or base-line fasting glucose concentration (com-

paring individuals consuming

1 servingof diet soda versus nonconsumers: 1.18[0.961.44] adjusted for waist circumfer-ence; 1.23 [1.001.51] adjusted for glu-cose; 1.37 [1.121.68] adjusted for HDLcholesterol; 1.39 [1.14 1.70] adjustedfor triglycerides; and 1.29 [1.061.58]adjusted for systolic and diastolic bloodpressure).

InteractionsThere were no significant interactions be-tween diet soda or sugar-sweetened sodaand age, sex, BMI, or waist circumference

Table 2Risk of incident metabolic syndrome and type 2 diabetes according to diet soda consumption categories in participants from MESA

Rare or never rare/never but 1

serving/week1 serving/week to 1

serving/day 1 serving/day Ptrend*

Metabolic syndrome

n 2,288 367 722 501Cases 478 95 169 129

HR (95% CI) 1.00 1.34 (1.071.67) 1.20 (1.001.43) 1.31 (1.071.60) 0.0031.00 1.42 (1.141.78) 1.28 (1.061.53) 1.36 (1.111.66) 0.001

1.00 1.31 (1.051.64) 1.13 (0.941.37) 1.18 (0.961.44) 0.061.00 1.30 (1.041.62) 1.15 (0.951.38) 1.17 (0.961.44) 0.06

Type 2 diabetesn 2,961 455 914 681

Cases 221 33 84 75HR (95% CI) 1.00 1.06 (0.731.52) 1.39 (1.071.80) 1.63 (1.242.13) 0.001

1.00 1.10 (0.761.59) 1.46 (1.121.89) 1.67 (1.272.20) 0.0011.00 1.00 (0.691.45) 1.23 (0.941.60) 1.40 (1.061.84) 0.01

1.00 0.98 (0.681.42) 1.25 (0.961.62) 1.38 (1.041.82) 0.01

n 5,011. *Ptrend with categorical variable modeled continuously. Model 1 adjusted for study site, age, sex, race/ethnicity, and energy intake. Model 2 adjustedfor the variables in model 1 above plus education, physical activity, smoking status, pack-years, and weekly or more supplement use. Adjusted for the variables inmodel 2 abovewaist circumference (centimeters). Adjustedfor thevariablesin model 2 abovewaistcircumference (centimeters) and BMI (weight in kilograms

divided by the square of height in meters).




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with respect to risk of metabolic syn-drome, metabolic syndrome compo-nents, or type 2 diabetes. Results werealso similar across race/ethnic strata. Fur-thermore, if Chinese were excluded from

analyses (a group in which alternativemetabolic syndrome criteria have beensuggested), results were quite similar; i.e.,greater diet soda intake remained associ-ated with greater risk of type 2 diabetesand metabolic syndrome (data notshown).

CONCLUSIONS In MESA, die tsoda consumption was positively associ-ated with both incident metabolic syn-drome and type 2 diabetes. Associationsbetween diet soda and risk of type 2 dia-

betes were of greater magnitude than theassociations observed between diet sodaand metabolic syndrome. Consistent withthese findings, diet soda was associatedwith development of high fasting glucoseand high waist circumference during fol-low-up but not with other metabolic syn-drome components, suggesting that inthis analysis, metabolic syndrome associ-ations were driven more by a pre-diabeticcondition than the syndrome per se.The frequency of diet beverage consump-tion in the general population and theeven greater reported consumption of

diet beverages in individuals at high riskfor these conditions make dissemina-tion of these findings to a wider audi-ence imperative.

Despite accumulating evidence of the

existence of these associations (1,2), weare cautious not to conclude causality be-tween diet soda and the diabetic or pre-diabetic condition. The possibility ofconfounding by other dietary and life-style/behavioral factors cannot be ex-cluded from these observational studies.

We pose three questions when interpret-ing our results: two that are predicated onan assumption of causality and one that isnot dependent on a causal interpretationof these findings.

Is the relation between diet soda andmetabolic disease mediated throughchanges in body weight orcomposition?

An association between diet soda con-sumption and subsequent weight gain isplausible. First, it has been hypothesizedthat artificial sweeteners may increasehedonistic desires for sweetness andmore energy-dense foods (10 12). Sec-ond, overconsumption of other foods/beverages may also occur in conjunctionwith diet beverage consumption owing tooverestimation of the number of calories

saved by substituting diet beverages forsugar-sweetened beverages (4). Third, theassociation between diet beverages andweight gain may be biased by early aware-ness of energy imbalance, i.e., diet bever-

age consumption may serve as a proxy forearly (failed) attempts to maintain weight.Nevertheless, empirical data have notuniversally supported these hypotheses.

Although data from one observationalstudy showed that women who con-sumed 5.8 g saccharin daily gainedslightly more weight than nonconsumersover 2 years (13), experimental data showthat participants randomly assigned to di-etary regimens that include artificiallysweetened foods and beverages do notgain more weight or consume more en-

ergy compared with those randomly as-signed to sugar-sweetened food/beverageregimens (1422). However, theidealde-sign, one that is randomized and long-term, is notably lacking. In the currentstudy, we found that the associations be-tween diet beverage consumption andrisk of type 2 diabetes were attenuated,but remained significant, when adjustedfor baseline BMI or waist circumferenceor changes in body weight or waist cir-cumference across examinations. There-fore, our data do not indicate that achange in body weight or fat distribution

Table 3Risk of developing metabolic syndrome components according to diet soda intake categories in participants from MESA

Rare or never

More often than rare/never

but1 serving/week1 serving/week to 1

serving/day 1 serving/day

Blood pressure*

n 1,990 322 602 449Cases 512 74 144 113

HR (95% CI) 1.00 (model 2) 1.07 (0.831.37) 1.11 (0.911.34) 1.17 (0.951.45)Waist circumference*

n 1,544 208 399 277Cases 282 44 93 81

HR (95% CI) 1.00 (model 2) 1.13 (0.821.57) 1.22 (0.951.55) 1.59 (1.232.07)HDL cholesterol*

n 1,881 306 609 434Cases 604 97 173 127

HR (95% CI) 1.00 (model 2) 1.12 (0.881.44) 0.96 (0.781.17) 1.05 (0.841.30)Triglycerides*

n 2,143 344 666 476Cases 499 78 156 115

HR (95% CI) 1.00 (model 2) 1.05 (0.821.33) 1.10 (0.911.33) 1.04 (0.841.28)Fasting glucose*

n 2,453 400 793 584Cases 664 97 215 177

HR (95% CI) 1.00 (model 2) 0.97 (0.781.21) 1.13 (0.961.32) 1.28 (1.081.52)

*Metabolicsyndrome componentsare defined as follows: highblood pressure: systolic bloodpressure130mmHgor diastolicbloodpressure85mmHg or takingantihypertensive mediation; high waist circumference:102 cm if male or 88 cm if female; low HDL cholesterol: 40 mg/dl if male or 50 mg/dl if female; hightriglycerides:150 mg/dl; high fasting glucose: 100 mg/dl. Model 2 adjusted for study site, age, sex, race/ethnicity, energy intake education, physical activity,smoking status, pack-years, and weekly supplement use or more.




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mediates the association between dietbeverage consumption and risk of type 2diabetes. However, associations betweendiet soda and metabolic syndrome werestrongly attenuated when adjusted forthese measures of adiposity. Consistentwith these data, only the metabolic syn-drome components high waist circumfer-

ence and high fasting glucose wereassociated with prospectively reporteddiet soda consumption. These results in-dicate that associations between diet sodaand our outcomes are largely mediatedby changes in adiposity and fasting glu-cose, pre-diabetic, or diabetic conditionsand not the totality of the metabolicsyndrome.

Could artificial sweetener (the con-stituent unique from sugar-sweetenedsoda) adversely affect biological processesrelated to insulin resistance, glucose reg-

ulation, and adiposity? Over the life of theMESA cohort, several artificial sweetenersfor sweetening diet beverages have beenused by thesoda industry. Thesweetenersmost commonly used in diet beverages hadalso changed from the initiation of MESA tothemostrecentexamination.These dynam-ics make it difficult to attribute our findingsto the biological effects of a particular artifi-cial sweetener. Mechanistic studies in ran-domized, controlled settings addressinghow artificial sweeteners consumed fromdiet beverages affect early markers of meta-bolic dysfunction are lacking (especially

considering true-to-life exposure to multi-plesweeteners).Datasuch as oursand thosethat preceded ours (1,2), suggest that suchresearch is warranted. Current literature ar-ticles provide data on single sweetenersonly, mostly aspartame (12,14,16,17,1924), with a few using saccharin (11,16), andnone using sucralose, which was more re-cently introduced to the beverage market.Only one study used a combination of arti-ficial sweeteners (but did not include sucra-lose) (15), and no studies were long termnor did they include measures of glycemic

control or insulin sensitivity.

Is diet soda a marker for anunhealthy lifestyle and/or dietarypattern that collectively leads tometabolic dysfunction?It is known that differences in consump-tion of a particular food are paralleled bydifferences in consumption of otherfoods. In the current study, dietary pat-terns of diet beverage consumers andnonconsumers were different in severalrespects (i.e., regular diet beverage con-sumers ate more whole grains, fruit, low-

fat dairy products, desserts, and coffeebut less high-fat dairy products, pro-cessed meat, refined grains, and sugar-sweetened soda). These differences areconsistent with dietary patterns that havebeen independently associated with alower risk of metabolic syndrome or type2 diabetes (1). Analogously, individuals

choosing to consume diet soda probablyfollow other healthy behaviors that influ-ence metabolic syndrome and type 2 dia-betes risk. These dietary and lifestylefactors are all potential confounders thatmay be difficult to accurately characterizein epidemiological studies such as ours.However, failure to adjust fully for theseprotective factors would mask a positiveassociation between diet soda and meta-bolic dysfunction (i.e., all are positiveconfounders).

Limitations of our estimation of diet

soda or artificial sweetener exposure shouldbe mentioned. Our food frequency ques-tionnaire ascertained diet soda consump-tion from a question that combinedunsweetened mineral water and diet soda.However, we suspect that the true associa-tionbetween diet sodaand outcomeswouldprobably be stronger than observed associ-ations due to dilution by the inclusion ofunsweetened mineral water. Artificialsweeteners are found in many types of pur-chased foods and are commonly added bythe individual to other beverages (e.g., cof-

fee). Therefore, random misclassification ofartificial sweetener exposure may exist, al-though diet soda consumers may also bemore likely to consume other artificiallysweetened foods.

In summary, daily diet soda con-sumption was associated with signifi-cantly greater risks of two metabolicsyndrome components (incident highwaist circumference and fasting glucose)and type 2 diabetes in this large, multi-ethnic cohort. These results corroboratefindings from the Atherosclerosis Risk inCommunities and Framingham studiesand show that stronger adverse associa-tions exist between diet soda and type 2diabetes. Diet soda consumption, eitherindependently or in conjunction withother dietary and lifestyle behaviors, maylead to weight gain, impaired glucosecontrol, and eventual diabetes.

Acknowledgments This research was sup-ported by Contracts N01-HC-95159 throughN01-HC-95165 and N01-HC-95169 from theNational Heart, Lung, and Blood Institute.

No potential conflicts of interest relevant tothis article were reported.

We thank the other investigators, the staff,and the participants of the MESA study fortheir valuable contributions.

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Diet Soda vs Metabolic Syndrome