Tomar dos gaseosas por día incrementa el riesgo a la salud
Un nuevo estudio científico determinó que incrementa la probabilidades de muerte, pero se desconoce exactamente la relación de causa - efecto de las bebidas gaseoas.
Un nuevo estudio científico detectó que aquellos que bebían dos o más vasos de cualquier tipo de gaseosa por día tenían un mayor riesgo de morir que las personas que bebían menos de una por mes.
La investigación abarcó a más de 450.000 personas de 10 países durante casi 20 años. Ninguna de las personas tenía cáncer, diabetes, enfermedad cardíaca o accidente cerebrovascular antes de su participación.
Los investigadores descubrieron que los hombres y mujeres que tomaban dos o más vasos al día de gaseosas endulzadas con azúcar tenían un mayor riesgo de morir por trastornos digestivos, mientras que los que bebían la misma cantidad de bebidas dietéticas tenían un mayor riesgo de morir por enfermedades cardiovasculares.
En este estudio, un vaso contenía 250 mililitros; la típica lata de refresco en todo el mundo contiene 355 mililitros con lo cual el resgo sería mayor que el estudiado.
“La evidencia empírica sugiere que el alto nivel de azúcar en la sangre y el alto consumo de azúcar pueden dañar la barrera intestinal, lo que lleva a un ‘intestino permeable’ y al acceso al sistema inmunitario intestinal”, dijo a CNN el Dr. Sharon Horesh Bergquist, profesor de medicina en la Facultad de Medicina de la Universidad Emory en Atlanta.
A su vez, esto altera que causa inflamación intestinal, altera la microbiota intestinal y aumenta la susceptibilidad a las infecciones intestinales, dijo el médico.
“Estas vías pueden aumentar la susceptibilidad a las enfermedades digestivas”. El consumo total de refrescos en el estudio también se asoció con un mayor riesgo de enfermedad de Parkinson, pero no con Alzheimer o cáncer.
Aquellos que consumieron más de una bebida azucarada por mes pero menos de dos por día parecieron experimentar un efecto de dosis: cuanto más bebían, mayor era el riesgo.
La sustitución de una bebida azucarada por día con una endulzada artificialmente redujo el riesgo de muerte prematura, pero beber cuatro o más bebidas endulzadas artificialmente aumentó el riesgo de muerte prematura por enfermedad cardiovascular en las mujeres. No se observó el mismo efecto para los hombres, y no se observó el riesgo de morir de cáncer.
Este novedoso estudio, así como otras investigaciones sobre la conexión entre la dieta y las bebidas azucaradas y los riesgos para la salud, es observacional y no puede mostrar causa y efecto. Según los investigadores, esa es una limitación importante, ya que es imposible determinar si la asociación se debe a un edulcorante artificial específico, un tipo de bebida, obesidad u otro problema de salud oculto.
“La causa detrás de estas asociaciones no está clara”, dijo Bergquist. “Otras posibles causas biológicas podrían atribuirse a la evidencia experimental que vincula el consumo de edulcorantes artificiales con los antojos de azúcar, la estimulación del apetito y la intolerancia a la glucosa”.
Desde otra perspectiva, Robert Rankin, presidente del Consejo de Control de Calorías, un grupo comercial de alimentos y bebidas bajos en calorías y dietéticos, dijo en un comunicado que “los edulcorantes bajos en calorías y sin calorías tienen un largo historial de seguridad y son herramientas importantes para control de peso y aquellos que controlan la diabetes. Este estudio muestra una imagen inexacta del papel importante de estos productos para los consumidores “.
Bergquist sugiere satisfacer los antojos de azúcar mediante la sustitución de alimentos naturalmente dulces como frutas y dátiles, que contienen “vitaminas, minerales y químicos bioactivos que promueven la salud llamados fitonutrientes”. “Empacan azúcar con fibra, lo que conduce a un aumento lento y constante, en lugar de agudo, del azúcar en la sangre”, dijo Bergquist.
Ella también sugiere comprometerse a un desafío sin azúcar durante al menos dos semanas porque “nuestras papilas gustativas cambian cada dos semanas”, dijo.
“Eso significa que si puedes superar los intensos antojos de azúcar durante las primeras dos semanas, tus papilas gustativas se adaptarán para encontrar alimentos naturales con azúcar más satisfactorios”.
Antecedentes sobre las bebidas gaseoas e impuestos al azúcar
Ya en febrero, la American Heart Association había publicado un estudio que encontró que beber dos o más bebidas endulzadas artificialmente al día está relacionado con un mayor riesgo de derrames cerebrales, ataques cardíacos y muerte prematura en mujeres mayores de 50 años.
Estudios anteriores han relacionado el alto nivel de consumo de refrescos endulzados con azúcar y endulzados artificialmente con riesgos elevados de obesidad, diabetes tipo 2 y enfermedades cardiovasculares
Otras investigaciones científicas han demostrado un vínculo entre las bebidas dietéticas y el accidente cerebrovascular, la demencia, la diabetes tipo 2, la obesidad y el síndrome metabólico, que pueden conducir a enfermedades cardíacas y diabetes, según CNN.
Algunas ciudades han tratado de frenar el consumo de refrescos imponiendo impuestos a las bebidas, con resultados mixtos. El consumo de refrescos y otras bebidas azucaradas cayó un 21 por ciento en los barrios de bajos ingresos de Berkeley, California, impuso un impuesto de 1 centavo por onza de refrescos en 2016, según el primer estudio para medir el impacto del impuesto. Un estudio separado del impuesto a las bebidas gaseosas de Filadelfia descubrió que no tenía mucho efecto sobre el consumo de azúcar, en parte porque los residentes que querían comprar bebidas gaseosas condujeron a áreas vecinas donde no había impuestos a las bebidas gaseosas. La industria de los refrescos ha cabildeado contra tales impuestos.
Anexo con fuente original y estudio científico sobre la evidencia de las bebidas gaseosas y el daño a la salud
September 3, 2019
Association Between Soft Drink Consumption and Mortality in 10 European Countries
Amy Mullee, PhD1,2,3; Dora Romaguera, PhD4,5; Jonathan Pearson-Stuttard, BMBCh6,7; et alVivian Viallon, PhD3; Magdalena Stepien, PhD3; Heinz Freisling, PhD3; Guy Fagherazzi, PhD8,9; Francesca Romana Mancini, PhD8,9; Marie-Christine Boutron-Ruault, MD8,9; Tilman Kühn, PhD10; Rudolf Kaaks, PhD10; Heiner Boeing, PhD11; Krasimira Aleksandrova, PhD12; Anne Tjønneland, MD13; Jytte Halkjær, PhD13; Kim Overvad, MD14; Elisabete Weiderpass, MD15; Guri Skeie, PhD16; Christine L. Parr, PhD17; J. Ramón Quirós, MD18; Antonio Agudo, PhD19; Maria-Jose Sánchez, MD, PhD20,21; Pilar Amiano, MS21,22; Lluís Cirera, MD21,23; Eva Ardanaz, MD21,24,25; Kay-Tee Khaw, MB26; Tammy Y. N. Tong, PhD27; Julie A. Schmidt, PhD27; Antonia Trichopoulou, MD28,29; Georgia Martimianaki, MSc28; Anna Karakatsani, MD28,30; Domenico Palli, MD31; Claudia Agnoli, MSc32; Rosario Tumino, MD33; Carlotta Sacerdote, MD34; Salvatore Panico, MD35; Bas Bueno-de-Mesquita, MD7,36,37,38; W. M. Monique Verschuren, PhD39; Jolanda M. A. Boer, PhD39; Roel Vermeulen, PhD40; Stina Ramne, MSc41; Emily Sonestedt, PhD41; Bethany van Guelpen, MD42; Pernilla Lif Holgersson, PhD42; Konstantinos K. Tsilidis, PhD7,43; Alicia K. Heath, PhD7; David Muller, PhD7; Elio Riboli, MD7; Marc J. Gunter, PhD3; Neil Murphy, PhD3
Author Affiliations Article Information
JAMA Intern Med. Published online September 3, 2019. doi:10.1001/jamainternmed.2019.2478
Question Is regular consumption of soft drinks associated with a greater risk of all-cause and cause-specific mortality?
Findings In this population-based cohort study of 451 743 individuals from 10 countries in Europe, greater consumption of total, sugar-sweetened, and artificially sweetened soft drinks was associated with a higher risk of all-cause mortality. Consumption of artificially sweetened soft drinks was positively associated with deaths from circulatory diseases, and sugar-sweetened soft drinks were associated with deaths from digestive diseases.
Meaning Results of this study appear to support ongoing public health measures to reduce the consumption of soft drinks.
Importance Soft drinks are frequently consumed, but whether this consumption is associated with mortality risk is unknown and has been understudied in European populations to date.
Objective To examine the association between total, sugar-sweetened, and artificially sweetened soft drink consumption and subsequent total and cause-specific mortality.
Design, Setting, and Participants This population-based cohort study involved participants (n = 451 743 of the full cohort) in the European Prospective Investigation into Cancer and Nutrition (EPIC), an ongoing, large multinational cohort of people from 10 European countries (Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom), with participants recruited between January 1, 1992, and December 31, 2000. Excluded participants were those who reported cancer, heart disease, stroke, or diabetes at baseline; those with implausible dietary intake data; and those with missing soft drink consumption or follow-up information. Data analyses were performed from February 1, 2018, to October 1, 2018.
Exposure Consumption of total, sugar-sweetened, and artificially sweetened soft drinks.
Main Outcomes and Measures Total mortality and cause-specific mortality. Hazard ratios (HRs) and 95% CIs were estimated using multivariable Cox proportional hazards regression models adjusted for other mortality risk factors.
Results In total, 521 330 individuals were enrolled. Of this total, 451 743 (86.7%) were included in the study, with a mean (SD) age of 50.8 (9.8) years and with 321 081 women (71.1%). During a mean (range) follow-up of 16.4 (11.1 in Greece to 19.2 in France) years, 41 693 deaths occurred. Higher all-cause mortality was found among participants who consumed 2 or more glasses per day (vs consumers of <1 glass per month) of total soft drinks (hazard ratio [HR], 1.17; 95% CI, 1.11-1.22; P < .001), sugar-sweetened soft drinks (HR, 1.08; 95% CI, 1.01-1.16; P = .004), and artificially sweetened soft drinks (HR, 1.26; 95% CI, 1.16-1.35; P < .001). Positive associations were also observed between artificially sweetened soft drinks and deaths from circulatory diseases (≥2 glasses per day vs <1 glass per month; HR, 1.52; 95% CI, 1.30-1.78; P < .001) and between sugar-sweetened soft drinks and deaths from digestive diseases (≥1 glass per day vs <1 glass per month; HR, 1.59; 95% CI, 1.24-2.05; P < .001).
Conclusions and Relevance This study found that consumption of total, sugar-sweetened, and artificially sweetened soft drinks was positively associated with all-cause deaths in this large European cohort; the results are supportive of public health campaigns aimed at limiting the consumption of soft drinks.
The frequent consumption of sugar-sweetened soft drinks increases energy intake, which can lead to weight gain and obesity.1-3 In 2010, the worldwide burden of adiposity-associated cardiovascular diseases, cancers, and type 2 diabetes associated with consumption of sugar-sweetened soft drinks was estimated to be 184 000 deaths.4 Reformulation of sugar-sweetened soft drinks, in which sugar is replaced with low- or no-calorie sweeteners, is being driven by consumer awareness and fiscal instruments, such as taxes.5 Artificially sweetened soft drinks have few or no calories; however, their long-term physiological and health implications are largely unknown.6-8
Whether regular consumption of soft drinks (total, sugar-sweetened, or artificially sweetened) is associated with greater all-cause and cause-specific mortality is uncertain, given that inconsistent findings were reported from previous prospective studies.9,10 Recently, a joint analysis of the Health Professionals Follow-up Study (HPFS) and Nurses’ Health Study (NHS) reported that a higher level of consumption of sugar-sweetened and artificially sweetened beverages was associated with greater all-cause mortality in the United States.11 Similarly, a positive association between artificially sweetened beverage consumption and all-cause mortality among US-based women was also reported by the Women’s Health Initiative Observational Study.12 Large-scale studies are required to examine the association between soft drink consumption and health outcomes, in particular research based in populations outside of the United States. To our knowledge, a large-scale European-based analysis of soft drink consumption and mortality outcomes has not been undertaken.
For cause-specific mortality, previous studies on soft drink consumption and cardiovascular disease mortality have found positive associations.11,13 However, whether these associations differed by type of circulatory diseases (eg, ischemic heart disease and cerebrovascular diseases) is uncertain. Similarly, scant data are available to date on mortality from other major chronic conditions such as cancers, digestive diseases, and neurodegenerative diseases.
We investigated the association of consuming total, sugar-sweetened, and artificially sweetened soft drinks with total and cause-specific mortality among participants in the European Prospective Investigation into Cancer and Nutrition (EPIC), an ongoing, large multinational cohort with more than 41 000 recorded deaths reported during the follow-up period.
EPIC is a multicenter cohort of 521 330 participants who were recruited between January 1, 1992, and December 31, 2000, predominantly from the general populations of 10 European countries (Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom).14,15 Written informed consent was provided by all study participants. Ethical approval for this study was provided by the International Agency for Research on Cancer and the institutional review boards of the local participating EPIC centers.
For the current analysis, we excluded participants who at baseline reported cancer (n = 22 537), heart disease (n = 12 619), stroke (n = 3683), or diabetes (n = 12 461); participants in the highest or lowest 1% of the distribution of the ratio between energy intake to estimated energy requirement (ie, those with implausible dietary intake data; n = 8828); and participants with missing soft drink consumption or missing follow-up information (n = 9459). The final study cohort included 451 743 participants (130 662 [28.9%] men; 321 081 [71.1%] women).
Assessment of Exposure
Dietary intake was assessed during the baseline enrollment visit (1992-2000) by country-specific instruments that were developed and validated within the various source populations in EPIC.14,15 Self-administered questionnaires were used in all centers, except in Greece, Spain, and Ragusa (Italy), where data were collected during personal interviews. In Malmö (Sweden), a combined semiquantitative food frequency questionnaire and 7-day dietary diary and diet interview was used. For soft drink consumption, participants recorded the number of glasses per month, week, or day; the structure of the questions varied somewhat by country and questionnaire. The dietary questionnaires for most countries collected information on the frequency of consumption (per glass) of “low calorie or diet fizzy soft drinks,” “fizzy soft drinks, eg cola, lemonade,” and “fruit squash or cordial.” Soft drink consumption (grams per day, which is roughly equivalent to the amount in milliliters; 1 glass was equal to approximately 250 mL) was calculated using typical glass sizes in each center.
Total soft drinks referred to a combination of soft drinks, carbonated and isotonic drinks, and diluted syrups. Total soft drink consumption was subdivided into sugar-sweetened and artificially sweetened soft drink consumption for all countries except Italy, Spain, and Sweden, where types of soft drinks were unmeasured. The reproducibility and validity of the dietary questionnaires were assessed in some countries,14-21 with correlations between repeated dietary questionnaires and with 24-hour dietary records ranging from 0.46 to 0.77 for soft or nonalcoholic drinks in the Netherlands, France, Germany, and Spain. Lifestyle questionnaires, administered at recruitment, were used as a source of information on educational attainment, smoking habits, alcohol intake, physical activity, reproductive and menstrual characteristics, and other variables.
Ascertainment of Deaths
Data on vital status as well as the cause and date of death were collected by EPIC centers through record linkages with cancer registries, boards of health, and death indices in Denmark, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom or through active follow-up (inquiries by mail or telephone to municipal registries or regional health departments or to physicians or hospitals) in Germany, Greece, and France. For the current study, follow-up of participants from baseline (1992-2000) occurred from December 2009 to December 2013 for countries with record linkage. The end of follow-up was considered to be the last known contact with participants in France (June 2008), Germany (December 2009), and Greece (December 2012). Loss to follow-up was relatively low at 1.5%.
International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes were used to classify the underlying cause of death. Deaths were grouped into common causes: cancer (ICD-10 codes C00-D48), circulatory diseases (ICD-10 codes I00-I99), and digestive diseases (ICD-10 codes K00-K93). Additional specific causes were breast cancer (ICD-10 code C50); colorectal cancer (ICD-10 code C18-C20); prostate cancer (ICD-10 code C61); cerebrovascular disease (ICD-10 codes I60-I69); ischemic heart disease (ICD-10 codes I20-I25); and the neurodegenerative diseases, Alzheimer (ICD-10 code G30) and Parkinson (ICD-10 code G20).
Hazard ratios (HRs) and 95% CIs for mortality were estimated using Cox proportional hazards regression models with age as the primary time metric. Time at study entry was age at recruitment, and exit time was age at death or the last date at which follow-up was considered complete in each EPIC center. Models were stratified by age at recruitment in 1-year categories, sex, and EPIC center. Soft drink consumption was categorized by the frequency of glasses consumed (<1 glass per month, 1 to 4 glasses per month, >1 to 6 glasses per week, 1 to <2 glasses per day, or ≥2 glasses per day, with 1 glass being equal to 250 mL). Linear trend tests across exposure groups were evaluated using the median category variables as continuous terms. Multivariable models were adjusted for alcohol consumption; smoking status, intensity, and duration; body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared); physical activity; educational status; menopausal status; ever use of menopausal hormone therapy; and dietary intakes of total energy, red and processed meats, coffee, fruit and vegetable juices, and fruits and vegetables. Further adjustment for dietary fiber intake resulted in virtually unchanged risk estimates, so this variable was not included in the final multivariable models. Sugar-sweetened and artificially sweetened soft drinks were also mutually adjusted.
The association between soft drink consumption and mortality was also assessed across subgroups of smoking status, BMI, physical activity, and alcohol consumption. Tests for interaction were performed with the likelihood ratio test of models with and without interaction terms. Heterogeneity across countries was explored using a meta-analysis approach.22 We further investigated the shape of the association between soft drink consumption and all-cause mortality using restricted cubic splines with knots defined by the midpoints of aforementioned categories. The proportional hazard assumption was satisfied using Schoenfeld residuals23 analyses.
In sensitivity analyses, we excluded BMI from the multivariable models to assess the potential mediating role of adiposity for the association between soft drinks and mortality. To investigate reverse causality, analyses were conducted excluding deaths within the first 8 years of follow-up. We examined the associations of sole consumption of sugar-sweetened and artificially sweetened soft drinks with mortality. In addition, we examined the associations between soft drink consumption and mortality according to the death ascertainment method (linkage or active follow-up), with nonconsumers of soft drinks as the reference group, and with adjustment of the multivariable models for the World Cancer Research Fund dietary score24 (rather than individual dietary covariates). As a negative control analysis, we also examined the associations between soft drink consumption and deaths from external causes. All statistical tests were 2-sided, and P < .05 was considered statistically significant. Data analyses were performed from February 1, 2018, to October 1, 2018.
Patients and Characteristics
Of the EPIC cohort of 521 330 participants, 451 743 (86.7%) were included in the study, among whom were 321 081 women (71.1%) and 130 662 men (28.9%) with a mean (SD) age of 50.8 (9.8) years. After a mean (range) follow-up of 16.4 (11.1 in Greece to 19.2 in France) years, 41 693 deaths (18 302 men and 23 391 women) were recorded. Of these deaths, 18 003 (43.2%) were from cancers, 9106 (21.8%) from circulatory diseases, and 1213 (2.9%) from digestive diseases. Compared with low consumers of soft drinks (<1 glass per month, high consumers (≥2 glasses per day) were younger (mean [IQR] age at recruitment, 52.2 [46.4-58.4] years vs 50.5 [38.4-56.6] years), more likely to be current smokers (46 154 [20.5%] vs 4706 [29.1%]), and more likely to be physically active (34 907 [15.5%] vs 4501 [27.8%]) (Table 1).
Soft Drink Consumption and Mortality
Higher all-cause mortality was found for participants who consumed 2 or more glasses per day (vs consumers of <1 glass per month) of total soft drinks (HR, 1.17; 95% CI, 1.11-1.22; P < .001), sugar-sweetened soft drinks (HR, 1.08; 95% CI, 1.01-1.16; P = .004), and artificially sweetened soft drinks (HR, 1.26; 95% CI, 1.16-1.35; P < .001) (Table 2). Similar associations were found for men and women (Table 2). Nonlinear J-shaped associations (nonlinear P < .001) were observed between all-cause mortality and total, sugar-sweetened, and artificially sweetened soft drinks, with higher risks observed at consumption levels of more than 125 mL per day for artificially sweetened soft drinks and more than 225 mL per day of sugar-sweetened soft drinks (eFigure in the Supplement). Among participants with a BMI lower than 25 (healthy weight), positive associations with all-cause mortality were found for total soft drinks (≥1 glass per day vs <1 glass per month; HR, 1.18; 95% CI, 1.11-1.25), sugar-sweetened soft drinks (HR, 1.11; 95% CI, 1.03-1.21), and artificially sweetened soft drinks (HR, 1.27; 95% CI, 1.12-1.43) (Figure).
The soft drink consumption and all-cause mortality associations were generally consistent across subgroups of other mortality risk factors. For sugar-sweetened soft drinks, a positive association was found among participants with a BMI of 30 or higher (obese) but not among those with a BMI between 25 and under 30 (overweight) (HR, 1.23; 95% CI, 1.10-1.39 vs HR, 0.98; 95% CI, 0.90-1.06; P = .002; Figure). Results remained similar when country-specific estimates were pooled in a random-effects meta-analysis (eTable 1 in the Supplement). No heterogeneity across countries was found for artificially sweetened soft drinks and all-cause mortality (I2 = 0%; P = .86); however, heterogeneity was detected for sugar-sweetened soft drinks (I2 = 63%; P = .01), although positive associations were found for all but 1 country.
Soft Drink Consumption and Cause-Specific Mortality
Higher circulatory diseases mortality risk was found for participants consuming 2 or more glasses per day (vs consumers of <1 glass per month) of total soft drinks (HR, 1.27; 95% CI, 1.14-1.40; P < .001) and artificially sweetened soft drinks (HR, 1.52; 95% CI, 1.30-1.78; P < .001) but not sugar-sweetened soft drinks (HR, 1.11; 95% CI, 0.95-1.30; P = .16) (Table 3). Similar results were found for men and women. Positive associations for ischemic heart disease mortality risk were found for total soft drinks (≥1 glass per day vs <1 glass per month; HR, 1.19; 95% CI, 1.06-1.33; P = .001) and artificially sweetened soft drinks (HR, 1.41; 95% CI, 1.11-1.79; P = .003) (Table 4), with no association for sugar-sweetened soft drinks. Total soft drinks were positively associated with cerebrovascular disease mortality risk (HR, 1.30; 95% CI, 1.12-1.50; P < .001), with positive statistically nonsignificant associations found for sugar-sweetened and artificially sweetened soft drinks (Table 4).
Total, sugar-sweetened, and artificially sweetened soft drink consumption was not associated with risk of deaths from overall cancer (Table 3), breast cancer, or prostate cancer (Table 4). Total soft drink consumption was positively associated with colorectal cancer deaths (≥1 glass per day vs <1 glass per month; HR, 1.25; 95% CI, 1.07-1.47; P = .004) (Table 4), with statistically nonsignificant associations found for sugar-sweetened and artificially sweetened soft drinks.
Higher level of consumption of total soft drinks and sugar-sweetened soft drinks (≥1 glass per day vs <1 glass per month; HR, 1.59; 95% CI, 1.24-2.05; P < .001), but not artificially sweetened soft drinks, was associated with digestive disease mortality. Similar associations were found for men and women (Table 3).
Total soft drink consumption was positively associated with risk of Parkinson disease mortality (≥1 glass per day vs <1 glass per month; HR, 1.59; 95% CI, 1.07-2.36; P = .02), with similar magnitude nonsignificant associations found for artificially sweetened and sugar-sweetened soft drinks (Table 4). Soft drinks were not associated with Alzheimer disease mortality.
Sugar-sweetened and artificially sweetened soft drink consumption was positively associated with circulatory disease and digestive disease mortality among participants with a healthy weight (eTable 2 in the Supplement). Similar positive associations between soft drink consumption and mortality outcomes were found when the multivariable models excluded BMI adjustment (eTable 3 in the Supplement), deaths that occurred during the first 8 years of follow-up were excluded (eTable 4 in the Supplement), nonconsumers of soft drinks were set as the reference group (eTable 5 in the Supplement), and multivariable models were adjusted for the World Cancer Research Fund dietary score rather than individual dietary covariates (eTable 6 in the Supplement). A similar pattern of results for all mortality end points was found for sole consumers of artificially sweetened and sugar-sweetened soft drinks (eTable 7 in the Supplement). The positive sugar-sweetened association was stronger for countries with active follow-up, compared with those with linkage follow-up (eTable 8 in the Supplement). No associations were found between soft drink consumption and deaths by external causes (eTable 9 in the Supplement).
In this large multinational European study, higher level of consumption of total, sugar-sweetened, and artificially sweetened soft drinks was associated with increased risk of death from all causes. The positive association between soft drink consumption and mortality was evident for both men and women. Only artificially sweetened, and not sugar-sweetened, soft drinks were associated with deaths from circulatory diseases, whereas for digestive disease deaths, only sugar-sweetened soft drinks were associated with higher risk.
The high level of consumption of sugar-sweetened and artificially sweetened soft drinks has previously been linked to elevated risks of obesity, type 2 diabetes, and cardiovascular disease.1,25-27 We found that sugar-sweetened soft drinks were positively associated with all-cause mortality, a result consistent with findings from an HPFS/NHS analysis11 but inconsistent with findings from smaller Singapore- and US-based studies.10,28 We also found positive associations between consumption of artificially sweetened soft drinks and all-cause mortality, a finding consistent with results of the HPFS/NHS and Women’s Health Initiative studies.11,12 Overall, to our knowledge, this current study was the largest to date to investigate the associations between soft drink consumption and mortality outcomes as well as the first comprehensive European-based analysis.
We found nonlinear J-shaped associations for soft drink consumption and all-cause mortality, with higher risks observed at consumption levels of more than 125 mL per day (half a glass) of artificially sweetened soft drinks and more than 225 mL per day (approximately 1 glass) of sugar-sweetened soft drinks, and the lowest risks found from drinking 50 mL per day. The reduced risk found at low consumption levels may be the result of reverse causality (analogous to what has been observed for alcohol consumption and all-cause mortality29-31), driven by participants with disease symptoms reporting nonconsumption of soft drinks.
The role of BMI in the soft drink consumption and mortality outcomes association is complex, with adiposity likely a mediating and confounding factor that varies by cause of death. In our analyses, results were unchanged between the multivariable models with or without BMI adjustment, suggesting that the observed associations may be independent of adiposity. In support of this hypothesis, positive associations were found between total, sugar-sweetened, and artificially sweetened soft drinks with deaths from all causes, circulatory diseases, and digestive diseases among participants with healthy weight. These results may suggest that soft drinks alter mortality risk independently of adiposity, possibly because of the high glycemic index of sugar-sweetened soft drinks,32 which elevates blood glucose levels and may in turn lead to insulin resistance and inflammation.33,34
For sugar-sweetened soft drinks, we found a positive association with all-cause mortality for participants who were obese but no association for participants who were overweight. The lack of association among overweight participants is inconsistent with the result of an analysis of the HPFS/NHS study, which found a positive association with all-cause mortality among overweight adults.11 It is unclear why we observed a positive association for sugar-sweetened soft drinks among obese but not among overweight participants. We cannot exclude the role of chance in these subgroup analyses, and additional large-scale prospective studies are required to examine these associations further.
In cause-specific analyses, we found positive associations between artificially sweetened soft drink consumption and deaths from circulatory diseases; these results are consistent with those in the HPFS/NHS and Women’s Health Initiative analyses.11,13 These results were largely based on the positive association between ischemic heart disease deaths and consumption of artificially sweetened soft drinks. Reverse causality is a possible explanation for this positive association, with unhealthy individuals at the study baseline (eg, those who were overweight or obese; those with prediabetes) switching from drinking sugar-sweetened to artificially sweetened soft drinks to control their body weight. However, this association persisted when deaths recorded in the first 8 years of follow-up were excluded. In addition, positive associations between artificially sweetened soft drinks and all-cause and circulatory diseases mortality were found among participants with healthy weight. Possible biological mechanisms that may explain the positive associations between artificially sweetened soft drinks and mortality outcomes are unclear. Limited experimental evidence suggests that artificial sweeteners may induce glucose intolerance,35 but further studies are needed into the possible adverse effects of the long-term consumption of artificial sweeteners commonly used in soft drinks, such as aspartame and acesulfame potassium.36
A higher level of soft drink consumption was associated with greater risk of death from digestive diseases, with a positive association only found for sugar-sweetened soft drinks. Hyperglycemia resulting from consumption of sugar-sweetened soft drinks may alter gut-barrier function and increase the risk of enteric infection.37 Furthermore, fructose, a sugar commonly used in soft drinks, promotes liver lipogenesis, which can lead to nonalcoholic fatty liver disease and lower insulin sensitivity.38-40
We observed no association between soft drink consumption and overall cancer mortality. This result is consistent with findings in most previous studies, which found little evidence of a direct association between soft drink consumption and cancer risk,2 but it is inconsistent with that in the HPFS/NHS analysis, which reported a positive association between sugar-sweetened beverages and cancer mortality.11 We did observe a positive association between total soft drink consumption and risk of colorectal cancer mortality, but our analyses could not ascertain whether sugar-sweetened or artificially sweetened soft drinks were factors in this association. In the HPFS/NHS analysis, a borderline positive association was observed between sugar-sweetened beverages and colon cancer mortality.11 Further studies into soft drinks and cancer are warranted to identify whether direct or indirect (through weight gain or overweight or obesity status, which are strong risk factors for multiple cancers41) associations exist for various cancer types.
In addition, we observed that a higher level of total soft drink consumption was associated with greater risk of Parkinson disease mortality, with positive nonsignificant associations found for sugar-sweetened and artificially sweetened soft drinks. To our knowledge, this study is the first to link soft drink consumption with Parkinson disease, and additional studies are required to examine this association.
To our knowledge, this study is the largest to date to investigate the association between soft drink consumption and mortality. However, it has several limitations. Given the observational design of the study, it is not possible to establish causality between soft drink consumption and mortality, and we recognize that the observed associations may be biased because of residual confounding. However, the large number of participants and recorded deaths (approximately 42 000) allowed us to conduct analyses by subgroups of other mortality risk factors, and we generally observed similar associations across subgroups of considered risk factors. Furthermore, the negative control analysis found no association between consumption of soft drinks and deaths from external causes. This study was also limited by a single assessment of soft drink consumption at baseline.
In this study, the high level of consumption of total, sugar-sweetened, and artificially sweetened soft drinks was associated with elevated risks of death from all causes. Positive associations were observed between sugar-sweetened soft drinks and digestive disease deaths as well as between artificially sweetened soft drinks and circulatory disease deaths. Further studies are needed to investigate the possible adverse health effects of artificial sweeteners. The results of this study are supportive of ongoing public health campaigns aimed at reducing the consumption of soft drinks.
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Accepted for Publication: May 12, 2019.
Corresponding Author: Neil Murphy, PhD, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France (email@example.com).
Published Online: September 3, 2019. doi:10.1001/jamainternmed.2019.2478
Author Contributions: Drs Gunter and Murphy contributed equally to this work. Drs Gunter and Murphy had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Romaguera, Tjønneland, Halkjær, Weiderpass, Ardanaz, Trichopoulou, Martimianaki, Tumino, Bueno-de-Mesquita, Riboli, Gunter, Murphy.
Acquisition, analysis, or interpretation of data: Mullee, Romaguera, Pearson-Stuttard, Viallon, Stepien, Freisling, Fagherazzi, Mancini, Boutron-Ruault, Kühn, Kaaks, Boeing, Aleksandrova, Tjønneland, Overvad, Weiderpass, Skeie, Parr, Quirós, Agudo, Sánchez Pérez, Amiano, Cirera, Ardanaz, Khaw, Tong, Schmidt, Trichopoulou, Martimianaki, Karakatsani, Palli, Agnoli, Sacerdote, Panico, Bueno-de-Mesquita, Verschuren, Boer, Vermeulen, Ramne, Sonestedt, Van Guelpen, Lif Holgerson, Tsilidis, Heath, Muller, Riboli, Gunter, Murphy.
Drafting of the manuscript: Mullee, Gunter, Murphy.
Critical revision of the manuscript for important intellectual content: Romaguera, Pearson-Stuttard, Viallon, Stepien, Freisling, Fagherazzi, Mancini, Boutron-Ruault, Kühn, Kaaks, Boeing, Aleksandrova, Tjønneland, Halkjær, Overvad, Weiderpass, Skeie, Parr, Quirós, Agudo, Sánchez Pérez, Amiano, Cirera, Ardanaz, Khaw, Tong, Schmidt, Trichopoulou, Martimianaki, Karakatsani, Palli, Agnoli, Tumino, Sacerdote, Panico, Bueno-de-Mesquita, Verschuren, Boer, Vermeulen, Ramne, Sonestedt, Van Guelpen, Lif Holgerson, Tsilidis, Heath, Muller, Riboli, Gunter, Murphy.
Statistical analysis: Mullee, Viallon, Freisling, Vermeulen, Tsilidis, Muller, Gunter, Murphy.
Obtained funding: Halkjær, Overvad, Quirós, Agudo, Khaw, Bueno-de-Mesquita, Verschuren, Vermeulen, Gunter.
Administrative, technical, or material support: Fagherazzi, Boutron-Ruault, Kühn, Kaaks, Boeing, Tjønneland, Overvad, Skeie, Quirós, Agudo, Khaw, Karakatsani, Palli, Bueno-de-Mesquita, Boer, Vermeulen, Muller, Gunter.
Supervision: Romaguera, Weiderpass, Amiano, Cirera, Ardanaz, Agnoli, Tumino, Bueno-de-Mesquita, Lif Holgerson, Riboli, Gunter, Murphy.
Conflict of Interest Disclosures: Dr Mullee reported receiving grants from University College Dublin and grants from International Agency for Research on Cancer during the conduct of the study. Dr Khaw reported receiving grants from the Medical Research Council during the conduct of the study. Dr Tong reported receiving grants from Cancer Research UK and grants from the Medical Research Council during the conduct of the study. Dr Schmidt reported receiving grants from Cancer Research UK and grants from the Medical Research Council during the conduct of the study. Dr Vermeulen reported receiving grants from The European Union during the conduct of the study. Dr Muller reported receiving grants from Cancer Research UK outside the submitted work. No other disclosures were reported.
Funding/Support: EPIC (European Prospective Investigation into Cancer and Nutrition) was funded by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); the Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); ERC-2009-AdG 232997 and Nordforsk, and Nordic Centre of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS) (grant PI13/00061 to Granada, and grant PI13/01162 to EPIC-Murcia), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain); Swedish Cancer Society, Swedish Research Council, and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (grant 14136 to EPIC-Norfolk, and grants C570/A16491 and C8221/A19170 to EPIC-Oxford) and Medical Research Council (grant 1000143 to EPIC-Norfolk, and grant MR/M012190/1 to EPIC-Oxford) (United Kingdom). Dr Mullee’s work was supported by an IARC-Ireland Postdoctoral Research Training Fellowship from the Irish Cancer Society.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: When authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization.
Additional Contributions: We thank all study participants and staff in each EPIC center for their valuable contribution to this research.
Additional Information: For information on how to submit an application for gaining access to EPIC data and/or biospecimens, please follow the instructions at http://epic.iarc.fr/access/index.php. Statistics Netherlands provided information on causes of death.
Malik VS, Pan A, Willett WC, Hu FB. Sugar-sweetened beverages and weight gain in children and adults: a systematic review and meta-analysis. Am J Clin Nutr. 2013;98(4):1084-1102. doi:10.3945/ajcn.113.058362PubMedGoogle ScholarCrossref
World Cancer Research Fund, American Institute for Cancer Research. Continuous update project expert report 2018. Diet, nutrition and physical activity and cancer: energy balance and obesity. https://www.wcrf.org/sites/default/files/Summary-of-Third-Expert-Report-2018.pdf. Accessed November 4, 2018.
Luger M, Lafontan M, Bes-Rastrollo M, Winzer E, Yumuk V, Farpour-Lambert N. Sugar-sweetened beverages and weight gain in children and adults: a systematic review from 2013 to 2015 and a comparison with previous studies. Obes Facts. 2017;10(6):674-693. doi:10.1159/000484566PubMedGoogle ScholarCrossref
Singh GM, Micha R, Khatibzadeh S, Lim S, Ezzati M, Mozaffarian D; Global Burden of Diseases Nutrition and Chronic Diseases Expert Group (NutriCoDE). Estimated global, regional, and national disease burdens related to sugar-sweetened beverage consumption in 2010. Circulation. 2015;132(8):639-666. doi:10.1161/CIRCULATIONAHA.114.010636PubMedGoogle ScholarCrossref
World Cancer Research Fund International. Building momentum: lessons on implementing a robust sugar sweetened beverage tax. https://www.wcrf.org/int/policy/our-publications/building-momentum-lessons-implementing-evidence-informed-nutrition. Accessed November 4, 2018.
Appleton KM, Tuorila H, Bertenshaw EJ, de Graaf C, Mela DJ. Sweet taste exposure and the subsequent acceptance and preference for sweet taste in the diet: systematic review of the published literature. Am J Clin Nutr. 2018;107(3):405-419. doi:10.1093/ajcn/nqx031PubMedGoogle ScholarCrossref
Borges MC, Louzada ML, de Sá TH, et al. Artificially sweetened beverages and the response to the global obesity crisis. PLoS Med. 2017;14(1):e1002195. doi:10.1371/journal.pmed.1002195PubMedGoogle ScholarCrossref
Mattes RD, Popkin BM. Nonnutritive sweetener consumption in humans: effects on appetite and food intake and their putative mechanisms. Am J Clin Nutr. 2009;89(1):1-14. doi:10.3945/ajcn.2008.26792PubMedGoogle ScholarCrossref
Barrington WE, White E. Mortality outcomes associated with intake of fast-food items and sugar-sweetened drinks among older adults in the Vitamins and Lifestyle (VITAL) study. Public Health Nutr. 2016;19(18):3319-3326. doi:10.1017/S1368980016001518PubMedGoogle ScholarCrossref
Odegaard AO, Koh WP, Yuan JM, Pereira MA. Beverage habits and mortality in Chinese adults. J Nutr. 2015;145(3):595-604. doi:10.3945/jn.114.200253PubMedGoogle ScholarCrossref
Malik VS, Li Y, Pan A, et al. Long-term consumption of sugar-sweetened and artificially sweetened beverages and risk of mortality in US adults. Circulation. 2019;139(18):2113-2125. doi:10.1161/CIRCULATIONAHA.118.037401PubMedGoogle ScholarCrossref
Mossavar-Rahmani Y, Kamensky V, Manson JE, et al. Artificially sweetened beverages and stroke, coronary heart disease, and all-cause mortality in the Women’s Health Initiative. Stroke. 2019;50(3):555-562. doi:10.1161/STROKEAHA.118.023100PubMedGoogle ScholarCrossref
Vyas A, Rubenstein L, Robinson J, et al. Diet drink consumption and the risk of cardiovascular events: a report from the Women’s Health Initiative. J Gen Intern Med. 2015;30(4):462-468. doi:10.1007/s11606-014-3098-0PubMedGoogle ScholarCrossref
Riboli E, Kaaks R. The EPIC project: rationale and study design. European Prospective Investigation into Cancer and Nutrition. Int J Epidemiol. 1997;26(suppl 1):S6-S14. doi:10.1093/ije/26.suppl_1.S6PubMedGoogle ScholarCrossref
Riboli E, Hunt KJ, Slimani N, et al. European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr. 2002;5(6B):1113-1124. doi:10.1079/PHN2002394PubMedGoogle ScholarCrossref
Kaaks R, Slimani N, Riboli E. Pilot phase studies on the accuracy of dietary intake measurements in the EPIC project: overall evaluation of results. European Prospective Investigation into Cancer and Nutrition. Int J Epidemiol. 1997;26(suppl 1):S26-S36. doi:10.1093/ije/26.suppl_1.S26PubMedGoogle ScholarCrossref
van Liere MJ, Lucas F, Clavel F, Slimani N, Villeminot S. Relative validity and reproducibility of a French dietary history questionnaire. Int J Epidemiol. 1997;26(suppl 1):S128-S136. doi:10.1093/ije/26.suppl_1.S128PubMedGoogle ScholarCrossref
Bohlscheid-Thomas S, Hoting I, Boeing H, Wahrendorf J. Reproducibility and relative validity of food group intake in a food frequency questionnaire developed for the German part of the EPIC project. European Prospective Investigation into Cancer and Nutrition. Int J Epidemiol. 1997;26(suppl 1):S59-S70. doi:10.1093/ije/26.suppl_1.S59PubMedGoogle ScholarCrossref
Ocké MC, Bueno-de-Mesquita HB, Goddijn HE, et al. The Dutch EPIC food frequency questionnaire. I. Description of the questionnaire, and relative validity and reproducibility for food groups. Int J Epidemiol. 1997;26(suppl 1):S37-S48. doi:10.1093/ije/26.suppl_1.S37PubMedGoogle ScholarCrossref
Pisani P, Faggiano F, Krogh V, Palli D, Vineis P, Berrino F. Relative validity and reproducibility of a food frequency dietary questionnaire for use in the Italian EPIC centres. Int J Epidemiol. 1997;26(suppl 1):S152-S160. doi:10.1093/ije/26.suppl_1.S152PubMedGoogle ScholarCrossref
EPIC-SPAIN. Relative validity and reproducibility of a diet history questionnaire in Spain. I. Foods. EPIC Group of Spain. European Prospective Investigation into Cancer and Nutrition. Int J Epidemiol. 1997;26(suppl 1):S91-S99. doi:10.1093/ije/26.suppl_1.S91PubMedGoogle ScholarCrossref
Greenland S, Longnecker MP. Methods for trend estimation from summarized dose-response data, with applications to meta-analysis. Am J Epidemiol. 1992;135(11):1301-1309. doi:10.1093/oxfordjournals.aje.a116237PubMedGoogle ScholarCrossref
Schoenfeld D. Partial residuals for the proportional hazards regression model. Biometrika. 1982;69(1):239-241. doi:10.1093/biomet/69.1.239Google ScholarCrossref
Romaguera D, Vergnaud A-C, Peeters PH, et al. Is concordance with World Cancer Research Fund/American Institute for Cancer Research guidelines for cancer prevention related to subsequent risk of cancer? Results from the EPIC study. Am J Clin Nutr. 2012;96(1):150-163. doi:10.3945/ajcn.111.031674PubMedGoogle ScholarCrossref
Imamura F, O’Connor L, Ye Z, et al. Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: systematic review, meta-analysis, and estimation of population attributable fraction. BMJ. 2015;351:h3576. doi:10.1136/bmj.h3576PubMedGoogle ScholarCrossref
Huang C, Huang J, Tian Y, Yang X, Gu D. Sugar sweetened beverages consumption and risk of coronary heart disease: a meta-analysis of prospective studies. Atherosclerosis. 2014;234(1):11-16. doi:10.1016/j.atherosclerosis.2014.01.037PubMedGoogle ScholarCrossref
Huang M, Quddus A, Stinson L, et al. Artificially sweetened beverages, sugar-sweetened beverages, plain water, and incident diabetes mellitus in postmenopausal women: the prospective Women’s Health Initiative observational study. Am J Clin Nutr. 2017;106(2):614-622. doi:10.3945/ajcn.116.145391PubMedGoogle ScholarCrossref
Paganini-Hill A, Kawas CH, Corrada MM. Non-alcoholic beverage and caffeine consumption and mortality: the Leisure World Cohort Study. Prev Med. 2007;44(4):305-310. doi:10.1016/j.ypmed.2006.12.011PubMedGoogle ScholarCrossref
Thun MJ, Peto R, Lopez AD, et al. Alcohol consumption and mortality among middle-aged and elderly U.S. adults. N Engl J Med. 1997;337(24):1705-1714. doi:10.1056/NEJM199712113372401PubMedGoogle ScholarCrossref
Ferrari P, Licaj I, Muller DC, et al. Lifetime alcohol use and overall and cause-specific mortality in the European Prospective Investigation into Cancer and nutrition (EPIC) study. BMJ Open. 2014;4(7):e005245. doi:10.1136/bmjopen-2014-005245PubMedGoogle ScholarCrossref
Millwood IY, Walters RG, Mei XW, et al; China Kadoorie Biobank Collaborative Group. Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500000 men and women in China. Lancet. 2019;393(10183):1831-1842. doi:10.1016/S0140-6736(18)31772-0PubMedGoogle ScholarCrossref
Atkinson FS, Foster-Powell K, Brand-Miller JC. International tables of glycemic index and glycemic load values: 2008. Diabetes Care. 2008;31(12):2281-2283. doi:10.2337/dc08-1239PubMedGoogle ScholarCrossref
Hu FB, Malik VS. Sugar-sweetened beverages and risk of obesity and type 2 diabetes: epidemiologic evidence. Physiol Behav. 2010;100(1):47-54. doi:10.1016/j.physbeh.2010.01.036PubMedGoogle ScholarCrossref
Liu S, Manson JE, Buring JE, Stampfer MJ, Willett WC, Ridker PM. Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity C-reactive protein in middle-aged women. Am J Clin Nutr. 2002;75(3):492-498. doi:10.1093/ajcn/75.3.492PubMedGoogle ScholarCrossref
Suez J, Korem T, Zeevi D, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014;514(7521):181-186. doi:10.1038/nature13793PubMedGoogle ScholarCrossref
Mortensen A. Sweeteners permitted in the European Union: safety aspects. Scandinavian Journal of Food and Nutrition. 2006;50(3):104-116. doi:10.1080/17482970600982719Google ScholarCrossref
Thaiss CA, Levy M, Grosheva I, et al. Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science. 2018;359(6382):1376-1383. doi:10.1126/science.aar3318PubMedGoogle ScholarCrossref
Stanhope KL. Role of fructose-containing sugars in the epidemics of obesity and metabolic syndrome. Annu Rev Med. 2012;63:329-343. doi:10.1146/annurev-med-042010-113026PubMedGoogle ScholarCrossref
Tappy L. Fructose-containing caloric sweeteners as a cause of obesity and metabolic disorders. J Exp Biol. 2018;221(Pt)(suppl 1):jeb164202. doi:10.1242/jeb.164202PubMedGoogle ScholarCrossref
Jensen T, Abdelmalek MF, Sullivan S, et al. Fructose and sugar: a major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018;68(5):1063-1075. doi:10.1016/j.jhep.2018.01.019PubMedGoogle ScholarCrossref
Murphy N, Jenab M, Gunter MJ. Adiposity and gastrointestinal cancers: epidemiology, mechanisms and future directions. Nat Rev Gastroenterol Hepatol. 2018;15(11):659-670. doi:10.1038/s41575-018-0038-1PubMedGoogle ScholarCrossref