Critical Reviews in Food Science and Nutrition

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Association of soft drink and 100% fruit

juice consumption with all-cause mortality,
cardiovascular diseases mortality, and cancer
mortality: A systematic review and dose-response
meta-analysis of prospective cohort studies

Bei Pan, Long Ge, Honghao Lai, Qi Wang, Qi Wang, Qian Zhang, Min Yin,
Sheng Li, Jinhui Tian, Kehu Yang & Jiancheng Wang

To cite this article: Bei Pan, Long Ge, Honghao Lai, Qi Wang, Qi Wang, Qian Zhang, Min
Yin, Sheng Li, Jinhui Tian, Kehu Yang & Jiancheng Wang (2022) Association of soft drink and
100% fruit juice consumption with all-cause mortality, cardiovascular diseases mortality,
and cancer mortality: A systematic review and dose-response meta-analysis of prospective
cohort studies, Critical Reviews in Food Science and Nutrition, 62:32, 8908-8919, DOI:
10.1080/10408398.2021.1937040

To link to this article: https://doi.org/10.1080/10408398.2021.1937040

View supplementary material Published online: 13 Jun 2021.

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CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
2022, VOL. 62, NO. 32, 8908–8919
https://doi.org/10.1080/10408398.2021.1937040

REVIEW

Association of soft drink and 100% fruit juice consumption with all-cause
mortality, cardiovascular diseases mortality, and cancer mortality: A systematic
review and dose-response meta-analysis of prospective cohort studies
Bei Pana
, Long Geb
, Honghao Laib, Qi Wangb, Qi Wangb, Qian Zhangc, Min Yind, Sheng Lie,
Jinhui Tianf,g, Kehu Yangf,g, and Jiancheng Wanga
a
Gansu Provincial Hospital, Lanzhou, China; bEvidence-Based Social Science Research Center, School of Public Health, Lanzhou University,
Lanzhou, China; cEvidence-Based Nursing Center, School of Nursing, Lanzhou University, Lanzhou, China; dThe Second Physical Examination
Center of The First Hospital, Lanzhou University, Lanzhou, China; eThe First People’s Hospital of Lanzhou City, Lanzhou, China; fEvidence-
Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; gKey Laboratory of Evidence Based Medicine
and Knowledge Translation of Gansu Province, Lanzhou, China

ABSTRACT KEYWORDS
Sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and 100% fruit juices 100% fruit juices; artificially
are frequently consumed and have been documented that they could lead to serious disease bur- sweetened beverages; dose-
den. However, inconsistent evidence on the association between SSBs, ASBs, and 100% fruit juices response; meta-analysis;
mortality; sugar-
consumption and mortality have been presented. PubMed, Embase, Web of Science, Cochrane sweetened beverages
Central Register of Controlled Trials, and PsycINFO were systematically searched. We conducted a
random-effects meta-analysis and dose-response meta-analysis to assess the association and calcu-
lated the pooled hazard ratio with 95% confidence interval. And we evaluated the certainty of evi-
dence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE)
approach. Thirteen studies with 1,539,127 participants proved eligible. An SSB-consumption
increase per 250 mL/day was associated with a 4% greater risk of all-cause mortality (5 more per
1000 persons; low certainty) and 8% greater risk of cardiovascular disease mortality (3 more per
1000 persons; low certainty). ASB-consumption increase per 250 mL/day demonstrated a 4%
greater risk of all-cause mortality (5 more per 1000 persons; low certainty) and 4% greater risk of
cardiovascular disease mortality (2 more per 1000 persons; low certainty). The association of SSBs
and ASBs with cancer mortality was not significant, with a very low certainty of evidence. There
was evidence of a linear dose-response association between SSB intake and cancer mortality, as
well as between ASB intake and all-cause mortality and cancer mortality. We observed a non-linear
dose-response association between ASB intake and CVD mortality and SSB intake and all-cause
and CVD mortality. Low certainty of evidence demonstrated that per 250 mL/day consumption
increase in SSBs and ASBs had a small impact on all-cause and cardiovascular disease mortality
but not on cancer mortality. The association of 100% fruit juice consumption with all-cause and
cardiovascular disease mortality was uncertain.

Introduction 8% greater risk of cardiovascular disease (CVD) (Yin et al.

Soft drinks can be classified as sugar-sweetened beverages
(SSBs) and artificially sweetened beverages (ASBs). Every
12 oz or 330 mL of SSBs contains 35 to 37.5 g of added
sugar, providing 140 to 150 kcal of energy, and it contributes
approximately 39% of added sugar to the USA diet. Further
SSBs are also the largest source of added sugar in most west-
ern countries and globally (World Health Organization;
Dietary Guidelines Advisory Committee 2015).
Consumption of SSBs is likely to be associated with a 19%
greater risk of type 2 diabetes (Drouin-Chartier et al. 2019),
14% greater risk of hypertension (Salgado et al. 2020), and
2020). In 2010, a national survey reported that globally,
180,000 adiposity-associated deaths could be attributed to
the consumption of SSBs, with 24.2% deaths from CVD,
72.3% deaths from diabetes, and 3.5% deaths from cancer
(Singh et al. 2015). Additionally, over 8.5 million disability-
adjusted life years were associated with SSB consumption6.
ASBs and 100% fruit juice are often considered as alterna-
tives to SSBs because ASBs have few or no calories, and fruit
juices contain some vitamins and phytonutrients that are
missing from most SSBs. However, the long-term health
implications of ASB consumption are largely unknown

CONTACT Long Ge gelong2009@163.com Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University. No. 199 Donggang
West Road, Chengguan District, Lanzhou 730000, China; Jiancheng Wang 30922329@qq.com Gansu Provincial Hospital. No. 204 Donggang West Road,
Chengguan District, Lanzhou 730000, China

Bei Pan and Long Ge contributed equally to the project and share co-first authorship.
Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.1937040.
ß 2021 Taylor & Francis Group, LLC

(Appleton et al. 2018; Borges et al. 2017), and fruit juices
always have high natural sugars, with evidence suggesting
that they have similar negative health effects to those of
SSBs (Mattes and Popkin 2009; Shefferly, Scharf, and
DeBoer 2016).
The association of the consumption of soft drinks and
100% fruit juices with mortality has been uncertain and
remains controversial. Prospective studies from the
European Perspective Investigation into Cancer and
Nutrition (EPIC) (Mullee et al. 2019) reported that con-
sumption of SSBs and ASBs was positively associated with
all-cause mortality but not with cancer mortality. However,
in the Health Professionals Follow-up Study (HPFS) (Malik
et al. 2019) and Nurses’ Health Study (NHS) (Malik et al.
2019), these findings were not reflected. The NHS reported
that consumption of SSBs, but not ASBs, could increase the
risk of all-cause mortality. Furthermore, the Singapore
Chinese Health Study (Odegaard et al. 2015) showed that
there was no significant association between SSBs and mor-
tality. A previous systematic review and meta-analysis sug-
gested that both ASBs and SSBs were associated with
cardiovascular disease risk but not with the risk of mortality
(Narain, Kwok, and Mamas 2016). This review failed to
investigate the dose-response association and only focused
on cardiovascular mortality. The association of soft drinks
with mortality from all-cause and cancer should also be
evaluated (Mullee et al. 2019; Malik et al. 2019; Odegaard
et al. 2015). Another systematic review showed that SSBs
were not associated with all-cause mortality; however, it did
not report an association for ASBs and fruit juices
(Schwingshackl et al. 2017). In addition, none of these sys-
tematic reviews assessed the certainty of evidence body with
an internationally recognized standard.
To clarify this issue, we conducted a comprehensive sys-
tematic review and dose-response meta-analysis to investi-
gate the association of consuming SSBs, ASBs, or 100% fruit
juices with mortality risk from all-cause, CVD, and cancer,
and used the Grading of Recommendations, Assessment,
Development and Evaluation (GRADE) approach to rate the
certainty of evidence and to interpret the research findings.
Method
We performed this systematic review and meta-analysis
according to the Meta-analysis of Observational Studies in
Epidemiology (MOOSE) checklist (Stroup et al. 2000). The
protocol for this study was registered on the International
Prospective Register of Systematic Reviews (PROSPERO).
The registration number is CRD42020152223.
Search strategy
We performed systematic searches of five databases from
their inception until 20 September 2019, including PubMed,
Embase, Web of Science, Cochrane Central Register of
Controlled Trials (CENTRAL), and PsycINFO. The search
was updated on 21 September 2020. The search strategies
were developed by senior researchers on evidence-based
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 8909
medicine (LG, JHT). Search terms included ‘beverages AND
mortality AND cohort’ (see Supplementary Table S1 for
detailed search strategy). We also tracked the references of
the included articles as well as relevant systematic reviews
and meta-analyses for additional eligible studies. We only
included studies published in English. There were no restric-
tions in terms of publication year or publication status.
Eligibility criteria
We included prospective cohort studies that assessed the
association of SSBs, ASBs, or 100% fruit juice with mortality
risk from all-cause, cancer, or cardiovascular diseases using
multivariable analysis (Cox proportional hazards models or
logistic regression models). Abstracts that reported the
results of multivariable analysis were also included in our
review. Studies were excluded if more than 20% of the sam-
ples in cohorts had major chronic illness at baseline. When
studies were from the same cohort with the same outcomes
of interest, we only included the latest or the longest follow-
up publication; if the duration of follow-up was the same,
we included publications with the most participants. The
definitions of SSBs, ASBs, and fruit juice are presented in
Supplementary Table S2.
Study selection
We managed the literature search records and performed
the study selection process using Rayyan online literature
management software (Ouzzani et al. 2016). Using a stand-
ardized eligibility form (see Supplementary Table S3 for
study eligibility form), teams of two reviewers (WQ and
LHH, PB and WQ) independently screened titles
and abstracts for possible inclusion. Any potential studies
and conflicting studies were subjected to full-text evaluation.
We resolved disagreements by consensus or adjudication by
a senior reviewer (GL), when necessary.
Data extraction
We created a standard data collection form for reviewers to
use when extracting data. After subjecting the data extrac-
tion form to pilot testing, teams of two reviewers (WQ and
LHH, PB and WQ) independently extracted the following
data: first author, geographic location of the study, year of
publication, study design, name of cohort, setting, propor-
tion of morbidities at baselines (including diabetes, hyper-
tension, cancer, depression, stroke, cardiovascular diseases,
and myocardial infarction), sample size, duration of follow-
up, mean age, sex, education, body mass index (BMI), total
energy consumption (kcal/day), methods used to assess bev-
erage intake, methods used to ascertain death, variables
adjusted in the multivariable model reported in statistical
analysis, and risk estimates (hazard ratio, relative risks, or
odds ratios) with their 95% confidence intervals. Any con-
flicts were resolved by consensus.
8910 B. PAN ET AL.
Risk of bias assessment
Teams of two reviewers (WQ and LHH, PB and WQ) inde-
pendently assessed the risk of bias of individual studies
using a modified version of the Newcastle-Ottawa Scale
comprising 7 questions (Wells et al; Evidence Partners), to
which we used response options of ‘definitely or probably
yes’ (assigned a low risk of bias) and ‘definitely or probably
no’ (assigned a high risk of bias). Any conflicts were
resolved by discussion or through adjudication by a senior
reviewer (GL).
We classified individual studies as having low risk or
high risk of bias according to the following criteria: 1) if 5
of the 7 questions were low risk (definitely or probably yes),
then studies were considered as having low risk; 2) if studies
did not meet the criteria for low risk of bias as detailed
above, they were considered as having high risk (Zeraatkar
et al. 2019).
Data synthesis
A hazard ratio (HR) and 95% confidence interval (CI) was
considered as a measure of the effect size to estimate the
association of SSBs, ASBs, and 100% fruit juice with mortal-
ity. Because the volume per serving of beverages ranged
from 237 mL to 355 mL in the included studies (median ¼
250 mL/day), for comparability, after we confirmed the most
frequently used unit in studies (mL/day), we standardized
measures of associated beverage consumption to HRs mL/
day, and study-specific HR estimates were calculated corre-
sponding to the impact of an increase in SSB or ASB intake
per 250 mL/day. In addition, to verify the similarity of
results, we conducted meta-analysis by comparing the high-
est category of exposure in each study with the lowest one
using the random-effects model. We used the authors’ cate-
gories to determine the highest- and lowest- consumption.
We pooled HRs and 95%CIs with random effects meta-ana-
lysis using the inverse-variance weighted method.
We conducted a dose-response meta-analysis using the
generalized least squares regression method to analyze the
trend estimation across categories of SSB, ASB, or fruit juice
consumption by employing a restricted cubic spline model
with knots at the 25th, 50th, and 75th percentiles
(Greenland and Longnecker 1992; Orsini et al. 2012).
Studies were considered for the dose-response meta-analysis
if they reported at least three consumption levels and esti-
mates of effect with corresponding 95%CIs. A Wald-type
test was used to test whether a non-linear relationship
existed (Orsini et al. 2012). The midpoint of the lower and
upper boundaries in each category was used as the corre-
sponding dose of consumption. For the open-ended upper
category, the midpoint of the category was set at 1.5 times
of the lower boundary (Rong et al. 2013). If the number of
cases or person-years by level of intake was not available, we
estimated them by dividing the total number of participants
or total number of person-years by the number of quantiles
(Zeraatkar et al. 2020).
Statistical heterogeneity across studies was assessed using
Cochrane’s Q test and quantified with I2 statistic (Higgins
and Thompson 2002). We planned to conduct meta-regres-
sion depend on age, duration of follow-up, risk of bias, and
study location (Schwingshackl et al. 2017; Imamura et al.
2016). Subgroup analyses was performed by prespecified var-
iables: age (﹤ 60 years old vs. 60 years old), sex (men vs.
women), duration of follow-up (﹤ 10 years vs. 10 years),
risk of bias (high risk of bias vs. low risk of bias), and study
location (USA vs. Europe vs. Asia) (Schwingshackl et al.
2017; Imamura et al. 2016). The P values of the interaction
test (P interaction) were calculated using meta-regression to
examine the subgroup differences. A P interaction  0.05
indicates a significant subgroup effect. We also conducted a
fixed-effect meta-analysis as a sensitivity analysis to verify
the similarity of results for random-effect meta-analysis.
Publication bias was assessed using the funnel plot when 10
or more studies were available.
We performed statistical analysis using Stata 15.1 soft-
ware (Stata Corp, College Station, TX) and Review Manager
5.3 (Nordic Cochrane Center, Copenhagen).
Certainty of evidence assessment
One reviewer (PB) rated the certainty (quality) of evidence
according to the GRADE approach, which was confirmed or
revised by a senior reviewer (GL) (Guyatt, Oxman, Sultan,
et al. 2011). Evidence from observational studies starts at
low certainty and may be downgraded to very low because
of serious risk of bias, imprecision, inconsistency, indirect-
ness and publication bias. The certainty of evidence could
also be increased to moderate or high certainty when a large
effect is observed, when all plausible biases would work in a
direction opposite to the observed effect, or when a dose–r-
esponse gradient is present (Guyatt, Oxman, Akl, et al.
2011). To calculate the absolute effects presented in the
GRADE summary table, we used population risks from the
Emerging Risk Factors Collaboration (ERFC) for all-cause
and CVD mortality outcomes (Sarwar et al. 2010). ERFC is
a consortium of 102 international cohorts, primarily from
North America and Western Europe28. For cancer mortality
outcomes, we used population risk from Global Cancer
Statistics (GLOBOCAN) produced by the International
Agency for Research on Cancer (Ferlay et al. 2015), which
comprised 184 national data registries and used age-specific
incidence and mortality rates to provide the cumulative risk
of developing or dying of cancer before the age of 75.
Patient involvement
No patients were involved in setting the research question
or the outcome measures, in developing plans for the design
or implementation of the study, or in the interpretation or
writing up of results. There are no plans to disseminate the
results of the research to study participants or the relevant
patient community.

Figure 1. Evidence search and selection.
Results
Study selection and baseline characteristics
Our search initially yielded 15,002 records and finally included
13 eligible articles, including 14 cohorts in the meta-analysis
(Mullee et al. 2019; Odegaard et al. 2015; Malik et al. 2019;
Mossavar-Rahmani et al. 2019; Ramne et al. 2019; Collin et al.
2019; Barrington and White 2016; Vyas et al. 2015; Khan et al.
2004; Tasevska et al. 2014; Paganini-Hill, Kawas, and Corrada
2007; Anderson et al. 2020; Zhang et al. 2021) (Figure 1).
Supplementary Table S4 provides the reference lists for the
excluded studies in full-text screen.
Table 1 and Supplementary Table S4 summarize the base-
line characteristics of the included studies. This meta-analysis
comprised 1,539,127 participants with 138,499 all-cause deaths,
32,493 CVD deaths, and 46,228 cancer deaths. Nine studies
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 8911
involving 780,531 participants were from the USA (Malik et al.
2019; Mossavar-Rahmani et al. 2019; Collin et al. 2019;
Barrington and White 2016; Tasevska et al. 2014; Paganini-
Hill, Kawas, and Corrada 2007; Zhang et al. 2021). Studies
enrolled both men and women, with a mean age of 58.33 years,
and a median proportion of women of 57.55%, and a median
follow-up period of 13.75 years. The median highest consump-
tion was 460 mL/day (interquartile range [IQR]: 370 to
750 mL/day) for SSBs and 750 mL/day (IQR: 400 to 900 mL/
day) for ASBs. Only three studies reported on 100% fruit juice,
and the mean highest consumption was 390 mL/day.
Risk of bias of individual study
Supplementary Tables S5 and S6 provide details on the risk
of bias assessment. Ten cohorts (Mullee et al. 2019;
8912 B. PAN ET AL.

Table 1. Baseline characteristics of included studies.

Beverage consumption
Age,
Sample Follow-up mean or Women Method Method of outcome
Author, year Country Cohort size period, y range (%) of assessment Types ascertainment
(Mossavar-Rahmani USA WHI-OS 93676 11.9 63.6 100.0 FFQ ASB Medical records; data linkage
et al. 2019; Vyas with the National
et al. 2015) Death Index
(Ramne et al. 2019) Sweden MDCS 24272 19.9 57.6 61.4 Modified SSB Death register
diet history
(Ramne et al. 2019) Sweden NSHDS 24475 20.1 48.6 53.7 FFQ SSB Death register
(Mullee et al. 2019) Denmark, France, EPIC 451743 16.4 50.8 71.1 Country-specific ASB, SSB Record linkages with cancer
Germany, instruments, registries, boards of
Greece, Italy health, and death indices
(Collin et al. 2019)] USA REGARDS 30183 6 63.6 40.7 FFQ SSB, fruit juice Medical records; death
certificates, and the
National Death Index
(Malik et al. 2019) USA NHS 121700 34 59.9 100.0 FFQ ASB, SSB Statistics records and the
National Death Index or
by reports from next of
kin or the postal
authorities.
(Malik et al. 2019) USA HPFS 51529 28 60.4 0.0 FFQ ASB, SSB Statistics records and the
National Death Index or
by reports from next of
kin or the postal
authorities.
(Odegaard Singapore SCHS 63257 16.3 54.04 55.7 FFQ SSB, fruit juice Death register
et al. 2015)
(Barrington and USA VITAL 77718 6.9 65.2 51.2 SFFQ SSB Washington State death
White 2016) records; the Social
Security Death Index; the
Western Washington
Surveillance Epidemiology
and End Results cancer
registry through linkage
based on participant
identifiers
(Paganini-Hill, USA LWCS 13978 13.17 73.6 100.0 Questionnaires SSB, ASB Death indexes; Death
Kawas, and certificate
Corrada 2007)
(Anderson UK UK Biobank 198285 6 56.1 56.0 Questionnaires SSB, ASB, Death register
et al. 2020) Fruit juice
(Khan et al. 2004) Japan Hokkaido study 3158 14.32 57.8 51.7 Questionnaires SSB Death records
(Tasevska USA NIH-AARP 353751 13 50.0-71.0 41.7 SFFQ SSB Annual linkage to the US
et al. 2014) Social Security
Administration Death
Master File.
(Zhang et al. 2021) USA NHANES 31402 7.9 47.08 49.55 Questionnaires SSB, ASB National Death Index records
Note: SSB: sugar-sweetened beverages; ASB: artificially sweetened beverages; CVD: cardiovascular disease; SFFQ: semiquantitative food frequency questionnaire;
WHI-OS: Women’s Health Initiative Observational Study; MDCS: Malm€ o Diet and Cancer Study; NSHDS: Northern Swedish Health and Disease Study; EPIC:
European Prospective Investigation into Cancer and Nutrition; REGARDS: Reasons for Geographic and Racial Differences in Stroke; NHS: Nurses’ Health Study;
SCHS: Singapore Chinese Health Study; VITAL: Vitamins and Lifestyle study; NIH-AARP: National Institutes of Health-American Association for Retired Persons;
REGARDS: Reasons for Geographic and Racial Differences in Stroke; LWCS: Leisure World Cohort Study; NHANES: National Health and Nutrition
Examination Survey

Odegaard et al. 2015; Ramne et al. 2019; Collin et al. 2019;
Barrington and White 2016; Khan et al. 2004; Tasevska et al.
2014; Paganini-Hill, Kawas, and Corrada 2007; Zhang et al.
2021) were at high risk of bias in the assessment of exposure
because they did not report on the validity of the beverage
measure or beverage measure only at baseline. One cohort
was classified as having a high risk of bias in the assessment
of confounders and assessment of outcomes (Khan et al.
2004). Two cohorts were classified as having a high risk of
bias in the adequate follow-up of cohorts (Collin et al. 2019;
Tasevska et al. 2014). Other domains were at a low risk of
bias. Overall, ten of 14 cohorts (Mullee et al. 2019;
Odegaard et al. 2015; Malik et al. 2019; Mossavar-Rahmani
et al. 2019; Ramne et al. 2019; Barrington and White 2016;
Vyas et al. 2015; Anderson et al. 2020; Zhang et al. 2021)
were classified as having a low risk of bias.
SSBs and the risk of mortality
Ten studies, including 12 cohorts (Mullee et al. 2019;
Odegaard et al. 2015; Malik et al. 2019; Ramne et al. 2019;
Collin et al. 2019; Barrington and White 2016; Khan et al.
2004; Tasevska et al. 2014; Anderson et al. 2020; Zhang
et al. 2021; Mullee et al. 2019; Malik et al. 2019; Odegaard
et al. 2015; Ramne et al. 2019; Collin et al. 2019; Barrington
and White 2016; Khan et al. 2004; Tasevska et al. 2014;
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 8913

Table 2. Summary of findings for beverages consumption (per 250 mL/day increase) and risk for mortality.
Population risk
per 1000 Risk difference GRADE
Cohorts, Participants, Mean persons over per 1000 certainty of
Outcomes n n Follow-up, y HR (95%CI) 10.8 y
person (95%CI) evidence Summary
SSBs
All- 11 1,088,542 15.88 1.04 (1.02 to 1.06) 113 5 (2 to 7) Low$ Per 250mL/day increase of
cause SSBs consumption may
mortality have small effect on all-
cause mortality
CVD mortality 5 345,606 18.62 1.08 (1.02 to 1.14) 41 3 (1 to 6) Low$ Per 250mL/day increase of
SSBs consumption is
likely to have very small
effect on CVD mortality
Cancer 6 797,349 18.25 1.02 (0.99 to 1.05) 105 2 (-1 to 5) Very low$¶ We are uncertain of the
mortality effects of Per 250mL/day
increase of SSBs
consumption and
cancer mortality
ASBs
All- 7 962,313 16.77 1.04 (1.00 to 1.09) 113 5 (0 to 10) Low$#⁑ Per 250mL/day increase of
cause ASBs consumption is
mortality likely to have small
effect on all-
cause mortality
CVD mortality 4 298,307 20.45 1.04 (1.00 to 1.08) 41 2 (0 to 3) Low$ Per 250mL/day increase
ASBs consumption may
have very small effect on
CVD mortality
Cancer 4 656,374 21.58 1.01 (0.98 to 1.05) 105 1 (-2 to 5) Very low$¶ We are uncertain of the
mortality effects of ASBs
consumption and
cancer mortality
100% Fruit juice


All- 2 261,542 11.15 0.88 (0.77 to 1.01) 113 14 (-25 to 2) Very low$¶ We are uncertain of the
cause effects of 100% fruit
mortality juice and all-
cause mortality
CVD mortality 1 63257 16.3 1.43 (0.88 to 2.33) 41 18 (-5 to 55) Very low$¶ We are uncertain of the
effects of 100% fruit
juice and CVD mortality
GRADE: Grading of Recommendations Assessment, Development and Evaluation. CVD: cardiovascular disease. SSBs: Sugar-sweetened beverages. ASBs: Artificially
sweetened beverages. HR: Hazard ratios.

Population risk of cancer mortality comes from Lifetime cumulative risk from GLOBOCAN 2012. Population risk of all-cause and CVD mortality comes from the
Emerging Risk Factors Collaboration.


There was no study reported the association between 100% fruit juice and cancer mortality.
$Certainty of evidence starts from low due to observational design.
#Upgraded one level as dose-response gradient is present (see Figure 2).
¶Downgraded one level for imprecision as confidence interval around absolute effect includes both small benefit and small harm.
⁑Downgraded one level for risk of bias as subgroup analysis shows significant differences between low- and high-risk of bias.

Anderson et al. 2020; Zhang et al. 2021) with 1,418,286 partici-
pants, reported on the association between consumption of
SSBs and the risk of mortality. Nine studies with 11 cohorts
(Mullee et al. 2019; Malik et al. 2019; Odegaard et al. 2015;
Ramne et al. 2019; Collin et al. 2019; Barrington and White
2016; Tasevska et al. 2014; Anderson et al. 2020; Zhang et al.
2021) were included in the dose-response meta-analysis. Table
2 presents the results of the possible impact of an increase in
SSB intake of 250 mL/day, and the corresponding forest plots
are presented in Supplementary Figures S4–S6.
Low certainty of evidence suggested that an SSB con-
sumption increase of 250 mL/day was associated with a 4%
greater risk of all-cause mortality (HR ¼ 1.04, 95%CI: 1.02
to 1.06; I2¼89%; absolute risk difference¼ 5 more per 1000
persons, 95%CI: 2 more to 7 more) and an 8% greater risk
of CVD mortality (HR ¼ 1.08, 95%CI: 1.02 to 1.14; I2¼70%;
absolute risk difference ¼ 4 more per 1000 persons, 95%CI:
1 more to 6 more). An increase in SSB intake of 250 mL/day
had no apparent effect on cancer mortality (HR ¼ 1.02,
95%CI: 0.99 to 1.05; I2¼63%; absolute risk difference ¼ 2
more per 1000 persons, 95%CI: 1 fewer to 5 more; very low
certainty). We found no evidence of publication bias for all-
cause mortality (see Supplementary Figure S7 for the result
of publication bias).
We observed a linear dose-response association between
consumption of SSBs and cancer mortality (n ¼ 6 cohorts, P
non-linearity¼0.7914) (Figure 2). And there was a non-linear
dose-response association between consumption of SSBs and
all-cause mortality (n ¼ 12 cohorts, P non-linearity¼0.001) and
CVD mortality (n ¼ 7 cohorts, P non-linearity¼0.007) (Figure 2).
Ten studies (Mullee et al. 2019; Odegaard et al. 2015;
Malik et al. 2019; Ramne et al. 2019; Collin et al. 2019;
Barrington and White 2019; Khan et al. 2004; Tasevska et al.
2014; Anderson et al. 2020; Zhang et al. 2021) were included
in the meta-analysis of highest category versus lowest cat-
egory. For all-cause mortality, the pooled HR was 1.11 (95%
CI: 1.05 to 1.19; I2¼83%); for CVD mortality, HR was 1.14
(95% CI: 1.02 to 1.27; I2¼59%); and for cancer mortality,
8914 B. PAN ET AL.
Figure 2. Dose-response association between SSB intake and mortality.
HR was 1.04 (95% CI: 0.97 to 1.11; I2¼44%)
(Supplementary Figures S1–S3).
Supplementary Table S8 presents the subgroup analysis.
Our subgroup analysis failed to identify the subgroup effect
in sex, age, duration of follow-up, risk of bias, and study
location for all-cause, CVD, and cancer mortality.
ASBs and the risk of mortality
Seven studies (Mullee et al. 2019; Malik et al. 2019;
Mossavar-Rahmani et al. 2019; Vyas et al. 2015; Paganini-
Hill, Kawas, and Corrada 2007; Anderson et al. 2020; Zhang
et al. 2021) with 962,313 participants focused on the con-
sumption of ASBs and the risk of mortality. These studies
were included in the dose-response meta-analysis (Table 2,
Supplementary Figures S4–S6).
Based on low certainty of evidence, an ASB intake
increase of 250 mL/day was associated with a 4% greater risk
of all-cause mortality (HR ¼ 1.04, 95%CI: 1.00 to 1.09;
I2¼92%; absolute risk difference ¼ 5 more per 1000 persons,
95%CI: 0 more to 10 more) and with a 4% greater risk of
CVD mortality (HR ¼ 1.04, 95%CI: 1.00 to 1.08; I2¼43%;
absolute risk difference ¼ 2 more per 1000 persons, 95%CI:
0 more to 3 more); however, it was not associated with can-
cer mortality (HR ¼ 1.01, 95%CI: 0.98 to 1.05; I2¼52%;
absolute risk difference ¼ 1 more per 1000 persons, 95%CI:
2 fewer to 5 more).
There was evidence of a linear dose-response association
of ASB intake with all-cause mortality (n ¼ 8 cohorts, P non-
linearity¼0.15) and with cancer mortality (n ¼ 4 cohorts, P
non-linearity¼0.36) (Figure 3). We observed a non-linear dose-
response association between ASB intake and CVD mortality
(n ¼ 4 cohorts, P non-linearity¼0.007).
All 7 studies (Mullee et al. 2019; Malik et al. 2019;
Mossavar-Rahmani et al. 2019; Vyas et al. 2015; Paganini-
Hill, Kawas, and Corrada 2007; Anderson et al. 2020; Zhang
et al. 2021) were included in the meta-analysis of highest
category versus lowest category. The pooled HR was 1.12
for all-cause mortality (95% CI: 1.05 to 1.20; I2¼78%), 1.13
for CVD mortality (95% CI: 1.03 to 1.24; I2¼0%), and 1.02
for cancer mortality (95% CI: 0.92 to 1.13; I2¼50%).
We found a statistically significant subgroup effect, in
which participants from Europe showed a stronger associ-
ation than those from the USA for all-cause mortality
(P ¼ 0.03), and studies with a high risk of bias showed a
stronger association than those with a low risk of bias for
all-cause mortality (P ¼ 0.04). We did not find significant
subgroup effects for other factors.
100% fruit juice and the risk of mortality
Only three studies (Barrington and White 2016; Khan et al.
2004; Anderson et al. 2020) involving 291,725 participants
reported on 100% fruit juice. We found that there was no
significant association between a 250 mL/day increase in
100% fruit juice intake and all-cause mortality (HR ¼ 0.88,
95%CI: 0.77 to 1.01; absolute risk difference ¼ 14 fewer per
1000 persons, 95%CI: 25 fewer to 2 more; very low cer-
tainty) and CVD mortality (HR ¼ 1.43, 95%CI: 0.88 to 2.33;
absolute risk difference ¼ 18 more per 1000 persons,
95%CI: 5 fewer to 55 more; very low certainty) (Table 2).
As regards the results from the meta-analysis of highest
category versus lowest category, we found a significant asso-
ciation of fruit juice intake with CVD mortality (HR ¼ 1.20;
95%CI ¼ 1.01 to 1.42; I2¼0; absolute risk difference ¼ 8
more per 1000 persons, 95%CI: 0 fewer to 17 more), but
not with all-cause mortality. No study has reported an asso-
ciation between 100% fruit juice and cancer mortality.

Figure 3. Dose-response association between ASB intake and mortality.
Discussion
This systematic review and meta-analysis of 14 cohorts with
1,539,127 participants showed that with a median follow-up
period of 13.75 years, the increased consumption of SSBs
and ASBs might have been associated with 5 to 6 more all-
cause mortality per 1000 persons, and 2 to 3 more CVD
mortality per 1000 persons. However, there was insufficient
evidence to show that an increase in SSB and ASB intake
was not associated with a greater risk of cancer mortality.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 8915
Subgroup analyses suggested that a 250 mL/day increase in
SSB consumption among participants from the USA and
Europe had a stronger association with risk of all-cause,
CVD, and cancer mortality than that among those from
Asia. We also found a stronger association between a
250 mL/day increase in ASB consumption among partici-
pants from Europe and all-cause and cancer mortality.
However, these subgroup analyses had low credibility for the
follow reasons: 1) only two studies were from Asia, and the
statistical power was insufficient; 2) the median consump-
tion of SSBs in the USA and Europe was higher than that in
Asia (135.90 mL/day vs. 140 mL/day vs. 108.32 mL/day); 3)
we were not confident in the subgroup variable measure
because most of the included studies were assessed as having
a high risk of bias in the domain of exposure measure; and
4) our subgroup analyses were based on comparisons
between studies, rather than within studies. Regarding 100%
fruit juice, the evidence was insufficient to confirm an asso-
ciation with all-cause and cause-specific mortality.
We used the GRADE system to rate the certainty of evi-
dence because it has been an internationally recognized
standard. The certainty of evidence started from low due to
observational design. We found a dose-response association
(gradient) between SSBs and cancer mortality, as well as
between ASBs and all-cause and cancer mortality (Figures 2
and 3). A dose-response gradient, however, may be less con-
vincing of a causal relationship in scenarios in which the
exposure of interest is highly correlated with other poten-
tially confounding exposures, for example, nutritional expo-
sures are highly correlated with one another (Trepanowski
and Ioannidis 2018). We only upgraded a dose-response
gradient of ASBs with all-cause mortality, but not of SSBs
and ASBs with cancer mortality. The reason was that both
dose-response meta-analysis and meta-analysis of the lowest
versus highest comparisons showed an insignificantly
increased risk of cancer mortality. The present evidence was
downgraded to low or very low certainty mainly because of
observational design and serious imprecision.
Strengths and limitations
Our review has several strengths. Our analysis was based on
approximately 1.54 million participants, including 138,499
cases of all-cause death, 32,493 cases of CVD death, and
46,2284 cases of cancer death. Because of the large sample
size, the meta-analysis could, therefore, provide sufficiently
reliable estimates. To the best of our knowledge, our review
is the first to comprehensively address associations between
beverages with respect to SSBs, ASBs, and 100% fruit juice
and mortality from all-cause, CVD, and cancer. We focused
not only on the highest versus lowest analyses but also dose-
response analyses, which provide the most convincing evi-
dence to assess these associations. In addition, we conducted
a comprehensive search of 5 primary databases; used explicit
eligibility criteria; and performed duplicate screening of
study eligibility, assessment of risk of bias, and data extrac-
tion. Furthermore, we presented the results with an absolute
8916 B. PAN ET AL.
effect that has been demonstrated as an easy-to-understand
approach for evidence users (Guyatt et al. 2008).
Our review has some limitations. First, this meta-analysis
was based on observational studies, which are prone to con-
founding. Second, most studies were from the USA and
Europe, and only one was from Asia. Therefore, the results
of subgroup analyses could have low credibility because of
the limited number of studies. Third, only three studies
reported on 100% fruit juice; thus, we did not conduct dose-
response analysis and subgroup analysis. Fourth, although
we used a random-effects meta-analysis, the quantity cat-
egory of soft drink and 100% fruit juice consumed varied
across studies. Such inconsistency may increase the hetero-
geneity of the meta-analysis. We conducted subgroup analy-
ses based on age, sex, duration of follow-up, risk of bias,
and study location to explore the sources of heterogeneity;
however, we did not find consistent factors that could
explain heterogeneity, and a high degree of heterogeneity
persisted in most subgroup analyses. Fifth, we only included
studies published in English, which might have led to lan-
guage bias. Sixthly, soft drinks and 100% fruit juice are
highly correlated with other potentially confounding expo-
sures, and covariates adjusted among different studies var-
ied, presenting a situation that is generally difficult to
address in meta-analyses. Seventh, the number of cohorts
included in our study was relatively small; hence, the find-
ings of the dose-response analyses using meta-regression
may not be sufficiently informative and the power of the
analyses may be relatively low. Eighth, some methodological
limitations were cited, for example, the data type of a dose-
response meta-analysis is unique and requires high data
integrity, in practical applications, many original studies
have not availed the required data, and the results obtained
through some estimation methods are often different (Xu
et al. 2015). Finally, included studies often used a recall-
based method to assess the dose of beverage consumption
that led to recall bias and might have underestimated or
overestimated the observed associations.
Comparison with other studies
The results of our study on CVD mortality differ from those
of previous systematic reviews and meta-analyses (Liu et al.
2018). Narain and colleagues (Narain, Kwok, and Mamas
2016) suggested an insignificant association between CVD
mortality and the consumption of both SSBs (3 studies with
198,429 participants, risk ratio: 1.03, 95%CI: 0.91 to 1.18)
and ASBs (2 studies with 134,818 participants, risk ratio:
1.09, 95%CI: 0.92 to 1.30). In contrast to these results, our
study observed a positive association of both SSBs and ASBs
with all-cause and CVD mortality. Results regarding all-
cause mortality from previous systematic reviews and meta-
analyses have been inconsistent. A systematic review
published in 2017, including 3 cohort studies with 187,402
participants (Schwingshackl et al. 2017), concluded that
there was no convincing association between SSBs and all-
cause mortality (risk ratio: 1.02, 95%CI: 0.97 to 1.06).
However, this study was limited by the small number of
patients and trails (n ¼ 3). Compared with these two studies,
our review included a greater number of studies (6 versus 3
studies for CVD mortality; 12 versus 5 studies for all-cause
mortality) and participants (1,539,127 versus 198,429 versus
191,604). We also found a 20% increased risk of CVD mortal-
ity for each additional serving of fruit juices per day in the
highest versus lowest comparison. Moreover, previous system-
atic reviews documented no association of increased incidence
of pancreatic cancer, bladder cancer, kidney cancer, esopha-
geal cancer, colon cancer, or prostate cancer with high con-
sumption of SSB (Schwingshackl et al. 2018; Boyle, Koechlin,
and Autier 2014). However, they only focused on the inci-
dence of cancer but not on the risk of cancer mortality.
Implications
Mortality and even cause-specific mortality are the most
important clinical outcomes; our findings supported the
harm posed by the increased consumption of SSBs and
ASBs and the need to consider this in the primary preven-
tion of all-cause mortality and CVD mortality. The investi-
gation of the impact of beverages consumption on mortality
is based on the fact that the compounds in SSBs, ABSs, or
fruit juice could be linked to specific disease mechanisms
because of their physiologic properties and biological activ-
ity. SSBs usually contain 1%–12% sugar, and their consump-
tion may increase blood glucose levels and appetite. Further,
the increasing risk effect of SSBs may be attributed to
impairments of the otherwise working regulation of hunger
and satiety (DiMeglio and Mattes 2000; Kregiel 2015). SSBs
are the largest source of sugar in the diet. Overconsumption
of fructose could affect liver fat formation through intestinal
flora and cause the depletion of adenosine triphosphate,
turnover of nucleotides, and generation of uric acid, which
in ture promotes the synthesis of triglycerides and increase
in insulin resistance, further leading to diabetes and CVD
(Malik and Hu 2015; Hallfrisch 1990; Johnson et al. 2013).
Advanced glycation end-products may be important factors
in the onset of cardiometabolic diseases and hasten aging
processes, and fructose leads to the formation of advanced
glycation end products (Serpen 2012). Considering the detri-
mental effects of SSBs, artificial sweeteners are commonly
added to beverages, which are labeled as ‘no added sugar’.
Artificial sweeteners can increase people’s desire for sweet
taste (Green and Murphy 2012), which leads to excessive
consumption of calories, weight gain, and increased risk of
disturbed glucose homeostasis (Kregiel 2015). Fruit juice is
high in naturally occurring sugar (Mattes and Popkin 2009),
and this study suggested that fruit juice did not have a clin-
ically beneficial effect on CVD mortality and thus, could not
suitably be considered as a healthier option. The American
Academy of Pediatrics (AAP), US Department of Health
and Human Services and US Department of Agriculture
(DGA), and the Robert Wood Johnson Foundation Healthy
Eating Research program (Heyman et al, 2017; US
Department of Health and Human Services & US
Department of Agriculture 2015; Robert Wood Johnson
Foundation: Healthy Eating Research 2013) also emphasized

that water and whole fruit were preferred to fruit juice. The
reason could be that fruit juice has less dietary fiber than
that in whole fruit and may provide extra dietary calories
(Auerbach et al. 2018). Therefore, our study supports the
concept that the risk of mortality from all-cause and CVD
could be associated with a higher consumption of SSBs,
ASBs, or fruit juice, and a more targeted intervention and
publicity program for these factors may be appropriate.
Conclusions
Our systematic review and meta-analysis demonstrated a
positive association between soft drink consumption and
risk of all-cause and CVD mortality. This study found that
neither ASBs nor fruit juice was a healthier alternative to
SSBs and supported the potential harm posed by the
increased consumption of soft drinks among people. The
magnitude of absolute effects, however, was small, and the
certainty of evidence was low to very low.
Competing interests
Dr. Ge received a grant from Ministry of Science and
Technology of China (2019YFC1709805), outside the submit-
ted work.
Funding
This research was supported by national research project
development plan of Gansu Provincial Hospital
(19SYPYB-18).
Patient consent
Not required.
Ethical approval
Not required.
Data sharing
All data are freely available within the appendices. No add-
itional data available.
Transparency
The manuscript’s guarantors (PB and GL) affirm that the
manuscript is an honest, accurate, and transparent account
of the study being reported; that no important aspects of the
study have been omitted; and that any discrepancies from
the study as planned (and, if relevant, registered) have
been explained.
Abbreviations
SSB sugar-sweetened beverage
ASB artificially sweetened beverage
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 8917
GRADE Grading of Recommendations Assessment, Development
and Evaluation
CVD cardiovascular disease
HR hazard ratio
BMI body mass index
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