Association between Sugar-Sweetened Beverage Consumption and the Risk of the Metabolic Syndrome: A Systematic Review and Meta-Analysis

(1) Background: The increasing occurrence of the metabolic syndrome (MetS) is largely related to harmful food habits. Among them, the consumption of sugar-sweetened beverages (SSBs) is noteworthy. However, to our knowledge, there are not enough high-quality methodological studies summarizing the association between the intake of SSBs and the MetS. Therefore, the aim of this study is to examine the existing published results on this association among adults by synthesizing the existing evidence. (2) Methods: Systematic review and meta-analysis of observational studies following the PRISMA guidelines. Relevant information was extracted and presented following the PRISMA recommendations. PubMed and SCOPUS databases were searched for studies published until June 2022 that assessed the association between SSB consumption (including soft drinks, bottled fruit juices, energy drinks, and milkshakes) and the occurrence of MetS. Random effect models were used to estimate pooled odds ratios (ORs) with their 95% coefficient interval, and I2 was used to assess heterogeneity. (3) Results: A total of 14 publications from 6 different countries were included in this meta-analysis (9 cross-sectional and 5 cohort studies). For the cross-sectional studies, which included 62,693 adults, the pooled OR for the risk of MetS was 1.35 (95% CI 1.15, 1.58; I2 57%) when the highest versus the lowest categories of SSB consumption were compared. For the cohort studies, which included 28,932 adults, the pooled OR was 1.18 (95% CI 1.06, 1.32; I2 70%). (4) Conclusions: The consumption of SSBs was positively associated with an increased risk of MetS. The published literature supports public health strategies and the need to reduce the consumption of SSBs to prevent MetS.


Introduction
The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that includes atherogenic dyslipidemia, abdominal obesity, high blood pressure, as well as high blood glucose. The MetS has been positively associated with the development of type 2 diabetes mellitus and cardiovascular disease (CVD) [1,2]. Thus, it has been showed that adults who have the MetS are at twice the risk of developing CVD over the next five-to-ten years when compared to adults without the MetS [3].
The high prevalence of MetS worldwide has turned it into a public health concern [4][5][6][7][8], varying from 12.5% to 31.4% according to the diagnosis definition used [7]. This increase is largely due to unhealthy eating habits among the population. Out of these unhealthy eating habits, the intake of added sugars is still exceeding the limits of 10% of the recommended daily calories [9,10]. There is a growing worry that the intake of added sugars derives in a positive energy balance, contributing to an increase in weight gain [9,10], obesity [10,11], type 2 diabetes [12,13], and finally an increased risk of developing the MetS and CVD [13,14].
Part of this intake of added sugars comes from sugar-sweetened beverage (SSB) consumption, which includes soft drinks, bottled fruit juices, energy drinks, as well as milkshakes. Artificially sweetened beverages (ASBs) are not considered to be SSBs, since sugar is not used within their manufacturing process.
The available evidence from cross-sectional studies has shown that SSB consumption is associated with a higher risk of MetS in adults [15,16], although cross-sectional studies cannot establish causality. Nevertheless, prospective studies showed inconclusive results. For example, a cohort study showed a positive association only in women [17], another only with a high SSB consumption [16], and some prospective studies showed no association [18,19].
The currently available evidence on the association of SSB consumption and MetS includes three previous meta-analyses. The first one was performed by Malik et al. in 2010 [20]. It has been twelve years since this publication, and an update is needed as new scientific evidence has been produced. On the other hand, the meta-analysis by Narain et al. [21] conducted in 2016 omitted relevant articles. Finally, the meta-analysis by Zhang et al. performed in 2020 [22] included some studies in which the independent association of SSBs could not be separated. For example, the results coming from dietary patterns, as well as from total sweetened beverages (comprising both SSBs as well as ASBs), were included in this meta-analysis. Finally, the distinction between cross-sectional and prospective analysis was not made, giving us a lesser likelihood of suggesting cause-effect relationships. It is important to differentiate studies with different epidemiological designs since in crosssectional designs causality cannot be associated, while the longitudinal designs help us to suggest cause-effect relationships. Mixing these two types of design in an analysis can alter the results obtained and modify the effect obtained in the long term by longitudinal studies.
Therefore, the aim of the present study was to update and summarize the current information on the association between the consumption of SSBs (soft drinks, bottled fruit juices, energy drinks, and milkshakes), and MetS in adults by performing a meta-analysis that includes the newly available evidence, avoids studies that were misclassified and shows results according to their study design.

Data Sources and SEARCHES
This meta-analysis followed the Cochrane Handbook for Systematic Reviews of Intervention [23], and was conducted according to the PRISMA statement recommendations. Results were reported according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) [24] and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines [25].
A review of observational studies was conducted to assess the association between the consumption of SSBs and the MetS. Data sources included Pubmed and SCOPUS from database inception to June 2022 (included). In addition, a secondary manual search was conducted, including articles from bibliographic references. Search terms reflected the main sources of SSBs, the outcome of interest, as well as a limitation for languages (Table 1). SCOPUS TITLE-ABS-KEY ("sugar sweetened soft drinks" OR "fruit juices" OR "energy drinks" OR "milkshakes") OR INDEXTERMS ("sugar sweetened beverages" OR "fruit and vegetable juices" OR "energy drinks") AND INDEXTERMS ("metabolic syndrome") AND (LIMIT-TO (SRCTYPE, "j")) AND (LIMIT-TO (DOCTYPE, "ar")) AND (LIMIT-TO (LANGUAGE, "English") OR LIMIT-TO (LANGUAGE, "Spanish")).

Study Selection
Inclusion criteria were defined based on the following aspects: (a) studies assessing the SSBs-MetS, soft drinks-MetS, or bottled fruit juices-MetS, or energy drinks-MetS, or milkshakes-MetS relationships in population-based epidemiological studies (cross-sectional or longitudinal studies) and conducted in human adults; (b) studies reported Hazard Ratios (HR), Relative Risk (RR) or Odds Ratio (OR) with 95% Confidence Intervals (CI); (c) and studies with sufficient information also reported on risk estimates for the MetS according to categories of SSB consumption or when SSB consumption was considered as a continuous variable.
Exclusion criteria were defined based on the following: (a) studies conducted in children, adolescents, or pregnant women, due to the fact that in these populations some criteria for the definition of the MetS are not normative, and therefore, the MetS definition could not be comparable; (b) studies assessing the association of the MetS with dietary patterns, or substitution analyses when substituting SSBs or ASBs; (c) studies reporting results on total sweetened beverages, without distinguishing their categories (SSBs and ASBs); (d) studies conducted in selected populations (e.g., on secondary cardiovascular prevention or on patients with kidney disease). (e) studies with low epidemiological quality because the validity of study results is threatened. Additionally, we excluded reviews, meta-analyses, conference articles, and articles for which the full text was not available, or articles with important missing information for the meta-analysis ( Figure 1).

Data Extraction and Quality Assessment
Two independent reviewers (AMC and BMF) extracted relevant data from the selected studies, including sample size, participants' characteristics, exposure measurement (sources of SSBs), dietary assessment, and diagnosis of the MetS, as well as the central estimates for the association (HR, RR, or OR) along with their 95% CIs for the MetS risk when comparing the highest vs. the lowest levels of SSB consumption. When models with different degrees of adjustment were reported, results from the fully adjusted models were selected.
Quality assessments for the included studies were performed using the Joanna Briggs Institute's (JBI) critical appraisal checklist for cross-sectional and longitudinal studies as appropriate [26]. We excluded studies rating lower than 7 out of 8 for cross-sectional designs, and lower than 9 out of 11 for cohort studies.

Statistical Methods/Analysis
We calculated pooled ORs for cross-sectional studies as well as cohort studies. Heterogeneity was assessed by using Cochran's Q and the I 2 statistic. A random effects models were used to estimate the pooled ORs with their 95% CI due to the fact that

Data Extraction and Quality Assessment
Two independent reviewers (AMC and BMF) extracted relevant data from the selected studies, including sample size, participants' characteristics, exposure measurement (sources of SSBs), dietary assessment, and diagnosis of the MetS, as well as the central estimates for the association (HR, RR, or OR) along with their 95% CIs for the MetS risk when comparing the highest vs. the lowest levels of SSB consumption. When models with different degrees of adjustment were reported, results from the fully adjusted models were selected.
Quality assessments for the included studies were performed using the Joanna Briggs Institute's (JBI) critical appraisal checklist for cross-sectional and longitudinal studies as appropriate [26]. We excluded studies rating lower than 7 out of 8 for cross-sectional designs, and lower than 9 out of 11 for cohort studies.

Statistical Methods/Analysis
We calculated pooled ORs for cross-sectional studies as well as cohort studies. Heterogeneity was assessed by using Cochran's Q and the I 2 statistic. A random effects models were used to estimate the pooled ORs with their 95% CI due to the fact that heterogeneity among studies was I 2 ε 50%. When an article reported data separately for men and women, we introduced the data as independent studies. Publication bias was examined through visual inspection of the funnel plots and by calculating the Egger's test [27] (p values < 0.05 indicate the presence of publication bias). Analyses were performed with Review Manager (version 5.4.1) and R statistical software (version 4.0.4).

Cross-Sectional Studies Results
In cross-sectional studies, which included 62,693 adults, the results show a 35% (pooled OR 1.35, 95%CI 1.15,1.58, p = 0.0002) increase in the MetS risk for adults with a high SSB consumption, with a moderate heterogeneity among the studies (I 2 = 57%; Pheterogeneity = 0.005) (Figure 2). A publication bias was not observed by examination of the funnel plot (Supplementary Figure S1) nor the Egger's test (p = 0.685).

Cohort Studies Results
The results for the analysis of cohort studies, which included 28,932 adults, show an 18% (pooled OR 1.18, 95%CI 1.06,1.32, p = 0.003) increase in the MetS risk for adults with a high SSB consumption, with a high heterogeneity among the studies (I 2 = 70%; Pheterogeneity = 0.003) (Figure 3). We observed publication bias by examination of the funnel plot (Supplementary Figure S2) and Egger's test (p = 0.019). Moreover, among cohort studies, a meta-regression was performed by studying the evolution of the logarithms of the OR versus the year of the publication of the articles. We found that for every one-year increase, the risk of the MetS increased by 2.3%, but without reaching statistical significance (p = 0.458).

Discussion
The findings from our meta-analyses, based on results from the 14 high-quality population-based epidemiological studies and including a total of 91,625 adults, show a

Cohort Studies Results
The results for the analysis of cohort studies, which included 28,932 adults, show an 18% (pooled OR 1.18, 95%CI 1.06,1.32, p = 0.003) increase in the MetS risk for adults with a high SSB consumption, with a high heterogeneity among the studies (I 2 = 70%; P heterogeneity = 0.003) (Figure 3). We observed publication bias by examination of the funnel plot (Supplementary Figure S2) and Egger's test (p = 0.019). Moreover, among cohort studies, a meta-regression was performed by studying the evolution of the logarithms of the OR versus the year of the publication of the articles. We found that for every one-year increase, the risk of the MetS increased by 2.3%, but without reaching statistical significance (p = 0.458).

Cross-Sectional Studies Results
In cross-sectional studies, which included 62,693 adults, the results show a 35% (pooled OR 1.35, 95%CI 1.15,1.58, p = 0.0002) increase in the MetS risk for adults with a high SSB consumption, with a moderate heterogeneity among the studies (I 2 = 57%; Pheterogeneity = 0.005) (Figure 2). A publication bias was not observed by examination of the funnel plot (Supplementary Figure S1) nor the Egger's test (p = 0.685).

Cohort Studies Results
The results for the analysis of cohort studies, which included 28,932 adults, show an 18% (pooled OR 1.18, 95%CI 1.06,1.32, p = 0.003) increase in the MetS risk for adults with a high SSB consumption, with a high heterogeneity among the studies (I 2 = 70%; Pheterogeneity = 0.003) (Figure 3). We observed publication bias by examination of the funnel plot (Supplementary Figure S2) and Egger's test (p = 0.019). Moreover, among cohort studies, a meta-regression was performed by studying the evolution of the logarithms of the OR versus the year of the publication of the articles. We found that for every one-year increase, the risk of the MetS increased by 2.3%, but without reaching statistical significance (p = 0.458).

Discussion
The findings from our meta-analyses, based on results from the 14 high-quality population-based epidemiological studies and including a total of 91,625 adults, show a

Discussion
The findings from our meta-analyses, based on results from the 14 high-quality population-based epidemiological studies and including a total of 91,625 adults, show a positive link between SSB consumption and the risk of the MetS. The results from crosssectional studies show that the adults in the highest category of consumption had a 35% greater risk of the occurrence of the MetS when compared with those in the lowest category of consumption. The corresponding result for the longitudinal studies was an 18% greater risk of the incidence of the MetS. For the cohort studies, some evidence of publication bias was identified.
Our results are in accordance with the previous meta-analyses that assessed the relationship between SSB consumption and the MetS, despite the existence of methodological differences. The meta-analysis by Malik et al. [20] pooled the results of three prospective cohort studies, in which SSB consumption was associated with a 20% increased risk of developing the MetS (pooled OR 1.20, 95%CI 1.02, 1.42), although some degree of error cannot be ruled out due to the inclusion of ASB consumption. The pooled results from the meta-analysis by Narain et al. [21], in which both children, as well as adults, were included, showed that the cross-sectional analysis suggested a 46% increased risk of the MetS (pooled OR 1.46, 95%CI 1.18, 1.81, p = 0.0005). Moreover, three prospective cohort studies were meta-analyzed, but statistical significance was not achieved (pooled OR 1.47, 95%CI 0.89, 2.43, p = 0.13). Again, in this meta-analysis, the results from ASB consumption were included. In the meta-analysis by Zhang et al. [22], the results suggested that there was a 56% increased risk of the MetS when the extreme groups of consumption were compared. As the previous one, it was conducted on both children, as well as in adults. They obtained a 19% increased risk for every 250 mL/day of SSBs consumed. In this last meta-analysis, they mixed cross-sectional and cohort studies, and, for some included studies, it was not possible to separate the effects of the consumption of SSBs from ASB consumption.
The positive association between SSB consumption and the risk of the MetS might be explained by multiple potential biological mechanisms. First of all, SSB consumption leads to weight gain, dyslipidemia, as well as insulin resistance due to the high added sugar content and their common elaboration with different varieties of fructose. The extra calories consumed from SSBs are not usually offset by a lower intake of energy from solid food nor with an increment in energy expenditure, in turn, leading to weight gain. SSBs, as forms of liquid carbohydrates, produce less satiety than the equivalent amount of carbohydrates from solid food [38]. Additionally, excessive SSB consumption increases lipogenesis secondary to hepatic fructose metabolism [39,40]. Moreover, fructose is metabolized by the liver, resulting in dyslipidemia [41] and liver-induced hyperuricemia, again leading to insulin resistance as well as an increased risk of the MetS [42,43]. Moreover, the high glycemic load after SSB consumption promotes pro-inflammatory cytokines released in response to hyperglycemia [44].
In our meta-analysis, it is of note that the number of servings was not comparable across studies, so we were only able to compare extreme categories of SSB consumption. Therefore, it is possible that some degree of non-differential misclassification somewhat weakened the pooled estimate. Moreover, there is a substantial variation in study designs and in the exposure assessment across studies, which can explain the large degree of heterogeneity. However, despite the existence of heterogeneity, the central estimates were greater than one in all cohort studies.
The publication bias was explored in our meta-analysis to assess the presence of findings in favor of positive results [45]. In cross-sectional studies, a visual inspection of funnel plots and a standard test suggested no evidence of a publication bias, but we observed a publication bias when the cohort studies were analyzed. However, there is of note that, among cohort studies, four studies have been published with results close to one. Moreover, the low number of articles included could contribute to publication bias, and Egger's test is less reliable when lower than 10 studies are meta-analyzed [46,47].
All the studies included in our meta-analysis considered adjustments for potential confounding factors, such as sociodemographic, clinical, as well as lifestyle and dietary factors. SSB consumption is usually associated with a higher intake of saturated, transsaturated fatty acids, daily caloric intake, lower dietary fiber [18], and lower levels of physical activity [30,31]. For most of the studies, a positive association persisted after adjustments, suggesting an independent effect of SSBs on the occurrence of MetS. However, some residual confounding due to an incomplete adjustment could still persist, resulting in an overestimation of the strength of the association. This overestimation could be more relevant among cross-sectional studies, as few studies adjusted their results for BMI nor dietary factors other than energy intake [28,30,31], while all prospective studies took into account dietary confounding factors.
Our study has some strengths. First, to explore the separate association between SSB consumption and MetS risk, not including those studies where ASB consumption could influence the results. Second, to update the evidence through the inclusion of original articles missed in previous meta-analyses. Third, we excluded the studies with incomplete data, misclassifications, or errors in data analysis, as well as studies with a low methodological quality. Fourth, the Cochrane Handbook for Systematic Reviews of Intervention and the PRISMA guidelines were followed when performing the meta-analysis as well as when reporting the results. Fifth, we show data on cross-sectional and cohort studies, performing separate analyses for each type of design. Lastly, we provide explanations for the weaker results in prospective studies.
Our study also has some limitations. Most of the included studies were cross-sectional, preventing us from establishing a temporal relationship between SSB consumption and the occurrence of the MetS, although separate analyses, according to their design, attenuated this limitation. Second, our results show a high degree of heterogeneity among studies. This heterogeneity might be related to differences in the exposure measurement, the MetS diagnosis criteria, the length of the follow-up periods, as well as the adjustment for confounders, although the association was positive for all the included cohort studies. Moreover, this meta-analysis is limited by the existing evidence. A scarcity of prospective cohort studies was shown, also resulting in publication bias. Finally, the number of servings was not comparable across studies, probably deriving an underestimation of the association.

Conclusions
A higher SSB consumption is positively associated with the MetS occurrence. In the future, the publication of more studies assessing the prospective association is desirable. Meanwhile, public health authorities must pay attention in order to implement general public strategies to discourage SSB consumption and promote the prevention of the MetS.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/nu15020430/s1, Figure S1: Cross-sectional studies funnel plot; Figure S2: Cohort studies funnel plot. Funding: This research was funded in part by CIBERCV and grants PI17/01709, PI19/00020, and PI19/00948 from the Instituto de Salud Carlos III (co-supported by the European Regional Development Fund 'Investing in your future').
Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.
Data Availability Statement: Data described in the manuscript, code book, and analytic code will be made available upon request pending on request from the corresponding author.