Findings from our meta-analyses show a clear link between SSB consumption and risk of metabolic syndrome and type 2 diabetes. Based on coefficients from three prospective cohort studies including 19,431 participants and 5,803 cases of metabolic syndrome, participants in the highest category of intake had a 20% greater risk of developing metabolic syndrome than those in the lowest category of intake. For type 2 diabetes, based on data from eight prospective cohort studies (nine data points), including 310,819 participants and 15,043 cases of type 2 diabetes, participants in the highest category of SSB intake had a 26% greater risk of developing type 2 diabetes than participants in the lowest category of intake.
Because we compared extreme quantiles of SSB intake, most often none or <1 serving/month with ≥1 or 2 servings/day, categories of intake between studies were not standardized. Therefore, it is possible that random misclassification somewhat attenuated the pooled estimate; however, results were similar to the dose-response analysis, which used data from all categories. For those studies that did not define serving size, a standard serving of 12 oz was assumed, which may over- or underestimate empirical SSB intake levels but should not materially affect our results. Indeed there is substantial variation in study design and exposure assessment, across studies, which may explain the large degree of between-study heterogeneity we observed. Meta-analyses are inherently less robust than individual prospective cohort studies but are useful in providing an overall effect size, while giving larger studies and studies with less random variation greater weight than smaller studies. Publication bias is always a potential concern in meta-analyses, but standard tests and visual inspection of funnel plots suggested no evidence of publication bias in our analysis. Ascertainment of unpublished results may have reduced the likelihood of publication bias. Because our analysis compared only the top with the bottom categories, we did not use data from the intermediate categories. Thus, the comparison of extreme categories was not statistically significant for the studies of Montonen et al. (14
), Paynter et al. (women) (15
), and Bazzano et al. (18
), even though the overall tests for trend in these studies were significant.
All studies included in our meta-analysis considered adjustment for potential confounding by various diet and lifestyle factors, and for most a positive association persisted, suggesting an independent effect of SSBs. However, residual confounding by unmeasured or imperfectly measured factors cannot be ruled out. Higher levels of SSB intake could be a marker of an overall unhealthy diet as they tend to cluster with factors such as higher intakes of saturated and trans fat and lower intake of fiber (12
). Therefore, incomplete adjustment for various diet and lifestyle factors could overestimate the strength of the positive association between SSB intake and risk of metabolic syndrome and type 2 diabetes. However, consistency of results from different cohorts reduces the likelihood that residual confounding is responsible for the findings. Longitudinal studies evaluating diet and chronic disease risk may also be prone to reverse causation, i.e., individuals change their diet because of symptoms of subclinical disease or related weight gain, which could result in spurious associations (24
). Although it is not possible to completely eliminate these factors, studies with longer durations of follow-up and repeated measures of dietary intake tend to be less prone to this process.
In several studies, type 2 diabetes was assessed by self-report; however, it has been shown in validation studies that self-report of type 2 diabetes is highly accurate according to medical record review (25
). The majority of studies used validated FFQs to measure SSB intake, which is the most robust method for estimating an individual's average dietary intake compared with other assessment methods such as 24-h diet recalls (26
). However, measurement error in dietary assessment is inevitable, but because the studies we considered are prospective in design, misclassification of SSB intake probably does not differ by case status. Such nondifferential misclassification of exposure is likely to underestimate the true association between SSB intake and risk of these outcomes.
SSBs are thought to lead to weight gain by virtue of their high added sugar content, low satiety potential and incomplete compensatory reduction in energy intake at subsequent meals after consumption of liquid calories, leading to positive energy balance (7
). Although SSBs increase risk of metabolic syndrome and type 2 diabetes, in part because of their contribution to weight gain, an independent effect may also stem from the high levels of rapidly absorbable carbohydrates in the form of added sugars, which are used to flavor these beverages. The findings by Schulze et al. (16
) suggested that approximately half of the effects of SSBs on type 2 diabetes were mediated through obesity. In a recent study among >88,000 women followed for 24 years, those who consumed ≥2 SSBs/day had a 35% greater risk of coronary heart disease compared with infrequent consumers after adjustment for other unhealthy lifestyle factors (RR 1.35 [95% CI 1.1–1.7, Ptrend
< 0.01) (27
). Additional adjustment for potential mediating factors including BMI, total energy, and incident type 2 diabetes attenuated the associations, but they remained statistically significant, suggesting that the effect of SSBs is not entirely mediated by these factors.
Because SSBs have been shown to raise blood glucose and insulin concentrations rapidly and dramatically (28
) and are often consumed in large amounts, they contribute to a high dietary glycemic load. High glycemic load diets are known to induce glucose intolerance and insulin resistance particularly among overweight individuals (9
) and can increase levels of inflammatory biomarkers such as C-reactive protein, which are linked to type 2 diabetes risk (29
). Findings from our cohorts indicate that a high dietary glycemic load also increases risk of developing cholesterol gallstone disease, which is associated with insulin resistance, metabolic syndrome, and type 2 diabetes (30
). Endogenous compounds in SSBs, such as advanced glycation end products, produced during the process of caramelization in cola-type beverages may also affect pathophysiological pathways related to type 2 diabetes and metabolic syndrome (31
). SSBs may also increase risk indirectly by inducing alterations in taste preferences and diet quality, resulting from habitual consumption of highly sweetened beverages, which has also been noted for artificially sweetened beverages (5
Short-term experimental studies suggest that fructose, which is a constituent of both sucrose and high-fructose corn syrup in relatively equal parts, may exert particularly adverse metabolic effects compared with glucose. Fructose is preferentially metabolized to lipid in the liver, leading to increased hepatic de novo lipogenesis, the development of high triglycerides, low HDL cholesterol, small, dense LDL, atherogenic dyslipidemia, and insulin resistance (32
). Recent evidence has also shown that fructose consumption may promote accumulation of visceral adiposity or ectopic fat deposition (10
), two key features of a dysmetabolic state increasing risk of type 2 diabetes and cardiovascular disease (33
), despite no difference in weight gain between glucose and fructose conditions (10
). In contrast, some studies have shown greater satiety and lower total energy intake after intake of fructose-containing beverages compared with glucose beverages (34
). Ghanim et al. (35
) found evidence of oxidative and inflammatory stress after intake of glucose but not fructose or orange juice. However, fructose has also been shown to increase blood pressure when administered acutely or when consumed as SSBs, an effect not observed with glucose administration or consumption of aspartame-sweetened beverages (36
). A number of prospective cohort studies have found positive associations between SSB consumption and incident hypertension (11
). Fructose is also the only sugar able to increase blood uric acid concentrations, and SSB consumption has been linked to development of hyperuricemia (serum uric acid level>7 mg/dl for men and >5.7 mg/dl for women) (38
) and gout (39
). Men who consumed ≥2 SSBs/day had an 85% greater risk of developing gout compared with infrequent consumers (RR 1.85 [95% CI 1.08–3.16]; Ptrend
< 0.001 for trend). No association was shown with diet soda. A recent randomized controlled trial among men in Spain showed that high doses of fructose increased blood pressure and induced features of metabolic syndrome and that pharmacologically lowering uric acid levels prevented the increase in mean arterial blood pressure (40
In summary, this meta-analysis has demonstrated that higher consumption of SSBs is significantly associated with development of metabolic syndrome and type 2 diabetes. It provides further support to limit consumption of these beverages in place of healthy alternatives such as water to reduce obesity-related chronic disease risk.