Metabolic Syndrome and Risk of Cancer

A Systematic Review and Meta-analysis

Katherine Esposito, MD, PHD; Paolo Chiodini, PHD; Annamaria Colao, MD; Andrea Lenzi, MD; Dario Giugliano, MD, PHD


Diabetes Care. 2012;35(11):2402-2411. 

In This Article


Our results from meta-analyses of prospective cohort studies indicate that metabolic syndrome is consistently associated with an increased risk of several cancers in adults. However, many of the reported associations are small (RR between 1.1 and 1.6) and might differ between sexes for some sites and also across populations. In particular, the associations were stronger in women for some cancers (pancreas and rectal), and the magnitude of the associations was highest for sex-specific cancers (endometrial and breast postmenopausal). Moreover, from analyses in which sufficient datasets existed, the association was stronger for colorectal cancer in female European populations (RR 1.64 [95% CI 1.17–2.28]; five datasets with 2,665 incident cancers) and became protective for prostate cancer in the white U.S. populations, which needs confirmation from future studies. Given the widespread diffusion of metabolic syndrome[1] and the increased cancer mortality associated with metabolic syndrome,[2] the findings of the present meta-analysis may have a clinical significance. At least for some common cancer sites (colorectal cancer in both sexes, liver cancer in men, and pancreas cancer in women), we are confident that the results are real, as the grading for study quality was moderate to high and overall risk of bias was low. Moreover, the inclusion of the few case-control studies did not change the overall estimates significantly. In general, the most robust association seems to be with colorectal cancer in both sexes and liver cancer in men. However, part of the association may be explained by the presence of obesity and overt hyperglycemia.

Mechanisms that link metabolic syndrome and cancer risk are not fully understood. Metabolic syndrome may be a surrogate marker for other cancer risk factors, such as decreased physical activity, consumption of high–calorie dense foods, high dietary fat intake, low fiber intake, and oxidative stress.[1] Excess adiposity, in particular visceral obesity, results in a state of chronic systemic low-grade inflammation, attributed to production of inflammatory cytokines by both adipocytes and infiltrating immune cells creating a protumorigenic environment.[51] By contrast, adiponectin levels are inversely associated with risk of some cancer, and some polymorphisms of adiponectin and its receptor genes are associated with multiple cancer risk.[52] The altered balance between proinflammatory and antiinflammatory cytokines driven by central obesity might contribute to insulin resistance, a core component of the metabolic syndrome. The IGF-1 axis has also been implicated in the progression of breast, pancreatic, and esophageal cancer:[53] levels of IGF are influenced by circulating insulin levels, with increasing insulin leading to decreased levels of IGF-binding proteins 1 and 2, thus increasing the bioavailability of IGF.

There were some limitations to this meta-analysis. Although not suggested by the formal statistical tests that we undertook, there is still a possibility of publication bias considering that the tests were likely to be underpowered. Moreover, we cannot exclude the possibility of residual confounding and bias because of misclassification. Although the included studies attempted to control for various known risk factors, the possibility of residual or unmeasured confounding cannot be ruled out. Single-point measurement increases the chance of random measurement error, which may underestimate the reported associations. Studies on the association between metabolic syndrome and cancer risk used different factors and cutoff points, which complicate comparisons between studies. Additionally, metabolic factors were not directly measured in some cohorts but replaced either by proxy indicators of the factor (i.e., hypercholesterolemia as a proxy indicator of high triglyceride and/or low HDL cholesterol levels), self-reported diagnosis of diseases (i.e., diabetes, hypertension), or specific drug use (antidiabetic, antihypertensive, and antidyslipidemic). However, there was a consistent positive association between studies, despite the use of different definitions.

There were also strengths to this analysis. Our pooled estimates for the primary end point were based on prospective analyses with detailed adjustment for a wide range of variables. We used uniform methods and subgroup analyses to better define associations across cancer types between sexes, populations, cancer subsites, and definitions of metabolic syndrome. Moreover, this is the first meta-analysis that entailed a comprehensive search for all studies that assessed association between metabolic syndrome and cancer risk.

Findings from this meta-analysis, which includes many recently published studies, suggest that metabolic syndrome is associated with increased risk of common cancers. The excess risk of cancer conferred by metabolic syndrome is low to moderate and in part explained by accompanying obesity of hyperglycemia. Nevertheless, the increasing prevalence of metabolic syndrome worldwide and the high incidence of some malignancies, particularly colorectal and breast cancers, imply that every year many cases of cancer are attributable to metabolic syndrome. Preventive strategies (primary prevention and early detection of cancer) are urgently needed, as has been suggested for patients affected by fully developed diseases, such as diabetes.[54] Moreover, patients with the metabolic syndrome, even in the absence of obesity or diabetes, should be encouraged to undergo appropriate cancer screenings, at least for some more frequently involved sites, as recommended for all people of their age and sex. More importantly, we need evidence of whether effective interventions to reduce the prevalence of metabolic syndrome in adult populations[55] will reduce cancer risk. The formulation of public health strategies based on sustained and bearable lifestyle changes can hopefully obtain significant results in the fight against cancer at the population level.