*Graduate Institute of Biostatistics, College of Public Health
§School of Medicine, College of Medicine, China Medical University
†Department of Healthcare Administration, College of Health Science, Asia University
‡Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
The authors declare that they have nothing to disclose.
Reprints: Cheng-Chieh Lin, MD, PhD, School of Medicine, College of Medicine, China Medical University, 91 Hsueh-Shih Road, Taichung 40421, Taiwan (e-mail: email@example.com).
In this issue of the journal, Jinjuvadia et al1 systematically reviewed case-control studies and cohort studies and then conducted a meta-analysis to explore the association between metabolic syndrome (MetS) and colorectal neoplasm.
It is well recognized that MetS is a cluster of endocrine-metabolic disturbances, which are characterized by insulin resistance, impaired glucose regulation, hypertension, raised triglycerides, and low high-density lipoprotein cholesterol.2 The World Health Organization (WHO) was the first to propose criteria for the diagnosis of MetS in 1998,3 followed by the European Group for the Study of Insulin Resistance (EGIR).4 In the WHO and EGIR definitions, the presence of insulin resistance was a prerequisite. In addition, WHO defined individuals with MetS as those showing at least 2 of 4 factors, which included hypertension, hyperlipidemia, obesity, and microalbuminuria. National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP-III) assigned MetS as a secondary target for intervention in 2001.5 The ATP-III definition required 3 of the following 5 factors to be present: increased waist circumference, hypertriglyceridemia, low high-density lipoprotein cholesterol, hypertension, and elevated fasting glucose. In 2005, the International Diabetes Federation (IDF) presented a MetS definition,6 in which central obesity was the prerequisite and different cutoff values for waist circumference were introduced for different ethnic groups. The American Heart Association and the National Heart, Lung and Blood Institute (AHA/NHLBI) modified the NCEP criteria by decreasing the glucose cutoff value from 110 to 100 mg/dL.7
MetS may lead to the development of colorectal cancer (CRC) through several mechanisms. Insulin may act directly on tissue as a mitogenic and antiapoptotic growth factor.2,8 Insulin can also increase insulin-like growth factor-1 bioactivity.2,9,10 The shared metabolic factors underlying both type 2 diabetes and cancer include visceral adiposity, inflammation, hyperglycemia, and hyperinsulinemia, all of which lead to increased insulin receptor substrate (IRS), and IRS potentially increases tumor cell growth and proliferation. Another possible reason is that IRS-associated PI3K11 signaling is compromised by insulin-resistant states, which can affect both the metabolic and mitogenic pathway.
A novel aspect of the current study is the analysis of a large collection of results from individual studies focusing on the association between MetS and CRC for the purpose of integrating the findings. This study described the existing research in the area of MetS and CRC and analyzed its characteristics including study design, characteristics of study subjects, type of neoplasm, potential confounding factors, and definitions of MetS. It also identified heterogeneity in effects among multiple studies and had increased statistical power to detect an association compared with individual studies. The methodology of a systematic review reduces the subjectivity of study comparisons by using systematic and explicit comparison procedures. Most importantly, it identifies data gaps in the knowledge base and suggests directions for future research.
The study by Jinjuvadia and colleagues considered 4 definitions of MetS: WHO, ATP-III, IDF, and AHA/NHLBI in addition to that with ≥3 metabolic abnormalities (based on ATP-III). The type of colorectal lesions included colorectal adenoma and cancer. The agreement between reviewers for inclusion or exclusion of studies was high, with a Cohen κ coefficient of 0.84. They included 18 studies (10 cohort and 8 case-control studies) in the final analysis.12–29 The authors were careful to evaluate the methodological quality of these studies by using the Newcastle-Ottawa Scale with an averaged 7.2 stars for the 10 cohort studies and an averaged 8.1 stars for the 8 case-control studies. Eighteen studies involving 703,992 individuals provided data to obtain the relative risk (RR) for CRC. Among them, 10 studies (7 cohort and 3 case-control studies) focused on CRC, 8 (3 cohort and 5 case-control studies) on colorectal adenoma, and 2 (2 cohort studies) on colorectal adenoma and cancer combined. Their findings indicated that individuals with MetS had increased risk for CRC (RR: 0.542; 95% confidence interval, 0.307-0.958), colorectal adenoma (1.37; 1.26-1.49), and CRC and adenoma combined (1.76; 1.16-2.66). Subgroup analyses revealed that the significant association between MetS and CRC remains similar, with little variation across subgroups of sex, the potential confounding factor of smoking, and various definitions of MetS, except for higher RR of CRC observed in case-control studies than in cohort studies. Findings on visual inspection of funnel plots and test results of Egger’s or Begg’s and Mazumdar’s showed no evidence of publication bias for CRC, colorectal adenoma, or CRC and adenoma combined.
In summary, the authors are to be congratulated for conducting this systematic review and meta-analysis. It seems from a large number of studies that there is epidemiologic evidence that MetS increases the risk for colorectal neoplasm. Most studies show the magnitude of risk for colorectal neoplasm in the individual with MetS as a hazard ratio between 1.3 and 2.0; however, the risk may be much higher in a few circumstances. This study described the existing research on the association between MetS and CRC. It also identified gaps in the data; for example, most studies did not consider possible confounding factors such as physical activity, fruit and vegetable consumption, body mass index, family history of colon cancer, and alcohol use. The limitations of this pooled analysis include some heterogeneity among studies and possible recall bias inherent from the case-control design. Although it is easy to recommend large prospective studies, avoiding confounding remains a challenge. Even with powerful techniques to control for confounding effects by multivariate regression, variations in other putative confounding factors may be relevant. For example, a genetic variant with opposite effects on the risk of MetS may confound the association between MetS and colorectal neoplasm. Most importantly, this study did not exclude those diagnosed as having cancer within 1 to 5 years of baseline in order to rule out the possibility of effect-cause relationship. This is the first published meta-analysis examining this topic. Larger prospective studies on this topic that avoid the drawbacks of previous studies are warranted.
1. Jinjuvadia R, Prateek L, Chetna J, et al. The association between metabolic syndrome and colorectal neoplasm: systemic review and meta-analysis. J Clin Gastroenterol. 2013;47:33–44
2. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome—a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med. 2006;23:469–480
3. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. 1999 Geneva World Health Organization
4. Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med. 1999;16:442–443
5. . Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;285:2486–2497
6. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome—a new worldwide definition. Lancet. 2005;366:1059–1062
7. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735–2752
8. Nagamani M, Stuart CA. Specific binding and growth-promoting activity of insulin in endometrial cancer cells in culture. Am J Obstet Gynaecol. 1998;179:6–12
9. Kaaks R, Lukanova A. Energy balance and cancer: the role of insulin and insulin-like growth factor-I. Proc Nutr Soc. 2001;60:91–106
10. Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev. 2002;11:1531–1543
11. Sun G, Kashyap SR. Cancer risk in type 2 diabetes mellitus: metabolic links and therapeutic considerations. J Nutr Metab. 2011;2011:708183
12. Ashbeck EL, Jacobs ET, Martínez ME, et al. Components of metabolic syndrome and metachronous colorectal neoplasia. Cancer Epidemiol Biomarkers Prev. 2009;18:1134–1143
13. Inoue M, Noda M, Kurahashi N, et al. Impact of metabolic factors on subsequent cancer risk: results from a large-scale population-based cohort study in Japan. Eur J Cancer Prev. 2009;18:240–247
14. Kim MC, Kim CS, Chung TH, et al. MONW phenotype is associated with advanced colorectal adenoma in Korean men. Obesity (Silver Spring). 2012;20:1876–1881
15. Pelucchi C, Negri E, Talamini R, et al. Metabolic syndrome is associated with colorectal cancer in men. Eur J Cancer. 2010;46:1866–1872
16. Stocks T, Lukanova A, Johansson M, et al. Components of the metabolic syndrome and colorectal cancer risk; a prospective study. Int J Obes (Lond). 2008;32:304–314
17. Stürmer T, Buring JE, Lee IM, et al. Metabolic abnormalities and risk for colorectal cancer in the physicians’ health study. Cancer Epidemiol Biomarkers Prev. 2006;15:2391–2397
18. Hu NC, Chen JD, Lin YM, et al. Stepwise relationship between components of metabolic syndrome and risk of colorectal adenoma in a Taiwanese population receiving screening colonoscopy. J Formos Med Assoc. 2011;110:100–108
19. Kang HW, Kim D, Kim HJ, et al. Visceral obesity and insulin resistance as risk factors for colorectal adenoma: a cross-sectional, case-control study. Am J Gastroenterol. 2010;105:178–187
20. Kim JH, Lim YJ, Kim YH, et al. Is metabolic syndrome a risk factor for colorectal adenoma? Cancer Epidemiol Biomarkers Prev. 2007;16:1543–1546
21. Morita T, Tabata S, Mineshita M, et al. The metabolic syndrome is associated with increased risk of colorectal adenoma development: the Self-Defense Forces health study. Asian Pac J Cancer Prev. 2005;6:485–489
22. Kaneko R, Sato Y, An Y, et al. Clinico-epidemiologic study of the metabolic syndrome and lifestyle factors associated with the risk of colon adenoma and adenocarcinoma. Asian Pac J Cancer Prev. 2010;11:975–983
23. Oh TH, Byeon JS, Myung SJ, et al. Visceral obesity as a risk factor for colorectal neoplasm. J Gastroenterol Hepatol. 2008;23:411–417
24. Ahmed RL, Schmitz KH, Anderson KE, et al. The metabolic syndrome and risk of incident colorectal cancer. Cancer. 2006;107:28–36
25. Bowers K, Albanes D, Limburg P, et al. A prospective study of anthropometric and clinical measurements associated with insulin resistance syndrome and colorectal cancer in male smokers. Am J Epidemiol. 2006;164:652–664
26. Liu CS, Hsu HS, Li CI, et al. Central obesity and atherogenic dyslipidemia in metabolic syndrome are associated with increased risk for colorectal adenoma in a Chinese population. BMC Gastroenterol. 2010;10:51 doi: 10.1186/1471-230X-10-51
27. Stocks T, Lukanova A, Bjørge T, et al. Metabolic factors and the risk of colorectal cancer in 580,000 men and women in the metabolic syndrome and cancer project (Me-Can). Cancer. 2011;117:2398–2407
28. Tsilidis KK, Brancati FL, Pollak MN, et al. Metabolic syndrome components and colorectal adenoma in the CLUE II cohort. Cancer Causes Control. 2010;21:1–10
29. Aleksandrova K, Boeing H, Jenab M, et al. Metabolic Syndrome and Risks of Colon and Rectal Cancer: the European Prospective Investigation into Cancer and Nutrition Study. Cancer Prev Res (Phila). 2011;4:1873–1883