Is Diabetes a Risk Factor for Colorectal Cancer

Throughout the world, adoption of a Western life style has paralleled an increase in the incidence of both type 2 diabetes mellitus and colorectal cancer. This is perhaps not surprising, as the major environmental determinants for type 2 diabetes, including body mass index (BMI), central obesity, physical inactivity, and Western dietary patterns are remarkably consistent with the constellation of risk factors that have been identified for colorectal cancer. Perhaps what has been less clear is whether diabetes, independent of these other risk factors, influences the risk of colorectal cancer. If so, such a finding would have potential implications for more vigorous lifestyle modification or cancer screening of individuals with type 2 diabetes. Moreover, understanding the mechanistic basis for such an association may provide fresh insights into the pathogenesis of both conditions. A number of early studies reported a higher risk of colon cancer among individuals with diabetes. These studies were limited by small sample size, reliance on death certificates and autopsies for endpoint ascertainment, and inability to control for important confounders including BMI and physical inactivity [1‐4]. As such, it was difficult to determine if the association between diabetes and colorectal cancer was merely a reflection of the greater prevalence of known lifestyle risk factors for cancer among those with diabetes. However, more recent high quality prospective studies have shown a significant, albeit more modest association between diabetes and risk of colorectal cancer even after accounting for shared risk factors for both diseases. One of these large, prospective studies, the Cancer Prevention Study, included 866,793 individuals, 15,847 of whom had diabetes [5]. Over 13 years of follow-up, an increased risk of colorectal cancer, even after accounting for BMI and physical inactivity, was noted in men with diabetes (RR = 1.30; 95 % CI 1.03‐1.65) and a modest non-significant elevation was seen in women with diabetes (RR = 1.16; 95 % CI 0.87‐1.53). In the Nurses’ Health Study, diabetes was similarly associated with an increase in the risk of colon cancer after adjustment for BMI and physical activity (multivariate-adjusted RR = 1.49; 95 % CI 1.09‐2.06) [6]. By 2005, several case‐control and cohort studies had examined this relationship, which was systematically reviewed by Larsson et al. [7]. In their metaanalysis of 6 case‐control and 9 cohort studies encompassing more than 2 million participants, a history of diabetes was associated with an increased risk of colorectal cancer (summary RR = 1.30, 95 % CI 1.20‐1.40). The results did not vary according to study design, geographic origin (United States vs. Europe), sex, or cancer site. However, not all subsequent studies have been consistent. In the Cancer Prevention Study II Nutrition Cohort, Campbell et al. [8] found a moderate increase in risk of colorectal cancer among men with diabetes (pooled RR = 1.24; 95 % CI 1.08‐1.44), but no such association among women. Inoue et al. [9] using the Japan Public Health Center-Based Prospective Study, observed no increase in risk of colon cancer with diabetes after excluding cancer cases diagnosed within 5 years of diagnosis of diabetes (HR = 1.19, 95 % CI 0.91‐1.55 for men and 1.14, 95 % CI 0.70‐1.87 for women). Similarly, data from the Japan