Diabetes and Colorectal Cancer Incidence in the Cohort of Swedish Men

The COSM was initiated in the autumn of 1997 when all men aged 45–79 years residing in Västmanland and Örebro counties in central Sweden received an invitation to participate in the study along with a questionnaire. Among 100,303 eligible men, 48,850 responded to the questionnaire. Information on demographic and lifestyle factors, diet, and medical history (including diabetes) was obtained from the mailed questionnaire.

For this analysis, we excluded men with missing or erroneous National Registration Numbers (n = 260), men who returned an incomplete questionnaire (n = 92), and men with a previously diagnosed cancer at baseline (n = 2,592). Men who reported onset of diabetes before age 30 years were also excluded (n = 356) because they were more likely to have type 1 diabetes. Thus, 45,550 men were followed up until a diagnosis of colorectal cancer or death, or until 30 June 2004.

Cox proportional hazards models (14) stratified by age in months were used to estimate the rate ratios (RRs). In stratified analyses, we evaluated whether the association between diabetes and colorectal cancer was modified by physical activity (<1, 1–3, and ≥4 h/week), BMI (<25 and ≥25 kg/m²), and waist circumference (<95 and ≥95 cm). The likelihood ratio test was used to assess the significance of interactions. Statistical analysis was conducted using SAS software (SAS Institute, Cary, NC).

On average, men with reported diabetes were older, had a lower educational attainment, had a higher BMI, and were more likely to smoke and use aspirin compared with nondiabetic men. Also, men with diabetes were less likely to exercise and to use multivitamins. Consumption of fruits, vegetables, dairy foods, and red meat was similar among diabetic and nondiabetic men.

During a mean follow-up of 6.2 years, 411 incident colorectal cancer cases occurred. Of these cancers, 98 were located in the proximal colon, 92 in the distal colon, and 156 in the rectum (subsite information was unavailable for 65 cancers). In both age-adjusted and multivariate analyses, reported diabetes was associated with a significant increased risk of colorectal cancer (Table 1). After controlling for potential confounders, the RR was 1.49 (95% CI 1.14–1.96). Further adjustment for waist circumference did not alter the findings materially (RR 1.48 [1.13–1.94]). Diabetes was related to statistically significant increased risk of both colon and rectal cancer (Table 1). Risk was elevated for proximal colon and distal colon cancer, although the results were not significant.

We conducted multivariate analyses within strata of physical activity, BMI, and waist circumference. We observed that the positive association between diabetes and colorectal cancer risk persisted in all subgroups (data not shown), and there was no apparent modification of the relationship by these factors (P > 0.25 for all interaction tests).

In this large population-based cohort, we found that men with diabetes had a statistically significant 49% increased risk of colorectal cancer after taking into account a large number of potential confounders. The excess cancer risk among diabetic men was observed for all subsites in the colorectum.

Our findings are consistent with most previous studies, showing an ∼20–60% increase in colorectal cancer risk in subjects with diabetes (9,13). To our knowledge, only four studies have investigated whether the association with diabetes varies according to subsite in the colon (10,11,12,13). In a case-control study conducted in Hawaii (11), history of diabetes was associated with a significant increased risk of distal colon cancer but not of proximal colon or rectal cancer in both men and women. In contrast, the Nurses’ Health Study (12) and the Iowa Women’s Health Study (13) found history of diabetes to be more strongly associated with proximal colon cancer, although the Nurses’ Health Study (12) showed a nonsignificant positive association also with distal colon can-cer. Neither of those two cohorts observed an association with rectal cancer, but the number of rectal cancer cases was limited (nine cases in each cohort). A study of diabetic patients using external population comparisons (10) reported significant excess risk throughout the colorectum.

The strengths of our study include a population-based and prospective design, large size, and detailed information on potential risk factors for colorectal cancer. Because of the relatively large number of colorectal cancer cases, we were able to examine the association with diabetes by subsite. Our study is limited by the reliance on self-reported information on diabetes. We were unable to distinguish between type 1 and type 2 diabetes, even though we excluded men with probable type 1 diabetes. The possibility of uncontrolled or residual confounding cannot be entirely eliminated. However, we were able to adjust for multiple potential confounders, and we observed little difference between the age-adjusted and multivariate models.

In conclusion, our findings based on a large population-based cohort of men provide evidence that diabetes may increase the risk of colorectal cancer. These results support the hypothesis that hyperinsulinemia or factors related to insulin resistance may play a role in colorectal cancer etiology.

Grant support for this study was provided by the Swedish Research Council/Longitudinal Studies, the Swedish Cancer Foundation, and the Swedish Foundation for International Cooperation in Research and Higher Education (STINT).