Introduction The relationship between diabetes and cancer is undoubtedly complex and many groups are working hard to answer the multitude of questions surrounding the issue. Unfortunately, the complexity of the issue makes research difficult and studies of the relationship between diabetes and cancer and plagued by issues regarding imbalance in baseline characteristics between subjects with and without diabetes, lack of precision in determining date of diabetes onset, an inability to clearly delineate the pre-diabetic and diabetes stages, and a general disregard of the pre-diabetes phase despite the many physiological changes that occur during this time. To date, no clear temporal relationship between type 2 diabetes mellitus (DM) and cancer has been defined. We hypothesized that the progressive physiological changes associated with the development of DM would increase cancer risk prior to clinical DM onset and examined the incidence of breast, prostate, and colon cancer before and after the onset of DM to define the period of greatest risk.
Methods We performed a matched cohort study using patient data from the Marshfield Clinic electronic medical record. We identified 11,236 (4,423 female) diabetic subjects who developed DM between January 1, 1995 and December 31, 2009 using current definitions of DM set forth by the American Diabetes Association. Date of DM onset, as determined by an algorithm utilizing administrative and clinical data, was defined as the reference date for diabetic subjects. Diabetic subjects were frequency matched to 54,365 (26,346 female) non-diabetic subjects by age, gender, smoking history, residence, and reference date. Cancer incidence before and after the reference date was assessed and risk models were adjusted for matching variables, body mass index, insurance status, and comorbidities. Primary outcomes included hazard ratio (HR) and number needed to be exposed to DM for one additional person to be harmed (NNEH) or benefit (NNEB). Analyses for breast cancer included female subjects, analyses for prostate cancer included male subjects only, and analyses for colon cancer included all subjects with gender stratification.
Results Overall cancer risk was increased in pre-diabetic women (HR=1.13, 95% CI 1.04–1.22, P=0.0036, NNEH=59 at DM onset), but not men (HR=0.95, 95% CI 0.87–1.02, P=0.1716, NNEB 197 at DM onset). After full adjustment for covariates, the HR for breast cancer in pre-diabetic women was 1.16 (95% CI 1.03–1.31, P=0.0150) and the NNEH was 99 at DM onset. Following DM diagnosis, the fully-adjusted HR for breast cancer in diabetic women was 1.07 (95% CI 0.90–1.28, P=0.4216) and the NNEH decreased from 1,377 at 3 years after DM onset to 350 at 10 years. The adjusted HR for prostate cancer in pre-diabetic men was 0.96 (95% CI 0.85–1.08, P=0.4752) and the NNEB was 974 at DM onset. The adjusted HR for prostate cancer in men after DM onset was 0.84 (95% CI 0.72–0.97, P=0.0167). At 15 years after DM onset, the NNEB decreased to 63 suggesting that the protective effect of DM on prostate cancer risk increased over time in diabetic men compared to their non-diabetic counterparts. Gender differences in colon cancer risk were observed in the pre-diabetes phase. In women, colon cancer risk was similar in diabetic and non-diabetic subjects before the reference date (HR=1.03, 95% CI 0.80–1.32, P=0.8392). In contrast, the risk of colon cancer in men preceding DM diagnosis was increased compared to non-diabetic subjects with an HR of 1.28 (95% CI 1.04–1.58, P=0.0223) and the NNEH decreased with time, reaching 263 at DM onset. Gender differences in colon cancer risk were also observed after the reference date, but there was no significant increase in colon cancer risk associated with DM in either men (HR=1.18, 95% CI 0.86–1.62, P=0.3004) or women (HR=1.30, 95% CI 0.94–1.81, P=0.1162).
Conclusions An increased risk of breast cancer in women and colon cancer in men was noted during the pre-diabetes phase. We did not observe an increase in the risk of any type of cancer after clinical DM onset, but did note a decrease in the risk of prostate cancer during this time. Taken together, these findings suggest that the pre-diabetic phase and its characteristic hyperinsulinemia may play an important role in the development of cancer. Inconsistencies in previous studies may be due to an inability to accurately pinpoint date of clinical DM onset and the resulting challenges in assessing the temporal relationship between DM and cancer. As DM progresses from the hyperinsulinemia that characterizes the pre-diabetes phase to the hyperglycemia that characterizes overt DM, the risk of cancer related to DM appears to change as well. More attention should be paid to the pre-diabetes phase, when the risk of cancer may be ameliorated through modification of potential risk factors.