To the best of our knowledge, this report is the largest study to examine SIRs and PAFs of diabetes on site-specific cancer incidence for Taiwanese population. This nationwide population-based cohort study included 474,686 patients with type 2 diabetes whose ages were ≥ 20 years at baseline. General population consists of approximately 10 million individuals who enrolled in NHI program with the same age limits but with no diabetes. All individuals in this study have been followed up for 10 to 11 years. In this retrospective nationwide population study, a diagnosis of DM was associated with 61%, 19%, 16%, 62%, and 32% increases in risks of liver, colorectal, oral, pancreatic, and kidney cancer incidences in Taiwanese men, respectively. A similar result was also observed in women, in which 55%, 16%, 14%, 44%, 36%, 19%, and 38% increases in liver, colorectal, breast, pancreas, endometrium, bladder, and kidney cancers were observed, respectively. This study showed similarity in magnitude of risks between men and women. Our study provided estimates for site-specific cancer risks for Taiwanese with type 2 diabetes by adjusting for population structure. In particular, association between diabetes and oral cancer has never been reported. Furthermore, proportions of total risks for site-specific cancers in Taiwanese population that can be attributed to type 2 diabetes were estimated using the entire populations with and without type 2 diabetes.
Studies on the relationship between diabetes and cancer using SIRs have indicated that diabetes has an increased risk of liver
[5, 6, 18], pancreas
, and lung
, cancers, whereas risk of prostate cancer is lower
. Diabetes is also associated with higher risk of breast cancer according to several studies
. By contrast, other studies have shown that diabetes is associated with lower risk for breast cancer
. The findings regarding increased risks of liver, colorectal, pancreatic, and kidney cancers are consistent with those in previous studies
[28–34]. We also observed higher risks of breast, bladder, and endometrium cancers in women, which is consistent with findings from previous studies
. A significant inverse association between diabetes and prostate cancer has been observed in men, which is also consistent with previous epidemiological studies
[19, 35–38], but inconsistent with those that show no associations
[30–34, 39]. At the other sites, we found a negative association for esophageal and laryngeal cancers in males, as well as for cervical and connective and other soft tissue cancers in females. However, previous epidemiological studies
[30–34, 40, 41] have found no evidence for an association with these cancers, although several studies have shown negative associations
Our study, along with previous studies, indicated that diabetes is a risk factor for cancers. Many possible biological mechanisms are involved in the association between DM and overall or a specific cancer. Diabetes may influence cancer by hyperinsulinemia, hyperglycemia, or inflammation as a result of metabolic and hormonal aberrations
. Diabetic individuals normally have hyperinsulinemia and are associated with reduced insulin sensitivity and compensatory hyperinsulinemia as well as increased insulin-like growth factor (IGF)-1 levels, which may stimulate cell proliferation in liver, pancreas, colon, ovary, breast, and other areas. Insulin and IGFs may promote tumor cell growth, which increases risk of cancers. Among cancers that we have studied, liver and pancreatic cancers were the two types that exhibited the highest SIRs associated with type 2 diabetes. Insulin is produced by pancreatic β cells through hepatic portal vein to liver, which, along with pancreas, is exposed to high insulin concentrations
. Considering inflammatory function of insulin, previous studies have shown a strong association between obesity and diabetes
. Obesity may increase risk of cancers because obese individuals have higher levels of leptin and lower levels of serum adiponectin
, which is associated with chronic inflammation
. Association between DM and cancer can also be associated with the changes in sex hormone levels that occur in several types of cancer, such as prostate cancer. Testosterone affects the growth of prostate gland
; in particular, a high testosterone level is associated with prostate cancer
. Previous studies have also indicated that diabetic men have lower testosterone levels
, which suggest a decreased risk in prostate cancer. Thus, decreased risk observed in this study is biologically plausible.
Our sensitivity analysis showed that estimated SIRs of many major cancers were similar to those from the analysis, in which cancer cases identified in 1999 were excluded as well as cancer cases obtained from Registry for Catastrophic Illness database, except for stomach cancer. These consistent findings showed that the results of our study were robust. For several cancers with lower incidence rates, such as nasopharyngeal, small intestine, and brain cancers, SIR estimates based on Registry for Catastrophic Illness database are not consistent with those in the other two methods. The possible explanation for this inconsistency is that our sample size is not large enough for such low incidence rates that SIR estimates are not reliable enough. To be conservative, we only discussed cancer types with SIRs that are consistent with main and sensitivity analyses.
Our study showed men with a diagnosis of type 2 DM were associated with increases in risks of liver, colorectal, oral, pancreatic, and kidney cancer incidences and women with a diagnosis of type 2 diabetes with increases in liver, colorectal, breast, pancreas, endometrium, bladder, and kidney cancers. These findings have important clinical implication: it is necessary to develop strategies of cancer-specific screening and prevention care in patients with type 2 diabetes for men and women. For future studies, what factors are associated with increased or decreased risks of site-specific cancer in patients with type 2 diabetes needs further investigation. In term of public health implication, we estimate that number of incident cases of liver, colorectal, pancreatic, and kidney cancers for men that can be attributable to type 2 diabetes by 272, 50, 194, 28, and 8, respectively; number of incident cases of liver, colorectal, breast, pancreatic, bladder, and kidney cancers for women by 105, 21, 50, 11, 4, and 5, respectively, based on number of incident cases from Taiwan National Registry for Cancer in 2010 and SIRs and PAFs of type 2 diabetes indicated in our study. These findings provide information for health policy makers on evaluation of the cost-effectiveness of cancer screening and prevention program.
Strengths and limitations
This study has several merits. First, this study is considered a large study that involved estimation of SIRs for cancer patients with type 2 diabetes. Thus, this study has sufficient capability to detect the effect of type 2 diabetes and to adjust according to several risk factors, such as age, gender, insurance premium, and urbanization degree of area registered for NIH program through standardization. Although Asia Pacific Cohort Studies Collaboration (APCSC) has examined associations between diabetes and cancer mortality with a large sample size (Lam et al.,
), our study has two advantages. One is that participants of APCSC are from thirty-six cohort Asian and Australasian studies with various ethnic origins, which may modify associations between diabetes and cancer incidences. The other is that APCSC has focused on cancer mortality, and cancer incidence has not been considered. Second, NHIRD included all diagnosed records. Thus, we can accurately determine cancer incidence and minimize the number of subjects in the cohort who were lost during follow-up period. Third, data with one-year left-censored for exploring the possibility of reverse causality had a negligible effect on original estimates. In addition, most of estimated SIRs are similar to those obtained from analysis, in which cancer incidences obtained from Registry for Catastrophic Illness database were used. The consistent findings from our sensitivity analysis indicated that our results are robust.
Several limitations of the study were also observed. First, we cannot obtain data of behavioral factors, such as smoking, alcohol consumption, obesity, body mass index, and physical activity. In addition, we cannot determine familial risks for diabetes to explain effects of genetic and environmental factors. Thus, independent effect of type 2 diabetes on cancer cannot be established. However, our study allows for rate comparison by adjusting for population structure of age, gender, insurance premium, and area registered for NIH program, which can be performed as the first step of this line of research. Second, diabetic patients may have taken medicine that affected cancer risks. Previous studies have also indicated that glucose-lowering medicines, such as metformin, may reduce risks of cancers in diabetic patients. On the contrary, sulfonylurea drugs or insulin are associated with increased cancer risks
. Thus the strength of association between type 2 diabetes and cancer estimated for different populations depend on prevalence of anti-diabetes medication in population with diabetes. Although we did not have information regarding glucose-lowering medications, it won’t confound our estimation for association between type 2 diabetes and cancer in our population.