In this survey, we examined the relationship between diabetes and risk of selected cancer in 44,262,443 discharges with 13,048,961 diabetes patients and 11,752,871 cases of 33 different cancers between 2005–15. Our analysis shows that diabetes might play a role in decreasing the risk of most selected cancers except for pancreatic cancer, and liver and intrahepatic cancers. These findings are based upon a number of adjusted multivariate logistic regression analyses. To the best of our knowledge, this is the first inpatient survey to investigate the relationship between diabetes and selected cancers in a large population.
Although some studies have shown that there is a mechanism for the link between diabetes and cancer in many site-specific cancers, there is widespread debate regarding the limitations of these studies for conclusive interpretation of the outcome 3–6. Enormous progress has been made in the understanding of diabetes and cancer etiology. A Mendelian randomization study revealed that there is little evidence in the Japanese population to support the genetic role of type 2 diabetes in cancer risk 4. Novel biomarkers of cancer found in tumor tissues and fluids such as DNA, mRNA, transcription factors, cell surface receptors, secreted proteins, and small metabolites, are being examined to determine cancer risk in prediabetic and non-diabetic individuals5. Some epidemiology studies report an increased incidence of cancers in some diseases including obesity, metabolic syndrome, polycystic ovary syndrome, insulin-resistant states, and diabetes10. The common mechanism linking these diseases to a cancer could be related to hyperinsulinemia, hyperglycemia, inflammation and oxidative stress5. Furthermore, oncogenic effects of some anti-hyperglycemic drugs is an important potential mechanism that might effect cancer progression11. Several studies have found that anti-hyperglycemic drugs have both a positive and negative effect on cancer progression. Based on the American Association of Clinical Endocrinologists and the American College of Endocrinology (AACE/ACE) consensus statement, metformin is thought to play a protective role in cancer development, while exogenous insulin use appears to be associated with an increased risk of cancer. The effect of newer diabetes medications on cancer progression remains uncertain9. While medication for the treatment of diabetes may affect cancer risk, the totality of evidence is not conclusive and future research is required. In addition, specific common risk factors for each type of cancer in the diabetic population have not yet been thoroughly established. In this regard, more research is needed to identify these common risk factors as well as a detailed mechanism to explain the relationship between cancer risk and diabetes. In summary, there are likely complex mechanisms that link diabetes and certain cancers. Whether diabetes leads to cancer or cancer induces diabetes is still unclear. More research needs to be conducted, specifically to obtain the etiology behind diabetes and cancer.
This study showed that patients with diabetes were more likely to have pancreatic and hepatic and intrahepatic cancers compared to non-diabetic patients. This finding broadly supports the work of other studies in this area linking diabetes with pancreatic and hepatic and intrahepatic cancer21–24. A population-based research study also found that within 3 years of first meeting the diabetes criteria, approximately 1% of people with diabetes at age 50 will be diagnosed with pancreatic cancer25. In addition, among individuals in five large prospective cohorts, the risk of pancreatic cancer among diabetic patients increased and was independently associated with increased circulating peripheral insulin resistance markers26–29. In a 2019 study, a nationwide cohort showed that metformin did not promote a survival benefit in individuals with pancreatic cancer–related diabetes30. Furthermore, a population-based cohort study found that for patients with diabetes, comorbidity with cirrhosis and/or hepatitis was associated with a high risk of developing increased risk of hepatocellular carcinoma31, 32. Notably, metformin therapy was associated with a reduced risk of hepatic and intrahepatic cancer in diabetic patients33. Further high-quality studies are needed to explain the mechanisms behind this relationship.
This study indicated that there was mild or no significant relationship between diabetes and kidney cancer, GI peritoneum cancers, uterine cancer, or bladder cancer. However, the findings of the current study do not completely support previous research. A recent Meta-analysis revealed that there was a positive association between diabetes and the risk of kidney cancer but points out that future research should attempt to determine whether this association is causative29. In addition, few studies have been carried out that show a strong relationship between diabetes and GI peritoneum cancers34. Additionally, the results of the current study on uterine cancer do not support the preceding studies. Analysis of two related statistical databases in England found significantly high odds ratios for uterine cancers (OR:1.52;1.04–2.16) in patients with diabetes35. One explanation that could justify the null finding found in our survey is the relatively low frequency of these cancers in general36. The National Health Insurance Study from Taiwan found that patients with diabetes are at increased risk of bladder cancer with a complex relationship scenario37. In the United States, a cohort study showed that the incidence of bladder cancer increased with anti-hyperglycemic medication (pioglitazone) in diabetics aged ≥65 years, but not in incident cohorts38. A meta-analysis showed a modest positive association between the incidence of bladder cancer and type 1 diabetes, which is not statistically significant39. In summary, there is a need for more extensive studies of the mentioned cancers to determine a positive, null, or negative relationship with diabetes.
The present study revealed that diabetes had a protective role for the remaining selected cancers, including prostate, lung and bronchus, colon, and rectal cancers. These results are partially consistent with the literature for these selected cancers. The results of the current study is consistent with the Cai H study, in which meta-analysis involving 11 cohort studies showed that diabetes is linked to a poor prognosis among those with prostate cancer40. The details of this association of diabetes with the incidence and prognosis of prostate cancer is still uncertain. However, there is a possible mechanism for the influence of medication, especially Metformin41, 42 and genetic factors43. Furthermore, one study showed that diabetes in patients with non-small cell lung cancer is associated with a lower risk of metastasis14. In contrast to previous studies, our current analysis showed no evidence that diabetes might increase breast, endometrial, kidney, colon, and rectal cancers. In addition, the findings of the current study do not support previous research regarding colon and rectum cancer.
The association between diabetes and the incidence and progression of cancer is not fully understood, but some associated variables, such as duration of disease, weight, etc., may have an influence requiring careful consideration. Furthermore, in a case-control study that was published in 2016, the duration of diabetes in the diabetic and non- diabetic subjects was not significantly different in relation to the progression to cancer44, but more research is needed. In addition, sedentary lifestyle, obesity and unhealthy diet are common risk factors for diabetes and cancer. Compared to normal weight individuals, obese patients with poorly controlled insulin-treated type 2 diabetes mellitus are prone to malignancies, particularly breast cancer in women and colorectal cancer in men44. The patient's lifestyle, including diet and physical activity, may change following diagnosis of diabetes via consultation with health care providers. This can increase the complexity of the interaction between diabetes and certain cancers and may help explain the relationship between diabetes and cancer risk.
The strengths of our study include vast nationwide hospital-based data, large sample size, and precise and accurately defined exposures, outcomes, and demographics by ICD-9-CM. In addition, important factors such as sex, age, race, obesity, cigarette smoking and alcohol consumption were extracted to conduct multivariate analysis. Due to the large sample size, this study is very robust. However, any small association may be statistically significant but may not be clinically valuable. Nonetheless, a number of limitations need to be addressed. First, we were unable to assess the details of the risk factors, genetic factors, and some confounding effects. Second, in the HCUP-NIS database, we cannot verify the time sequence between cancers and diabetes or other confounders. A standard prospective cohort study is needed to find a precise and accurate association. Third, while we included confounding factors such as age, sex, race, smoking, alcohol, and obesity in multivariate logistic regression, there is a lack of other confounding factors in the database, such as occupational exposures, environmental exposures, and medication of diabetic patients.