This community-based, prospective study provides support for the following conclusions. First, adults with treated diabetes were more likely to develop cancer than their nondiabetic counterparts, especially pancreatic cancer. Second, diabetic adults were more likely to die of cancer than their nondiabetic counterparts. Third, diabetes was associated with greater cancer-specific case fatality for adults with cancer, particularly with colorectal cancer. Fourth, in patients with cancer, individuals with diabetes had higher all-cause mortality than those without diabetes. Fifth, in individuals with diabetes, the AFs due to diabetes were larger for cancer case fatality and total mortality than for cancer incidence, with the exception of pancreatic cancer. Thus, diabetes appears to exert a greater influence downstream on the risk of mortality in people with cancer than on upstream risk of incident cancer.
Our study is consistent with prior literature in several ways, including our overall relationship of diabetes with incident cancer (7
) and our estimates for diabetes-related risk of incident pancreatic cancer (5
), risk of mortality owing to cancer of the pancreas and colon (7
), and risk of all-cause mortality in cancer patients (9
). A unique strength of our study, however, is its quantification of the influence of diabetes on cancer outcomes across the full range of its clinical history, from risk of incident cancer to risk of cancer death, case fatality, and all-cause mortality in cancer patients. Previous studies did not adopt this more global perspective, instead focusing more specifically on individual relationships with particular cancers, separating the impact on incidence from the impact on mortality.
Type 2 diabetes (which accounts for >90% of prevalent cases of diabetes in the U.S.) shares common lifestyle risk factors with several cancer types. These factors include obesity (12
) and physical inactivity (13
), which increase the risk of insulin resistance and compensatory hyperinsulinemia. An important role of hyperinsulinemia in colorectal and pancreatic carcinogenesis is supported by in vitro studies, animal models, and several epidemiologic studies (14
). Another mechanism may be that hyperglycemia itself promotes tumor growth (15
), but results are not consistent among studies (16
We found preexisting diabetes to be an independent risk factor for death from cancer in adults with any cancer and for colorectal cancer death among adults with colorectal cancer. Possible explanations for diabetes-related case fatality include tumor proliferation due to hyperinsulinemia and hyperglycemia (17
), less aggressive cancer treatment resulting from the presence of diabetes-related comorbidities (18
), poorer response to cancer treatment in adults with diabetes (19
), and suboptimal cancer screening practices related to diabetes status (20
Diabetes is a strong independent predictor of all-cause mortality in patients with a variety of cancer types. Diabetes-related cardiovascular disease no doubt plays a major role here. It is possible that cancer’s adverse effects on thrombosis and oxygenation, as well as the cardiovascular risks imposed by cancer surgery, will create adverse biological interactions (21
). Besides, the urgent need to treat cancer might distract from optimal care for diabetes and related conditions (22
). For these reasons, some experts favor all-cause mortality as an end point in cancer outcomes research that is not biased by attribution of cause of death and captures the full effect of possible interactions (23
A main strength of our study is the availability of data on cancer incidence and mortality across multiple cancer types in the same population that allowed us to isolate the effects of diabetes on cancer incidence from its effects on cancer case fatality and death from all causes. Other strengths of our study include a community-based cohort, comprehensive ascertainments of cancer and mortality, data on potential confounders, and 17 years of follow-up that offered the opportunity to study long-term associations.
Nevertheless, several limitations deserve mention. First, the diagnosis of diabetes and fasting glucose data were not available in the study, and diabetes status was not updated during follow-up. We therefore relied exclusively on self-reported use of diabetes medications at baseline to identify cases of diabetes. Thus, the diabetic individuals in our study may be later in the natural history of their diabetes than in other studies. The consequent misclassification of adults with undiagnosed and untreated diabetes as nondiabetic likely biased our results toward the null. Second, as a result of the lack of fasting blood assessment, we were not able to isolate the effects on cancer from hyperglycemia, diabetes, or antidiabetes treatment (e.g., insulin). Third, it is possible that detection bias occurred if adults with diabetes had more frequent contact with their physicians and therefore were more likely to be detected with cancer; although we attempted to rule out this bias by conducting a subgroup analysis among participants who presumably accessed care because they had been treated for hypertension and/or high cholesterol. Fourth, we lacked optimal data to characterize adiposity: BMI was calculated based on self-reported weight and height (which tend to underestimate true BMI), and we lacked data on waist circumference or percent body fat. Residual confounding by adiposity is therefore a potential concern. Fifth, we had a limited number of cases to investigate less common cancer sites, such as endometrial, lymphoma, esophageal, and liver cancers. Sixth, given the significant difference between diabetic and nondiabetic individuals at baseline, even the multiple adjustments for covariates leave the possibility of residual confounding. Finally, our sample was almost entirely white; generalizability to nonwhite populations warrants further investigation.
Our study suggests that for many common cancers like colon, breast, and prostate, diabetes exerts a stronger adverse influence downstream, after cancer occurs, than upstream, in relation to incident cancer risk. Whether improvements in diabetes management might reduce the risk of mortality in cancer patients with preexisting cancer deserves further attention.