Our study aimed to compare mortality among cancer patients with and without pre-existing diabetes, accounting for diabetes treatment type and diabetes duration. The results suggest that mortality of cancer patients with pre-existing diabetes is higher relative to non-diabetic patients for all cancers combined and for most individual cancer sites. In general, the highest mortality was found for OHA- or insulin-treated patients, suggesting that cancer patients with more intensive diabetes treatment have a larger degree of comorbidity at the time of cancer diagnosis, and hence poorer survival. Diabetes duration at cancer diagnosis did not influence the prognosis.
Further, we found a general increase in mortality over time since cancer diagnosis among diabetic patients relative to non-diabetic patients, which began 1 year after the cancer diagnosis. Mortality rates were higher with respect to more intensive treatment of diabetes, and highest for insulin-treated patients relative to non-diabetic patients.
Other studies investigating cancer survival related to diabetes status have also reported higher mortality related to treatment with insulin and sulfonylureas compared with metformin or no glucose-lowering treatment [5–10]. Several explanations for the observed association between pre-existing diabetes in cancer patients and increased all-cause mortality may be offered. The theoretical biological mechanism related to the increased mortality with insulin treatment relates to the hypothesis that hyperinsulinaemia brought about by exposure to insulin or by insulin resistance will accelerate the growth rate and thereby the progression of cancer. Furthermore, differences in cancer treatment between patients with and without diabetes may contribute to increased cancer-related mortality. Patients with diabetes often have other diabetes-related comorbid conditions, such as ischaemic heart disease, chronic kidney disease and neuropathy, that may influence clinical decisions .
In this context, van de Poll-Franse et al , in a Dutch study based on the Eindhoven Cancer Registry, found that diabetic patients with oesophageal, colon, breast or ovarian cancer were treated less aggressively than those without diabetes after controlling for age, cancer stage and sex. Further, patients with pre-existing diabetes may have poorer response to cancer treatment, including increased infection risk and intraoperative mortality. Finally, diabetic patients may on average present with more aggressive cancer at diagnosis than non-diabetic individuals, due either to masking of cancer symptoms because of symptoms related to diabetes or, theoretically, to an influence of diabetic therapy on the pre-diagnostic progression of the cancer. It is also possible that the excess mortality risk related to diabetes is independent of cancer and cancer treatment. Diabetes is a well-established risk factor for cardiovascular mortality in adults without cancer, and the microvascular and macrovascular damage associated with the disease is likely to induce disease and sometimes death regardless of cancer status. In our study, the excess mortality with diabetes was primarily seen for cancer types with long survival rates, such as breast, prostate and colorectal cancers, for which ‘competing’ cause of death is likely. This is in agreement with findings from other studies . On the other hand, for cancers with short survival times, such as pancreas, liver and lung cancers, mortality was less influenced by diabetes or treatment status. Surprisingly, however, mortality after pancreas and liver cancer was largely unaffected by diabetes status even though diabetes and glucose-lowering drugs are strongly related to risk of these cancers. Such findings support the notion that the observed association between glucose-lowering treatment, particularly insulin, and cancer, is a result of reverse causality or confounding by indication due to progressive hyperglycaemia, hepatic insulin resistance and beta cell dysfunction already present in the initial cancer stages .
The study was conducted using nationwide data covering the entire Danish population, and thus there was no selection bias with regard to entry into the study population. Further, the available information on diabetes duration and treatment type (i.e. DM NoMed, DM + OHA or DM + Ins) facilitated computation of precise estimates of diabetes effect on survival after cancer diagnosis. Finally, the comprehensive Danish registration system ensured that all emigrations and deaths in the study population were properly accounted for.
We had no useful information on stage of cancer at diagnosis or specific cancer therapy. For most cancer sites, e.g. the prostate, the completeness and validity of cancer staging is low , and the available information in hospital registers on specific cancer therapy was also incomplete and only available from 2002 . Hence, we were not able to explore whether differences in mortality were related to differences in severity of cancer disease at diagnosis or to differences in cancer treatment regimens. Information on medication use defined as redeemed prescriptions for OHAs or insulin did not include information on specific type or dosage.
Many factors influence the risk of both diabetes and cancer mortality, including comorbidities, obesity, insulin resistance, diet (including alcohol intake) and smoking history. The outcome of interest was death after cancer diagnosis; however, were not able to account for comorbidities or competing risks for death.
Cancer patients with pre-existing diabetes experienced elevated mortality rates compared with the non-diabetic cancer population. Mortality was highest when diabetes and cancer diagnoses occurred within 1 year and among OHA- and insulin-treated patients. For all cancers combined, diabetic patients receiving no glucose-lowering medications presented long-term mortality rate ratios of 1.55 for men and 1.77 for women. The corresponding rate ratios were 1.52 and 2.01 among diabetic patients on OHA treatment, and 5.05 and 6.54 among insulin-treated patients, for men and women, respectively.
Diabetic patients using OHAs or insulin had higher mortality rates following stomach, colorectal, kidney, or bladder cancers, or melanoma of the skin or multiple myeloma. Diabetic patients with breast, uterus or ovarian cancer experienced higher mortality if treated with OHAs and highest mortality if treated with insulin. Men with prostate cancer and pre-existing diabetes also presented increased mortality if treated with OHAs or insulin.
In conclusion, our study provides strong support for the notion that pre-existing diabetes increases mortality among cancer patients, and that the excess mortality is larger among patients with diabetes treated with OHAs or, particularly, insulin. Several potential explanations for the impaired prognosis of cancer patients who also suffer from diabetes can be offered, including increased comorbidity, delayed cancer diagnosis due to masking of cancer symptoms, interaction with cancer therapy, and perhaps a direct effect of glucose-lowering regimens inducing more progressive cancer at diagnosis and/or impaired prognosis. In any case, it is crucial that cancer patients with diabetes receive optimal diabetic treatment as well as any cancer-specific therapy; a therapeutic challenge typically demanding close collaboration between oncologists and endocrinologists.