Diabetes and cancer (2): evaluating the impact of diabetes on mortality in patients with cancer

Abstract

In this paper we address methodological aspects of aetiological importance in the link between diabetes and mortality in patients with cancer. We identified nine key points on the cancer pathway at which confounding may arise-cancer screening use, stage at diagnosis, cancer treatment selection, cancer treatment complications and failures, peri-treatment mortality, competing risks for long-term mortality, effects of type 2 diabetes on anti-cancer therapies, effects of glucoselowering treatments on cancer outcome and differences in tumour biology. Two types of mortality studies were identified: (1) inception cohort studies that evaluate the effect of baseline diabetes on cancer-related mortality in general populations, and (2) cohorts of patients with a cancer diagnosis and preexisting type 2 diabetes. We demonstrate, with multiple examples from the literature, that pre-existing diabetes affects presentation, cancer treatment, and outcome of several common cancer types, often to varying extents. Diabetes is associated with increased all-cause mortality in cancer patients, but the evidence that it influences cancer-specific mortality is inconsistent. In the absence of data that address the potential biases and confounders outlined in the above framework, we caution against the reporting of cancer-related mortality as a main endpoint in analyses determining the impact of diabetes and glucose-lowering medications on risk of cancer.

Impact of cancer on adherence to glucose-lowering drug treatment in individuals with diabetes

“…Another study showed that individuals with diabetes and recent HbA 1c values >9.0% (75 mmol/mol; OR 1.5; 95% CI 1.3, 1.7) had higher mortality than those with recent 'normal' HbA 1c values between 6.5% (48 mmol/mol) and 9% (75 mmol/mol) [18]. Thus, the drop in MPR observed among patients with cancer in our study might have negatively influenced survival via the aforementioned mechanisms and may (partly) explain the established association between diabetes, cancer and survival [1][2][3].…”

“…Although the impact of cancer was more pronounced among cancers with a worse prognosis and among those with more advanced TNM stages, the difference in prognosis associated with these cancers seemed to only partly explain the impact of cancer on medication adherence. The decline in adherence seen among users of GLDs with cancer might negatively affect survival and (partly) explain the established association between diabetes, cancer and survival [1][2][3]. In future studies, the reason for the decline in MPR needs to be further elucidated among the different cancer types-is it the patient who prioritises the fight against cancer or the advice of the physician to stop the treatment?…”

“…Cancer patients with diabetes have a significantly higher overall mortality risk than those without diabetes [1][2][3]. To understand the association between diabetes and cancer, the American Diabetes Association and American Cancer Society reviewed the state of science regarding this in 2010 [4].…”

Observational studies of the association between glucose-lowering medications and cardiovascular outcomes: addressing methodological limitations

“…characterised by similar healthcare utilisation, medical conditions and diabetes duration or severity) and use appropriate methods to account for confounding, such as propensity score methods. In spite of the methodological issues identified in this review, and illustrated in this text, improper practices with regard to study design and analysis persist in observational studies that attempt to assess the effect of glucose-lowering medications on other clinical outcomes as well [129][130][131][132]. Greater attention to the principles described in this paper would serve to address certain research practices that are particularly susceptible to spurious findings and may mislead the medical community.…”

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

“…Despite the logistic challenges, trials should incorporate companion translational research, bearing in mind that the cost of these studies is small relative to the overall cost of trial execution, yet the information gained can be strategically important. Although the private sector has had limited involvement in studies of metformin in view Work is underway to interpret retrospective data in a manner that minimizes possible biases (114), and analysis of cancer incidence in cohorts where metformin use for diabetes treatment or prevention was randomized will be important.…”