Letter to the Editor in Response to “Association between severity of diabetic complications and risk of cancer in middle-aged patients with type 2 diabetes”

Dear Editor,

I recently read the article titled “Association between severity of diabetic complications and risk of cancer in middle-aged patients with type 2 diabetes”¹, which provides valuable insights on the relation between the risk of cancer development and diabetes severity, being the first to address this association. However, I believe there are several limitations that could be highlighted to strengthen the findings further.

Firstly, while the study adjusts for a variety of known confounders, it does not account for other potential unmeasured variables like physical activity, diet, changes in treatment guidelines through the study period, or genetic predispositions to both diabetes and cancer, which could influence the observed associations. Secondly, the study uses data from the Taiwan National Health Insurance Research Database, limiting generalizability as it primarily reflects the Taiwanese population. Factors like healthcare systems, genetic differences, and lifestyle factors may cause variable associations between cancer risk and diabetes in different populations; hence, replication in more diverse populations could help validate the conclusions. Reliance on a single database affects the robustness of the study.

Additionally, since this is a retrospective and observational study, it does find a relationship between the two factors but does not definitively conclude that one factor causes the other, that is it does prove an association but not a cause-and-effect relationship. Moreover, even though steps have been taken to reduce reverse causality, there may still be some patients with undiagnosed or early-stage cancer that were not identified and could influence the course of diabetes complications.

The study also has some potential biases, including selection bias—data on patients who are unable to access healthcare, with non-medication managed diabetes or undiagnosed early complications may be missing, or data on those who are lost to follow-up may differ from those who remained in the study, leading to overestimation or underestimation of cancer risk in the wider population—and medication use—the study does account for it; however, patients with more severe diabetic complications may be prescribed more aggressive treatments, which can influence cancer risk. There could also be a potential overlap between cancer and diabetes treatments that is not addressed, confounding the results. Additionally, exclusion of patients diagnosed with cancer within the first year of their diabetes diagnosis could result in survival bias, impacting generalizability.

Furthermore, the follow-up period for this study is 13 years, which may not capture the influence of diabetes complications on cancers that take longer to manifest; a longer follow-up would provide more comprehensive insights. The current study also does not consider various subtypes of a particular cancer; the risk associated with different subtypes may vary, and it does not provide much information on glycemic levels during the study period; glycemic variability can impact both factors independently; hence, it is important to consider this to fully understand the association. Additionally, the impact of chronic diseases like cardiovascular diseases, chronic kidney diseases, and autoimmune disorders is not accounted for and may be a source of confounding results.

I believe that future studies addressing these limitations could offer a more comprehensive understanding of the relationship between diabetes complications and cancer risk, ultimately leading to more refined treatment and prevention strategies.

The authors declare no conflict of interest.

Approval of the research protocol: N/A.

Informed consent: N/A.

Approval date of registry and the registration no. of the study/trial: N/A.

Animal Studies: N/A.