Regarding the importance of considering insulin treatment, the meta-analysis Dr. Kim referenced [2], which indicates an elevated CRC risk associated with exogenous insulin use, is indeed pertinent to our research context. We recognize the complexity that insulin treatment introduces, especially in interpreting the association between diabetes management and CRC risk. In response, we have revisited our data to assess the availability and impact of insulin treatment information on our study population. The results were similar after further adjustment for insulin treatment, although the association of per % increment of HbA1c with CRC risk was attenuated, with hazard ratio of 1.22 (95% confidence interval [CI], 0.93 to 1.61) for overall population, 1.39 (95% CI, 0.97 to 1.98) for women and 1.08 (95% CI, 0.69 to 1.70) for men.

We also greatly appreciate Dr. Kim’s comments concerning the potential influence of changes in confounding factors such as socioeconomic status, obesity, smoking, lifestyles, and disparities in colonoscopy procedures on CRC incidence. We understand the concerns about the changes in these factors potentially confounding the association between glucose intolerance status and CRC risk. However, after careful consideration and review of our study design and data, we believe that adjusting for the changes in these factors in our analysis may not be necessary, since changes in confounders during follow-up cannot impact the glycemia levels at baseline. Our rationale is based on the specific aims and scope of our research, which focuses on the direct relationship between baseline glycemic indicators and CRC risk, rather than the broader set of risk factors for CRC. We have implemented stringent criteria and statistical controls to select confounders (i.e., common causes of both exposure and outcome) and minimize confounding effects, focusing specifically on variables directly related to our research question. As changes in risk factors, if any, during the follow-up are unlikely to influence the baseline glycemic levels, they would not confound the association between baseline glycemic indicators and CRC risk. We appreciate Dr. Kim’s input and understand the importance of considering a wide array of potential confounders in epidemiological research.

Dr. Kim’s emphasis on the rising incidence of CRC in individuals under 50 underscores an important area for further research. We share the anticipation for future studies that delve deeper into this younger demographic, which remains underexplored yet critically important. We also concur with Dr. Kim’s perspective on the need for research approaches that align with the principles of precision medicine, especially given the global increase in diabetes. Such studies could greatly enhance our understanding and enable more tailored prevention strategies for CRC, considering individual variations in glucose metabolism.