It is important to point out that none of these variables were observed to confound the association between insulin use and cancer incidence. For this study, we started with more than 20,000 patients and after careful selection process we only had 54 cancers cases. This suggests that with careful selection of patients, only a very small proportion are valid for looking at specific CHIR-99021 interactions like the one between glargine dose and cancer incidence. This also indicates importance of meticulous selection and adjustments to attain decisive answer to this unclear interaction. More recently, the ORIGIN study showed that there was no increase of cancer incidence with glargine treatment over 6 years in subjects with prediabetes or early diabetes when compared to standard-care. But the ORIGIN study population consisted of people who would not normally be prescribed insulin and the study had no active comparator such as NPH insulin. This may explain the significant differences in the baseline characteristics between ORIGIN and our study including comorbidities, diabetic complications, and other medications. Indeed, there is the possibility that physicians tend to start or switch to insulin glargine in patients who are already more prone to developing cancers. Patients who are generally less healthy are more likely to be prescribed easily administered daily insulin glargine than other types of insulin; this allocation bias is one of the limitations of previous studies. Our work yielded contrasting results using an active comparator study design. That is, the study mimics a treatment decision between two long acting insulins rather than comparing treated with untreated patients. Even hat physicians do not channel specific patients based on their BMI, smoking status, nor HbA1c preferentially to any of the long acting insulins compared here. Several studies have shown a correlation between glargine dose and cancer risk. In order to investigate this relationship, we prospectively categorized cumulative insulin dose and found that adjustment of insulin dose did not change the neutral effect of glargine insulin on the incidence of cancer. In this context, we had several advantages in the study design. We utilized new NPH users as an active comparator and there was no significant difference between groups with regard to diabetes severity and other potential cancer risks. We also adopted sophisticated methodology to perform a retrospective longitudinal study using EMR data. We applied strict and innovative criteria to obtain new users of glargine and NPH without prevalent cancer during 19 months prior to insulin initiation. This latent period helped us exclude indolent cancer cases in which cancer might be already present before diagnosis. Using this process, new glargine or NPH users without indolent cancers could be selected precisely, which suggests that these methods can be used as an example for future studies attempting to utilize EMR data. We also accounted for clinical visits and hospitalizations, which might have led to higher chance of cancer detection. We believe that the method used in this study can act as a potential model for others who may try to use EMR data for pharmacoepidemiologic study. There are also several limitations of this study. First, the followup duration was not long enough to estimate the risk of some cancers although our average length of follow-up is comparable to previous studies. Moreover, the number of study subjects was no as substantial as that of recent studies. In addition, due to the limited number of cancer cases, we could not evaluate individual cancer risk.