Elderly Women and the Risk of Breast Cancer When Initiating Certain Insulins

Insulin has changed the game in managing people with diabetes but has the potential to cause unwanted severe adverse effects in women 65 years of age and older.  This study looked at whether some forms of insulin and breast cancer risk are linked.

Designed to overcome the limitations of neutral protamine Hagedorn insulin, long-acting insulin analogs such as glargine and detemir have become novel treatments in the management of chronic disease, diabetes. These structurally altered human insulins are thought to influence mitogenicity, which raised concerns in scientists about the potential glargine had to be carcinogenic.  

Previously, in vitro studies found that glargine had an eightfold more potent mitogenic property than regular insulin. Also, glargine had a substantially higher proliferative effect on breast cancer cells compared with other insulins. Contrarily, there are additional studies that have decided that in vivo metabolites of glargine, M1 and M2, were not mitogenic and are most measurable after insulin glargine administration with very little to none of the intact molecule detectable. Furthermore, these concerns led to the conduction of other studies, which yielded inconsistent results. The objective is this study was to determine whether the initiation of glargine, compared with the introduction of NPH or insulin detemir, is associated with an increased risk of breast cancer in women with diabetes.  

The study population consisted of female Medicare beneficiaries who were 65 years of age or older, enrolled in fee-for-service Medicare Part A, Part B, and Part D. Participants were eligible for inclusion if they initiated study insulin (either glargine, detemir, or NPH) between September 2006 and September 2015, and in the 270 days before the date of the qualifying prescription, they had continuous enrollment in Medicare, had no prior cancer diagnosis, and did not receive a prescription for one of the study insulins. Exclusion criteria were based on if the patient was in a skilled nursing facility or nursing home or if they received the index prescription from a long-term care pharmacy or were receiving hospice care on the index date. Additionally, kidney transplant recipients, patients undergoing dialysis, and anyone who entered Medicare for reasons other than age were excluded.  

All statistical analyses were based on IPTW-adjusted cohorts, which accounted for any potential confounding by baseline factors. Standard Cox proportional hazard models were used to determine crude breast cancer incidence rates per 1,000 person-years as well as 95% confidence intervals. To determine the incidence of breast cancer among glargine users compared with users of NPH and detemir, a weighted Cox proportional hazards regression with robust was used that estimated weight-adjusted hazard ratios and 95% confidence intervals.  

Upon the conclusion of this study, researchers were able to determine that every use of glargine was not associated with an increased risk of breast cancer compared to NPH or detemir. For NPH, the hazard ratio was 0.97, and a 95% confidence interval 0.88-1.06.  For detemir, the hazard ratio was 0.98, and a 95% confidence interval 0.92-1.05. Researchers also found that there was no increased risk seen with glargine use compared with either NPH or detemir by the duration of insulin use, length of follow-up, or cumulative dose of insulin. Finally, there was no increased risk of breast cancer observed in medium or high dose glargine users compared with low dose users.  

To conclude, female Medicare beneficiaries 65 years of age and older who use glargine are not associated with an increased risk of breast cancer compared with NPH or detemir. Furthermore, in patients with five or more years follow-up, no difference was seen in breast cancer risk at different cumulative doses of glargine or detemir. The limitations of this study were significant for it being observational with possible subjection to confounding by factors not adjusted for in the analysis, generalizability outside the age of 65 years and older are limited, and data of identification of cancer diagnoses and potentially essential covariates such as BMI and smoking.  

Practice Pearls: 

• Older women are thought to have an increased risk of developing breast cancer due to glargine use. 
• Despite inconsistent data from previous trials, researchers found that the use of glargine was not associated with an increased risk of breast cancer compared to NPH or detemir.  
• Limitations exist that confound by factors not adjusted for in the analysis.  

Bradley, Marie C., et al. “Similar Breast Cancer Risk in Women Older Than 65 Years Initiating Glargine, Detemir, and NPH Insulins.” Diabetes Care, American Diabetes Association, 15 Feb. 2020, care.diabetesjournals.org/content/early/2020/02/14/dc19-0614. 

Deonna Andrews, PharmD Candidate 2020 of Florida Agricultural & Mechanical University College of Pharmacy and Pharmaceutical Sciences  

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