Need an add-on to metformin? Consider this
Sulfonylureas have been the preferred add-on therapy to metformin for T2DM, but a study finds that DPP-4s have lower risks of death, CV events, and hypoglycemia.
PRACTICE CHANGER
Consider a dipeptidyl peptidase-4 inhibitor before a sulfonylurea for patients with type 2 diabetes mellitus who require therapy in addition to metformin.
Ou SM, Shih CJ, Chao PW, et al. Effects of clinical outcomes of adding dipeptidyl peptidase-4 inhibitors versus sulfonylureas to metformin therapy in patients with type 2 diabetes mellitus. Ann Intern Med. 2015;163:663-672.1
STRENGTH OF RECOMMENDATION
B: Based on limited-quality, patient-oriented data from a high-quality, population-based cohort study.
WHAT’S NEW
Lower risks of death, CV events, and hypoglycemia
This study found that when added to metformin, DPP-4 inhibitors were associated with lower risks for all-cause mortality, cardiovascular events, and hypoglycemia when compared to sulfonylureas. Additionally, DPP-4 inhibitors did not increase the risk of hospitalization for heart failure. A recent multicenter observational study of nearly 1.5 million patients on the effects of incretin-based treatments, including both DPP-4 inhibitors and GLP-1 agonists, similarly found no increased risk of hospitalization for heart failure, with DPP-4 inhibitors compared to other combinations of oral T2DM agents.8
CAVEATS
Did unmeasured confounders play a role?
Unmeasured confounders potentially bias all observational population cohort results. In this study, in particular, there may have been unmeasured, but significant, patient factors that providers used to choose diabetes medications. Also, the study did not evaluate diabetes control, although previous studies have shown similar glucose control between sulfonylureas and DPP-4 inhibitors when they were added to metformin.6
Another caveat is that the results from this study group may not be fully generalizable to other populations due to physiologic differences. People of Asian ancestry are at risk of developing T2DM at a lower body mass index than people of European ancestry, which could affect the outcomes of interest.9
Furthermore, the study did not evaluate outcomes based on whether patients were taking first-, second-, or third-generation sulfonylureas. Some sulfonylureas, such as glyburide, carry a higher risk of hypoglycemia, which could bias the results if a large number of patients were taking them.10
Lastly, the study only provides guidance when choosing between a sulfonylurea and a DPP-4 inhibitor for second-line pharmacotherapy. The GRADE trial, due to be completed in 2023, is comparing sulfonylureas, DPP-4 inhibitors, GLP-1 agonists, and insulin as add-on medications to metformin, and may provide more data on which to base treatment decisions.11
CHALLENGES TO IMPLEMENTATION
DPP-4s have a higher price tag than sulfonylureas
Sulfonylureas and DPP-4 inhibitors are both available as generic medications, but the cost of DPP-4 inhibitors remains significantly higher.12 Higher copays and deductibles could affect patient preference. Furthermore, for patients without health insurance, sulfonylureas are available on the discounted drug lists of many major retailers, while DPP-4 inhibitors are not.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
