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Authors: Grace E. Collinson, BS, Pharmacy Student, Northeastern University, Boston, MA and Debra J. Reid, Pharm.D., BC-ADM, CDE, BCACP

What role could a combination of a GLP-1 receptor agonist and basal insulin have in the management of patients with type 2 diabetes? We know that both classes are among the most efficacious for lowering A1c and they are frequently used in combination, but could combining the two into a once daily injection create a convenient, effective, and clinically relevant addition to standard care?

GLP-1 receptor agonists have been shown to produce clinically meaningful A1c reductions and weight loss, and pose a low risk of hypoglycemia. To date, cardiovascular benefit has also been demonstrated with one drug in the class, liraglutide. Basal insulin has been a cornerstone of diabetes management for years and is effective in lowering glucose, however, is associated with hypoglycemia and often leads to weight gain.

What is intriguing about combining these two classes is the proposed balancing of side effects. In theory, the weight gain and hypoglycemia associated with basal insulin will be counteracted by the weight loss and lower risk of hypoglycemia associated with GLP-1 agonists. Additionally, the lower doses and slower titration of the GLP-1 component is expected to reduce the nausea commonly associated with GLP-1 therapy.

Before the end of this year, the FDA is expected to approve two new combination basal insulin/GLP-1 agonist products, insulin degludec/liraglutide (IDegLira, Novo Nordisk) and insulin glargine/lixisenatide (IGlarLixi, Sanofi). IDegLira is already approved in Europe and marketed under the brand name Xultophy. See the comparison table below: 

Phase 3 trials for both IDegLira and IGlarLixi have demonstrated efficacy compared to insulin glargine (IGlar) in patients with type 2 diabetes. The DUAL V trial compared IDegLira to IGlar and found that IGlarLixi produced significantly greater A1c reductions, weight loss, and fewer episodes of hypoglycemia. The LIXILAN-L trial compared IGlarLixi to IGlar and found similar benefits, with the exception of reduced episodes of hypoglycemia. See trial summary table below: 

Important differences in the study designs limit our ability to directly compare IDegLira and IGlarLixi. For example, the dose of insulin glargine in the comparison group in LIXILAN-L was limited to 60 units daily, while DUAL V set no daily limit and the mean dose of insulin glargine in the comparison group was 66 units daily. Additionally, doses of both investigational agents were titrated to reach a predefined fasting blood glucose goals, however the target in DUAL V was 71-90 mg/dL vs. <100 mg/dL in LIXILAN-L. Until head-to-head trials between these two agents are conducted, direct comparisons will be difficult to elucidate.

Questions remain about what role these combination products will have in clinical practice. Will their use be reserved as a next step for patients who are uncontrolled on a basal insulin or GLP-1 agonist, or will they be used as an aggressive first-line injectable treatment for patients after metformin? As with all combination products, there may be some challenges with dose titration, as the fixed dose ratio does not allow for increasing or decreasing one agent without the other. Clinicians will need to consider patient specific factors in their decision to initiate either IDegLira or IGlarLixi and only time will tell where these products will fit in the treatment of type 2 diabetes.