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Glycemic Benefits of Lixisenatide

What benefits can lixisenatide provide when added to basal insulin regimen?

Lixisenatide was approved by the FDA on July 27, 2016 for treatment of type 2 diabetes in adults. The drug has been approved since 2013 in Europe under the trade name of Lyxumia® as once-daily dosing regimen for type 2 diabetes. Like other agents within its class, lixisenatide is known to promote insulin secretion after meals and suppress the release of glucagon from the pancreas. Therefore, helping with diabetes management in those patients not receiving adequate control on other oral agents or insulin regimens. In previous trials, lixisenatide has shown to reduce postprandial blood glucose to a greater extent than other agents like liraglutide and insulin glargine. In a recent clinical trial, these findings have been observed to a certain extent. It has consistently demonstrated adequate glycemic control, weight reduction, and low risk of hypoglycemia. It has a pronounced effect on postprandial glucose and A1c reduction is obtained through reductions in fasting blood glucose. Trials have also demonstrated cardiovascular benefits from the use of GLP-1 agonists.

Recently, Matthew C. Riddle, MD from the Oregon Health & Science University of Portland, Oregon and colleagues conducted a clinical trial where the benefits of lixisenatide were further expanded. A two arm, double blind randomized placebo-controlled phase III clinical trial was conducted to examine the efficacy and safety of once-daily lixisenatide when added to basal insulin regimen alone or with metformin. In this 24-week trial, patients with long-standing type 2 diabetes inadequately controlled on basal insulin with or without metformin, were randomized to receive once-daily lixisenatide or placebo. A change in A1c at 24 weeks was the primary endpoint. Secondary endpoints included changes in fasting blood glucose from baseline, changes in weight, changes in self-monitoring glucose, and changes in glucose 2 hours after meals. A total of 495 patients received treatment in 15 different countries.

At the end of the study, there was a clinically significant drop in A1c from baseline. The mean A1c at baseline was 8.4 + 0.9% and it declined to 7.8% + 1.2% at 24 weeks. Whereas in the placebo group A1c change was from 8.4 + 0.8 to 8.1 + 1.2% (95% CI -0.6 to -0.2; p= 0.0002). Additionally, the majority of patients receiving lixisenatide obtained A1c levels of < 6.5% and <7% when compared to placebo (<7%; p<0.0001 vs < 6.5%; p=0.0003). Furthermore, no difference was observed in fasting blood glucose despite an initial decrease in levels at the beginning of the study. Body weight changes were more robust in the lixisenatide group that in the placebo group (1.8 kg vs 0.5 kg; LS mean change -1.3 kg; P<0.0001). Through self-monitoring readings, it was seen that the biggest effect of lixisenatide on glucose levels was after meals and the smallest was  before breakfast. Furthermore, incidents of hypoglycemia were greater in the lixisenatide group than in the placebo group, however they were documented during the first week of treatment (p=0.174). Other adverse events reported in the study group, were gastrointestinal related (i.e nausea and vomiting).

In conclusion, the use of once-daily lixisenatide provides significant reductions in A1c, obtaining a 0.7% reduction from baseline. However, these results need to be explored in longer treatment regimens. The incidence of hypoglycemia seemed to be limited to skipped meals and/or the initial phase of treatment. Therefore, these findings warrant closer monitoring in patients initiating GLP-1 treatment. Prominent glucose reductions can be obtained with the lixisenatide after meals, as observed in self-monitoring values. Consequently, the side effect profile of this regimen is tolerable and in those cases of nausea and vomiting, these events seemed to be self-limiting. The addition of this newly approved GLP-1 agonist to basal insulin regimen with or without metformin provides clinically significant benefits in type 2 diabetes management. Riddle and colleagues suggest that once-daily dosing lixisenatide can be implemented as an alternative to rapid-acting insulin or other agents to improve glucose levels; it can potentially be implemented prior to basal insulin treatment.

Practice Pearls:

  • Once-daily dosing of lixisenatide provides significant reductions in A1c when used in conjunction with basal insulin with or without metformin.
  • Lixisenatide is well tolerated and provides weight reduction benefits.
  • Titration of basal insulin in combination with lixisenatide can help patients obtain A1c levels of less than 7%

References:

Riddle, Matthew C. et al. “Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled by Established Basal Insulin: A 24-Week, Randomized, Placebo-Controlled Comparison (GetGoal-L).” Diabetes Care 36.9 (2013): 2489–2496. PMC. Web. 31 Aug. 2016.

Anderson, Sarah L., and Jennifer M. Trujillo. “Lixisenatide in Type 2 Diabetes: Latest Evidence and Clinical Usefulness.” Therapeutic Advances in Chronic Disease 7.1 (2016): 4–17. PMC. Web. 31 Aug. 2016.

Researched and prepared by Pablo A. Marrero-Núñez – USF College of Pharmacy Student Delegate –  Doctor of Pharmacy Candidate 2017 – University of South Florida – College of Pharmacy