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Safety And Efficacy Of New Long-Acting Exenatide Formulation

Once-weekly exenatide formulation can provide as much benefit as the traditional twice-daily dosing.

Type 2 diabetes is a chronic disease that increases the risk of cardiovascular events and other major complications. Injectable non-insulin therapies such GLP-1 agonist have been effectively used to improve glycemic control and decrease metabolic disbalances in this population. They have been shown to decrease systolic BP, decrease triglycerides, increase sodium excretion and promote weight loss.  Exenatide is a notable example within this class and it has been used for over 10 years. This agent, however, requires twice-daily dosing, which may increase risk of nonadherence among patients. A new formulation of exenatide, which enables once-a-week dosing may result in better compliance and therefore a more attractive choice for patients with T2D.

A phase III, randomized, controlled, open-label study (DURATION-NEO-1) was conducted to compare efficacy, safety and tolerability of Exenatide BID versus modified release Exenatide once-weekly. The trial lasted a total of 52 weeks and included 375 patients with T2D already taking metformin, sulfonylurea, pioglitazone or any combination of the previous agents. Patients with pancreatitis, CKD stage 4+, cancer or active cardiovascular disease were excluded. One group received 2mg of once-weekly Exenatide, the other group received up to 10ug twice daily. Primary endpoints included the mean change in HBA1C from baseline until the first half of the study (28 weeks) while secondary endpoints included the incidence of adverse effects.

HbA1c was reduced by −1.4% and −1.0%, in once-weekly and twice-daily exenatide groups respectively (p = 0.0072). More patients achieved HbA1C <7.0% with exenatide once-weekly (49.3%) than with exenatide BID (43.2%) although not statistically significant (p = 0.225). Body weight was reduced from baseline with both exenatide once-weekly (−1.49 ± 0.28 kg) and exenatide BID (−1.89 ± 0.36 kg) (P = 0.37 for the difference). After 28 weeks, there was no significant between-group difference in change in body weight. Both exenatide groups’ participants had reductions in systolic blood pressure (difference: 0.8 ± 1.6 mm Hg; nominal p = 0.61). Diastolic BP increased slightly with exenatide once-weekly and decreased with exenatide BID (difference, 2.0 ± 0.9 mm Hg; p=0.03). There were no clinically significant changes in lipid panels or other cardiovascular risk factors, including high-sensitivity C-reactive protein, BNP or urinary albumin/creatinine ratio.

Gastrointestinal adverse events, including nausea, vomiting and diarrhea were reported in 22.7% (exenatide once-weekly) and 35.6% (exenatide BID) of patients. Discontinuation of participants from the study was minimal and less notably in the once-weekly treatment dosing. Minor incidences of hypoglycemia occurred most often with concomitant sulfonylurea use. Nodules were the most common injection site-related adverse effects in the exenatide once-weekly group (12.7%) but were less frequent with exenatide BID (0.7%); in most cases, nodules were single mild events, and were reported during the first 2 months of treatment.

The use of sulfonylurea was significant for the change in Fasting Plasma Glucose (FPG) over 28 weeks, meaning it was associated with a lesser FPG response to exenatide (P = .024). No severe hypoglycemia occurred during the study; minor incidences occurred most often with concomitant sulfonylurea use. Exenatide once-weekly was associated with an improved adverse event profile and fewer treatment discontinuations than was exenatide BID. (1)

Longer-acting exenatide developed after exenatide BID, was introduced to reduce dosing frequency and improve compliance. Although both formulations effectively decreased HbA1C, the once-weekly formulation had better results. Compliance was high among both groups and was therefore unlikely to have had any impact on the HbA1C differences between groups. The authors considered exenatide once-weekly as a potential alternative to exenatide BID for the treatment of type 2 diabetes. The concomitant use sulfonylurea was found to reduce the efficacy of exenatide and increase risk of hypoglycemia between both groups. This study has some limitations; however, the open-label design may have contributed to some bias in the study. The sample size was not large enough to draw conclusions to be made on potential differences between patients with different demographics and their response to treatment.

Practice Pearls:

  • Once-weekly exenatide injection may offer patients with T2D better glycemic control and better compliance profiles as compared to the twice-daily dosing.
  • Sulfonylureas may decrease the therapeutic efficacy of exenatide.
  • The use of exenatide may cause weight loss, gastrointestinal side effects, and injection side reactions.

References:

Carol H. Wysham MD, Julio Rosenstock MD. Efficacy and tolerability of the new autoinjected suspension of exenatide once weekly versus exenatide twice daily in patients with type 2 diabetes. Diabetes, obesity and metabolism. A journal of pharmacology and therapeutics. August 2017.

 

Fabio Rodriguez, PharmD. candidate 2018, LECOM School of Pharmacy