A phase 2 randomized controlled trial demonstrated clinically significant changes in glycemic control.
GLP-1 agonists have been used for the last few years in diabetes management as add-on therapy to oral agents in patients who fail therapy. GLP-1 agonists, like exenatide, target various pathophysiological disturbances in diabetes that include insulin secretion through a glucose-dependent mechanism, suppression of glucose-dependent glucagon secretion, delaying gastric emptying and promoting satiety. Exenatide is widely prescribed due to its multiple dosing regimens. It has been approved as a twice-daily subcutaneous injection (Byetta) and as a once-weekly subcutaneous injection regimen (Bydureon). Exenatide, has been under review recently for a once-monthly regimen and has shown promise using a novel polymer base for its sustained delivery.
In a recent randomized single-blinded phase 2 controlled trial, Carol Wysham and colleagues evaluated the safety and efficacy of once-monthly exenatide versus once-weekly exenatide. The once-monthly dosing contained microspheres in Miglyol and the weekly dosing contained microspheres in aqueous solution. Patients were eligible if they were on diet and exercise or on metformin, pioglitazone or both. They were later randomized in four different arms of treatment; one arm consisting of 2 mg weekly, and the other arms of 5 mg, 8 mg, and 11 mg monthly. Patients at baseline had the following characteristics: mean age of 50 years, A1c of 8.5%, fasting blood glucose levels of 184 mg/dL, and body weight of 98kg. A total of 110 patients were enrolled and these were followed for 20 weeks. The primary endpoint of study was an A1c reduction at the end of the 20-week period. Secondary outcomes for the study looked into changes in FPG, body weight, and systolic blood pressure.
Results from the primary endpoint analysis showed similar reductions in A1c in all treatment arms (mean A1c -1.54% + 1.26%)(p=0.392). Patients with an A1c greater than 9% had a greater reduction than those who had an A1c less than 9%. Consequently, proportions of patients obtaining an A1c of less than 7% were 48% for the once-weekly dosing and 50%, 57%, and 70% in the 5 mg, 8 mg, and 11 mg once-monthly dosing, respectively, thereby highlighting the possibility of obtaining greater A1c reductions with 11 mg of exenatide. Fasting blood glucose levels changed from baseline in all groups (mean SD +: -34 + 48 mg/dL in the once-weekly dosing regimen vs -25 + 43, -30 + 52, and -49 + 49 mg/dL in the 5 mg, 8 mg, and 11 mg monthly regimens, respectively). No clear relationship was observed for changes in blood pressure.
In terms of safety and efficacy, no deaths were reported in the study. Only two incidences of cardiovascular complications were reported, including acute coronary syndrome and myocardial infarction. The most common adverse reactions reported in the 11 mg once-monthly group was gastrointestinal related. Nausea, vomiting, and diarrhea peaked at 8 weeks, however these were variable and self-limiting. The most frequent observed adverse reactions were headache and nausea in the once-monthly suspension. Injection-site reactions were reported and did not seem to be dose related. Additionally, no major or minor events of hypoglycemia and hyperglycemia occurred. Weight reduction was observed in all groups, however those patients in the 8 mg once-monthly regimen had the least weight reduction. Those patients in the once-weekly regimen obtained greater weight reduction.
In conclusion, the use of exenatide once-monthly dosing in Miglyol suspension improved glucose levels and weight. All doses of the exenatide monthly suspension provided clinically significant reductions in A1c. Both regimens, once weekly and once monthly, provided significant glycemic control. The observed results from this study highlight the safety and tolerability of this new regimen. Authors emphasized that treatment satisfaction was observed with all regimens and providing a once-monthly dosing provides flexibility in dosing. Hence, delaying or moving up doses by several days will unlikely affect the safety and efficacy of the medication. Therefore, the development of a once-monthly exenatide regimen in a Miglyol suspension can potentially help with medication adherence in type 2 diabetes management.
- Once-monthly exenatide provides significant A1c reductions in those patients with levels above 9%.
- Improved patient adherence can be obtained from once-monthly exenatide while obtaining similar benefits seen in once weekly doses.
- Once-monthly exenatide dosing is well-tolerated and shows significant improvements in glycemic control and weight.
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
Wysham, Carol H., Leigh Macconell, and Elise Hardy. “Efficacy and Safety of Multiple Doses of Exenatide Once-Monthly Suspension in Patients With Type 2 Diabetes: A Phase 2 Randomized Clinical Trial.” Diabetes Care Dia Care (2016): Dc160238. Web
Qiao, Qing et al. “Adherence to GLP-1 Receptor Agonist Therapy Administered by Once-Daily or Once-Weekly Injection in Patients with Type 2 Diabetes in Germany.” Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 9 (2016): 201–205. PMC. Web. 24 Aug. 2016.