Once Weekly GLP-1 Receptor Agonist Phase II Trial


Despite the side effects experienced at a high dose, a long-acting GLP-1 agonist proceeds to phase III trials.

Administration of the long-acting glucagon-like peptide (GLP)-1 receptor agonist semaglutide resulted in a dose-dependent reduction in both HbA1c and weight in patients with type 2 diabetes, according to the results of a phase II study.

Semaglutide, which is administered once weekly, is being further explored in a phase III study at doses of 0.5 mg and 1.0 mg with a 4-week dose escalation.

“Semaglutide potentially offers potent glucose-lowering efficacy with a similar overall safety profile compared with other available GLP-1 receptor agonists, providing a robust basis for further investigation,” wrote researcher Michael A. Nauck, of the Diabetes Centre, Bad Lauterberg, Germany, and colleagues in Diabetes Care. “Glucose-lowering medications administered once weekly have the potential to improve patient adherence and, therefore, may impact treatment outcomes and quality of life.”

The dose, efficacy, and safety of semaglutide were investigated in a 12-week randomized, double-blind phase II trial. The researchers enrolled 412 patients and randomly assigned them to subcutaneous semaglutide once weekly without dose escalation (0.1 mg to 0.8 mg), with dose escalation (E; 0.4 mg steps to 0.8 or 1.6 mg over 1 to 2 weeks), open-label liraglutide, or placebo.

The primary endpoint of the study was the change in HbA1c from baseline. After 12 weeks of treatment, patients assigned to semaglutide had a dose-dependent response to the GLP-1 receptor agonist. Semaglutide reduced HbA1c levels from baseline by -0.6% to -1.7%. As many as 81% of patients achieved an HbA1c of less than 7% compared with 57% of patients assigned 1.8-mg liraglutide and 15% of those assigned placebo.

The average change in HbA1c for patients assigned any dose of semaglutide was significantly greater compared with placebo (P<0.05). Patients assigned semaglutide 1.6 mg E had greater reductions in HbA1c compared with liraglutide 1.2 mg and 1.8 mg.

In addition, patients assigned semaglutide 1.6 mg E had reductions in weight of as much as -4.8 kg compared with baseline. The study showed that weight reductions in patients assigned semaglutide were significantly greater than those seen in patients assigned to placebo (P<0.001). Reductions in weight with semaglutide 0.8 mg and 1.6 mg were also greater compared with those seen with liraglutide 1.2 and 1.8 mg doses, and with semaglutide 0.8 mg, 0.8 mg E, and 1.6 mg E compared with liraglutide 1.2 mg.

No major episodes of hypoglycemia occurred and the incidence of minor hypoglycemia was low, according to the researchers.  A total of 11% of patients withdrew from the trial due to adverse events, the majority of which were gastrointestinal (86.7%). The researchers found that the incidence of nausea, vomiting, and withdrawal from the study due to gastrointestinal adverse events increased with the dose of semaglutide. Up to 29.8% of patients in the semaglutide 1.6 mg E group withdrew due to treatment emergent adverse events compared with 4.4% in the placebo group and 10.0% in the liraglutide groups.

“While the overall gastrointestinal side effects were not unexpected, the incidence of gastrointestinal side effects observed with the highest dose of semaglutide was not considered acceptable,” the researchers wrote. “Semaglutide 1.6 mg has not, therefore, been taken forward into phase 3.”

Nauck MA, et al. A phase 2, randomized, dose-finding study of the novel once-weekly human GLP-1 analog, semaglutide, compared with placebo and open-label liraglutide in patients with type 2 diabetes. Diabetes Care. 10 Sept 2015 [Epub ahead of print].


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