Once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide is non‐inferior to once‐daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26‐week randomized phase III study

Abstract

AimsTo examine the efficacy and safety of once‐weekly dulaglutide monotherapy (0.75 mg) compared with placebo and once‐daily liraglutide (0.9 mg) in Japanese patients with type 2 diabetes.MethodsThis was a phase III, 52‐week (26‐week primary endpoint), randomized, double‐blind, placebo‐controlled, open‐label comparator (liraglutide) trial comparing 492 Japanese patients with type 2 diabetes (dulaglutide, n = 281; liraglutide, n = 141; and placebo, n = 70) who were aged ≥20 years. Patients and investigators were blinded to treatment assignment for dulaglutide and placebo but not for liraglutide. The primary objective evaluated the superiority of dulaglutide versus placebo on change from baseline in glycated haemoglobin (HbA1c) at 26 weeks. Analyses were performed on the full analysis set.ResultsAt 26 weeks, once‐weekly dulaglutide was superior to placebo and non‐inferior to once‐daily liraglutide for HbA1c change from baseline [least squares mean difference: dulaglutide vs placebo −1.57% (95% confidence interval −1.79 to −1.35); dulaglutide vs liraglutide −0.10% (95% confidence interval −0.27 to 0.07)]. The most frequently reported adverse events were nasopharyngitis, constipation, diarrhoea, nausea, abdominal distension and decreased appetite; only decreased appetite was different between the dulaglutide and liraglutide groups [dulaglutide, n = 2 (0.7%); liraglutide, n = 8 (5.8%); p = 0.003]. Nine (1.8%) patients experienced hypoglycaemia [dulaglutide, n = 6 (2.1%); liraglutide, n = 2 (1.5%); placebo, n = 1 (1.4%)], with no event being severe.ConclusionsIn Japanese patients with type 2 diabetes, once‐weekly dulaglutide (0.75 mg) was superior to placebo and non‐inferior to once‐daily liraglutide (0.9 mg) for reduction in HbA1c at 26 weeks. Dulaglutide was safe and well tolerated.

Analysis of efficacy and safety of dulaglutide 0.75 mg stratified by sex in patients with type 2 diabetes in 2 randomized, controlled phase 3 studies in Japan

“…To evaluate changes in HbA1c and body weight by sex, subgroup analyses were conducted using the mixed model for repeated measures used for the primary efficacy analyses in the studies [8,9], with a term for sex and terms for treatment-by-sex, visit-by-sex, and treatment-by-sex-by-visit interactions added. Least-squares mean changes for HbA1c and body weight by treatment and sex were estimated.…”

“…Least-squares mean changes for HbA1c and body weight by treatment and sex were estimated. To further explore the relationship between changes in HbA1c and body weight, changes from baseline in HbA1c and body weight at endpoint for individual patients were presented on scatter plots, and Pearson correlations between the changes weeks of treatment in 2 randomized, controlled phase 3 studies in Japanese patients with T2D, dulaglutide 0.75 mg was shown to be noninferior to liraglutide 0.9 mg [8] for changes in HbA1c and superior to insulin glargine [9] for changes in HbA1c, with a lower incidence of hypoglycemia. In the third phase 3 study (nonrandomized, noncontrolled) in Japanese patients, dulaglutide 0.75 was overall safe and effective over 52 weeks of treatment when used in combination with a single oral hypoglycemic agent from among 5 classes (sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinedione, or glinides) [10].…”

“…Dulaglutide is a once weekly GLP-1 receptor agonist approved in Japan at a dose of 0.75 mg. After 26 apy study" [8,12], which was a 52-week study that had the primary endpoint at 26 weeks, and 2) "the combination study" [9], which was a 26-week study. The monotherapy study randomized patients to dulaglutide, liraglutide 0.9 mg, or placebo; after 26 weeks of treatment, patients treated with placebo were switched to dulaglutide.…”

Subgroup analysis of phase 3 studies of dulaglutide in Japanese patients with type 2 diabetes

“…gov (NCT01584232, NCT01558271, NCT01468181). Study design and methods for each study have been previously reported [7][8][9][10].…”

“…In phase 3 studies in Japanese patients with T2D, once weekly dulaglutide 0.75 mg has shown superiority to insulin glargine (in a randomized, 26-week, open-label study of dulaglutide in combination with sulfonylureas [SU] and/or biguanides [BG]) and non-inferiority to liraglutide 0.9 mg/day (in a randomized monotherapy study in which dulaglutide was compared to placebo [double-blind] and to liraglutide 0.9 mg/day [open-label]; the study had a 26-week primary endpoint and a 52-week treatment period) in HbA1c changes [7][8][9]. Also, in a nonrandomized, open-label, long-term (52-week) phase 3 safety study in Japanese patients with T2D, once weekly dulaglutide 0.75 mg was overall well-tolerated in combination with a single oral hypoglycemic agent (SU, BG, α-glucosidase inhibitors, thiazolidinediones, or glinides) [10].…”