Efficacy and safety of an expanded dulaglutide dose range: A phase 2, placebo‐controlled trial in patients with type 2 diabetes using metformin

Abstract

Aims: Dulaglutide, a once weekly GLP-1 receptor agonist, is approved at two doses (1.5 and 0.75 mg) for treatment of type 2 diabetes (T2D). Two higher doses of dulaglutide (3.0 and 4.5 mg) were evaluated for safety and efficacy to determine whether these doses warrant further study for improved control of glucose and body weight.Materials and methods: This 18-week, double-blind, phase 2 trial randomized 318 patients with T2D using ≥1500 mg metformin, to receive subcutaneous injection of placebo (n = 82), dulaglutide 1.5 mg (n = 81), dulaglutide 3.0 mg (n = 79) or dulaglutide 4.5 mg (n = 76). The primary objective was superiority of dulaglutide doses over placebo in reduction of HbA1c at 18 weeks. Secondary objectives included superiority of dulaglutide over placebo in change from baseline in body weight and fasting serum glucose (FSG) at 18 weeks. Investigational doses of dulaglutide were compared to the 1.5 mg dose as an exploratory objective. Results: HbA1c reduction at 18 weeks was significantly greater with dulaglutide vs placebo (placebo, −0.44% ± 0.10% [−4.8 ± 1.1 mmol/mol]; dulaglutide 1.5 mg, −1.23% ± 0.10% [−13.5 ± 1.1 mmol/mol]; dulaglutide 3.0 mg, −1.31% ± 0.10% [−14.3 ± 1.1 mmol/mol]; dulaglutide 4.5 mg, −1.40% ± 0.10% [−15.3 ± 1.1 mmol/mol]; P < 0.001, each dose), as were changes in body weight (placebo, −1.6 ± 0.39 kg; dulaglutide 1.5 mg, −2.8 ± 0.39 kg; dulaglutide 3.0 mg, −3.9 ± 0.39 kg; dulaglutide 4.5 mg, −4.1 ± 0.41 kg; P < 0.001, each dose). All three dulaglutide doses significantly reduced FSG from baseline (1.5 mg, −36.2 ± 4.7 mg/dL [−2.0 ± 0.3 mmol/L]; 3.0 mg, −34.5 ± 4.5 mg/dL [−1.9 ± 0.3 mmol/L]; 4.5 mg, −38.0 ± 4.7 mg/dL [−2.1 ± 0.3 mmol/L]) vs placebo (−12.4 ± 4.5 mg/dL [−0.7 ± 0.3 mmol/L]) (P < 0.001, all). Safety profiles of the higher doses were consistent with the established safety profile for dulaglutide. Gastrointestinal events were mostly mild to moderate, and was dose-related for nausea.Conclusion: All three dulaglutide doses were superior to placebo in improving glycaemic control and reducing body weight in participants with T2D using metformin. The potential for doses of dulaglutide of 3.0 and 4.5 mg to provide additional

Effect of the glucagon‐like peptide‐1 analogue liraglutide versus placebo treatment on circulating proglucagon‐derived peptides that mediate improvements in body weight, insulin secretion and action: A randomized controlled trial

“…Second, GLP‐1A AUC at the end of the study, an indicator of liraglutide concentration, is linearly associated with many physiologically important GLP‐1 actions. These results provide biological evidence and confirmation of the clinically observed dose‐response effect of liraglutide 8 and other GLP‐1 receptor agonists 10 to promote weight loss and increase the ISR 11 …”

Association of glucagon-like peptide 1 analogs and agonists administered for obesity with weight loss and adverse events: a systematic review and network meta-analysis

“…After classification of the active durations of treatments based on the predefined drug-dosage combinations, 53 of these RCTs provided two-group comparisons consisting of a placebo group and one drugdosage group (dulaglutide 1.5mg, 2 trials; [28,29]…”

GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art

“…Daily doses up to 3.0 mg are approved for liraglutide (1.8 mg is the maximum dose for treating type 2 diabetes) [ 65 ], and clinical trials have tested semaglutide at up to 0.4 mg per day (that is, corresponding to 2.8 vs 1.0 mg per week for type 2 diabetes) [ 68 ]. Doses of up to 4.5 mg per week (vs a maximum of 1.5 mg for type 2 diabetes) are being explored for dulaglutide [ 85 ]. In subjects tolerating these higher doses of GLP-1 RAs, substantially greater reductions in body weight were observed than with “conventional” doses typically employed to treat type 2 diabetes.…”