Once-Weekly Efpeglenatide Dose-Range Effects on Glycemic Control and Body Weight in Patients With Type 2 Diabetes on Metformin or Drug Naive, Referenced to Liraglutide.

Abstract

To explore the efficacy, safety, and tolerability of once-weekly efpeglenatide, a long-acting glucagon-like peptide 1 receptor agonist (GLP-1 RA), in early type 2 diabetes (T2D) (drug naive or on metformin monotherapy). EXCEED 203 was a 12-week, randomized, placebo-controlled, double-blind, parallel-group, dose-ranging study of efpeglenatide once weekly referenced to open-label liraglutide 1.8 mg (exploratory analysis). Participants, ∼90% on metformin monotherapy, were randomized to one of five efpeglenatide doses (0.3, 1, 2, 3, or 4 mg q.w.; <i>n</i> = 181), placebo (<i>n</i> = 37), or liraglutide (≤1.8 mg daily; <i>n</i> = 36). The primary efficacy end point was change in HbA_1c from baseline to week 13. From a baseline HbA_1c of 7.7-8.0% (61.0-63.9 mmol/mol), all efpeglenatide doses ≥1 mg significantly reduced HbA_1c versus placebo (placebo-adjusted least squares [LS] mean changes 0.6-1.2%, <i>P</i> < 0.05 for all) to a final HbA_1c of 6.3-6.8% (45.4-50.6 mmol/mol); masked efpeglenatide 4 mg was noninferior to open-label liraglutide. Greater proportions treated with efpeglenatide ≥1 mg than placebo achieved HbA_1c <7% (61-72% vs. 24%, <i>P</i> < 0.05 for all), and greater reductions in body weight were observed with efpeglenatide 3 and 4 mg versus placebo (placebo-adjusted LS mean differences -1.4 and -2.0 kg, respectively, <i>P <</i> 0.05 for both). Rates of nausea and vomiting were consistent with other GLP-1 RAs and rapidly subsided after the initial 2 weeks. No neutralizing antibodies were detected with efpeglenatide. Efpeglenatide once weekly led to significant reductions in HbA_1c and weight, with a safety profile consistent with the GLP-1 RA class in patients with early T2D mostly on metformin monotherapy.