LY2189265, a long-acting glucagon-like peptide-1 analogue, showed a dose-dependent effect on insulin secretion in healthy subjects

Abstract

To assess the safety, tolerability, pharmacokinetics, pharmacodynamics and potential immunogenicity of single, escalating subcutaneous injections of a once-weekly glucagon-like peptide-1 analogue in healthy subjects. This phase 1, three-period, crossover, double-blind, placebo-controlled study investigated single, escalating subcutaneous doses of LY2189265 (LY) ranging from 0.1 to 12 mg; approximately six subjects were randomized to each dose. Parameters of safety, including adverse events, were assessed. The pharmacokinetic profile was assessed over 14 days. Pharmacodynamic parameters (glucose and insulin concentrations) were measured following a step-glucose infusion (day 3) and as part of an oral glucose tolerance test (OGTT) (day 5). LY was generally well tolerated with some increase in gastrointestinal symptoms with escalating doses. There were small dose-dependent increases in pulse rate with doses ≥1.0 mg and diastolic blood pressure with doses ≥3.0 mg. The half-life of LY was approximately 90 h, with C(max) occurring between 24 and 48 h in most subjects. Evidence of increase in glucose-dependent insulin secretion and suppression of serum glucose excursions were observed during an OGTT at all doses compared to placebo; no episodes of hypoglycaemia occurred. No subjects developed antibodies to LY2189265. LY showed an acceptable safety profile and exhibited the expected glucagon-like peptide-1 pharmacological effects on glucose suppression and insulin secretion with a half-life that supports once-weekly dosing.