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Pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of the novel dual glucose‐dependent insulinotropic polypeptide/glucagon‐like peptide‐1 agonist RG 7697 in people with type 2 diabetes mellitus
Author(s) -
Schmitt Christophe,
Portron Agnès,
Jadidi Shirin,
Sarkar Neena,
DiMarchi Richard
Publication year - 2017
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.13024
Subject(s) - postprandial , medicine , pharmacokinetics , placebo , gastric emptying , pharmacodynamics , tolerability , endocrinology , liraglutide , insulin , diabetes mellitus , type 2 diabetes mellitus , type 2 diabetes , adverse effect , nausea , crossover study , pharmacology , stomach , alternative medicine , pathology
Aims To investigate the pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of RG 7697, a dual glucose‐dependent insulinotropic polypeptide/glucagon‐like peptide‐1 agonist, in patients with type 2 diabetes mellitus (T2 D ). Methods A total of 56 patients with T2 D received once‐daily subcutaneous (s.c.) injection of RG 7697 (0.25‐2.5 mg) or placebo for 14 days in a randomized, double‐blind, dose‐escalation study. Adverse events ( AE s), vital signs, ECG s and routine laboratory variables were intensively monitored. Drug concentrations, fasting glycaemic variables, 24‐hour glucose profiles, glycated haemoglobin ( HbA1c ) and antibody formation were measured. Several meal tolerance and gastric emptying tests were performed during the study. Results Daily s.c. injections of RG 7697 were well tolerated by the majority of participants with T2 D . The most frequently reported AE s with RG 7697 were diarrhoea, nausea and decreased appetite. Asymptomatic events of hypoglycaemia were relatively uniformly distributed across dose groups including placebo. Pharmacokinetic steady‐state was achieved within 1 week. Meaningful reductions in fasting, postprandial and 24‐hour plasma glucose profile were observed at doses ≥0.75 mg, and were associated with numerical decreases in HbA1c (−0.67% [2.5‐mg dose] vs −0.21% [placebo]). Decrease in postprandial insulin at doses ≥1.1 mg suggested improvement in insulin sensitivity. Minimum delay in gastric emptying and body weight reductions numerically greater than placebo (− 3.0 kg vs −0.9 kg) were seen at the highest dose of 2.5 mg. Conclusions Daily doses of RG 7697 for 2 weeks were well tolerated by the majority of patients with T2 D . Pharmacokinetic data supported once‐daily dosing and pharmacodynamic effect displayed dose‐dependent reductions in fasting and postprandial plasma glucose, without increasing the risk of hypoglycaemia.