Pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of the novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist RG7697 in people with type 2 diabetes mellitus.
AIMS
To investigate the pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of RG7697, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist, in patients with type 2 diabetes mellitus (T2D).


METHODS
A total of 56 patients with T2D received once-daily subcutaneous (s.c.) injection of RG7697 (0.25-2.5 mg) or placebo for 14 days in a randomized, double-blind, dose-escalation study. Adverse events (AEs), vital signs, ECGs 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 RG7697 were well tolerated by the majority of participants with T2D. The most frequently reported AEs with RG7697 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 RG7697 for 2 weeks were well tolerated by the majority of patients with T2D. 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.
['Schmitt|Christophe|C|0000-0001-8001-5584', 'Portron|Agnès|A|', 'Jadidi|Shirin|S|', 'Sarkar|Neena|N|', 'DiMarchi|Richard|R|']
D000328:Adult D000368:Aged D001786:Blood Glucose D003924:Diabetes Mellitus, Type 2 D004305:Dose-Response Relationship, Drug D004311:Double-Blind Method D015507:Drugs, Investigational D005260:Female D005749:Gastric Inhibitory Polypeptide D052216:Glucagon-Like Peptide 1 D006801:Humans D007004:Hypoglycemic Agents D008297:Male D008875:Middle Aged
pharmacodynamics pharmacokinetics safety type 2 diabetes mellitus NNC0090-2746 RG7697, RO6811135 dual GIP/GLP-1 agonist