Premium
Efficacy and safety of the glucagon receptor antagonist PF‐06291874: A 12‐week, randomized, dose‐response study in patients with type 2 diabetes mellitus on background metformin therapy
Author(s) -
Kazierad David J.,
Chidsey Kristin,
Somayaji Veena R.,
Bergman Arthur J.,
Calle Roberto A.
Publication year - 2018
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.13440
Subject(s) - metformin , medicine , placebo , endocrinology , type 2 diabetes , type 2 diabetes mellitus , diabetes mellitus , gastroenterology , insulin , alternative medicine , pathology
Aims To conduct a dose‐response assessment of the efficacy and safety of the glucagon receptor antagonist PF‐06291874 in adults with type 2 diabetes (T2DM) using stable doses of metformin. Materials and Methods This randomized, double‐blind, statin‐stratified, placebo‐controlled, 4‐arm, parallel‐group study was conducted in patients with T2DM who were receiving background metformin. After an 8‐week, non‐metformin oral antidiabetic agent washout period, 206 patients were randomized to placebo or PF‐06291874 (30, 60 or 100 mg once daily) for 12 weeks. Glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG) and safety endpoints were assessed at baseline and post baseline. Results Dose‐dependent mean reductions from baseline in HbA1c for PF‐06291874 ranged from −0.67% (−7.29 mmol/mol) to −0.93% (−10.13 mmol/mol), and for FPG from −16.6 to −33.3 mg/dL after 12 weeks of dosing. The incidence of hypoglycaemia was low and was similar between groups receiving PF‐06291874 and placebo. Small, non‐dose‐dependent increases in LDL cholesterol (<10%) and blood pressure (BP) (systolic BP > 2 mm Hg; diastolic BP > 1 mm Hg) were observed with PF‐06291874. Modest non‐dose‐dependent median increases were observed across PF‐06291874 groups at 12 weeks for alanine aminotransferase (range, 37.6‐48.7 U/L vs placebo) and aspartate aminotransferase (range, 33.3‐36.6 U/L vs placebo); these were not associated with bilirubin changes. Small increases were observed in body weight (< 0.5 kg) in each PF‐06291874 group vs placebo. Conclusions In patients with T2DM, PF‐06291874 significantly lowered HbA1c and glucose, was well tolerated and carried a low risk of hypoglycaemia. Small, non‐dose‐related increases in BP, lipids and hepatic transaminases were observed.