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. Issue 11 (30th July 2018)

• Record Type: Journal Article
• Authors: Kazierad, David J.; Chidsey, Kristin; Somayaji, Veena R.; Bergman, Arthur J.; Calle, Roberto A.
• Is Part Of: Diabetes, obesity & metabolism. Volume 20:Issue 11(2018)
• Page Start: 2608
• Page End: 2616
• Publication Date: 2018-07-30
• Subjects: glucagon receptor -- metformin -- pharmacodynamics -- phase 2 studies; Diabetes -- Periodicals; Obesity -- Periodicals; Metabolism -- Disorders -- Periodicals; Clinical pharmacology -- Periodicals; 616.462
• DOI: 10.1111/dom.13440
• Languages: English
• ISSNs: 1462-8902

Abstract

Abstract : 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.