Contrasting Effects of Lixisenatide and Liraglutide on Postprandial Glycemic Control, Gastric Emptying, and Safety Parameters in Patients With Type 2 Diabetes on Optimized Insulin Glargine With or Without Metformin: A Randomized, Open-Label Trial

摘要

OBJECTIVEThis mechanistic trial compared the pharmacodynamics and safety of lixisenatide and liraglutide in combination with optimized insulin glargine with/without metformin in type 2 diabetes (T2D).RESEARCH DESIGN AND METHODSThis was a multicenter, randomized, open-label, three-arm trial comparing lixisenatide 20 mu g and liraglutide 1.2 and 1.8 mg once daily for 8 weeks in combination with insulin glargine after optimized titration. The primary end point was change from baseline to week 8 in incremental area under the postprandial plasma glucose curve for 4 h after a standardized solid breakfast (AUC PPG(0030-0430 h)). Changes from baseline in gastric emptying, 24-h plasma glucose profile, HbA(1c), fasting plasma glucose (FPG), 24-h ambulatory heart rate and blood pressure, amylase and lipase levels, and adverse events (AEs) were also assessed.RESULTSIn total, 142 patients were randomized and treated. Lixisenatide 20 mu g achieved greater reductions of AUC PPG(0030-0430 h) compared with liraglutide (marginal mean [95% one-sided CI] treatment difference, -6.0 [-7.8] h mmol/L [-108.3 (-140.0) h mg/dL] vs. liraglutide 1.2 mg and -4.6 [-6.3] h mmol/L [-83.0 (-114.2) h mg/dL] vs. liraglutide 1.8 mg; P < 0.001 for both), and gastric emptying was delayed to a greater extent than with liraglutide 1.2 and 1.8 mg (P < 0.001 for treatment comparisons). FPG was unchanged in all treatment arms. At week 8, mean SD HbA(1c) was 6.2 +/- 0.4% (44 +/- 5 mmol/mol), 6.1 +/- 0.3% (44 +/- 4 mmol/mol), and 6.1 +/- 0.3% (44 +/- 4 mmol/mol) for lixisenatide 20 mu g and liraglutide 1.2 and 1.8 mg, respectively. At week 8, both liraglutide doses increased marginal mean +/- SE 24-h heart rate from baseline by 9 +/- 1 bpm vs. 3 +/- 1 bpm with lixisenatide (P < 0.001). Occurrence of symptomatic hypoglycemia was higher with lixisenatide; gastrointestinal AEs were more common with liraglutide. Lipase levels were significantly increased from baseline with liraglutide 1.2 and 1.8 mg (marginal mean +/- SE increase 21 +/- 7 IU/L for both; P < 0.05).CONCLUSIONSLixisenatide and liraglutide improved glycemic control in optimized insulin glargine-treated T2D albeit with contrasting mechanisms of action and differing safety profiles.