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

Abstract

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 mg 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. 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 6 SD HbA 1c was 6.2 6 0.4% (44 6 5 mmol/mol), 6.1 6 0.3% (44 6 4 mmol/mol), and 6.1 6 0.3% (44 6 4 mmol/mol) for lixisenatide 20 mg and liraglutide 1.2 and 1.8 mg, respectively. At week 8, both liraglutide doses increased marginal mean 6 SE 24-h heart rate from baseline by 9 6 1 bpm vs. 3 6 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 6 SE increase 21 6 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.

Reduction of postprandial glucose by lixisenatide vs sitagliptin treatment in Japanese patients with type 2 diabetes on background insulin glargine: A randomized phase IV study (NEXTAGE Study)

“…Our data thus lend support to the theory that incretin‐based therapies (and GLP‐1 receptor agonists in particular) appear well‐suited for use in Asian and Japanese patients with T2D,28, 30 as these populations are predisposed to insulin deficiency rather than insulin resistance, which may manifest via a profound underlying GLP‐1 insufficiency 40. The findings of the present study are also consistent with studies in Western patients with T2D inadequately controlled on metformin or on optimized Gla‐100, as once‐daily pre‐breakfast lixisenatide was associated with significantly greater reductions in PPG, postprandial C‐peptide, and postprandial glucagon relative to pre‐breakfast liraglutide 31, 32. Gastric emptying was also substantially slower in the lixisenatide than the liraglutide study group 31, 32…”

“…Indeed, greater exposure to postprandial C‐peptide (and hence insulin) was observed in the sitagliptin group than in the lixisenatide group, which is consistent with the inverse association of C‐peptide levels with glycaemic variability and with post‐meal glucose rise in T2D (both of which were higher in the sitagliptin group) 38. In previous studies, there was a direct relationship between PPG AUC after breakfast and gastric emptying with lixisenatide 20 µg once daily,32, 39 which was not observed with placebo 39…”

“…Lixisenatide was associated with a pronounced improvement in postprandial hyperglycaemia compared with placebo in these studies,25, 26, 27, 29 including studies in Asian patients exclusively 28, 30. Further, lixisenatide had a greater postprandial effect on blood glucose levels than the longer‐acting GLP‐1 receptor agonist liraglutide in patients with T2D insufficiently controlled on metformin, with or without insulin glargine 31, 32…”

Benefits of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide, Versus Insulin Glargine and Lixisenatide Monocomponents in Type 2 Diabetes Inadequately Controlled on Oral Agents: The LixiLan-O Randomized Trial

“…Lixi (Lyxumia; Sanofi, Paris, France) is a once-daily, prandial GLP-1 RA with a predominant PPG-lowering effect mainly through delayed gastric emptying and reduction of glucagon release (11). Lixi and insulin glargine (iGlar) 100 units have similar physicochemical features, allowing both components to be mixed as a defined fixed-ratio iGlar:Lixi formulation (iGlarLixi or LixiLan) and delivered through a single daily injection.…”

Prandial Options to Advance Basal Insulin Glargine Therapy: Testing Lixisenatide Plus Basal Insulin Versus Insulin Glulisine Either as Basal-Plus or Basal-Bolus in Type 2 Diabetes: The GetGoal Duo-2 Trial

“…Lixisenatide (Lyxumia; Sanofi, Paris, France) is a oncedaily prandial GLP-1 RA with robust postprandial glucose (PPG)-lowering effect, predominantly via delayed gastric emptying and glucose-dependent reductions in glucagon release (6)(7)(8)(9).…”