Propensity-score-matched comparative analyses of simultaneously administered fixed-ratio insulin glargine 100 U and lixisenatide (iGlarLixi) vs sequential administration of insulin glargine and lixisenatide in uncontrolled type 2 diabetes

Abstract

Aim: To conduct two exploratory analyses to compare indirectly the efficacy and safety of simultaneous administration of insulin glargine 100 U (iGlar) and the glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide (Lixi) as a single-pen, titratable, fixed-ratio combination (iGlarLixi [LixiLan trials]) vs sequential administration of iGlar + Lixi (GetGoal Duo trials) in people with type 2 diabetes (T2D).

Materials and methods: Propensity-score matching based on baseline covariates was used to compare simultaneous iGlarLixi vs sequential combination of iGlar + Lixi with the addition of Lixi in patients who did not reach the glycated haemoglobin (HbA1c) goal of <53 mmol/mol (<7%) after short-term use of iGlar alone (LixiLan-O vs GetGoal Duo-1 comparison) and vs sequential addition of Lixi in uncontrolled patients after long-term use of iGlar alone (LixiLan-L vs GetGoal Duo-2 comparison).

Results: In both analyses, compared with sequential iGlar + Lixi, iGlarLixi led to significantly greater HbA1c reductions with associated weight loss and significantly more patients reaching target HbA1c <53 mmol/mol despite lower insulin doses. Symptomatic hypoglycaemia rates were similar, despite greater HbA1c reductions with iGlarLixi. Lower rates of gastrointestinal adverse events were observed with iGlarLixi, probably as a result of the more gradual titration of Lixi with iGlarLixi.

Conclusions: Indirect propensity-score-matched exploratory comparisons suggest that early treatment with a simultaneous, titratable, fixed-ratio combination of basal insulin and a GLP-1RA (iGlarLixi) may be more effective and possess better gastrointestinal tolerability than a sequential approach of adding a GLP-1RA in patients with uncontrolled T2D initiating or intensifying basal insulin therapy.

Trial registration: ClinicalTrials.gov NCT00975286 NCT01768559 NCT02058160 NCT02058147.

Keywords: GLP-1; glycaemic control; insulin therapy; type 2 diabetes.

Conflict of interest statement

J.R. has served on advisory panels and as a consultant for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Intarcia, Janssen, Novo Nordisk and Sanofi; and has received research support from AstraZeneca, Boehringer Ingelheim, Bristol‐Myers Squibb, Eli Lilly, Genentech, GlaxoSmithKline, Intarcia, Janssen, Lexicon, Merck, Novartis, Novo Nordisk, Pfizer and Sanofi. Y.H. has served on advisory panels and as a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Regeneron and Sanofi, has received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol‐Myers Squibb, Gan & Lee, Grifolis, Hamni, Intarcia, Lexicon, Merck, Novo Nordisk and Sanofi, and has served on a speakers' bureau for Amarin, Amgen, AstraZeneca, Janssen, Merck, Novo Nordisk, Regeneron and Sanofi. J.V. has served on a speakers' bureau for Ethicon, Eli Lilly, Medtronic, MSD, Novo Nordisk and Sanofi, has served on advisory panels for Jansen, Novo Nordisk and Sanofi, and has served as a consultant for Medtronic. F.J.A.B. has served on advisory panels for Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, LifeScan, Medtronic, Merck, Novartis, Novo Nordisk, Pfizer, Roche and Sanofi, and has received research support from Abbott, AstraZeneca, Boehringer Ingelheim, Bayer, Eli Lilly, GlaxoSmithKline, LifeScan, Merck, Novo Nordisk, Pfizer, Sanofi and Servier. F.G. has served on advisory panels for AstraZeneca, Novo Nordisk and Sanofi, has served as a consultant for AstraZeneca, Boehringer Ingelheim, Lifescan, Roche Diabetes Care, Sanofi and Takeda, and has received research support from Eli Lilly and Takeda. M. L. has served as a consultant for BDM Consulting, Inc. and Sanofi. R.P. is an employee and stock/shareholder of Sanofi. J.M. has served on a speakers' bureau for AstraZeneca, Berlin‐Chemie, Boehringer Ingelheim, Bristol‐Myers Squibb, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Novo Nordisk, Novartis, Servier and Sanofi‐Aventis, has served on advisory panels for AstraZeneca, Bristol‐Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi‐Aventis, and has received research support from Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk and Sanofi‐Aventis.

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1

End‐of‐study outcomes including A, change in glycated haemoglobin (HbA1c), B, weight change and C, absolute mean insulin glargine 100 U (iGlar) dose at end of treatment period. n indicates number of patients included in analysis (modified intention‐to‐treat [mITT] population); there were small variations in the number of patients meeting the criteria for inclusion in LixiLan and GetGoal Duo mITT populations based on variable measured. *No least squares (LS) mean difference or P value has been included for the comparison of the final mean iGlar dose at end of treatment period in LixiLan‐L vs GetGoal Duo‐2 as mean insulin doses showed significant difference at baseline (66 ± 32 U vs 35 ± 9 U; P < 0.0001). Lixi, lixisenatide

Figure 2

A, Time (95% CI) to first glycated haemoglobin (HbA1c) value

Figure 3

Occurrence of symptomatic hypoglycaemia (safety population). Symptomatic hypoglycaemia defined as plasma glucose ≤3.9 mmol/L (≤70 mg/dL). iGlar, insulin glargine 100 U; Lixi, lixisenatide