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Abstract
Objective: The LixiLan clinical trials of insulin glargine (iGlar)/lixisenatide fixed-ratio combination (iGlarLixi) investigated the safety and efficacy of iGlarLixi versus iGlar: LixiLan-O (NCT02058147) in patients with type 2 diabetes (T2D) inadequately controlled on oral antidiabetes drugs (OADs) and LixiLan-L (NCT02058160) in patients with T2D inadequately controlled on basal insulin ± OADs. In these two trials, both iGlar and iGlarLixi were titrated to a maximum (capped) dose of 60 units. We evaluated whether this may have affected the reported glycemic efficacy of iGlar, and the glycemic differences observed between treatment with iGlarLixi and iGlar.
Methods: The efficacy of iGlar under uncapped conditions was simulated in a two-step approach. First, a model characterizing the relationship between iGlar dose and fasting self-measured plasma glucose (f-SMPG) was developed. Then, the relationship between glycated hemoglobin A1c (A1C) and f-SMPG was established to translate simulated f-SMPG responses to A1C responses.
Results: Most patients achieved stable f-SMPG at ∼60 units/day, with no further reduction with increasing insulin dose. In comparisons of observed/capped and simulated/uncapped changes in mean A1C from baseline to Week 30, iGlarLixi consistently demonstrated treatment benefit compared with iGlar. Uncapping resulted in a slightly higher mean iGlar dose in both LixiLan-O (+0.72 units) and LixiLan-L (+2.1 units), without marked impact on f-SMPG or A1C change from baseline.
Conclusion: Uncapping the iGlar dose in LixiLan-O and LixiLan-L would not have led to significant improvements in mean A1C reduction in the iGlar arm, supporting the conclusion that iGlarLixi provides additional, clinically relevant glycemic control versus iGlar alone.
Transparency
Declaration of funding
This study was supported by funding from Sanofi US, Inc. All authors contributed equally to the interpretation of results and content of the manuscript.
Declaration of financial/other relationships
W.S., E.N. and E.S. have disclosed that they are employees and stock/shareholders of Sanofi. R.B., M.L. and Z.M. have disclosed that they are employees of Sanofi. J.P.F. has disclosed that he has sat on advisory panels for AstraZeneca and Sanofi; is a consultant for AstraZeneca, Bristol-Myers Squibb Company, Novo Nordisk Inc. and Sanofi; provides research support for AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb Company, Eli Lilly and Company, Ionis Pharmaceuticals, Janssen Pharmaceuticals, Lexicon Pharmaceuticals, Johnson and Johnson, Ligand Pharmaceuticals, Merck & Co., Mylan, Novartis AG, Novo Nordisk, Pfizer, Sanofi, Theracos and VtV Therapeutics; and has participated in a speakers bureau for Sanofi.
CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Acknowledgements
The authors would like to thank Dr Zhaoling Meng, Dr Yujun Wu, Dr John Newton and Dr Jaap Madema for their input during earlier stages of data interpretation for this publication.
The authors received writing/editorial support in the preparation of this manuscript provided by Michael van der Veer PhD and Rasilaben Vaghjiani PhD of Excerpta Medica, funded by Sanofi US, Inc.