Long-term efficacy and safety of combined insulin and glucagon-like peptide-1 therapy: Evidence from the LEADER trial

Abstract

Aim: Glucagon-like peptide-1 receptor agonist (GLP-1RA) and insulin combination therapy is an effective treatment option for type 2 diabetes, but long-term data are lacking. The aim was to assess the long-term efficacy of the GLP-1RA liraglutide in subgroups by insulin use in the LEADER trial.

Materials and methods: LEADER assessed cardiovascular (CV) safety and efficacy of liraglutide (1.8 mg) versus placebo (plus standard of care therapy) in 9340 patients with type 2 diabetes and high risk of CV disease, for up to 5 years. We analyzed CV events, metabolic parameters and hypoglycaemia post hoc in three subgroups by baseline insulin use (basal-only insulin, other insulin or no insulin). Insulin was a non-random treatment allocation as part of standard of care therapy.

Results: At baseline, 5171 (55%) patients were not receiving insulin, 3159 (34%) were receiving basal-only insulin and 1010 (11%) other insulins. Insulin users had a longer diabetes duration and slightly worse glycaemic control (HbA1c) than the no-insulin subgroup. Liraglutide reduced HbA1c and weight versus placebo in all three subgroups (P < .001), and severe hypoglycaemia rate in the basal-only insulin subgroup. The need for insulin was less with liraglutide. CV risk reduction with liraglutide was similar to the main trial results in the basal-only and no-insulin subgroups.

Conclusions: In patients on insulin, liraglutide improved glycaemic control, weight and need for insulin versus placebo, for at least 36 months with no increased risk of severe hypoglycaemia, while maintaining CV safety/efficacy, supporting the combination of liraglutide and insulin for management of type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT01179048.

Keywords: glucagon-like peptide-1 analogue; insulin analogues; insulin therapy; liraglutide; type 2 diabetes.

Conflict of interest statement

C.J.T. has served on advisory panels for MSD and Novo Nordisk; and speaker's bureau for Novo Nordisk. He has received research support from AstraZeneca. S.J. has served on advisory panels for AstraZeneca, Boehringer Ingelheim, MSD, and Novo Nordisk; and on speakers' bureau of AstraZeneca, Boehringer Ingelheim, Eli Lilly, Menarini Group, MSD, Novo Nordisk (and Foundation), and Roche. C.D. has served on an advisory panel for Medscape, and has acted as a consultant for Novo Nordisk. He has received research support from Merck & Co. S.C.B. has received research grants (includes principal investigator, collaborator or consultant and pending grants as well as grants already received) from Healthcare and Research Wales (Welsh Government) and Novo Nordisk. He has received other research support from Healthcare and Research Wales (Welsh Government) and honoraria from Novo Nordisk, Sanofi, Lilly, Boehringer Ingelheim, and Merck. He has an ownership interest in Gycosmedia (diabetes online news service). J.B.B. has been an advisor, with all fees paid to the University of North Carolina, for Adocia, AstraZeneca, Dance Biopharm, Eli Lilly, MannKind, NovaTarg, Novo Nordisk, Senseonics, and vTv Therapeutics. He has received grant support from Novo Nordisk, Sanofi, and vTv Therapeutics. He is a consultant to Cirius Therapeutics Inc., CSL Behring, and Neurimmune AG. He holds stock options in Mellitus Health, PhaseBio, and Stability Health. He is supported by a grant from the National Institutes of Health (UL1TR002489). M.A.N. has served on advisory boards or consulted for AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Fractyl, GlaxoSmithKline, Intarcia, Menarini/Berlin Chemie, Merck, Sharp & Dohme, and Novo Nordisk. His institution has received grant support from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., GlaxoSmithKline, Intarcia, Menarini/Berlin‐Chemie, Merck, Sharp & Dohme, Novartis Pharma, and Novo Nordisk A/S. He has served on speakers' bureau of AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., GlaxoSmithKline, Menarini/Berlin Chemie, Merck, Sharp & Dohme, Novo Nordisk A/S, and Sun Pharma. J.R.P. is Chair of Clinical Studies Group 6 for Diabetes UK. He has served on advisory boards for AstraZeneca and Novo Nordisk, and has acted as a consultant for Novo Nordisk, and as a speaker for Pfizer. He has received research support from Merck, Itamar Medical, and Janssen Pharmaceuticals. He has served as a member of endpoint committees for Boehringer Ingelheim, Applied Clinical Intelligence, Bayer, and Quintiles. N.R.P. has received personal speaker fees from Servier, Takeda, and Novo Nordisk; and has served on advisory boards for AstraZeneca and Novo Nordisk (in relation to type 2 diabetes). He has received research grants for his research group relating to type 2 diabetes from Diabetes UK, NIHR EME, Julius Clinical, and the British Heart Foundation, with a pending grant from Novo Nordisk. R.E.P. has received research grants from Gilead Sciences, Lexicon Pharmaceuticals, Ligand Pharmaceuticals Inc., Lilly, Merck, Novo Nordisk, Sanofi‐Aventis US LLC, and Takeda; has acted as a speaker for AstraZeneca, Novo Nordisk, and Takeda; and as a consultant for AstraZeneca, Boehringer Ingelheim, Eisai, Inc., GlaxoSmithKline, Janssen Scientific Affairs LLC, Ligand Pharmaceuticals Inc., Lilly, Merck, Novo Nordisk, Pfizer, and Takeda. All payments are made directly to his employer (AdventHealth). H.V.B.K.S., H.B.‐T. and E.S. are full‐time employees of Novo Nordisk. H.V.B.K.S. and H.B.‐T. also hold stocks in Novo Nordisk. B.Z. has received consulting fees from Merck, Novo Nordisk, Sanofi‐Aventis, Eli Lilly, AstraZeneca, Janssen, and Boehringer Ingelheim.

© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1

Change in HbA1c from baseline in liraglutide and placebo‐treatment groups, according to baseline insulin use: A, basal‐only insulin, B, other insulin and C, no insulin

Figure 2

Risk of first major adverse cardiovascular event with liraglutide versus placebo, according to subgroups by insulin use. IU, international unit; MACE, major adverse cardiovascular events; N, number of patients analyzed. *Patients not treated with insulin at baseline, censored if initiating insulin before MACE. †P‐value for interaction between randomized treatment and any insulin/no‐insulin subgroups. Time to first MACE with liraglutide versus placebo analyzed using a Cox proportional‐hazards model with treatment as a covariate