Addition of exenatide BID to insulin glargine: a post-hoc analysis of the effect on glycemia and weight across a range of insulin titration

Abstract

Background and objective:

In a 30 week, double-blind, randomized, controlled Phase 3 study in patients with type 2 diabetes mellitus, the addition of fixed-dose exenatide twice daily (BID) to titrated insulin glargine resulted in significant glycated hemoglobin (HbA_1c) lowering and weight loss without increased hypoglycemia risk versus titrated insulin glargine alone. Because individualized insulin titration contributed to these results, this post-hoc analysis examined the results in the context of the degree of insulin titration that occurred.

Methods:

Subjects on pre-existing insulin glargine (with or without oral antidiabetes agents) were randomized to placebo (n = 123) or exenatide BID (n = 138; 5 µg for 4 weeks, then 10 µg ongoing). Insulin glargine was titrated in both arms per the Treat-to-Target algorithm. Tertiles (T1, T2, T3) were based on change in insulin dose from baseline to endpoint. Change in HbA_1c, hypoglycemia risk, and weight gain were assessed per insulin dose tertile.

Results:

The population comprised adult patients (mean age = 59 y) with type 2 diabetes and an HbA_1c level between 7.0% and 10.5% (mean HbA_1c = 8.4%). Insulin titration ranged from modest reductions in T1 to substantial increases in T3. Greater improvements in HbA_1c were demonstrated with exenatide BID versus placebo in all tertiles (statistically significant in T2 and T3). With exenatide BID, more subjects achieved HbA_1c <7.0% vs. placebo: T1, 44% vs. 29% (P = not significant); T2, 65% vs. 26%; T3, 54% vs. 29% (P < 0.05 for T2 and T3). Incidence of hypoglycemia was numerically lower with exenatide BID in all tertiles. Adjunctive exenatide BID was associated with statistically significantly greater weight loss (T1, T2) or mitigation of weight gain (T3) compared with placebo. Rates of nausea (42% vs. 8%), diarrhea (18% vs. 7%), and vomiting (18% vs. 4%) were higher with exenatide BID than with placebo and did not vary by tertile.

Conclusions:

Addition of fixed-dose exenatide BID to optimized insulin glargine, regardless of the extent of insulin titration, significantly improved glycemia without increasing hypoglycemia risk, while mitigating insulin-induced weight gain in this post-hoc analysis.

Trial registration: ClinicalTrials.gov identifier: NCT00765817.

Keywords::

• Diabetes
• Exenatide
• GLP-1 receptor agonist
• Insulin

Transparency

Declaration of funding

The design and conduct of the study were supported by Amylin Pharmaceuticals, San Diego, CA, USA, and Eli Lilly and Company, Indianapolis, IN, USA. Editorial support was provided by Bristol-Myers Squibb, Princeton, NJ, USA, and AstraZeneca, Wilmington, DE, USA.

Declaration of financial/other relationships

J.B.B. has disclosed that he has received grant/research funds from Amylin Pharmaceuticals Inc., Andromeda, AstraZeneca, Boehringer Ingelheim, GmbH & Co. KG, Bristol-Myers Squibb Company, Eli Lilly and Company, GI Dynamics, GlaxoSmithKline, Halozyme Therapeutics, F. Hoffmann-La Roche Ltd, Intarcia Therapeutics, Johnson & Johnson, Lexicon, Macrogenics, Medtronic, Merck, Novo Nordisk A/S, Orexigen Therapeutics Inc., Osiris Therapeutics Inc., Pfizer Inc., Sanofi, Takeda, and ToleRx. He is a contracted advisor to Amylin Pharmaceuticals Inc., Andromeda, Astellas, AstraZeneca, Bayhill Therapeutics, Inc., Boehringer Ingelheim GmbH & Co. KG, Bristol-Myers Squibb Company, Catabasis, Cebix Inc., CureDM, Diartis Pharmaceuticals, Elcelyx Therapeutics Inc., Eli Lilly and Company, Exsulin, Genentech, GI Dynamics, GlaxoSmithKline, Halozyme Therapeutics, F. Hoffmann-La Roche Ltd, Intarcia Therapeutics, Johnson & Johnson, Lexicon, LipoScience, Macrogenics, Medtronic, Merck, Metabolic Solutions Development Co., Metabolon Inc., Metavention, Novan, Novo Nordisk A/S, Orexigen Therapeutics Inc., Osiris Therapeutics Inc., Pfizer Inc., PhaseBio Pharmaceuticals Inc., Quest Diagnostics, Rhythm Pharmaceuticals, Sanofi, Spherix Inc., Takeda, ToleRx, Transpharma Medical Ltd, TransTech Pharma, Veritas, and Verva. JH has disclosed that she is a former employee of Amylin and Bristol-Myers Squibb and is a current employee of AstraZeneca. L.M. has disclosed that she is a former employee of Amylin and Bristol-Myers Squibb, and is a current consultant/advisor for Bristol-Myers Squibb. S.M. has disclosed that he is a former employee of Amylin and Bristol-Myers Squibb. R.P. has disclosed that he is a former employee of Amylin and Bristol-Myers Squibb, and a former Amylin shareholder. M.W. has disclosed that he is a former employee of Amylin and Bristol-Myers Squibb and former stockholder of Amylin.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

The authors thank Meredith Rogers MS, of Bristol-Myers Squibb, for providing writing and editorial assistance. Dr. Buse’s effort was supported in part by the National Center for Research Resources, Grant UL1RR025747, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000083. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Previous presentation: Preliminary results were presented at EASD 2012 – Wintle M, Pencek R, Han J et al. Addition of fixed-dose exenatide to insulin glargine therapy improved glycaemic control without increasing hypoglycaemia or weight gain across a range of insulin titration. Diabetologia 2012;55[Suppl 1]:Abstr #804.