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1
Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
2
National Institute of Diabetes, Nutrition and Metabolic Diseases, "NC Paulescu", Bucharest, Romania.
3
National Research Institute, Los Angeles, California.
4
2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
5
Division of Endocrinology, Diabetes & Metabolic Diseases, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania.
6
AstraZeneca, Gaithersburg, Maryland.
7
Dallas Diabetes Research Center at Medical City, Dallas, Texas.
1
Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
2
National Institute of Diabetes, Nutrition and Metabolic Diseases, "NC Paulescu", Bucharest, Romania.
3
National Research Institute, Los Angeles, California.
4
2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
5
Division of Endocrinology, Diabetes & Metabolic Diseases, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania.
6
AstraZeneca, Gaithersburg, Maryland.
7
Dallas Diabetes Research Center at Medical City, Dallas, Texas.
This multicentre, double-blind study (ClinicalTrials.gov identifier:
NCT02229383
) randomized (1:1) patients with persistent hyperglycaemia after an 8-week titration phase (glycated haemoglobin [HbA1c] 7.0%-10.5% [53-91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2-hour postprandial glucose, and mean daily IG dose.
Of 464 randomized patients (mean: age, 58 years; HbA1c, 8.5% [69 mmol/mol]; diabetes duration, 11.3 years), 91% completed 28 weeks. Exenatide QW + IG vs placebo + IG significantly reduced HbA1c (least-squares mean difference, -0.73% [-8.0 mmol/mol]; 95% confidence interval, -0.93%, -0.53% [-10.2, -5.8 mmol/mol]; P < .001; final HbA1c, 7.55% [59 mmol/mol] and 8.24% [67 mmol/mol], respectively); body weight (-1.50 kg; -2.17, -0.84; P < .001); and 2-hour postprandial glucose (-1.52 mmol/L [-27.5 mg/dL]; -2.15, -0.90 [-38.7, -16.2]; P < .001). Significantly more exenatide QW + IG-treated patients vs placebo + IG-treated patients reached HbA1c <7.0% (<53 mmol/mol) (32.5% vs 7.4%; P < .001); daily IG dose increased by 2 and 4 units, respectively. Gastrointestinal and injection-site adverse events were more frequent with exenatide QW + IG (15.1% and 7.8%, respectively) than with placebo + IG (10.8% and 3.0%, respectively); hypoglycaemia incidence was similar between the exenatide QW + IG (29.7%) and placebo + IG (29.0%) groups, with no major hypoglycaemic events.
C. G. served as the international coordinating investigator in the trial discussed in this paper, and has participated in scientific advisory boards of and has received consulting fees from Alfa Wasserman, AstraZeneca, Bayer AG, Berlin‐Chemie Mennarini, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi. J. P. F. has received research support from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol‐Myers Squibb, Eli Lilly, IONIS, Janssen, Johnson and Johnson, Ligand, Merck, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi, Theracos and vTv Therapeutics, and has participated in scientific advisory boards of and has received consulting fees from AstraZeneca, Bristol‐Myers Squibb, Novo Nordisk, Sanofi and Theracos. A. S. has no conflicts of interest to report. S. J. has received consulting fees from AstraZeneca, Eli Lilly and Janssen. H. W. is a consultant for AstraZeneca. E. H. is an employee of and stockholder in AstraZeneca. J. R. has received research support from AstraZeneca, Boehringer Ingelheim, Bristol‐Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Hanmi, Intarcia, Janssen, Lexicon, Merck, Novo Nordisk, Pfizer and Sanofi, and has served on advisory boards of or received consulting honoraria from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Intarcia, Janssen, Novo Nordisk and Sanofi.
Patient disposition and study flow. *One patient did not enter the IG titration phase as the patient was not using the IG dose necessary to be eligible for randomization; however, the patient was randomized and approved to continue in the study. Abbreviations: IG, insulin glargine; ITT, intention‐to‐treat; QW, once weekly
A, Mean HbA1c from screening to week 28. B, Proportion of patients achieving HbA1c <7.0% (<53 mmol/mol) and HbA1c <7.0% (<53 mmol/mol) without body weight gain at week 28 and without hypoglycaemia over 28 weeks. C, LSM change in 2‐hour PPG from baseline to week 28. D, Mean FPG from screening to week 28. E, Mean insulin dose from screening to week 28. F, LSM change in body weight from screening to week 28. *Nominal
P
< .001 based on mixed‐effects model for repeated measures analysis of change from baseline, including treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0% [<75 or ≥75 mmol/mol]), baseline sulphonylurea use stratum, week and treatment‐by‐week interaction as fixed factors and baseline value as a covariate. †Screening visit (S) was a minimum of 7 days and a maximum of 14 days before the week −8 visit. Values for HbA1c, FPG and IG dose are observed values at each time point. Error bars show mean ± SE. These analyses exclude measurements after initiation of rescue therapy or after premature discontinuation of study treatment. To convert 2‐hour PPG or FPG from mmol/L to mg/dL, multiply by 18. Abbreviations: FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; IG, insulin glargine; LSM, least‐squares mean; PPG, postprandial glucose; QW, once weekly; SE, standard error
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