Safety and efficacy of once-weekly dulaglutide versus sitagliptin after 2 years in metformin-treated patients with type 2 diabetes (AWARD-5): a randomized, phase III study

R S Weinstock, B Guerci, G Umpierrez, M A Nauck, Z Skrivanek, Z Milicevic, R S Weinstock, B Guerci, G Umpierrez, M A Nauck, Z Skrivanek, Z Milicevic

Abstract

Aims: To compare the once-weekly glucagon-like peptide-1 (GLP-1) receptor dulaglutide with the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin after 104 weeks of treatment.

Methods: This AWARD-5 study was a multicentre, double-blind trial that randomized participants to dulaglutide (1.5 or 0.75 mg) or sitagliptin 100 mg for 104 weeks or placebo (reported separately) for 26 weeks. Change in glycated haemoglobin (HbA1c) concentration from baseline was the primary efficacy measure. A total of 1098 participants with HbA1c concentrations ≥7.0% (≥53.0 mmol/mol) and ≤9.5% (≤80.3 mmol/mol) were randomized, and 657 (59.8%) completed the study. We report results for dulaglutide and sitagliptin at the final endpoint.

Results: Changes in HbA1c at 104 weeks were (least squares mean ± standard error) -0.99 ± 0.06% (-10.82 ± 0.66 mmol/mol), -0.71 ± 0.07% (-7.76 ± 0.77 mmol/mol) and -0.32 ± 0.06% (-3.50 ± 0.66 mmol/mol) for dulaglutide 1.5 mg, dulaglutide 0.75 mg and sitagliptin, respectively (p < 0.001, both dulaglutide doses vs sitagliptin). Weight loss was greater with dulaglutide 1.5 mg (p < 0.001) and similar with 0.75 mg versus sitagliptin (2.88 ± 0.25, 2.39 ± 0.26 and 1.75 ± 0.25 kg, respectively). Gastrointestinal adverse events were more common with dulaglutide 1.5 and 0.75 mg versus sitagliptin (nausea 17 and 15% vs 7%, diarrhoea 16 and 12% vs 6%, vomiting 14 and 8% vs 4% respectively). Pancreatic, thyroid, cardiovascular and hypersensitivity safety were similar across groups.

Conclusions: Dulaglutide doses provided superior glycaemic control and dulaglutide 1.5 mg resulted in greater weight reduction versus sitagliptin at 104 weeks, with acceptable safety.

Trial registration: ClinicalTrials.gov NCT00734474.

Keywords: diabetes; dulaglutide; sitagliptin.

© 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Study design and participant disposition during the AWARD‐5 trial. (A) Study design and (B) participant disposition. aRandomization. bPrimary endpoint. cFinal endpoint, d Placebo period lasted for 26 weeks, followed by a switch to sitagliptin to keep the arm blinded. Only participants assigned to selected dulaglutide doses (1.5 and 0.75 mg) and comparators continued forward in the study and are represented in this figure. Adverse events included cases of severe or worsening hyperglycaemia based on prespecified criteria provided in Table S2 ‘Physicians decision’ and ‘lack of efficacy’ may have included cases of inadequate glucose control that did not meet these prespecified criteria.
Figure 2
Figure 2
Efficacy measures through 104 weeks. (A) Change in glycated haemoglobin (HbA1c) from baseline at 104 weeks, analysis of covariance LOCF. (B) HbA1c over time, mixed‐effects model for repeated measures (MMRM). (C) Percentage of participants achieving (HbA1c) targets at 104 weeks, logistic regression LOCF. (D) Change in fasting plasma glucose (FPG) over time, MMRM. (E) Change in weight over time, MMRM. Data presented are least squares (LS) means ± standard error (s.e.), with the exception of panel (C). #p < 0.05 versus sitagliptin; ##p < 0.001 vs sitagliptin.
Figure 3
Figure 3
Percentage of participants experiencing (A) nausea, (B) diarrhoea and (C) vomiting by week.

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