Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study

Background For patients with type 2 diabetes who do not achieve target glycaemic control with conventional insulin treatment, advancing to a basal-bolus insulin regimen is often recommended. We aimed to compare the efficacy and safety of long-acting glucagon-like peptide-1 receptor agonist dulaglutide with that of insulin glargine, both combined with prandial insulin lispro, in patients with type 2 diabetes. Methods We did this 52 week, randomised, open-label, phase 3, non-inferiority trial at 105 study sites in 15 countries. Patients (aged >= 18 years) with type 2 diabetes inadequately controlled with conventional insulin treatment were randomly assigned (1: 1: 1), via a computer-generated randomisation sequence with an interactive voice-response system, to receive once-weekly dulaglutide 1.5 mg, dulaglutide 0.75 mg, or daily bedtime glargine. Randomisation was stratified by country and metformin use. Participants and study investigators were not masked to treatment allocation, but were unaware of dulaglutide dose assignment. The primary outcome was a change in glycated haemoglobin A(1c) (HbA(1c)) from baseline to week 26, with a 0 .4% non-inferiority margin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01191268. Findings Between Dec 9, 2010, and Sept 21, 2012, we randomly assigned 884 patients to receive dulaglutide 1.5 mg (n=295), dulaglutide 0.75 mg (n=293), or glargine (n=296). At 26 weeks, the adjusted mean change in HbA(1c) was greater in patients receiving dulaglutide 1.5 mg (-1.64% [95% CI -1.78 to -1.50], -17.93 mmol/mol [-19.44 to -16.42]) and dulaglutide 0.75 mg (-1.59% [-1.73 to -1.45], -17.38 mmol/mol [-18.89 to -15.87]) than in those receiving glargine (-1.41% [-1.55 to -1.27], -15.41 mmol/mol [-16.92 to -13.90]). The adjusted mean difference versus glargine was -0.22% (95% CI -0.38 to -0.07, -2.40 mmol/mol [-4.15 to -0.77]; p=0 .005) for dulaglutide 1.5 mg and -0.17% (-0.33 to -0.02, -1.86 mmol/mol [-3.61 to -0.22]; p=0 .015) for dulaglutide 0.75 mg. Five (< 1%) patients died after randomisation because of septicaemia (n=1 in the dulaglutide 1.5 mg group); pneumonia (n=1 in the dulaglutide 0.75 mg group); cardiogenic shock; ventricular fibrillation; and an unknown cause (n=3 in the glargine group). We recorded serious adverse events in 27 (9%) patients in the dulaglutide 1.5 mg group, 44 (15%) patients in the dulaglutide 0.75 mg group, and 54 (18%) patients in the glargine group. The most frequent adverse events, arising more often with dulaglutide than glargine, were nausea, diarrhoea, and vomiting. Interpretation Dulaglutide in combination with lispro resulted in a significantly greater improvement in glycaemic control than did glargine and represents a new treatment option for patients unable to achieve glycaemic targets with conventional insulin treatment.