title: 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.
abstract: 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 A1c (HbA1c) 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.
  
  
  RESULTS
  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 HbA1c 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Eli Lilly and Company.
authors.affiliation: Department of Endocrinology, Ochsner Medical Center, New Orleans, LA, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Blonde
authors.affiliation: Endocrine and Diabetes Center, Karlstad Hospital, Örebro University, Örebro, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Jendle
authors.affiliation: Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Jorge
authors.initials: J
authors.lastname: Gross
authors.affiliation: Section of Endocrinology and Metabolism, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Woo
authors.affiliation: Lilly Diabetes, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Honghua
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Lilly Diabetes, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Jessie L
authors.initials: JL
authors.lastname: Fahrbach
authors.affiliation: Lilly Research Laboratories, Vienna, Austria. Electronic address: milicevic_zvonko@lilly.com.
authors.forename: Zvonko
authors.initials: Z
authors.lastname: Milicevic
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D004763:Glucagon-Like Peptides / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006442:Glycated Hemoglobin / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage*; D000069036:Insulin Glargine; D061268:Insulin Lispro / Q000008:administration & dosage*; D049528:Insulin, Long-Acting / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D019518:Postprandial Period; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004763:Glucagon-Like Peptides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007141:Immunoglobulin Fc Fragments; D000069036:Insulin Glargine; D061268:Insulin Lispro; D049528:Insulin, Long-Acting; D011993:Recombinant Fusion Proteins; C555680:dulaglutide