title: Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes.
abstract: BACKGROUND
  A fixed-ratio combination of the basal insulin analogue insulin degludec and the glucagon-like peptide-1 (GLP-1) analogue liraglutide has been developed as a once-daily injection for the treatment of type 2 diabetes. We aimed to compare combined insulin degludec-liraglutide (IDegLira) with its components given alone in insulin-naive patients.
  
  
  METHODS
  In this phase 3, 26-week, open-label, randomised trial, adults with type 2 diabetes, HbA1c of 7-10% (inclusive), a BMI of 40 kg/m(2) or less, and treated with metformin with or without pioglitazone were randomly assigned (2:1:1) to daily injections of IDegLira, insulin degludec, or liraglutide (1·8 mg per day). IDegLira and insulin degludec were titrated to achieve a self-measured prebreakfast plasma glucose concentration of 4-5 mmol/L. The primary endpoint was change in HbA1c after 26 weeks of treatment, and the main objective was to assess the non-inferiority of IDegLira to insulin degludec (with an upper 95% CI margin of 0·3%), and the superiority of IDegLira to liraglutide (with a lower 95% CI margin of 0%). This study is registered with ClinicalTrials.gov, number NCT01336023.
  
  
  RESULTS
  1663 adults (mean age 55 years [SD 10], HbA1c 8·3% [0·9], and BMI 31·2 kg/m(2) [4·8]) were randomly assigned, 834 to IDegLira, 414 to insulin degludec, and 415 to liraglutide. After 26 weeks, mean HbA1c had decreased by 1·9% (SD 1·1) to 6·4% (1·0) with IDegLira, by 1·4% (1·0) to 6·9% (1·1) with insulin degludec, and by 1·3% (1·1) to 7·0% (1·2) with liraglutide. IDegLira was non-inferior to insulin degludec (estimated treatment difference -0·47%, 95% CI -0·58 to -0·36, p<0·0001) and superior to liraglutide (-0·64%, -0·75 to -0·53, p<0·0001). IDegLira was generally well tolerated; fewer participants in the IDegLira group than in the liraglutide group reported gastrointestinal adverse events (nausea 8·8 vs 19·7%), although the insulin degludec group had the fewest participants with gastrointestinal adverse events (nausea 3·6%). We noted no clinically relevant differences between treatments with respect to standard safety assessments, and the safety profile of IDegLira reflected those of its component parts. The number of confirmed hypoglycaemic events per patient year was 1·8 for IDegLira, 0·2 for liraglutide, and 2·6 for insulin degludec. Serious adverse events occurred in 19 (2%) of 825 patients in the IDegLira group, eight (2%) of 412 in the insulin degludec group, and 14 (3%) of 412 in the liraglutide group.
  
  
  CONCLUSIONS
  IDegLira combines the clinical advantages of basal insulin and GLP-1 receptor agonist treatment, resulting in improved glycaemic control compared with its components given alone.
  
  
  BACKGROUND
  Novo Nordisk.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, and NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK. Electronic address: stephen.gough@ocdem.ox.ac.uk.
authors.forename: Stephen C L
authors.initials: SC
authors.lastname: Gough
authors.affiliation: Atlanta Diabetes Associates, Atlanta, GA, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Bode
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Woo
authors.affiliation: Endocrine and Metabolic Consultants, Rockville, MD, USA.
authors.forename: Helena W
authors.initials: HW
authors.lastname: Rodbard
authors.affiliation: Coffs Harbour Diabetes Clinic, Coffs Harbour, NSW, Australia.
authors.forename: Sultan
authors.initials: S
authors.lastname: Linjawi
authors.affiliation: Novo Nordisk, Søborg, Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Poulsen
authors.affiliation: Novo Nordisk, Søborg, Denmark.
authors.forename: Lars H
authors.initials: LH
authors.lastname: Damgaard
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Buse
mesh_terms: D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004338:Drug Combinations; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D049528:Insulin, Long-Acting / Q000008:administration & dosage*; D000069450:Liraglutide; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D004338:Drug Combinations; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D049528:Insulin, Long-Acting; D000069450:Liraglutide; C517652:hemoglobin A1c protein, human; C571886:insulin degludec