title: Efficacy and safety of insulin degludec three times a week versus insulin glargine once a day in insulin-naive patients with type 2 diabetes: results of two phase 3, 26 week, randomised, open-label, treat-to-target, non-inferiority trials.
abstract: BACKGROUND
  Results of an exploratory phase 2 study showed that insulin degludec, a basal insulin with an action profile of longer than 42 h, provided similar glycaemic control when injected three times a week (IDeg 3TW) to once-daily insulin glargine (IGlar OD). To provide further evidence, we did two phase 3 trials to compare the efficacy and safety of IDeg 3TW with IGlar OD in insulin-naive patients with type 2 diabetes.
  
  
  METHODS
  In two 26 week, randomised, open-label, parallel group, non-inferiority trials IDeg was injected Monday, Wednesday, and Friday before breakfast (IDeg 3TW(AM)) in the AM trial (94 sites in seven countries) or with the evening meal (IDeg 3TW(PM)) in the PM trial (89 sites in seven countries), and compared with IGlar OD. Adults with type 2 diabetes (HbA(1c) 7.0-10.0%; body-mass index ≤45 kg/m(2)) were randomly allocated (1:1) without stratification by a central interactive response system to IDeg 3TW or IGlar OD. Both groups continued taking metformin with or without dipeptidyl peptidase-4 inhibitors. Insulin was titrated to achieve a prebreakfast self-monitored blood glucose (SMBG) concentration of between 3.9 and less than 5.0 mmol/L. The primary outcome was non-inferiority of IDeg 3TW compared with IGlar OD, as assessed by change in HbA(1c) from baseline to 26 weeks (non-inferiority limit of 0.4%) by ANOVA in an intent-to-treat analysis (full analysis set). These trials are registered with ClinicalTrials.gov, numbers NCT01068678 and NCT01076647.
  
  
  RESULTS
  We recruited 460 patients for the AM trial (IDeg 3TW(AM), n=230; IGlar OD, n=230) and 467 patients for the PM trial (IDeg 3TW(PM), n=233; IGlar OD, n=234). After 26 weeks, mean HbA decreased by 0.9% (IDeg 3TW(AM)) and 1.3% (IGlar OD) in the AM trial, and by 1.1% (IDeg 3TW(PM)) and 1.4% (IGlar OD) in the PM trial. Non-inferiority was not confirmed in either trial (estimated treatment difference [IDeg 3TW(AM)-IGlar OD] 0.34%, 95% CI 0.18-0.51; [IDeg 3TW(PM)-IGlar OD] 0.26%, 0.11-0.41). Across the two trials, rates of confirmed hypoglycaemia (SMBG <3.1 mmol/L or severe [needing assistance]) ranged from 1.0 to 1.6 episodes per patient-year and were similar for IDeg 3TW(AM) and IGlar OD (estimated rate ratio [ERR] 1.04, 95% CI 0.69-1.55), but higher for IDeg 3TW(PM) than for IGlar OD (ERR 1.58, 1.03-2.43). The rate of nocturnal confirmed hypoglycaemia was higher for IDeg 3TW(AM) than for IGlar OD (ERR 2.12, 1.08-4.16); we noted no significant difference between IDeg 3TW(PM) and IGlar OD (ERR 0.60, 0.21-1.69).
  
  
  CONCLUSIONS
  The inferior glycaemic control and increased risk of hypoglycaemia with IDeg 3TW compared with IGlar OD do not support a three-times-weekly dosing regimen.
  
  
  BACKGROUND
  Novo Nordisk.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada. Electronic address: zinman@lumenfield.ca.
authors.forename: Bernard
authors.initials: B
authors.lastname: Zinman
authors.affiliation: Department of Internal Medicine, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: J Hans
authors.initials: JH
authors.lastname: DeVries
authors.affiliation: Atlanta Diabetes Associates, Atlanta, GA, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Bode
authors.affiliation: Royal Surrey County Hospital, Guildford, Surrey, UK.
authors.forename: David
authors.initials: D
authors.lastname: Russell-Jones
authors.affiliation: Keenan Research Centre in the Li Ka Shing Knowledge Institute of St Michael's Hospital, University of Toronto, Toronto, Canada.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Leiter
authors.affiliation: Novo Nordisk, Princeton, NJ, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Moses
authors.affiliation: Novo Nordisk, Søborg, Denmark.
authors.forename: Thue
authors.initials: T
authors.lastname: Johansen
authors.affiliation: Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Ratner
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000453:epidemiology; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting / Q000008:administration & dosage* / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D049528:Insulin, Long-Acting; D000069036:Insulin Glargine; C571886:insulin degludec