title: Insulin degludec/insulin aspart produces a dose-proportional glucose-lowering effect in subjects with type 1 diabetes mellitus.
abstract: OBJECTIVE
  To evaluate the pharmacodynamic dose-response relationship of insulin degludec/insulin aspart (IDegAsp), a novel, soluble co-formulation of the ultra-long-acting basal insulin, insulin degludec (IDeg), with the rapid-acting prandial insulin (IAsp), across different doses in patients with type 1 diabetes (T1DM).
  
  
  METHODS
  This was a randomized, single-centre, double-blind, four-period, incomplete block, crossover trial. A cohort of 33 people with T1DM received single doses (0.4, 0.6 or 0.8 U/kg) of IDegAsp or the comparator, biphasic insulin aspart 30, in a randomized sequence of four treatment periods, each separated by a washout of 13-21 days. Pharmacodynamic response was assessed using a 26-h euglycaemic glucose clamp, with blood glucose stabilized at a target of 5.5 mmol/l (100 mg/dl).
  
  
  RESULTS
  A rapid onset of action and a distinct peak attributable to IAsp was observed in the glucose infusion rate (GIR) profile, followed by a separate, flat and stable basal glucose-lowering effect attributable to the IDeg component. The mean area under the GIR curve over 24 h (AUC(GIR,0-24 h)), and the mean maximum GIR (GIR(max)) increased with increasing dose level of IDegAsp. A dose-response relationship for IDegAsp was demonstrated for AUC(GIR,0-24 h) and GIR(max), indicating dose proportionality. A dose-concentration relationship was also observed for both the basal and bolus components of IDegAsp.
  
  
  CONCLUSIONS
  IDegAsp has a clear dose-response relationship, indicating the clinical potential for straightforward titration according to individual patient needs.
authors.affiliation: Profil, Neuss, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Heise
authors.affiliation: Profil, Neuss, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Nosek
authors.affiliation: Profil, Neuss, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Klein
authors.affiliation: Profil, Neuss, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Coester
authors.affiliation: Novo Nordisk A/S, Søborg, Denmark.
authors.forename: A L
authors.initials: AL
authors.lastname: Svendsen
authors.affiliation: Novo Nordisk A/S, Søborg, Denmark.
authors.forename: H
authors.initials: H
authors.lastname: Haahr
mesh_terms: D000328:Adult; D019540:Area Under Curve; D061265:Biphasic Insulins / Q000008:administration & dosage*; D001786:Blood Glucose / Q000032:analysis* / Q000378:metabolism; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D049528:Insulin, Long-Acting / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D061265:Biphasic Insulins; D001786:Blood Glucose; D004338:Drug Combinations; D007004:Hypoglycemic Agents; D049528:Insulin, Long-Acting; C578220:insulin degludec, insulin aspart drug combination
keywords: dose-response relationship; pharmacodynamics; type 1 diabetes