title: Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide.
abstract: BACKGROUND
  * Patients with Type 2 diabetes are likely to have or to develop renal impairment, which affects the pharmacokinetics of some antidiabetic treatments. * Whether dosing of the once-daily human glucagon-like peptide-1 analogue liraglutide should be modified in patients with renal impairment has not previously been studied.
  
  
  CONCLUSIONS
  * Renal dysfunction was not found to increase the exposure of liraglutide. * Hence, no dose adjustment is expected to be required in patients with Type 2 diabetes and renal impairment treated with liraglutide.
  
  
  OBJECTIVE
  To investigate whether dose adjustment of the once-daily human glucagon-like peptide-1 analogue liraglutide is required in patients with varying stages of renal impairment.
  
  
  METHODS
  A cohort of 30 subjects, of whom 24 had varying degrees of renal impairment and six had normal renal function, were given a single dose of liraglutide, 0.75 mg subcutaneously, and completed serial blood sampling for plasma liraglutide measurements for pharmacokinetic estimation.
  
  
  RESULTS
  No clear trend for change in pharmacokinetics was evident across groups with increasing renal dysfunction. While the between-group comparisons of the area under the liraglutide concentration-curve (AUC) did not demonstrate equivalence [estimated ratio AUC(severe)/AUC(healthy) 0.73, 90% confidence interval (CI) 0.57, 0.94; and AUC (continuous ambulatory peritoneal dialysis)(CAPD)/AUC(healthy) 0.74, 90% CI 0.56, 0.97], the regression analysis of log(AUC) for subjects with normal renal function and mild-to-severe renal impairment showed no significant effect of decreasing creatinine clearance on the pharmacokinetics of liraglutide. The expected AUC ratio between the two subjects with the lowest and highest creatinine clearance in the study was estimated to be 0.88 (95% CI 0.58, 1.34) (NS). Degree of renal impairment did not appear to be associated with an increased risk of adverse events.
  
  
  CONCLUSIONS
  This study indicated no safety concerns regarding use of liraglutide in patients with renal impairment. Renal dysfunction was not found to increase exposure of liraglutide, and patients with Type 2 diabetes and renal impairment should use standard treatment regimens of liraglutide. There is, however, currently limited experience with liraglutide in patients beyond mild-stage renal disease.
authors.affiliation: Novo Nordisk A/S, Bagsvaerd, Denmark. lvj@novonordisk.com
authors.forename: Lisbeth V
authors.initials: LV
authors.lastname: Jacobsen
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hindsberger
authors.forename: Richard
authors.initials: R
authors.lastname: Robson
authors.forename: Milan
authors.initials: M
authors.lastname: Zdravkovic
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D054795:Incretins / Q000493:pharmacokinetics*; D007668:Kidney / Q000187:drug effects*; D000069450:Liraglutide; D008297:Male; D008875:Middle Aged; D009520:New Zealand; D055815:Young Adult
chemical_list: D054795:Incretins; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1