WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• 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. WHAT THIS STUDY ADDS• 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. AIMSTo 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. METHODSA 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. RESULTSNo 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 concentrationcurve (AUC) did not demonstrate equivalence [estimated ratio AUCsevere/AUChealthy 0.73, 90% confidence interval (CI) 0.57, 0.94; and AUC (continuous ambulatory peritoneal dialysis)CAPD/AUChealthy 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. CONCLUSIONSThis 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.

Background: The prevalence of type 2 diabetes (T2D) in youth is increasing. Treatment options beyond metformin and insulin are needed. The safety, tolerability, pharmacokinetics, and pharmacodynamics of liraglutide once daily in youth (10-17 years old) with T2D were investigated in a randomized, double-blind, placebo-controlled trial. Subjects and Methods: Youth treated with diet/exercise alone or with metformin and having a hemoglobin A 1c (HbA 1c ) level of 6.5-11% were randomized to liraglutide (n = 14) or placebo (n = 7). Starting at 0.3 mg/day, doses were escalated weekly to 0.6, 0.9, 1.2, and 1.8 mg/day (or placebo equivalent) for 5 weeks. Results: Nineteen participants completed the trial. Baseline characteristics were similar between groups, with mean (SD) values for age of 14.8 (2.2) years, weight of 113.2 (35.6) kg (range, 57-214 kg), diabetes duration of 1.7 (1.4) years, and HbA 1c level of 8.1% (1.2%). No serious adverse events (AEs), including severe hypoglycemia, occurred. Transient gastrointestinal AEs were most common at lower liraglutide doses during dose escalation. No significant changes in safety and tolerability parameters occurred. There was no evidence of pancreatitis or lipase elevations above three times the upper normal limit; calcitonin levels remained within the normal range. For liraglutide 1.8 mg, mean half-life was 12 h, and clearance was 1.7 L/h. After 5 weeks, the decline in HbA 1c level was greater with liraglutide versus placebo (-0.86 vs. 0.04%, P = 0.0007), whereas mean body weight remained stable ( -0.50 vs. -0.54 kg, P = 0.9703). Conclusions: Liraglutide was well tolerated in youth with T2D, with safety, tolerability, and pharmacokinetic profiles similar to profiles in adults.

ClinicalTrials.gov: NCT01789086.

Liraglutide is an acylated glucagon-like peptide-1 analogue with 97 % amino acid homology with native glucagon-like peptide-1 and greatly protracted action. It is widely used for the treatment of type 2 diabetes mellitus, and administered by subcutaneous injection once daily. The pharmacokinetic properties of liraglutide enable 24-h exposure coverage, a requirement for 24-h glycaemic control with once-daily dosing. The mechanism of protraction relates to slowed release from the injection site, and a reduced elimination rate owing to metabolic stabilisation and reduced renal filtration. Drug exposure is largely independent of injection site, as well as age, race and ethnicity. Increasing body weight and male sex are associated with reduced concentrations, but there is substantial overlap between subgroups; therefore, dose escalation should be based on individual treatment outcome. Exposure is reduced with mild, moderate or severe renal or hepatic impairment. There are no clinically relevant changes in overall concentrations of various drugs (e.g. paracetamol, atorvastatin, griseofulvin, digoxin, lisinopril and oral combination contraceptives) when co-administered with liraglutide. Pharmacodynamic studies show multiple beneficial actions with liraglutide, including improved fasting and postprandial glycaemic control (mediated by increased insulin and reduced glucagon levels and minor delays in gastric emptying), reduced appetite and energy intake, and effects on postprandial lipid profiles. The counter-regulatory hormone response to hypoglycaemia is largely unaltered. The effects of liraglutide on insulin and glucagon secretion are glucose dependent, and hence the risk of hypoglycaemia is low. The pharmacokinetic and pharmacodynamic properties of liraglutide make it an important treatment option for many patients with type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-015-0343-6) contains supplementary material, which is available to authorized users.