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Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment.

ABSTRACT: Renal disease is a frequent comorbidity of type 2 diabetes mellitus (T2DM) and an important factor complicating the choice of glucose-lowering drugs. The aim of this analysis was to evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (5?mg/day) in mono, dual or triple oral glucose-lowering regimens in subjects with T2DM and mild or moderate renal impairment (RI).In this pooled analysis of three 24-week, placebo-controlled, phase 3 trials, subjects with mild (estimated glomerular filtration rate (eGFR) 60-<90?ml/min/1.73?m(2) , n?=?838) or moderate RI (30-<60?ml/min/1.73?m(2), n?=?93) were compared with subjects with normal renal function (?90?ml/min/1.73?m(2), n?=?1212).Subjects with RI were older, had longer duration of diabetes, and increased prevalence of diabetes-related comorbidities. After 24?weeks, linagliptin achieved consistent placebo-corrected mean glycated haemoglobin (HbA1c) changes across the three renal function categories: normal (-0.63%; p?

SUBMITTER: Groop PH

PROVIDER: S-EPMC4288982 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment.

Groop P-H PH Del Prato S S Taskinen M-R MR Owens D R DR Gong Y Y Crowe S S Patel S S von Eynatten M M Woerle H-J HJ

Diabetes, obesity & metabolism 20140324 6

<h4>Aims</h4>Renal disease is a frequent comorbidity of type 2 diabetes mellitus (T2DM) and an important factor complicating the choice of glucose-lowering drugs. The aim of this analysis was to evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (5 mg/day) in mono, dual or triple oral glucose-lowering regimens in subjects with T2DM and mild or moderate renal impairment (RI).<h4>Methods</h4>In this pooled analysis of three 24-week, placebo-controlled, phase ...[more]

PMID: 24612167

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Project description:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Linagliptin is an oral, highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved in the United States, Europe and elsewhere in 2011 for the treatment of type 2 diabetes mellitus. • The elimination of linagliptin is primarily non-renal. Therefore, a potential effect of hepatic impairment on the elimination of linagliptin may have important implications for dosing recommendations. WHAT THIS STUDY ADDS: • This study shows that mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing as compared with normal hepatic function. • No linagliptin dose adjustment is required in patients with any degree of hepatic impairment. AIM: To investigate whether hepatic impairment affects linagliptin pharmacokinetics, pharmacodynamics and tolerability. METHOD: This open label, parallel group, single centre study enrolled patients with mild (n= 8), moderate (n= 9) or severe (n= 8) hepatic impairment and healthy subjects (n= 8). Groups were matched with regard to age, weight and gender. Primary endpoints were linagliptin exposure following 5 mg linagliptin once daily for 7 days in patients with mild and moderate hepatic impairment vs. healthy subjects or after a single 5 mg dose for patients with severe hepatic impairment vs. healthy subjects. RESULTS: In mild hepatic impairment, steady-state linagliptin exposure was slightly lower than in healthy subjects [AUC(?,ss) geometric mean ratio (GMR) 75.5%, 90% confidence interval (CI) 61.6%, 92.5%, and C(max,ss) GMR 64.4%, 90% CI 43.2%, 96.0%]. Exposure also tended to be lower in moderate hepatic impairment (AUC(?,ss) GMR 85.5%, 90% CI 70.2%, 104.2% and C(max,ss) GMR 92.3%, 90% CI 62.8%, 135.6%). After a single dose, AUC(0,24 h) in patients with severe hepatic impairment was similar to that in healthy subjects (GMR 100.4%, 90% CI 75.0%, 134.3%) and C(max) was lower (GMR 77.0%, 90% CI 44.9%, 132.3%). Accumulation based on AUC or C(max) and renal excretion of unchanged linagliptin (? 7%) were comparable across groups. Median plasma DPP-4 inhibition was similar in healthy subjects (91%), and patients with mild (90%) and moderate (89%) hepatic impairment at steady-state trough concentrations, and in patients with severe hepatic impairment 24 h after a single dose (84%). Linagliptin was well tolerated. CONCLUSION: Mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing compared with normal hepatic function. Dose adjustment with linagliptin is not required in patients with hepatic impairment.

Dataset Information

Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment.

Publications

Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment.

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