Dipeptidyl peptidase‐4 inhibitors: pharmacokinetics, efficacy, tolerability and safety in renal impairment

Abstract

The dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of blood glucose-lowering therapy with proven efficacy, tolerability and safety. Four of the five commercially available DPP-4 inhibitors are subject to significant renal clearance, and pharmacokinetic studies in people with renal impairment have led to lower recommended doses based on creatinine clearance in order to prevent drug accumulation. Data from these pharmacokinetic studies and from supratherapeutic doses in healthy individuals and people with uncomplicated diabetes during development suggest, however, that there is a wide therapeutic margin. This should protect against toxicity if people with renal impairment are inadvertently prescribed higher doses than recommended. Doses appropriate to renal function are associated with reductions in HbA1c that are equivalent to those observed in people with type 2 diabetes who do not have renal impairment. Recent large-scale cardiovascular safety trials of saxagliptin and alogliptin have identified heart failure as a potential concern and renal impairment may increase the risk of this complication. Although the incidence of pancreatitis does not appear to be significantly increased by DPP-4 inhibitor therapy, renal impairment is also an independent risk factor. Additional data from other ongoing DPP-4 inhibitor cardiovascular safety trials should provide a more precise assessment of the risks of these uncommon complications, including in people with renal impairment.

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

“…Approximately 7.2% (3.6 mg) of a 50-mg oral dose was removed after 3 h of hemodialysis. 74 The AUC of alogliptin was about 10% lower and C max was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects. 71,75 Alogliptin pharmacokinetics were not significantly altered in subjects with mild to moderate hepatic impairment.…”

“…74 In patients with severe renal impairment (creatinine clearance ≥ 15 to < 30 mL/min) and end-stage renal disease (creatinine clearance < 15 mL/min or requiring dialysis), a 3.2-to 3.8-fold increase in plasma AUC of alogliptin were observed, and the recommended dose is 6.25 mg once daily. 74 The C max of alogliptin was increased 1.1-to 1.4-fold. Metabolite exposure remained low in all subjects.…”

“…However, dose adjustment for patients with mild renal impairment (creatinine clearance ≥ 60 mL/min) is not recommended. 74 In patients with moderate renal impairment (creatinine clearance ≥ 30 to <60 mL/ min), a 2.1-fold increase in plasma AUC of alogliptin was observed, and the recommended dose is 12.5 mg once daily. 74 In patients with severe renal impairment (creatinine clearance ≥ 15 to < 30 mL/min) and end-stage renal disease (creatinine clearance < 15 mL/min or requiring dialysis), a 3.2-to 3.8-fold increase in plasma AUC of alogliptin were observed, and the recommended dose is 6.25 mg once daily.…”

Short-term outcomes of patients with Type 2 diabetes mellitus treated with canagliflozin compared with sitagliptin in a real-world setting

“…(4) DPP-4 inhibitors can also be used in renal failure, although some agents need dose adjustment, (21) and are probably safe even in older patients with T2DM. (22) This study was not without limitations.…”

Dipeptidyl peptidase-4 inhibitors

“…Renal function should be monitored to allow appropriate dose choice, although this is not required for linagliptin because of its primarily non-renal route of elimination. However, given the wide therapeutic window, it is doubtful that any drug accumulation would lead to unfavorable outcomes if the normal therapeutic doses are inadvertently used in subjects with impaired renal function [16].…”