Pharmacokinetics, safety, and efficacy of DPP-4 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus and renal or hepatic impairment. A systematic review of the literature

Abstract

Renal or hepatic impairment, often encountered in patients with type 2 diabetes, influences the pharmacokinetics and bioavailability of antihyperglycemic agents. An emerging concern is whether pharmacotherapy with incretin-based agents, the most recent drug classes to be introduced for type 2 diabetes, can be safely used in patients with renal insufficiency or hepatic damage. This literature review examines the results of studies on these novel drug classes, with a view to provide the practitioner with a balanced, evidence-based position when considering incretin-based therapies in patients with type 2 diabetes and impaired kidney or liver function. All currently available dipeptidyl peptidase-4 (DPP-4) inhibitors appear to be appropriate pharmacotherapeutic choices in patients with declining renal function, with linagliptin affording the added advantage of not requiring dose adjustment or periodic monitoring of drug-related kidney function. In contrast, caution is warranted with the use of glucagon-like peptide-1 (GLP-1) receptor agonists in patients with moderate or severe renal impairment. The slightly wider evidence base for liraglutide than for exenatide or lixisenatide is not sufficient to support its use in severe renal impairment. What little evidence there is for incretin-based therapies in hepatic impairment has come from a few past hoc analysis of clinical trials, with most precautions and warnings reflecting the paucity of knowledge about incretin efficacy or safety in this condition.

Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus

“…This is of major importance because the dosage of DPP-4 inhibitors (except linagliptin) should be adjusted to the glomerular filtration rate and there are restrictions regarding the use of GLP-1 receptor agonists in presence of moderate to severe kidney insufficiency [14,22] .…”

“…A higher risk of lactic acidosis with metformin, of hypoglycaemia with sulphonylureas or hepatotoxicity with the first commercialized thiazolidinedione (troglitazone) has been reported [10] . The scarce review papers about the management of diabetic patients with CLD focused on general management rather than on the specific use of glucose-lowering agents [11,12] .In this context, the place of new medications, such as incretinbased therapies, was almost not considered, except in recent reviews [13,14] .…”

Diabetic Kidney Disease: A Report From an ADA Consensus Conference

“…All of the currently available DPP-4 inhibitors can be used in CKD, but sitagliptin, saxagliptin, and alogliptin require downward dose titration based on eGFR (105)(106)(107)(108). Linagliptin, in contrast, does not require dose adjustment based on kidney function (109,110).…”

Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists

“…The half-life of liraglutide is five time longer than exenatide; therefore, exenatide treatment requires twice-daily injections in patients. Moreover, while exenatide is mainly eliminated in the kidney, liraglutide is fully degraded within the body and no specific organ or enzyme is responsible for its elimination (Giorda et al 2014). Exenatide administration also results in higher frequency of antibody formation than that of liraglutide (Buse et al 2011).…”