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Baptist Gallwitz Department of Medicine IV, Eberhard-Karls University, Tübingen, Germany Abstract: Dipeptidyl-peptidase-IV (DPP-4) inhibitors are oral antidiabetic agents that can be administered as monotherapy in patients with contraindications to metformin or metformin intolerance, and in combination with other oral compounds and/or insulin. DPP-4 inhibitors act in a glucose-dependent manner and only increase insulin secretion and inhibit glucagon secretion under hyperglycemic conditions. Renal impairment is frequent in type 2 diabetes as a result of microvascular complications and diabetes treatment, and options in these patients are limited. Linagliptin is a DPP-4 inhibitor with a hepatobiliary route of elimination. In comparative studies, it was noninferior to metformin and sulfonylureas in lowering glycated hemoglobin (HbA1c) and improving glycemic parameters. It can be used throughout all stages of renal impairment without dose adjustments. This review gives an overview of linagliptin in various stages of chronic kidney disease and has a focus on efficacy and safety parameters from clinical studies in patients with impaired renal function. These data are interpreted in the context of type 2 diabetes therapy in general. Keywords: type 2 diabetes, renal impairment, oral antidiabetic drugs, incretin based therapies, DPP-4 inhibitors, linagliptin

Baptist GallwitzDepartment of Medicine IV, Eberhard-Karls-University Tübingen, Tübingen, GermanyAbstract: The first dipeptidyl-peptidase-IV (DPP-4) inhibitor for the treatment of type 2 diabetes became available in 2006. Since then, the number of DPP-4 inhibitors has increased and DPP-4 inhibitors have developed into an important drug class. DPP-4 inhibitors act by increasing endogenous GLP-1 and GIP concentrations. Via this mechanism, insulin secretion is glucose-dependently stimulated and glucagon secretion inhibited. This results in a low risk for hypoglycemia. Furthermore, DPP-4 inhibitors are weight-neutral. Linagliptin is a novel DPP-4 inhibitor that, in contrast to the other members of this drug class, is eliminated by a biliary/hepatic route rather than by renal elimination. This property allows the use of linagliptin in type 2 diabetic patients with normal kidney function as well as in patients with renal insufficiency without dose adjustments. In comparative clinical studies, linagliptin was noninferior to other established antidiabetic agents, especially to metformin and sulfonylurea. It showed a superior safety profile over glimepiride regarding hypoglycemia, weight gain, a composite cardiovascular endpoint, and stroke. This review gives an overview on the efficacy and safety of linagliptin in comparison to the classical oral antidiabetic drugs as well as to the other DPP-4 inhibitors.Keywords: type 2 diabetes, oral antidiabetic drugs, incretin-based therapies, DPP-4 inhibitors, linagliptin

Baptist GallwitzDept Medicine IV, Tübingen University, Otfried-Müller-Str, 10, 72076 Tübingen, GermanyAbstract: Saxagliptin is a novel dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor) for the treatment of type 2 diabetes, with a duration profile for once daily dosing. It is highly selective for DPP-4 in comparison to other enzymes of the dipeptidyl peptidase family. DPP-4 inhibitors elevate plasma concentrations of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). This effect results in a glucose-dependent stimulation of insulin secretion and an inhibition of glucagon secretion without an intrinsic risk for hypoglycemia. In comparison to sulfonylureas and thiazolidinediones that promote weight gain, DPP-4 inhibitors are weight neutral. Saxagliptin has been approved by the FDA for the US and by the EMEA for Europe in 2009. Clinical trials showed a dose-dependent inhibition of DPP-4 by saxagliptin in doses ranging from 2.5 to 100 mg daily without serious side effects. Type 2 diabetic patients receiving 5 mg to 10 mg saxagliptin once daily had a significant lowering of HbA1c and glycemic parameters along with good tolerability and safety. Saxagliptin has demonstrated a good efficacy for glycemic parameters in various patient populations either in monotherapy or in combination with metformin and other oral antidiabetic drugs as well as a favorable cardiovascular profile. With its high selectivity for DPP-4 and its clinical and cardiovascular profile, saxagliptin is an attractive novel DPP-4 inhibitor.Keywords: type 2 diabetes, diabetes therapy, DPP-4 inhibitors, incretin based therapy, GLP-1, saxagliptin