Nitta K (ed): Chronic Kidney Diseases – Recent Advances in Clinical and Basic Research. Contrib Nephrol. Basel, Karger, 2015, vol 185, pp 98–115 (DOI: 10.1159/000380974)
DPP-4 Inhibitors in Diabetic Patients with Chronic Kidney Disease and End-Stage Kidney Disease on Dialysis in Clinical Practice Masanori Abe · Kazuyoshi Okada Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
Numerous drugs with different mechanisms of action and different pharmacologic profiles are being used with the aim of improving glycemic control in patients with type 2 diabetes. The therapeutic options for patients with type 2 diabetes and chronic kidney disease (CKD) are limited because the patients’ reduced glomerular filtration rate results in the accumulation of certain drugs and/or their metabolites. Although recommended oral antidiabetic agents for patients with CKD differ between countries, all of the currently available dipeptidyl peptidase-4 (DPP-4) inhibitors can be used in not only patients with CKD but also patients with end-stage kidney disease on dialysis, and these inhibitors’ use is increasing. Numerous clinical trials have shown that DPP-4 inhibitors provide effective and consistent glycemic control with a good tolerability profile and without severe hypoglycemia or weight gain. The glucose-lowering effect of DPP-4 inhibitors in diabetic patients with CKD is similar to the changes seen when DPP-4 inhibitors are prescribed to patients without CKD. Therefore, kidney function is unaffected by treatment with DPP-4 inhibitors. Moreover, DPP-4 inhibitors reduce the levels of glycated albumin, which is a better indicator of glycemic control than glycated hemoglobin is, without hypoglycemia in patients with end-stage kidney disease undergoing dialysis. Furthermore, it has been suggested that DPP-4 inhibitors might have a kidney-protective effect since they can potentially reduce the incidence of albuminuria. Although
Downloaded by: UCONN Storrs 137.99.31.134 - 5/21/2015 6:25:25 PM
Abstract
these results suggest that DPP-4 inhibitors can protect against diabetic nephropathy, insufficient evidence is available to conclude that this class of agent directly prevents or decreases nephropathy in humans independently from improved glucose control. Further long-term studies are needed to address whether DPP-4 inhibitors reduce the development and progression of diabetic nephropathy and improve cardiovascular outcomes in diabetic patients with CKD. Here, we describe the clinical efficacy and safety of DPP-4 inhibitors for patients with CKD, including those receiving dialysis. © 2015 S. Karger AG, Basel
Type 2 diabetes mellitus is a well-recognized risk factor for nephropathy and chronic kidney disease (CKD) and is the most common cause of end-stage kidney disease (ESKD) during dialysis therapy. The standards of diabetes care recommend reducing the risk or slowing the progression of CKD by optimizing glycemic control. However, most of the drugs available to treat hyperglycemia are affected by kidney function and should therefore be either avoided or used at reduced doses in patients with CKD [1]. In recent years, medications that enhance incretin activity, or dipeptidyl peptidase 4 (DPP-4) inhibitors, have emerged as important new treatments for type 2 diabetes. Incretins, such as glucagon-like peptide 1 (GLP-1) and glucagondependent insulinotropic polypeptide, are secreted after meals and act directly on pancreatic β cells to stimulate glucose-dependent insulin secretion. GLP-1 has multiple roles in the regulation of glucose metabolism, including in the brain, stomach, and vasculature. However, intrinsic incretins are inactivated rapidly by DPP-4, and as a result, DPP-4 inhibitors have been developed for the treatment of type 2 diabetes. DPP-4 inhibitors are associated with additional benefits compared to other antidiabetic agents: these inhibitors do not induce hypoglycemia because they control blood glucose regulation by both insulin and glucagon secretion, depending on blood glucose levels. Additionally, the inhibitors may be able to protect pancreatic β cell function and volume, in contrast to sulfonylureas, and may decrease blood glucose levels without weight gain. Furthermore, all of the currently available DPP-4 inhibitors can be used in not only patients with CKD but also patients with ESKD on dialysis [2]. A meta-analysis has shown that DPP-4 inhibitors appear to be especially effective in Asian patients [3]. The purpose of the present review is to integrate recently published literature in a contemporary evaluation of the clinical efficacy and safety of DPP4 inhibitors in type 2 diabetic patients with CKD or ESKD who are undergoing dialysis.
DPP-4 Inhibitors and Chronic Kidney Disease Nitta K (ed): Chronic Kidney Diseases – Recent Advances in Clinical and Basic Research. Contrib Nephrol. Basel, Karger, 2015, vol 185, pp 98–115 (DOI: 10.1159/000380974)
99
Downloaded by: UCONN Storrs 137.99.31.134 - 5/21/2015 6:25:25 PM
Introduction
Antihyperglycemic Strategies for Diabetic Patients with Chronic Kidney Disease
CKD, including diabetic nephropathy, progressively increases the risk of cardiovascular disease and ESKD, depending on its severity. Furthermore, albuminuria in CKD is a risk factor for both ESKD and cardiovascular disease [4]. Blockade of the renin-angiotensin-aldosterone system (RAAS) provides kidney and cardiovascular protection beyond a simple lowering of blood pressure (BP), and the beneficial effects of agents that can block this system have been linked to concomitant changes in albuminuria. Thus, reductions in albuminuria in patients with type 2 diabetes are associated with a significant reduction in the risk of ESKD. These findings suggest that albuminuria may be an important therapeutic target for preventing the progression of diabetic nephropathy and might also offer cardiovascular protection. Therefore, in 2009, the Kidney Disease: Improving Global Outcomes organization recommended that individuals be classified according to albuminuria stage as well as glomerular filtration rate (GFR) [4]. Although inhibitors of the RAAS are currently the most effective pharmacological strategy for kidney protection and the reduction of proteinuria, intensive glycemic control also improves the onset of microalbuminuria and macroalbuminuria [5, 6]. The main approach for preserving kidney function in diabetic nephropathy is to lower glucose levels. Several studies revealed that a reduction in hemoglobin A1c (HbA1c) levels is paralleled by a reduction in albuminuria [6]. However, aggressive treatment of hyperglycemia, which used to be the quintessential goal of diabetes management, may increase the risk of hypoglycemia and glucose variability, leading to poor outcomes, as demonstrated in several recent large controlled trials of intensive treatment for diabetic patients without CKD, such as Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and the Veteran Affairs Diabetes Trial (VADT) [7–9]. Hence, whereas hyperglycemia was traditionally the main focus of attention, contemporary medicine considers the occurrence of hypoglycemia as an even more significant challenge in the management of type 2 diabetes.
Metformin, the most commonly used antihyperglycemic agent for type 2 diabetes mellitus, is excreted renally and is contraindicated, per current US Food and Drug Administration (FDA) prescribing information, in men with a serum
100
Abe · Okada Nitta K (ed): Chronic Kidney Diseases – Recent Advances in Clinical and Basic Research. Contrib Nephrol. Basel, Karger, 2015, vol 185, pp 98–115 (DOI: 10.1159/000380974)
Downloaded by: UCONN Storrs 137.99.31.134 - 5/21/2015 6:25:25 PM
Antihyperglycemic Agents in Patients with Chronic Kidney Disease or End-Stage Kidney Disease on Dialysis
creatinine (sCr) >1.5 mg/dl and in women with an sCr >1.4 mg/dl. The Japanese Society of Nephrology and British National Formulary recommend cessation if GFR
DPP-4 Inhibitors in Diabetic Patients with Chronic Kidney Disease and End-Stage Kidney Disease on Dialysis in Clinical Practice Masanori Abe · Kazuyoshi Okada Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
Numerous drugs with different mechanisms of action and different pharmacologic profiles are being used with the aim of improving glycemic control in patients with type 2 diabetes. The therapeutic options for patients with type 2 diabetes and chronic kidney disease (CKD) are limited because the patients’ reduced glomerular filtration rate results in the accumulation of certain drugs and/or their metabolites. Although recommended oral antidiabetic agents for patients with CKD differ between countries, all of the currently available dipeptidyl peptidase-4 (DPP-4) inhibitors can be used in not only patients with CKD but also patients with end-stage kidney disease on dialysis, and these inhibitors’ use is increasing. Numerous clinical trials have shown that DPP-4 inhibitors provide effective and consistent glycemic control with a good tolerability profile and without severe hypoglycemia or weight gain. The glucose-lowering effect of DPP-4 inhibitors in diabetic patients with CKD is similar to the changes seen when DPP-4 inhibitors are prescribed to patients without CKD. Therefore, kidney function is unaffected by treatment with DPP-4 inhibitors. Moreover, DPP-4 inhibitors reduce the levels of glycated albumin, which is a better indicator of glycemic control than glycated hemoglobin is, without hypoglycemia in patients with end-stage kidney disease undergoing dialysis. Furthermore, it has been suggested that DPP-4 inhibitors might have a kidney-protective effect since they can potentially reduce the incidence of albuminuria. Although
Downloaded by: UCONN Storrs 137.99.31.134 - 5/21/2015 6:25:25 PM
Abstract
these results suggest that DPP-4 inhibitors can protect against diabetic nephropathy, insufficient evidence is available to conclude that this class of agent directly prevents or decreases nephropathy in humans independently from improved glucose control. Further long-term studies are needed to address whether DPP-4 inhibitors reduce the development and progression of diabetic nephropathy and improve cardiovascular outcomes in diabetic patients with CKD. Here, we describe the clinical efficacy and safety of DPP-4 inhibitors for patients with CKD, including those receiving dialysis. © 2015 S. Karger AG, Basel
Type 2 diabetes mellitus is a well-recognized risk factor for nephropathy and chronic kidney disease (CKD) and is the most common cause of end-stage kidney disease (ESKD) during dialysis therapy. The standards of diabetes care recommend reducing the risk or slowing the progression of CKD by optimizing glycemic control. However, most of the drugs available to treat hyperglycemia are affected by kidney function and should therefore be either avoided or used at reduced doses in patients with CKD [1]. In recent years, medications that enhance incretin activity, or dipeptidyl peptidase 4 (DPP-4) inhibitors, have emerged as important new treatments for type 2 diabetes. Incretins, such as glucagon-like peptide 1 (GLP-1) and glucagondependent insulinotropic polypeptide, are secreted after meals and act directly on pancreatic β cells to stimulate glucose-dependent insulin secretion. GLP-1 has multiple roles in the regulation of glucose metabolism, including in the brain, stomach, and vasculature. However, intrinsic incretins are inactivated rapidly by DPP-4, and as a result, DPP-4 inhibitors have been developed for the treatment of type 2 diabetes. DPP-4 inhibitors are associated with additional benefits compared to other antidiabetic agents: these inhibitors do not induce hypoglycemia because they control blood glucose regulation by both insulin and glucagon secretion, depending on blood glucose levels. Additionally, the inhibitors may be able to protect pancreatic β cell function and volume, in contrast to sulfonylureas, and may decrease blood glucose levels without weight gain. Furthermore, all of the currently available DPP-4 inhibitors can be used in not only patients with CKD but also patients with ESKD on dialysis [2]. A meta-analysis has shown that DPP-4 inhibitors appear to be especially effective in Asian patients [3]. The purpose of the present review is to integrate recently published literature in a contemporary evaluation of the clinical efficacy and safety of DPP4 inhibitors in type 2 diabetic patients with CKD or ESKD who are undergoing dialysis.
DPP-4 Inhibitors and Chronic Kidney Disease Nitta K (ed): Chronic Kidney Diseases – Recent Advances in Clinical and Basic Research. Contrib Nephrol. Basel, Karger, 2015, vol 185, pp 98–115 (DOI: 10.1159/000380974)
99
Downloaded by: UCONN Storrs 137.99.31.134 - 5/21/2015 6:25:25 PM
Introduction
Antihyperglycemic Strategies for Diabetic Patients with Chronic Kidney Disease
CKD, including diabetic nephropathy, progressively increases the risk of cardiovascular disease and ESKD, depending on its severity. Furthermore, albuminuria in CKD is a risk factor for both ESKD and cardiovascular disease [4]. Blockade of the renin-angiotensin-aldosterone system (RAAS) provides kidney and cardiovascular protection beyond a simple lowering of blood pressure (BP), and the beneficial effects of agents that can block this system have been linked to concomitant changes in albuminuria. Thus, reductions in albuminuria in patients with type 2 diabetes are associated with a significant reduction in the risk of ESKD. These findings suggest that albuminuria may be an important therapeutic target for preventing the progression of diabetic nephropathy and might also offer cardiovascular protection. Therefore, in 2009, the Kidney Disease: Improving Global Outcomes organization recommended that individuals be classified according to albuminuria stage as well as glomerular filtration rate (GFR) [4]. Although inhibitors of the RAAS are currently the most effective pharmacological strategy for kidney protection and the reduction of proteinuria, intensive glycemic control also improves the onset of microalbuminuria and macroalbuminuria [5, 6]. The main approach for preserving kidney function in diabetic nephropathy is to lower glucose levels. Several studies revealed that a reduction in hemoglobin A1c (HbA1c) levels is paralleled by a reduction in albuminuria [6]. However, aggressive treatment of hyperglycemia, which used to be the quintessential goal of diabetes management, may increase the risk of hypoglycemia and glucose variability, leading to poor outcomes, as demonstrated in several recent large controlled trials of intensive treatment for diabetic patients without CKD, such as Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and the Veteran Affairs Diabetes Trial (VADT) [7–9]. Hence, whereas hyperglycemia was traditionally the main focus of attention, contemporary medicine considers the occurrence of hypoglycemia as an even more significant challenge in the management of type 2 diabetes.
Metformin, the most commonly used antihyperglycemic agent for type 2 diabetes mellitus, is excreted renally and is contraindicated, per current US Food and Drug Administration (FDA) prescribing information, in men with a serum
100
Abe · Okada Nitta K (ed): Chronic Kidney Diseases – Recent Advances in Clinical and Basic Research. Contrib Nephrol. Basel, Karger, 2015, vol 185, pp 98–115 (DOI: 10.1159/000380974)
Downloaded by: UCONN Storrs 137.99.31.134 - 5/21/2015 6:25:25 PM
Antihyperglycemic Agents in Patients with Chronic Kidney Disease or End-Stage Kidney Disease on Dialysis
creatinine (sCr) >1.5 mg/dl and in women with an sCr >1.4 mg/dl. The Japanese Society of Nephrology and British National Formulary recommend cessation if GFR
