Mild Renal Impairment and Efficacy and Safety of Liraglutide
Mild Renal Impairment and Efficacy and Safety of Liraglutide
Objective: To determine the effect of mild renal impairment (RI) on the efficacy and safety of liraglutide in patients with type 2 diabetes mellitus.
Methods: In this meta-analysis, we examined the 6 LEAD (Liraglutide Effect and Action in Diabetes) studies. Data from patients with type 2 diabetes who had normal renal function, mild RI, or moderate or severe RI were pooled for analysis. Renal function was measured by creatinine clearance as determined by the Cockcroft-Gault equation: normal renal function = creatinine clearance >89 mL/min; mild RI = 60 mL/min ≤ creatinine clearance ≤ 89 mL/min; and moderate or severe RI = creatinine clearance <60 mL/min. The meta-analysis included patients administered once-daily liraglutide (1.2 or 1.8 mg) or placebo as either monotherapy or in combination with oral antidiabetic drugs for 26 weeks. In addition, a pooled analysis of all phase 2 and 3 liraglutide trials was done to examine rates of altered renal function.
Results: Mild RI did not affect the estimated treatment differences in hemoglobin A1c Patients with normal renal function demonstrated decreases in body weight and systolic blood pressure with either dosage of liraglutide, whereas patients in either RI group also demonstrated a decrease in body weight and systolic blood pressure, but these differences were not significant compared with differences observed in the placebo group. Liraglutide treatment vs placebo was safe and well tolerated in patients with mild RI, as there were no significant differences in rates of renal injury, minor hypoglycemia, or nausea. A trend towards increased nausea was observed in patients with moderate or severe RI receiving liraglutide, although the number of patients in this treatment group was too low to determine significance.
Conclusion:Mild RI, as determined by the Cockcroft-Gault equation, had no effect on the efficacy and safety of liraglutide in this meta-analysis.
Type 2 diabetes mellitus (T2DM) is a major risk factor for progressive chronic kidney disease, and approximately 20% to 40% of patients with T2DM develop diabetic nephropathy. Worldwide, diabetic nephropathy is the leading cause of end-stage renal disease. Treatment considerations that address glycemia for diabetic patients with renal impairment (RI) are complex and limited, and there is no consensus on how to most safely achieve the recommended glycemic targets. The ability to achieve tight glycemic control in the setting of RI may be offset by adverse events and complications imposed by some antidiabetic agents. Metformin, for instance, is contraindicated in patients with RI because it is cleared by the kidney. Other oral antidiabetic drugs such as thiazolidinediones and sulfonylureas, although not contraindicated in RI, can cause edema and fluid retention (thiazolidinediones) or an increased risk of hypoglycemia (sulfonylureas). In addition, initial dosage selection and dosage escalation with sulfonylureas should be conservative in patients with T2DM and RI. Finally, acarbose (an a-glucosidase inhibitor), is excreted by the kidneys and is not recommended for patients with diabetes complicated by RI.
Insulin therapy is also associated with safety issues in patients with RI because approximately 30% to 80% of systemic insulin is metabolized in the kidney. Significant RI may lead to reduced insulin clearance and prolonged insulin effects, most notably severe hypoglycemia Persons with RI also tend to have reduced appetite, less muscle mass, and reduced gluconeogenesis, which may make accurately dosing and titrating basal insulin more difficult. Therefore, frequent dosage adjustments may be required.
Glucagonlike peptide 1 (GLP-1), a member of the incretin family of hormones, rapidly lowers blood glucose through glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion. GLP-1 also delays gastric emptying and induces satiety, thereby resulting in weight loss. Native GLP-1 has a short half-life because of metabolism by dipeptidyl-peptidase 4 and other endopeptidases. A number of current therapies have used dipeptidyl-peptidase 4 inhibition to prolong the half-life of endogenous GLP-1. Dipeptidyl-peptidase 4 inhibitors such as sitagliptin and saxagliptin lower blood glucose and modestly raise circulating GLP-1 levels. Sitagliptin and saxagliptin can be used by patients with RI, although both are excreted intact in the urine and both require dosage adjustment in patients with moderate and severe RI.
Because of its short half-life, native GLP-1 is not a viable molecule for diabetes therapy. To address this issue, dipeptidyl-peptidase 4–resistant GLP-1 receptor agonists, such as exenatide and liraglutide, have been developed. Exenatide (synthetic exendin-4) shares 53% homology with human GLP-1. Twice-daily exenatide can decrease hemoglobin A1c by 0.5% to 1.0% and is associated with weight loss. Exenatide, like native GLP-1 and its metabolites, is cleared primarily by glomerular filtration and should not be used in patients with severe RI or end-stage renal disease. Recently, the US Food and Drug Administration recommended caution when using exenatide in patients with moderate RI based on reports of acute renal failure associated with exenatide use.
Liraglutide is a human GLP-1 analogue currently approved for once-daily treatment of T2DM. Numerous studies have revealed that liraglutide effectively lowers hemoglobin A1c as monotherapy (17) and in combination with oral antidiabetic drugs, with a very low risk of hypoglycemia. Liraglutide also decreases fasting and postprandial glucose, promotes weight loss, and reduces systolic blood pressure.
Unlike native GLP-1 and exenatide, liraglutide is not cleared by the glomerulus and its pharmacokinetics are not substantially altered in nondiabetic patients with varying degrees of RI. Furthermore, liraglutide is metabolized by endopeptidases found in the circulation and in a variety of tissues. These physiologic and pharmacologic properties may offer some clear advantages of liraglutide in the setting of RI. The purpose of this meta-analysis was to determine whether mild RI affected the efficacy and safety of liraglutide in patients with T2DM. In addition, a pooled safety analysis was done to further assess the renal safety of liraglutide.
Abstract and Introduction
Abstract
Objective: To determine the effect of mild renal impairment (RI) on the efficacy and safety of liraglutide in patients with type 2 diabetes mellitus.
Methods: In this meta-analysis, we examined the 6 LEAD (Liraglutide Effect and Action in Diabetes) studies. Data from patients with type 2 diabetes who had normal renal function, mild RI, or moderate or severe RI were pooled for analysis. Renal function was measured by creatinine clearance as determined by the Cockcroft-Gault equation: normal renal function = creatinine clearance >89 mL/min; mild RI = 60 mL/min ≤ creatinine clearance ≤ 89 mL/min; and moderate or severe RI = creatinine clearance <60 mL/min. The meta-analysis included patients administered once-daily liraglutide (1.2 or 1.8 mg) or placebo as either monotherapy or in combination with oral antidiabetic drugs for 26 weeks. In addition, a pooled analysis of all phase 2 and 3 liraglutide trials was done to examine rates of altered renal function.
Results: Mild RI did not affect the estimated treatment differences in hemoglobin A1c Patients with normal renal function demonstrated decreases in body weight and systolic blood pressure with either dosage of liraglutide, whereas patients in either RI group also demonstrated a decrease in body weight and systolic blood pressure, but these differences were not significant compared with differences observed in the placebo group. Liraglutide treatment vs placebo was safe and well tolerated in patients with mild RI, as there were no significant differences in rates of renal injury, minor hypoglycemia, or nausea. A trend towards increased nausea was observed in patients with moderate or severe RI receiving liraglutide, although the number of patients in this treatment group was too low to determine significance.
Conclusion:Mild RI, as determined by the Cockcroft-Gault equation, had no effect on the efficacy and safety of liraglutide in this meta-analysis.
Introduction
Type 2 diabetes mellitus (T2DM) is a major risk factor for progressive chronic kidney disease, and approximately 20% to 40% of patients with T2DM develop diabetic nephropathy. Worldwide, diabetic nephropathy is the leading cause of end-stage renal disease. Treatment considerations that address glycemia for diabetic patients with renal impairment (RI) are complex and limited, and there is no consensus on how to most safely achieve the recommended glycemic targets. The ability to achieve tight glycemic control in the setting of RI may be offset by adverse events and complications imposed by some antidiabetic agents. Metformin, for instance, is contraindicated in patients with RI because it is cleared by the kidney. Other oral antidiabetic drugs such as thiazolidinediones and sulfonylureas, although not contraindicated in RI, can cause edema and fluid retention (thiazolidinediones) or an increased risk of hypoglycemia (sulfonylureas). In addition, initial dosage selection and dosage escalation with sulfonylureas should be conservative in patients with T2DM and RI. Finally, acarbose (an a-glucosidase inhibitor), is excreted by the kidneys and is not recommended for patients with diabetes complicated by RI.
Insulin therapy is also associated with safety issues in patients with RI because approximately 30% to 80% of systemic insulin is metabolized in the kidney. Significant RI may lead to reduced insulin clearance and prolonged insulin effects, most notably severe hypoglycemia Persons with RI also tend to have reduced appetite, less muscle mass, and reduced gluconeogenesis, which may make accurately dosing and titrating basal insulin more difficult. Therefore, frequent dosage adjustments may be required.
Glucagonlike peptide 1 (GLP-1), a member of the incretin family of hormones, rapidly lowers blood glucose through glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion. GLP-1 also delays gastric emptying and induces satiety, thereby resulting in weight loss. Native GLP-1 has a short half-life because of metabolism by dipeptidyl-peptidase 4 and other endopeptidases. A number of current therapies have used dipeptidyl-peptidase 4 inhibition to prolong the half-life of endogenous GLP-1. Dipeptidyl-peptidase 4 inhibitors such as sitagliptin and saxagliptin lower blood glucose and modestly raise circulating GLP-1 levels. Sitagliptin and saxagliptin can be used by patients with RI, although both are excreted intact in the urine and both require dosage adjustment in patients with moderate and severe RI.
Because of its short half-life, native GLP-1 is not a viable molecule for diabetes therapy. To address this issue, dipeptidyl-peptidase 4–resistant GLP-1 receptor agonists, such as exenatide and liraglutide, have been developed. Exenatide (synthetic exendin-4) shares 53% homology with human GLP-1. Twice-daily exenatide can decrease hemoglobin A1c by 0.5% to 1.0% and is associated with weight loss. Exenatide, like native GLP-1 and its metabolites, is cleared primarily by glomerular filtration and should not be used in patients with severe RI or end-stage renal disease. Recently, the US Food and Drug Administration recommended caution when using exenatide in patients with moderate RI based on reports of acute renal failure associated with exenatide use.
Liraglutide is a human GLP-1 analogue currently approved for once-daily treatment of T2DM. Numerous studies have revealed that liraglutide effectively lowers hemoglobin A1c as monotherapy (17) and in combination with oral antidiabetic drugs, with a very low risk of hypoglycemia. Liraglutide also decreases fasting and postprandial glucose, promotes weight loss, and reduces systolic blood pressure.
Unlike native GLP-1 and exenatide, liraglutide is not cleared by the glomerulus and its pharmacokinetics are not substantially altered in nondiabetic patients with varying degrees of RI. Furthermore, liraglutide is metabolized by endopeptidases found in the circulation and in a variety of tissues. These physiologic and pharmacologic properties may offer some clear advantages of liraglutide in the setting of RI. The purpose of this meta-analysis was to determine whether mild RI affected the efficacy and safety of liraglutide in patients with T2DM. In addition, a pooled safety analysis was done to further assess the renal safety of liraglutide.