Journal of Pharmacy Practice http://jpp.sagepub.com/
Alogliptin: Safety, Efficacy, and Clinical Implications Adriane B. Marino and Sabrina W. Cole Journal of Pharmacy Practice published online 13 February 2014 DOI: 10.1177/0897190014522063 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2014/02/13/0897190014522063
Published by: http://www.sagepublications.com
On behalf of:
New York State Council of Health-system Pharmacists
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Alogliptin: Safety, Efficacy, and Clinical Implications Adriane B. Marino, PharmD1, and Sabrina W. Cole, PharmD, BCPS1
Abstract Purpose: Alogliptin is the newest dipeptidyl peptidase 4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes either alone or in combination with other antidiabetic agents. The purpose of this review is to highlight the clinical studies that led to Food and Drug Administration approval of alogliptin and to provide insight into the place in therapy for the management of type 2 diabetes mellitus. Summary: As a DPP-4 inhibitor, alogliptin raises postprandial levels of glucagon-like peptide 1, leading to insulin secretion and glucose homeostasis. When given as monotherapy, alogliptin has the ability to reduce glycoslate hemoglobin A1c (HbA1c) by 0.4% to 1.0%. Combination therapy yielded similar reductions with some variability depending on the agent with which alogliptin was combined. The mean HbA1c reduction seen with alogliptin is relative to the degree of HbA1c elevation at baseline. Alogliptin appears to be weight neutral and is relatively well tolerated with few adverse effects. Furthermore, alogliptin has proven to result in comparable efficacy and tolerability in the elderly as in the younger population. Conclusion: Alogliptin alone or in combination with other antidiabetic agents has shown a significant reduction in HbA1c while remaining safe and tolerable. The efficacy profile of alogliptin is comparable to other DPP-4 inhibitors. Additional long-term research is necessary with regard to longstanding efficacy and effects on beta-cell function. Keywords alogliptin, dipeptidyl peptidase 4 (DPP-4) inhibitor, type 2 diabetes, oral antidiabetic agent
Approximately 26 million children and adults in the United States have diabetes. This alarming total is over 8.3% of the population and an additional 79 million people have prediabetes. Listed as the seventh leading cause of death, diabetes increases the risk of heart disease or stroke by up to 4 times.1 Elevated glycoslate hemoglobin A1c (HbA1c) is directly linked to increased risk of complications of diabetes, heart disease, and mortality.2-4 Despite the need for intensive glucose control, less than half of adults in the United States with type 2 diabetes reach the target HbA1c of less than 7%.5 For most patients, achieving and maintaining type 2 diabetes mellitus (T2DM) treatment goals require a combination of antidiabetic agents. Utilizing antidiabetic agents with a variety of mechanisms of action has an additive effect. More recently, the role of incretin hormone response has been explored and targeted for new antidiabetic therapies. Glucagon-like peptide 1 (GLP-1) is an incretin hormone released in the intestine and plays a role in glucose homeostasis and insulin secretion. Native GLP-1 increases glucose-dependent insulin secretion, decreases glucagon secretion, and slows gastric emptying in healthy individuals but these effects are often blunted in patients with type 2 diabetes. Unfortunately, native GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) but with DPP-4 inhibition, the incretin system is enhanced and the actions of GLP-1 proceed.
The first DPP-4 inhibitor, sitagliptin, was launched in the United States in 2006. Saxagliptin and linagliptin were approved in 2009 and 2011, respectively. In January 2013, the Food and Drug Administration (FDA) approved a fourth DPP-4 inhibitor, alogliptin. Alogliptin, a DPP-4 inhibitor, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Alogliptin was also approved as part of 2 combination products, alogliptin/metformin and alogliptin/pioglitazone. Alogliptin has been studied as monotherapy and in combination with metformin, glyburide, pioglitazone, and insulin. The objectives of this article are to highlight the clinical studies that led to FDA approval of alogliptin and to provide insight into the place in therapy for the management of T2DM.
Pharmacology and Pharmacokinetics Alogliptin, an orally bioavailable benzoate salt, is a selective inhibitor of DPP-4 activity that increases serum concentrations of incretin by slowing inactivation of the hormone, which leads 1
Wingate University School of Pharmacy, Wingate, NC, USA
Corresponding Author: Adriane B. Marino, Wingate University School of Pharmacy, 515 N. Main St, Wingate, NC 28174, USA. Email: [email protected]
Downloaded from jpp.sagepub.com at OTTO-VON-GUERICKE-UNIVERSITAET on October 27, 2014
2
Journal of Pharmacy Practice
to a reduction in fasting and postprandial glucose (PPG) concentrations.6 The pharmacokinetic parameters of alogliptin are similar in healthy subjects and patients with type 2 diabetes. Alogliptin has 100% bioavailability, without change following intake of a high-fat meal; therefore, aloglipitin may be administered without regard to food. It is well distributed into tissues and achieves peak plasma concentrations 1 to 2 hours following the dose, with a mean terminal half-life of approximately 21 hours. Alogliptin has weak protein binding with 20% bound to proteins in the plasma. It does not undergo extensive metabolism and the majority (60%-71%) of the dose is excreted unchanged in the urine. Currently, there are no data on the pharmacokinetic parameters in pediatric patients. Gender, age, and race did not have a meaningful impact on the pharmacokinetics of alogliptin in clinical trials. In patients with moderate hepatic impairment, the reduction in total and peak exposure to alogliptin was not determined to be clinically significant (10% and 8%, respectively); therefore, no dosage reductions are warranted. Exposure following alogliptin administration has not been studied in patients with severe hepatic impairment. Dosage adjustment in patients with mild renal impairment is not necessary since the 1.2-fold increase in plasma area under the curve (AUC) is not considered to be clinically important. However, dosage modifications are recommended in patients with moderate and severe renal impairment and end-stage renal disease, given the 2-, 3-, and 4-fold increases in plasma AUC following alogliptin administration, respectively.
Dosing and Administration Alogliptin is available as a 6.25, 12.5, and 25 mg tablet. The recommended dose in patients with normal renal function or mild renal impairment (creatinine clearance [CrCl] 60 mL/ min) is 25 mg administered once daily without regard to food. Dose adjustment is necessary in patients with moderate or severe renal impairment or end-stage renal disease. In patients with a CrCl 30 mL/min but
Alogliptin: Safety, Efficacy, and Clinical Implications Adriane B. Marino and Sabrina W. Cole Journal of Pharmacy Practice published online 13 February 2014 DOI: 10.1177/0897190014522063 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2014/02/13/0897190014522063
Published by: http://www.sagepublications.com
On behalf of:
New York State Council of Health-system Pharmacists
Additional services and information for Journal of Pharmacy Practice can be found at: Email Alerts: http://jpp.sagepub.com/cgi/alerts Subscriptions: http://jpp.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Feb 13, 2014 What is This?
Downloaded from jpp.sagepub.com at OTTO-VON-GUERICKE-UNIVERSITAET on October 27, 2014
Review Journal of Pharmacy Practice 1-8 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014522063 jpp.sagepub.com
Alogliptin: Safety, Efficacy, and Clinical Implications Adriane B. Marino, PharmD1, and Sabrina W. Cole, PharmD, BCPS1
Abstract Purpose: Alogliptin is the newest dipeptidyl peptidase 4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes either alone or in combination with other antidiabetic agents. The purpose of this review is to highlight the clinical studies that led to Food and Drug Administration approval of alogliptin and to provide insight into the place in therapy for the management of type 2 diabetes mellitus. Summary: As a DPP-4 inhibitor, alogliptin raises postprandial levels of glucagon-like peptide 1, leading to insulin secretion and glucose homeostasis. When given as monotherapy, alogliptin has the ability to reduce glycoslate hemoglobin A1c (HbA1c) by 0.4% to 1.0%. Combination therapy yielded similar reductions with some variability depending on the agent with which alogliptin was combined. The mean HbA1c reduction seen with alogliptin is relative to the degree of HbA1c elevation at baseline. Alogliptin appears to be weight neutral and is relatively well tolerated with few adverse effects. Furthermore, alogliptin has proven to result in comparable efficacy and tolerability in the elderly as in the younger population. Conclusion: Alogliptin alone or in combination with other antidiabetic agents has shown a significant reduction in HbA1c while remaining safe and tolerable. The efficacy profile of alogliptin is comparable to other DPP-4 inhibitors. Additional long-term research is necessary with regard to longstanding efficacy and effects on beta-cell function. Keywords alogliptin, dipeptidyl peptidase 4 (DPP-4) inhibitor, type 2 diabetes, oral antidiabetic agent
Approximately 26 million children and adults in the United States have diabetes. This alarming total is over 8.3% of the population and an additional 79 million people have prediabetes. Listed as the seventh leading cause of death, diabetes increases the risk of heart disease or stroke by up to 4 times.1 Elevated glycoslate hemoglobin A1c (HbA1c) is directly linked to increased risk of complications of diabetes, heart disease, and mortality.2-4 Despite the need for intensive glucose control, less than half of adults in the United States with type 2 diabetes reach the target HbA1c of less than 7%.5 For most patients, achieving and maintaining type 2 diabetes mellitus (T2DM) treatment goals require a combination of antidiabetic agents. Utilizing antidiabetic agents with a variety of mechanisms of action has an additive effect. More recently, the role of incretin hormone response has been explored and targeted for new antidiabetic therapies. Glucagon-like peptide 1 (GLP-1) is an incretin hormone released in the intestine and plays a role in glucose homeostasis and insulin secretion. Native GLP-1 increases glucose-dependent insulin secretion, decreases glucagon secretion, and slows gastric emptying in healthy individuals but these effects are often blunted in patients with type 2 diabetes. Unfortunately, native GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) but with DPP-4 inhibition, the incretin system is enhanced and the actions of GLP-1 proceed.
The first DPP-4 inhibitor, sitagliptin, was launched in the United States in 2006. Saxagliptin and linagliptin were approved in 2009 and 2011, respectively. In January 2013, the Food and Drug Administration (FDA) approved a fourth DPP-4 inhibitor, alogliptin. Alogliptin, a DPP-4 inhibitor, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Alogliptin was also approved as part of 2 combination products, alogliptin/metformin and alogliptin/pioglitazone. Alogliptin has been studied as monotherapy and in combination with metformin, glyburide, pioglitazone, and insulin. The objectives of this article are to highlight the clinical studies that led to FDA approval of alogliptin and to provide insight into the place in therapy for the management of T2DM.
Pharmacology and Pharmacokinetics Alogliptin, an orally bioavailable benzoate salt, is a selective inhibitor of DPP-4 activity that increases serum concentrations of incretin by slowing inactivation of the hormone, which leads 1
Wingate University School of Pharmacy, Wingate, NC, USA
Corresponding Author: Adriane B. Marino, Wingate University School of Pharmacy, 515 N. Main St, Wingate, NC 28174, USA. Email: [email protected]
Downloaded from jpp.sagepub.com at OTTO-VON-GUERICKE-UNIVERSITAET on October 27, 2014
2
Journal of Pharmacy Practice
to a reduction in fasting and postprandial glucose (PPG) concentrations.6 The pharmacokinetic parameters of alogliptin are similar in healthy subjects and patients with type 2 diabetes. Alogliptin has 100% bioavailability, without change following intake of a high-fat meal; therefore, aloglipitin may be administered without regard to food. It is well distributed into tissues and achieves peak plasma concentrations 1 to 2 hours following the dose, with a mean terminal half-life of approximately 21 hours. Alogliptin has weak protein binding with 20% bound to proteins in the plasma. It does not undergo extensive metabolism and the majority (60%-71%) of the dose is excreted unchanged in the urine. Currently, there are no data on the pharmacokinetic parameters in pediatric patients. Gender, age, and race did not have a meaningful impact on the pharmacokinetics of alogliptin in clinical trials. In patients with moderate hepatic impairment, the reduction in total and peak exposure to alogliptin was not determined to be clinically significant (10% and 8%, respectively); therefore, no dosage reductions are warranted. Exposure following alogliptin administration has not been studied in patients with severe hepatic impairment. Dosage adjustment in patients with mild renal impairment is not necessary since the 1.2-fold increase in plasma area under the curve (AUC) is not considered to be clinically important. However, dosage modifications are recommended in patients with moderate and severe renal impairment and end-stage renal disease, given the 2-, 3-, and 4-fold increases in plasma AUC following alogliptin administration, respectively.
Dosing and Administration Alogliptin is available as a 6.25, 12.5, and 25 mg tablet. The recommended dose in patients with normal renal function or mild renal impairment (creatinine clearance [CrCl] 60 mL/ min) is 25 mg administered once daily without regard to food. Dose adjustment is necessary in patients with moderate or severe renal impairment or end-stage renal disease. In patients with a CrCl 30 mL/min but
