503626
research-article2013
AOPXXX10.1177/1060028013503626Annals of PharmacotherapyNigro et al
Review Article-New Drug Approvals
Canagliflozin, a Novel SGLT2 Inhibitor for Treatment of Type 2 Diabetes
Annals of Pharmacotherapy 47(10) 1301–1311 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013503626 aop.sagepub.com
Stefanie C. Nigro, PharmD, BCACP, BC-ADM1, Daniel M. Riche, PharmD, BCPS, CDE2,3, Michelle Pheng, PharmD4, and William L. Baker, PharmD, FCCP, BCPS5
Abstract Objective: To evaluate the available clinical data on canagliflozin and provide formulary considerations as to its place in the current treatment approach of type 2 diabetes mellitus (T2DM). Data Sources: A systematic review of the literature in MEDLINE and Web of Science was performed through July 2013 using the key words and medical subject headings canagliflozin, JNJ-28431754, TA-7284, and sodium-glucose co-transporter 2 inhibitor. A manual search of references from reports of clinical trials or review articles was performed to identify additional relevant studies. Study Selection and Data Extraction: Citations eligible for inclusion were in vitro or in vivo evaluations of canagliflozin with no restrictions on patient population or indication used. Data related to the patient populations and outcomes of interest were extracted from each citation. Data Synthesis: Five clinical trials (n = 2775 subjects) have been published evaluating canagliflozin in patients with T2DM. A single study evaluated canagliflozin monotherapy, while the others included various add-on therapies. Four studies included placebo groups with 2 others using sitagliptin as an active control. Compared with placebo (+0.14%), canagliflozin monotherapy at doses of 100 to 300 mg/d decreases hemoglobin A1c by −0.77% to −1.03% from baseline. Reductions in fasting plasma glucose, body weight, and systolic blood pressure were seen. Because of the increase in glucosuria with the drug, patients (especially females) are at increased risk of genital mycotic infections. The overall safety of canagliflozin (eg, cardiovascular, oncologic, pancreatic, bone) is also yet to be fully elucidated. Conclusions: Canagliflozin is comparable to second-line oral medications in terms of effectiveness but has limitations in affordability and long-term safety data. Keywords canagliflozin, SGLT2 inhibitor, type 2 diabetes mellitus
Introduction Nearly 26 million Americans (8.3%) are diagnosed with diabetes and an additional 79 million at risk for developing the disease.1 Current clinical practice guidelines strongly emphasize treatment and prevention strategies that include individualized patient care planning, early lifestyle interventions, and the use of pharmacotherapy (Table 1)2,3 to help minimize the growing burden of disease.4,5 The pathogenesis of type 2 diabetes mellitus (T2DM) is complex and multifactorial. Characteristics of T2DM have been expanded from diminished (or absent) insulin secretion, increased gluconeogenesis and decreased peripheral uptake of glucose to include a multitude of pathophysiologic abnormalities.7 Discovery of neurotransmitter dysfunction and an impaired incretin effect has led to the development of newer drug therapies (ie, dipeptidyl peptidase-4 inhibitors [DPP-4] inhibitors and glucagon-like peptide 1 [GLP-1] agonists) and
an expansion of the clinical utility of existing therapies (ie, bromocriptine, colesevelam). Most recently, the kidney has been the target for drug development. It is estimated that >90% of all filtered glucose is reabsorbed by the sodium-glucose transporter 2 (SGLT2) in the kidney’s proximal tubule.8 Therefore, glucose homeostasis can be maintained via decreased 1
Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA 2 School of Pharmacy, The University of Mississippi, Jackson, MS, USA 3 Cardiometabolic Clinic, The University of Mississippi Medical Center, Jackson, MS, USA 4 CVS Pharmacy, Middletown, CT, USA 5 University of Connecticut, Storrs, CT, USA Corresponding Author: William L. Baker, School of Pharmacy, University of Connecticut, 69 N. Eagleville Rd, Unit 3092, Storrs, CT 06269-3092, USA. Email: [email protected]
Downloaded from aop.sagepub.com at Library - Periodicals Dept on October 6, 2014
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Annals of Pharmacotherapy 47(10)
Table 1. Oral and Non-Insulin Injectables for Type 2 Diabetes.2,4,6. Medication Class
Proposed Site of Action
Sulfonylureas (glyburide, glipizide, glimepiride Biguanide (metformin) α-Glucosidase inhibitors (acarbose, miglitol) Dipeptidyl peptidase-4 inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin) Amylin agonist (pramlintide) Thiazolidinediones (pioglitazone, rosiglitazone) Glinides (repaglinide, nateglinide) Glucagon-like, peptide-1 receptor agonists (exenatide, exenatide extended-release, liraglutide) DA-2 agonist (bromocriptine) Bile acid sequestrant (colesevelam) Sodium-glucose transport inhibitors (canaglifozin)
Expected HbA1c Lowering With Monotherapy (%)
Pancreas (beta cells) Liver, peripheral tissue Small intestine GI tract
1.0-2.0 1.0-2.0 0.5-0.8 0.5-0.8
Pancreas (alpha cells) Adipose and peripheral tissue Pancreas (beta cells) GI tract and liver
0.5-1.0 0.5-1.4 0.5-1.5 0.5-1.0
Brain Small intestine, liver Kidney
400 mg daily). The RTG is the glucose concentration below which minimal UGE occurs, and above which UGE rises in direct proportion to plasma glucose. It is calculated from the plasma glucose profiles, UGE, and glomerular filtration rate. Urinary glucose excretion was also similarly increased in a dose-dependent manner by ~70 g with canagliflozin doses >200 mg. Fasting plasma glucose (FPG) and serum insulin concentrations were generally similar among the treatment groups. These results were repeated in a phase 1b study of patients with T2DM who were on stable doses of insulin either alone or in combination with other oral antihyperglycemic agents (AHA) and were not optimally controlled.22 Subjects were randomized to receive either canagliflozin 100 mg daily, 300 mg twice daily, or placebo for 28 days in addition to their other therapies. The change from baseline of UGE for canagliflozin 100 mg daily and 300 mg twice daily was 67 g/d and 153 g/d versus placebo (P < .05 for both). The change from baseline of RTG was similarly decreased versus placebo (P < .05 for both). Canagliflozin 100 mg daily and 300 mg twice daily also significantly reduced FPG (−38.0 mg/dL and −42.3 mg/dL) and hemoglobin A1c (HbA1c) (−0.37% and −0.55%) from baseline versus placebo (+8.6 mg/dL, and −0.19%, respectively; P < .05 for both).
Pharmacokinetics Following oral administration, canagliflozin has a mean absolute oral bioavailability of approximately 65%.3 Administration with a high-fat meal does not affect this absorption. Canagliflozin is extensively distributed into tissues, with a mean steady-state volume of distribution of 119 L, and is 99% bound to plasma proteins.3 Hepatic conversion of canagliflozin to two inactive O-glucuronide metabolites (M5 and M7) is its primary mode of metabolism, with minimal (~7%) additional metabolism by the CYP3A4 isoenzyme.3,23 Median tmax values for canagliflozin, M5, and M7 were 1.5 to 2.0, 1.75 to 4.5, and 2.0 to 3.0 hours, respectively, regardless of dose. The terminal elimination half-life for canagliflozin was 14 to 16 hours, which was independent of dose. Renal excretion of canagliflozin, M5, and M7 was
research-article2013
AOPXXX10.1177/1060028013503626Annals of PharmacotherapyNigro et al
Review Article-New Drug Approvals
Canagliflozin, a Novel SGLT2 Inhibitor for Treatment of Type 2 Diabetes
Annals of Pharmacotherapy 47(10) 1301–1311 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013503626 aop.sagepub.com
Stefanie C. Nigro, PharmD, BCACP, BC-ADM1, Daniel M. Riche, PharmD, BCPS, CDE2,3, Michelle Pheng, PharmD4, and William L. Baker, PharmD, FCCP, BCPS5
Abstract Objective: To evaluate the available clinical data on canagliflozin and provide formulary considerations as to its place in the current treatment approach of type 2 diabetes mellitus (T2DM). Data Sources: A systematic review of the literature in MEDLINE and Web of Science was performed through July 2013 using the key words and medical subject headings canagliflozin, JNJ-28431754, TA-7284, and sodium-glucose co-transporter 2 inhibitor. A manual search of references from reports of clinical trials or review articles was performed to identify additional relevant studies. Study Selection and Data Extraction: Citations eligible for inclusion were in vitro or in vivo evaluations of canagliflozin with no restrictions on patient population or indication used. Data related to the patient populations and outcomes of interest were extracted from each citation. Data Synthesis: Five clinical trials (n = 2775 subjects) have been published evaluating canagliflozin in patients with T2DM. A single study evaluated canagliflozin monotherapy, while the others included various add-on therapies. Four studies included placebo groups with 2 others using sitagliptin as an active control. Compared with placebo (+0.14%), canagliflozin monotherapy at doses of 100 to 300 mg/d decreases hemoglobin A1c by −0.77% to −1.03% from baseline. Reductions in fasting plasma glucose, body weight, and systolic blood pressure were seen. Because of the increase in glucosuria with the drug, patients (especially females) are at increased risk of genital mycotic infections. The overall safety of canagliflozin (eg, cardiovascular, oncologic, pancreatic, bone) is also yet to be fully elucidated. Conclusions: Canagliflozin is comparable to second-line oral medications in terms of effectiveness but has limitations in affordability and long-term safety data. Keywords canagliflozin, SGLT2 inhibitor, type 2 diabetes mellitus
Introduction Nearly 26 million Americans (8.3%) are diagnosed with diabetes and an additional 79 million at risk for developing the disease.1 Current clinical practice guidelines strongly emphasize treatment and prevention strategies that include individualized patient care planning, early lifestyle interventions, and the use of pharmacotherapy (Table 1)2,3 to help minimize the growing burden of disease.4,5 The pathogenesis of type 2 diabetes mellitus (T2DM) is complex and multifactorial. Characteristics of T2DM have been expanded from diminished (or absent) insulin secretion, increased gluconeogenesis and decreased peripheral uptake of glucose to include a multitude of pathophysiologic abnormalities.7 Discovery of neurotransmitter dysfunction and an impaired incretin effect has led to the development of newer drug therapies (ie, dipeptidyl peptidase-4 inhibitors [DPP-4] inhibitors and glucagon-like peptide 1 [GLP-1] agonists) and
an expansion of the clinical utility of existing therapies (ie, bromocriptine, colesevelam). Most recently, the kidney has been the target for drug development. It is estimated that >90% of all filtered glucose is reabsorbed by the sodium-glucose transporter 2 (SGLT2) in the kidney’s proximal tubule.8 Therefore, glucose homeostasis can be maintained via decreased 1
Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA 2 School of Pharmacy, The University of Mississippi, Jackson, MS, USA 3 Cardiometabolic Clinic, The University of Mississippi Medical Center, Jackson, MS, USA 4 CVS Pharmacy, Middletown, CT, USA 5 University of Connecticut, Storrs, CT, USA Corresponding Author: William L. Baker, School of Pharmacy, University of Connecticut, 69 N. Eagleville Rd, Unit 3092, Storrs, CT 06269-3092, USA. Email: [email protected]
Downloaded from aop.sagepub.com at Library - Periodicals Dept on October 6, 2014
1302
Annals of Pharmacotherapy 47(10)
Table 1. Oral and Non-Insulin Injectables for Type 2 Diabetes.2,4,6. Medication Class
Proposed Site of Action
Sulfonylureas (glyburide, glipizide, glimepiride Biguanide (metformin) α-Glucosidase inhibitors (acarbose, miglitol) Dipeptidyl peptidase-4 inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin) Amylin agonist (pramlintide) Thiazolidinediones (pioglitazone, rosiglitazone) Glinides (repaglinide, nateglinide) Glucagon-like, peptide-1 receptor agonists (exenatide, exenatide extended-release, liraglutide) DA-2 agonist (bromocriptine) Bile acid sequestrant (colesevelam) Sodium-glucose transport inhibitors (canaglifozin)
Expected HbA1c Lowering With Monotherapy (%)
Pancreas (beta cells) Liver, peripheral tissue Small intestine GI tract
1.0-2.0 1.0-2.0 0.5-0.8 0.5-0.8
Pancreas (alpha cells) Adipose and peripheral tissue Pancreas (beta cells) GI tract and liver
0.5-1.0 0.5-1.4 0.5-1.5 0.5-1.0
Brain Small intestine, liver Kidney
400 mg daily). The RTG is the glucose concentration below which minimal UGE occurs, and above which UGE rises in direct proportion to plasma glucose. It is calculated from the plasma glucose profiles, UGE, and glomerular filtration rate. Urinary glucose excretion was also similarly increased in a dose-dependent manner by ~70 g with canagliflozin doses >200 mg. Fasting plasma glucose (FPG) and serum insulin concentrations were generally similar among the treatment groups. These results were repeated in a phase 1b study of patients with T2DM who were on stable doses of insulin either alone or in combination with other oral antihyperglycemic agents (AHA) and were not optimally controlled.22 Subjects were randomized to receive either canagliflozin 100 mg daily, 300 mg twice daily, or placebo for 28 days in addition to their other therapies. The change from baseline of UGE for canagliflozin 100 mg daily and 300 mg twice daily was 67 g/d and 153 g/d versus placebo (P < .05 for both). The change from baseline of RTG was similarly decreased versus placebo (P < .05 for both). Canagliflozin 100 mg daily and 300 mg twice daily also significantly reduced FPG (−38.0 mg/dL and −42.3 mg/dL) and hemoglobin A1c (HbA1c) (−0.37% and −0.55%) from baseline versus placebo (+8.6 mg/dL, and −0.19%, respectively; P < .05 for both).
Pharmacokinetics Following oral administration, canagliflozin has a mean absolute oral bioavailability of approximately 65%.3 Administration with a high-fat meal does not affect this absorption. Canagliflozin is extensively distributed into tissues, with a mean steady-state volume of distribution of 119 L, and is 99% bound to plasma proteins.3 Hepatic conversion of canagliflozin to two inactive O-glucuronide metabolites (M5 and M7) is its primary mode of metabolism, with minimal (~7%) additional metabolism by the CYP3A4 isoenzyme.3,23 Median tmax values for canagliflozin, M5, and M7 were 1.5 to 2.0, 1.75 to 4.5, and 2.0 to 3.0 hours, respectively, regardless of dose. The terminal elimination half-life for canagliflozin was 14 to 16 hours, which was independent of dose. Renal excretion of canagliflozin, M5, and M7 was
