Canagliflozin (Invokana), a Novel Oral Agent For Type-2 Diabetes

DrUG FOrECAST Canagliflozin (Invokana), a Novel Oral Agent For Type-2 Diabetes Sheila Sarnoski-Brocavich, BS, MS, PharmD, BCACP, CGP; and Olga Hilas, PharmD, MPH, BCPS, CGP INTRODUCTION The prevalence of diabetes in the U.S. has more than tripled, from 5.6 million to 20.9 million over the last three decades, with type-2 diabetes accounting for 90% to 95% of the diagnosed cases. 1,2 It is projected that one in three American adults will have diabetes in 2050 if this trend continues. 3 Type-2 diabetes mellitus is a progressive disease resulting from an insulin secretory defect characterized by insulin resistance and some degree of insulin deficiency. 4 The prevalence of the disease is increased in obese patients, minority populations, and the elderly. 2,5 Chronic long-term hyperglycemia associated with diabetes is the cause of serious complications, including blindness, kidney failure, amputations, and death. 2 The economic burden associated with complications of diabetes in the U.S. was $245 billion in 2012. 6 Oral hypoglycemia agents and insulin are standard therapeutic approaches, along with lifestyle modifications, to manage type-2 diabetes and to prevent Dr. Sarnoski-Brocavich is Assistant Clinical Professor in Clinical Pharmacy Practice at St. John s University College of Pharmacy and Health Sciences, in Queens, New York, and Ambulatory Care Affiliate Pharmacy Faculty at Queens Hospital Center in Jamaica, New York. Dr. Hilas is Associate Clinical Professor in Clinical Pharmacy Practice at St. John s University College of Pharmacy and Health Sciences in Queens. She is also a Clinical Pharmacy Manager of Internal Medicine/ Geriatrics at New York Presbyterian Hospital, Weill Cornell Medical Center, in New York, New York. Drug Forecast is a regular column coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi & Associates in New York, New York. Disclosure: The authors report that they have no commercial or financial relationships in regard to this article. complications. 7,8 Despite current available therapies, about 50% of patients in the U.S. are not achieving their goals for glycosylated hemoglobin (HbA 1c ), blood pressure, and low-density lipoprotein-cholesterol (HDL-C) levels, as recommended by the American Diabetes Association (ADA), and 81.2% are reported to be deficient in meeting all three goals. 8 Metformin (Glucophage, Bristol-Myers Squibb) is considered the initial standard of care unless it is contraindicated. 7 Insulin with or without additional agents can be added to treat newly diagnosed type-2 diabetes in patients with elevated glucose or elevated HbA 1c levels. 7 A second oral agent such as a glucagon-like peptide (GLP) receptor agonist, a dipeptidyl peptidase IV (DPP-4) inhibitor, a peroxisome proliferator-activated receptor (PPAR) agonist, or insulin may be required if non-insulin monotherapy has been ineffective in achieving HbA 1c goals within 3 to 6 months. 7 Recent recommendations from the ADA and the European Association for the Study of Diabetes (EASD), along with the American Association of Clinical Endocrinologists (AACE), advise a patient-centered approach to management. 9,10 Preferred medications are those that carry a low risk of hypoglycemia, minimize the risk of weight gain, are easy to administer, are cost-effective, and are safe to use. 10 In March 2013, the FDA approved canagliflozin (Invokana, Janssen) as an adjunct to diet and exercise for adults with type-2 diabetes mellitus. This is the first oral agent in a novel class of diabetes drugs known as sodium glucose co-transporter-2 (SGLT-2) inhibitors. 11 Current research has focused on the role of the kidney in glucose homeostasis and has identified the role of SGLT-2 in mediating the reabsorption of filtered glucose in the proximal tubule. 11,12 The inhibition of SGLT-2 provides a novel mechanism to lower elevated plasma glucose levels in diabetic patients. 12,13 PHARMACOLOGY AND MECHANISM OF ACTION 14 18 SGLT-2 is a high-capacity, low-affinity transporter located in the brush border of the membrane of the early segment of the proximal tubule. Canagliflozin is an SGLT-2 inhibitor that increases glucose excretion in the urine by reducing reabsorption of filtered glucose and lowering the renal glucose threshold. The structural formula of canagliflozin is shown in Figure 1. PHARMACOKINETICS AND PHARMACODYNAMICS 11,14,17 Canagliflozin is rapidly absorbed in the gastrointestinal (GI) tract. It has a relative oral bioavailability of 65% and reaches peak concentrations within 1 to 2 hours. It can be taken without regard to food, but it is recommended that it be taken before the first meal of the day to allow for the potential to reduce postprandial plasma glucose excursions resulting from delayed intestinal glucose absorption. Canagliflozin is highly protein-bound, mostly to albumin at 99%. The half-lives of 100 mg and 300 mg are 10.6 hours and 13.1 hours, respectively. The drug is metabolized primarily into two inactive metabolites by uridine diphosphate glucuronosyl transferase (UGT) enzymes: UGT 1A9 and UGT 2B4 via glucuronidation. Approximately 7% of the drug also undergoes oxidation via cytochrome Figure 1 Structure of canagliflozin. 656 P&T November 2013 Vol. 38 No. 11

P450 (CYP) isoenzymes. Canagliflozin is eliminated largely unchanged in the feces (41.5%) and as metabolites in the urine (30.5%). Removal by dialysis is negligible, and hepatic involvement is minimal. CLINICAL EFFICACY 19 21 Several phase 2 and phase 3 clinical trials have been conducted to evaluate the efficacy and safety of canagliflozin. Three important studies have been published and may aid in determining the role of canagliflozin in the treatment of type-2 diabetes. Table 1 summarizes the significant findings of each trial. Stenlof et al. 19 A randomized, double-blind, placebocontrolled phase 3 study was conducted to compare the efficacy and safety of canagliflozin and placebo in patients with type- 2 diabetes mellitus that was not controlled with diet and exercise. This multicenter, multinational study enrolled 584 patients between 18 and 80 years of age. Patients had to have one of the following criteria: (1) they were not receiving an antihyperglycemic agent at screening with HbA 1c between 7% and 10%, or (2) they were taking an antihyperglycemic agent as monotherapy (except for a PPAR-g agonist) or metformin and sulfonylurea combination therapy. Patients who were not taking an antihyperglycemic drug underwent a 2-week, single-blind, placebo run-in period. Those who were receiving antihyperglycemic treatment had an 8-week washout and a diet/exercise period, followed by a 2-week placebo run-in phase. All patients then received canagliflozin 100 mg daily, canagliflozin 300 mg daily, or placebo once daily for 26 weeks. The primary endpoint was the change in HbA 1c from baseline. Secondary endpoints included the proportion of patients who achieved HbA 1c below 7%; changes in fasting plasma glucose (FPG) levels, 2-hour postprandial glucose (PPG) levels, and systolic blood pressure (BP); and the percentage of change in body weight, high-density lipoprotein-cholesterol (HDL-C) levels, and triglyceride levels. At 26 weeks, HbA 1c values were significantly reduced with canagliflozin 100 mg daily and 300 mg daily compared with placebo ( 0.77%; 1.03%, and 0.14%, respectively; P < 0.001 for both canagliflozin groups). Similar reductions in HbA 1c were noted among patients who had not used an antihyperglycemic agent before the study and those who underwent a washout period of anti-hyperglycemic therapy. More patients receiving canagliflozin 100 mg and 300 mg also achieved HbA 1c goals of below 7% (44.5% and 62.4%, respectively) and below 6.5% (17.8% and 28.4%, respectively), compared with patients receiving placebo (20.6% and 5.3%, respectively; P < 0.001 for both canagliflozin groups). Fewer patients receiving canagliflozin 100 mg and 300 mg (2.6% and 2%, respectively), compared with placebo patients (22.7%), required glycemic rescue therapy. These doses also brought about greater reductions in FPG levels over the 26-week study period; the differences in least-squares mean changes were 2 mmol/l and 2.4 mmol/l, respectively; P < 0.001 for both canagliflozin groups). Reported differences in least-squares mean changes for 2-hour PPG levels were 2.7 mmol/l with canagliflozin 100 mg and 3.6 mmol/l with 300 mg (P < 0.001 for both canagliflozin groups). Differences in least-squares mean changes in systolic BP from baseline were also significant at 26 weeks for canagliflozin 100 mg or 300 mg, compared with placebo ( 3.7 mm Hg and 5.4 mm Hg, respectively; P < 0.001 for both canagliflozin groups). Rapid reductions in body weight were observed during the first 6 weeks of canagliflozin treatment, with progressive decreases seen in patients receiving 300 mg and smaller weight reductions in patients receiving 100 mg over the final 20 weeks of the study. Least-squares mean changes in body weight with both 100 mg and 300 mg were significant compared with placebo ( 1.9 kg and 2.9 kg, respectively; P < 0.001 for both canagliflozin groups). Statistically significant HDL-C elevations were reported at week 26 (differences in least-squares mean changes of 6.8% for 100 mg and 6.1% for 300 mg vs. placebo; P < 0.001 for both canagliflozin groups). Nonsignificant reductions in triglyceride levels were also noted for both canagliflozin doses compared with placebo at the end of the treatment period. Adverse events (ADEs) were reported in 61% of patients receiving canagliflozin 100 mg, in 59.9% of patients receiving 300 mg, and in 52.6% of those receiving placebo. Most ADEs were described as mild to moderate in severity. Compared with placebo patients, the canagliflozin treatment groups experienced more genital mycotic infections, urinary tract infections (UTIs), and ADEs associated with osmotic diuresis and reduced intravascular volume. Hypoglycemia was observed in 3.6% of the canagliflozin 100-mg group, in 3% of the 300-mg group, and in 2.6% of the placebo group; no severe cases were reported. One percent of patients in the placebo group and 2.6% of those receiving canagliflozin discontinued treatment because of ADEs. Two deaths (one placebo patient and one patient receiving canagliflozin 100 mg) were reported but were not found to be associated with the treatments. The authors concluded that treatment with canagliflozin in patients with type-2 diabetes that had been inadequately controlled with diet and exercise improved glycemic control, reduced body weight, and was well tolerated. Rosenstock et al. 20 Another randomized, double-blind, placebo-controlled, parallel-group, multicenter, multinational phase 3 study was conducted to evaluate the efficacy and safety of various canagliflozin doses in patients with type-2 diabetes that had not been adequately controlled with metformin. Eligibility criteria included patients 18 to 65 years of age with type-2 diabetes for a period of at least 3 months; HbA 1c level of 7% or higher; 10.5% or fewer receiving metformin alone for 3 months or more at a dose of 1,500 mg/day or higher; a body mass index (BMI) of 25 to 45 kg/m 2 (24 to 45 kg/m 2 for Asian descendants); and serum creatinine levels below 1.5 mg/dl for men and below 1.4 mg/dl for women. Patients (n = 451) received canagliflozin 50, 100, 200, or 300 mg once daily; canagliflozin 300 mg twice daily; or placebo. An arm receiving sitagliptin (Januvia, Merck) 100 mg once daily was also included as an active-reference treatment group but was not compared with the canagliflozin groups. All patients underwent a 3- to 4-week pretreatment screening phase, followed by a 12-week treatment phase and a 2-week post-treatment phase. The primary endpoint was the change in HbA 1c from baseline to the completion of treatment. The secondary endpoints Vol. 38 No. 11 November 2013 P&T 657

Table 1 Evaluating the Use of Canagliflozin in Type-2 Diabetes: Significant Findings From Three Clinical Trials Study Endpoints Results Stenlof et al. 19 Primary: a 1. Change in HbA 1c Canagliflozin 100 mg daily: 0.77% b Canagliflozin 300 mg daily: 1.03% b Placebo 0.14% Secondary: a 1. Proportion of patients who achieved HbA 1c < 7% 2. Change in FPG 3. Change in 2-hour PPG 4. Change in systolic BP 5. Change in body weight 6. Change in HDL-C Canagliflozin 100 mg daily: 44.5% b Canagliflozin 300 mg daily: 62.4% b Placebo: 20.6% Canagliflozin 100 mg daily: 1.5 mmol/l b,c Canagliflozin 300 mg daily: 1.9 mmol/l b,c Placebo: 0.5 mmol/l Canagliflozin 100 mg daily: 2.4 mmol/l b,c Canagliflozin 300 mg daily: 3.3 mmol/l b,c Placebo: 0.3 mmol/l Canagliflozin 100 mg daily: 3.3 mm Hg b,c Canagliflozin 300 mg daily: 5 mm Hg b,c Placebo: 0.4 mmhg Canagliflozin 100 mg daily: 2.5 kg b,c Canagliflozin 300 mg daily: 3.4 kg b,c Placebo: 0.5 kg Canagliflozin 100 mg daily: 11.2% b,c Canagliflozin 300 mg daily: 10.6% c,d Placebo: 4.5% Rosenstock et al. 20 Primary: e Change in HbA 1c Secondary: e 1. Percentage of patients who achieved HbA 1c < 7% 2. Percentage of patients who achieved HbA 1c < 6.5% 3. Change in FPG 0.79%, b 0.76%, b 0.70%, b and 0.92% b (respectively) Canagliflozin 300 mg twice daily: 0.95% b Sitagliptin 100 mg daily: 0.74% b Placebo: 0.22% Canagliflozin > 100 mg daily: 53% 72% f Sitagliptin 100 mg daily: 65% f Placebo: 34% Canagliflozin > 100 mg daily: 27% 42% f Sitagliptin 100 mg daily: 45% f Placebo: 13% 16.2 mg/dl, b 25.2 mg/dl, b 27 mg/dl, b and 25.2 mg/dl b (respectively) Canagliflozin 300 mg twice daily: 23.4 mg/dl b Sitagliptin 100 mg daily: 12.6 mg/dl Placebo: 3.6 mg/dl 658 P&T November 2013 Vol. 38 No. 11

Table 1 Evaluating the Use of Canagliflozin in Type-2 Diabetes: Significant Findings From Three Clinical Trials (continued) Study Endpoints Results Rosenstock 4. Mean weight reduction et al. 20 2.3 kg, b 2.6 kg, b 2.7 kg, b and 3.4 kg b (respectively) continued Canagliflozin 300 mg twice daily: 3.4 kg b Sitagliptin 100 mg daily: 0.6 kg Placebo: 1.1 kg Schernthaner et al. 21 5. Change in UGC ratio Primary: g Change in HbA 1c 1. Percentage of patients who achieved HbA 1c < 7% 2. Percentage of patients who achieved HbA 1c < 6.5% Secondary: g 1. Changes in FPG 2. Change in systolic BP 3. Change in body weight 4. Change in HDL-C 35.4 mg/mg, b 51.5 mg/mg, b 50.5 mg/mg, b and 49.4 mg/mg b (respectively) Canagliflozin 300 mg twice daily: 61.6 mg/mg b Sitagliptin 100 mg daily: 1.9 mg/mg Placebo: 1.9 mg/mg Canagliflozin 300 mg daily: 1.03% c,h Sitagliptin 100 mg daily: 0.66% Canagliflozin 300 mg daily: 47.6% c,h Sitagliptin 100 mg daily: 35.3% Canagliflozin 300 mg daily: 22.5 % c,h Sitagliptin 100 mg daily: 18.8% Canagliflozin 300 mg daily: 28.7 mg/dl c,h Sitagliptin 100 mg daily: 2.2 mg/dl Canagliflozin 300 mg daily: 5.1 mm Hg c,h Sitagliptin 100 mg daily: 0.9 mm Hg Canagliflozin 300 mg daily: 2.3 kg c,h Sitagliptin 100 mg daily: 0.1 kg Canagliflozin 300 mg daily: 7.6% c,h Sitagliptin 100 mg daily: 0.6% BP = blood pressure; FGP = fasting plasma glucose; HBA 1c = glycosylated hemoglobin; HDL-C = high-density lipoprotein-cholesterol; PPG = postprandial glucose; UGC = urinary glucose-to-creatinine. a Results at 26 weeks (from baseline). b P < 0.001, compared with placebo. c Least-squares mean change. d P < 0.01, compared with placebo. e Results at 12 weeks (from baseline). f P < 0.05, compared with placebo. g Results at 52 weeks (from baseline). h P < 0.001, compared with sitagliptin. included the change in the percentage of patients who achieved HbA 1c below 7% and below 6.5% and changes in FPG, body weight, and an overnight urinary glucose-to-creatinine (UGC) ratio after 12 weeks. Forty-nine patients discontinued treatment before the end of the 12-week period. A similar number of patients in all treatment arms discontinued therapy. At 12 weeks, efficacy analyses revealed significant changes in HbA 1c from baseline for canagliflozin 50, 100, 200, or 300 mg once daily and canagliflozin 300 mg twice daily compared with placebo ( 0.79%, 0.76%, 0.70%, 0.92%, 0.95% and 0.22%, respectively; P < 0.001 for all canagliflozin doses), with a 0.74% reduction for the sitagliptin arm (P < 0.001 vs. placebo). Fifty-three to 72% of patients who received 100 mg or more of canagliflozin and 65% of those who received sitagliptin achieved HbA 1c values below 7%, compared with 34% of those in the placebo group. HbA 1c values below 6.5% were also achieved by 27%, 42%, and 32% of patients receiving canagliflozin 100 and 300 mg once daily and 300 mg twice daily, Vol. 38 No. 11 November 2013 P&T 659

respectively, as well as 45% of those who received sitagliptin, compared with the placebo group (13%). Significant and greater mean reductions in FPG levels were noted for all canagliflozin groups at 3 weeks and were maintained throughout the 12-week treatment period (16.2, 25.2, 27, 25.2, and 23.4 mg/ dl, respectively, vs. 3.6 mg/dl in the placebo group; P < 0.001 for all canagliflozin doses). Sitagliptin reduced FPG levels by 12.6 mg/dl, but the change was not statistically significant compared with placebo. At week 12, changes in body weight and UGC ratios were also statistically significant, compared with placebo. Mean weight reductions from baseline for canagliflozin subjects were 2.3, 2.6, 2.7, 3.4, and 3.4 kg, respectively, compared with 1.1 kg for placebo. A weight reduction of 0.6 kg was also seen in the sitagliptin patients, but this change was not statistically significant when compared with placebo. Increases in UGC ratios were reported for all canagliflozin patients (35.4, 51.5, 50.5, 49.4, and 61.6 mg/mg) and were significantly greater than for placebo patients (1.9 mg/mg; P < 0.001). The sitagliptin patients experienced reductions in the UGC ratio ( 1.9 mg/mg). HDL-C levels were significantly increased with canagliflozin 300 mg twice daily, and triglyceride levels were significantly reduced with 300 mg once daily and twice daily, compared with placebo (P < 0.001, P = 0.025, and P = 0.001, respectively). ADEs were reported in 26% to 56% of canagliflozin patients, 35% of sitagliptin patients, and 40% of placebo patients. Most ADEs were described as mild to moderate in severity. Nine canagliflozin patients and two placebo patients discontinued therapy because of ADEs, mainly gastrointestinal disorders. Compared with the placebo group, patients receiving the study drug experienced more genital infections (2% vs. 3 8%, respectively), particularly in female patients (3% vs. 13% 25%, respectively). Low and similar incidences of hypoglycemia, UTIs, polyuria (excess diuresis), pollakiuria (abnormal frequency of urination) and hypovolemia-associated ADEs were observed among all study participants. Small reductions in systolic BP were also noted with canagliflozin treatment. (Polyuria can be associated with diabetes; 660 P&T November 2013 Vol. 38 No. 11 pollakiuria is thought to be associated with psychological stress.) The authors concluded that the addition of canagliflozin treatment to inadequate metformin monotherapy in patients with type-2 diabetes was relatively well tolerated and resulted in significant improvement of glycemic control while yielding favorable effects on body weight, HDL-C levels, and triglyceride levels. Schernthaner et al. 21 In a 52-week, randomized, doubleblind, active-controlled, phase 3 study, the efficacy and safety of canagliflozin were evaluated and compared with sitagliptin in patients with type-2 diabetes who were not responding adequately to metformin and sulfonylurea therapy. This multicenter, multinational trial enrolled patients 18 years of age or older with type- 2 diabetes who were following a stable regimen of metformin (1,500 mg/day or higher) and a sulfonylurea (half-maximal daily doses or more) and HbA 1c values between 7% and 10.5%. Eligible patients underwent a singleblind 2-week placebo run-in period, followed by double-blind randomization to receive either canagliflozin 300 mg once daily or sitagliptin 100 mg once daily. A 4-week post-treatment period followed the 52-week treatment period. The primary endpoint was the change in HbA 1c from baseline to week 52. Secondary endpoints included changes in systolic BP; body weight; and FPG, HDL-C, and triglyceride levels. The authors analyzed non-inferiority between the treatment groups, but they also evaluated superiority if non-inferiority was determined. Of the 756 patients initially assigned to active-treatment, 464 completed the 52-week treatment period and were included in the efficacy and safety analyses. Approximately 33% of the canagliflozin group and 44% of the sitagliptin group stopped therapy because of the need for glycemic rescue therapy, elevated creatinine levels (>1.4 for men or 1.3 for women), estimated glomerular filtration rate (egfr) (<55 60 ml/minute/1.73 m 2, depending on labeling national labeling of metformin), or intolerable ADEs. At the end of 52 weeks, canagliflozin 300 mg daily was found to be noninferior to sitagliptin 100 mg daily in terms of HbA 1c changes from baseline, with least-squares mean changes of 1.03% and 0.66%, respectively. Differences in least-squares means were 0.37% (95% confidence interval [CI], 0.5 to 0.25). Further analysis revealed that canagliflozin was also superior to sitagliptin in reducing HbA 1c values, and more canagliflozin patients achieved HbA 1c goals of less than 7% (47.6% vs. 35.3%, respectively) and less than 6.5% (22.5% vs. 18.8%, respectively). At the end of the treatment period, reductions in FPG levels were greater among patients who received canagliflozin than those who received sitagliptin. Least-squares mean changes were 28.7 mg/dl and 2.2 mg/dl, respectively. The difference in least-squares means was 5.9 mm Hg (P < 0.001). Systolic BP was also significantly reduced with canagliflozin compared with sitagliptin ( 5.1 vs. 0.9 mm Hg, respectively). The difference in least-squares means was 5.9 mm Hg (P < 0.001). Canagliflozin patients experienced significantly greater weight loss than the sitagliptin group. Least-squares mean changes were 2.3 kg and 0.1 kg, respectively; the difference in least-squares means was 2.4 kg (P < 0.001). Elevations in HDL-C were also significantly greater with canagliflozin than with sitagliptin. Least-squares mean changes were 7.6% and 0.6%, respectively; the difference in least-squares means was 7% (95% CI, 4.6 9.3). Similar modest elevations in triglycerides and low-density lipoprotein-cholesterol (LDL-C) were also noted, with statistically significant greater elevations in LDL-C with canagliflozin (11.7% vs. 5.2%, respectively); the difference in least-squares means was 6.4% (95% CI, 1.7 11.2). The incidence of ADEs was similar for both treatment groups. A higher rate of genital mycotic infections in females and one discontinuation of canagliflozin were reported at the end of the study. Fewer than 2% of canagliflozin ADEs were associated with osmotic diuresis (e.g., thirst and pollakiuria). Similar incidences of hypoglycemia and UTIs were observed in both the canagliflozin and sitagliptin groups. The authors concluded that canagliflozin provided greater glycemic control and weight reductions than sitagliptin, but it resulted in more mycotic infections in patients with type-2 diabetes who had received metformin and sulfonylurea therapy. continued on page 665

continued from page 660 ADVERSE DRUG REACTIONS 17,19 21 In clinical trials, canagliflozin was generally associated with a higher incidence of genital mycotic infections, UTIs, increased urination, and ADEs associated with osmotic diuresis and reduced intravascular volume. Uncircumcised men and both men and women with a history of genital mycotic infections were predisposed to recurrent mycotic genital infections requiring oral or topical antifungal treatment and antimicrobial therapy. Decreases in egfr, serum urate, alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and alkaline phosphatase levels have also been observed in patients treated with canagliflozin, in addition to increases in serum creatinine, blood urea nitrogen, hemoglobin, hematocrit, and bilirubin compared with placebo and other active treatments. INDICATIONS AND USAGE 17 Canagliflozin is approved for adults with type-2 diabetes mellitus who require improved glycemic control in addition to diet and exercise. This drug has not been studied and is not recommend for patients with type-1 diabetes mellitus or diabetic ketoacidosis. DRUG INTERACTIONS 17 UGT enzyme inducers (e.g., rifampin, phenytoin, ritonavir)may decrease the plasma levels ans efficacy of canagliflozin. The canagliflozin dose can be increased to 300 mg once daily (1) in patients with an egfr exceeding 60 ml/minute/1.73 m 2, (2) in those requiring a UGT enzyme inducer and additional glycemic control, and (3) in those currently tolerating a dose of 100 mg once daily. Alternative antihyperglycemic agents are suggested in patients with an egfr of 45 to 60 ml/ minute/1.72 m 2 who require additional glycemic management. There appear to be no significant interactions between canagliflozin and CYP450 enzymes 1A2, 2A6, 3A4, 2B6, 2C9, 2C19, 2D6, and 2E1. Digoxin plasma concentrations may be increased with the concomitant administration of canagliflozin; therefore, monitoring is advised. CONTRAINDICATIONS 17 Canagliflozin is contraindicated in patients with a severe hypersensitivity reaction to the drug, in individuals with severe renal impairment (an egfr below 30 ml/minute/1.73 2 ), in those with endstage renal disease, and in patients on dialysis. PRECAUTIONS AND WARNINGS 17 Volume status should be assessed and corrected before canagliflozin is initiated in patients with low BP, in those using diuretics or drugs that interfere with the renin angiotensin aldosterone system (RAS), or in those with impaired renal function. Symptomatic hypotension was observed more frequently in patients receiving the 300-mg dose, in those with impaired renal function, in those receiving loop diuretics, and in people 75 years of age or older. Caution is warranted if the egfr is below 60 ml/minute/1.73 m 2. Frequent monitoring of renal function is recommended during the initiation of therapy. Monitoring of serum potassium levels is also recommended upon the initiation of canagliflozin therapy in patients with renal impairment and in those taking medications that can interfere with potassium secretion to avoid the risk of hyperkalemia. Prescribers should also exercise caution for patients who are using insulin or insulin secretagogues. Dose adjustments of the insulin or insulin secretagogues may be needed to avoid hypoglycemia. Patients taking canagliflozin should be informed about and monitored for signs and symptoms of genital mycotic infections. Uncircumcised males and patients with a history of genital mycotic infections may be at increased risk and may require treatment. It is also recommended that LDL-C levels be monitored, as dose-related increases in LDL-C levels have been observed with this medication. Canagliflozin has been designated as a Pregnancy Category C drug. Well-controlled studies have not been conducted in pregnant women, and it is unknown whether this medication is excreted in human milk. There is no evidence to support its use in lactation. DOSAGE AND ADMINISTRATION 17 The recommended starting dose of canagliflozin is 100 mg once daily before the first meal. Patients who need additional glycemic control can increase the dose to 300 mg once daily if the 100-mg dose was well tolerated and the egfr was 60 ml/minute/1.73 m 2 or greater. The dose should not exceed 100 mg once daily in patients with moderate renal impairment (egfr, 45 60 ml/minute/1.73 m 2 ), and therapy should not be initiated if the egfr is below 45 ml/minute/1.73 m 2. COST 22 Canagliflozin (Invokana) is sold as 100-mg film-coated, yellow capsuleshaped tablets and as 300-mg film-coated, white capsule-shaped tablets. According to the 2013 edition of Red Book, the average wholesale price of a bottle of 30 tablets (100 mg or 300 mg) is $236.10, and a bottle of 90 tablets (100 mg or 300 mg) is $789.30. CONCLUSION Treatment options for type-2 diabetes are often limited by the degree of glycemic control provided and by safety profiles. Canagliflozin is a novel agent that may aid in achieving glycemic goals in many patients with type-2 diabetes who are also following diet and exercise regimens and who have not responded adequately to other antihyperglycemic agents. This drug is generally well tolerated and may yield additional favorable effects, for example, on BP and body weight. REFERENCES 1. Number (in millions) of civilian, noninstitutionalized persons with diagnosed diabetes, United States, 1980 2011. CDC Data Sheet. Available at: www.cdc.gov. Accessed June 24, 2013. 2. Centers for Disease Control and Prevention (CDC). National Diabetes Fact Sheet, 2011. Available at: www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed June 20, 2013. 3. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the U.S. adult population: Dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr 2010;8:29. 4. Diagnosis and classification of diabetes mellitus. Diabetes Care 2013;36(Suppl 1);S67 S74. 5. Nguyen NT, Nguyen XM, Lane J, Wang P. Relationship between obesity and diabetes in a U.S. adult population: Findings from the National Health and Nutrition Examination survey, 1999 2006. Obes Surg 2011;21:351 355. 6. Economic costs of diabetes in the U.S. in 2012. Diabetes Care 2013;36:1033 1046. 7. American Diabetes Association. Standards of medical care in diabetes 2013. Diabetes Care 2013;36(Suppl 1);S11 S66. 8. Stark Casagrande S, Fradkin JE, Saydah SH. The prevalence of meeting A 1c, blood pressure, and LDL goals among people Vol. 38 No. 11 November 2013 P&T 665

with diabetes, 1988 2010. Diabetes Care, February 15, 2013 (online). 9. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: Patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364 1379. 10. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE Comprehensive diabetes management algorithm. Endocr Pract 2013;19(2):327 336. 11. Nomura S, Sakamaki S, Hongu M, et al. Discovery of canagliflozin, a novel c-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem 2010;53: 6355 6360. 12. Valentine V. The role of the kidney and sodium-glucose co-transporter-2 inhibition in diabetes management. Clin Diabetes 2012:30;151 155. 13. FDA approves Invokana to treat type 2 diabetes: First in a new class of diabetes drugs. March 29, 2013. Available at: www.fda.gov/newsevents/newsroom/ PressAnnouncements/Ucm345848.htm. Accessed May 20, 2013. 14. Neumiller JJ, White JR Jr, Campbell RK. Sodium-glucose co-transport inhibitors: Progress and therapeutic potential in type 2 diabetes mellitus. Drugs 2010;70:377 385. 15. Kim Y, Babu AR. Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes. Diabetes Metab Syndr Obes 2012;5:313 327. 16. Idris I, Donnelly R. Sodium-glucose cotransporter-2 inhibitors: An emerging new class of oral antidiabetic drug. Diabetes Obes Metab 2009;11(2):79 88. 17. Invokana (canagliflozin), prescribing information. Titusville, N.J.: Janssen; March 2013. 18. AMCP Dossier Invokana (canagliflozin). Titusville, N.J.: Janssen MedInfo; April 15, 2013. 19. Stenlof K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013;15:378 382. 20. Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotranstporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 2012; 35:1232 1238. 21. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea. Diabetes Care 2013;36(19):2508 2515. 22. Red Book Online 2013. Available at: www. micromedexsolutions.com. Accessed July 1, 2013. n 666 P&T November 2013 Vol. 38 No. 11