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.
656 P&T
®
• November 2013 • Vol. 38 No. 11
complications.7,8 Despite current available therapies, about 50% of patients in the U.S. are not achieving their goals for glycosylated hemoglobin (HbA1c), 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 HbA1c 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 HbA1c 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 ACTION14–18
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 PHARMACODYNAMICS11,14,17
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.
DrUG FORECAST 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 EFFICACY19–21
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 type2 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 HbA1c 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 HbA1c from baseline. Secondary endpoints included the proportion of patients who achieved HbA1c 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, HbA1c 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 re-
ductions in HbA1c 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 HbA1c 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; HbA1c 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/m2 (24 to 45 kg/m2 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 HbA1c from baseline to the completion of treatment. The secondary endpoints
Vol. 38 No. 11 • November 2013 • P&T 657 ®
DrUG FORECAST Table 1 Evaluating the Use of Canagliflozin in Type-2 Diabetes: Significant Findings From Three Clinical Trials Study
Endpoints
Stenlof et al.19
a
Primary: 1. Change in HbA1c
Results • 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 HbA1c < 7%
Rosenstock et al.20
• Canagliflozin 100 mg daily: 44.5%b • Canagliflozin 300 mg daily: 62.4%b • Placebo: 20.6%
2. Change in FPG
• Canagliflozin 100 mg daily: –1.5 mmol/Lb,c • Canagliflozin 300 mg daily: –1.9 mmol/Lb,c • Placebo: 0.5 mmol/L
3. Change in 2-hour PPG
• Canagliflozin 100 mg daily: –2.4 mmol/Lb,c • Canagliflozin 300 mg daily: –3.3 mmol/Lb,c • Placebo: 0.3 mmol/L
4. Change in systolic BP
• Canagliflozin 100 mg daily: –3.3 mm Hgb,c • Canagliflozin 300 mg daily: –5 mm Hgb,c • Placebo: 0.4 mmHg
5. Change in body weight
• Canagliflozin 100 mg daily: –2.5 kgb,c • Canagliflozin 300 mg daily: –3.4 kgb,c • Placebo: –0.5 kg
6. Change in HDL-C
• Canagliflozin 100 mg daily: 11.2%b,c • Canagliflozin 300 mg daily: 10.6%c,d • Placebo: 4.5%
Primary:e Change in HbA1c
• Canagliflozin 50, 100, 200, and 300 mg daily: –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%
Secondary:e 1. Percentage of patients who achieved HbA1c < 7% 2. Percentage of patients who achieved HbA1c < 6.5% 3. Change in FPG
• 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% • Canagliflozin 50, 100, 200, and 300 mg daily: –16.2 mg/dL,b –25.2 mg/dL,b –27 mg/dL,b and –25.2 mg/dLb (respectively) • Canagliflozin 300 mg twice daily: –23.4 mg/dLb • Sitagliptin 100 mg daily: –12.6 mg/dL • Placebo: 3.6 mg/dL
658 P&T • ®
November 2013 • Vol. 38 No. 11
DrUG FORECAST Table 1 Evaluating the Use of Canagliflozin in Type-2 Diabetes: Significant Findings From Three Clinical Trials (continued) Study
Endpoints
Results
Rosenstock et al.20 continued
4. Mean weight reduction
• Canagliflozin 50, 100, 200, and 300 mg daily: –2.3 kg,b –2.6 kg,b –2.7 kg,b and –3.4 kgb (respectively) • Canagliflozin 300 mg twice daily: –3.4 kgb • Sitagliptin 100 mg daily: –0.6 kg • Placebo: –1.1 kg
5. Change in UGC ratio
• Canagliflozin 50, 100, 200, and 300 mg daily: 35.4 mg/mg,b 51.5 mg/mg,b 50.5 mg/mg,b and 49.4 mg/mgb (respectively) • Canagliflozin 300 mg twice daily: 61.6 mg/mgb • Sitagliptin 100 mg daily: –1.9 mg/mg • Placebo: 1.9 mg/mg
Schernthaner Primary:g Change in HbA1c et al.21
• Canagliflozin 300 mg daily: –1.03%c,h • Sitagliptin 100 mg daily: –0.66%
1. Percentage of patients who achieved HbA1c < 7%
• Canagliflozin 300 mg daily: 47.6%c,h • Sitagliptin 100 mg daily: 35.3%
2. Percentage of patients who achieved HbA1c < 6.5%
• Canagliflozin 300 mg daily: 22.5 %c,h • Sitagliptin 100 mg daily: 18.8%
Secondary:g 1. Changes in FPG
• Canagliflozin 300 mg daily: –28.7 mg/dLc,h • Sitagliptin 100 mg daily: –2.2 mg/dL
2. Change in systolic BP
• Canagliflozin 300 mg daily: –5.1 mm Hgc,h • Sitagliptin 100 mg daily: 0.9 mm Hg
3. Change in body weight
• Canagliflozin 300 mg daily: –2.3 kgc,h • Sitagliptin 100 mg daily: 0.1 kg
4. Change in HDL-C
• Canagliflozin 300 mg daily: 7.6%c,h • Sitagliptin 100 mg daily: 0.6%
BP = blood pressure; FGP = fasting plasma glucose; HBA1c = 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 HbA1c 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 HbA1c 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 HbA1c values below 7%, compared with 34% of those in the placebo group. HbA1c 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 ®
DrUG FORECAST 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;
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 type2 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 HbA1c 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 HbA1c 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) (