Canagliflozin

Abstract

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Generic Name: Canagliflozin

Proprietary Name: Invokana (Janssen Pharmaceuticals)

Approval Rating: 1S

Therapeutic Class: Sodium-Glucose Cotransporter 2 Inhibitors

Similar Drugs: Dapagliflozin, Empagliflozin, Tofogliflozin

Sound- or Look-Alike Names: Canakinumab, Caspofungin, Dapagliflozin

Indications

Canagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.¹ Canagliflozin is not approved for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.¹

Clinical Pharmacology

Canagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor and a low-potency SGLT1 inhibitor.^2-5

In healthy individuals, more than 99% of the plasma glucose that is filtered in the kidneys is reabsorbed. The reabsorption process is mediated by 2 SGLTs: SGLT1, which is expressed in the gut, heart, trachea, and kidney; and SGLT2, which is expressed primarily in the kidney. Approximately 90% of renal glucose reabsorption is facilitated by SGLT2 in the S1 segment of the proximal tubule, and the other 10% is facilitated by SGLT1 in the distal S3 segment of the proximal tubule.^1,2,6

Canagliflozin lowers plasma glucose in a dose-dependent manner by lowering the renal threshold for glucose and increasing urinary glucose excretion through renal SGLT2 inhibition.^1,3,7 At maximally effective concentrations, the renal threshold for glucose is reduced by about 66%.⁸ In patients with type 2 diabetes, canagliflozin dosages of 100 mg or greater daily increased urinary glucose excretion, lowered the renal threshold for glucose, lowered 24-hour and fasting plasma glucose (FPG), and improved beta-cell function.^1,9 From a baseline renal threshold for glucose of 240 mg/dL, canagliflozin 300 mg once daily in type 2 diabetic patients lowered renal threshold for glucose to 70 to 90 mg/dL over a 24-hour period.¹ In healthy type 2 diabetic patients, a single dose of canagliflozin 300 mg also delayed intestinal glucose absorption; this resulted in lower postprandial glucose and insulin levels, which may be related to dose-dependent SGLT1 inhibition.^1,4,5,10

Pharmacokinetics

Following oral administration, the median time to peak plasma concentration is 1 to 2 hours and mean bioavailability is approximately 65%.¹ Administration with a high-fat meal has no effect on the pharmacokinetics of canagliflozin.¹ The area under the curve (AUC) and peak concentrations increase in a dose-dependent manner.^1,11,12 Steady state is reached in 4 to 5 days, and the steady-state volume of distribution is 119 L in healthy patients. Canagliflozin is 99% bound to plasma proteins, mainly albumin.¹

The elimination half-life is 10.6 and 13.1 hours for the 100 and 300 mg doses, respectively. Canagliflozin is metabolized primarily by glucuronidation via uridine diphosphate glucuronosyltransferase (UGT) 1A9 and UGT2B4 to 2 inactive metabolites. Approximately 7% of canagliflozin is oxidized by cytochrome P450 3A4.¹

Following a single oral dose of radiolabeled canagliflozin, 41.5%, 7%, and 3.2% were recovered in the feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Approximately 33% of the dose was recovered in urine, 30.5% as O-glucuronide metabolites and less than 1% as unchanged canagliflozin.^1,12

Comparative Efficacy

Indication: Treatment of Type 2 Diabetes Mellitus in Patients not Optimally Controlled with Oral Antidiabetic Agents and/or Insulin

Guidelines

Guideline: Standards of Medical Care in Diabetes, American Diabetes Association

Reference: American Diabetes Association, 2013¹³

Comments: Unless contraindicated, metformin is recommended as first-line therapy at the time of diagnosis in patients with type 2 diabetes mellitus. If metformin, at maximal tolerated doses, does not achieve or maintain the target hemoglobin A_1c (HbA_1c) over 3 to 6 months, a second oral agent, a glucagonlike peptide-1 (GLP-1) receptor agonist, or insulin should be added. SGLT2 inhibitors were not addressed in the guidelines.

Studies

Drug: Canagliflozin vs Placebo

Reference: Wilding JP, et al, 2012¹⁴

Study Design: Randomized, double-blind, placebo-controlled, multicenter study

Study Funding: Janssen Research & Development, LLC

Patients: 469 adult patients with type 2 diabetes inadequately controlled with metformin and a sulfonylurea. Mean age was 56.7 years, mean HbA_1c was 8.1%, mean FPG was 9.5 mmol/L, and mean body mass index (BMI) was 33 kg/m².

Intervention: Oral canagliflozin 100 or 300 mg/day or placebo for 26 weeks.

Results:

Primary Endpoint(s):

•  • Change in HbA_1c from baseline: −0.9% with 100 mg dose and −1.1% with 300 mg dose compared with −0.2% with placebo (P < .001). The placebo-adjusted change was −0.71% with the 100 mg dose and −0.92% with the 300 mg dose.

Secondary Endpoint(s):

•  • Percentage of subjects who achieved HbA_1c less than 7%: 25.2% with the 100 mg dose and 38.6% with the 300 mg dose (both Ps < .001 vs placebo).

•  • Placebo-adjusted change in FPG from baseline: −1.24 mmol/L with the 100 mg dose and −1.92 mmol/L with the 300 mg dose (both Ps < .001 vs placebo).

•  • Placebo-adjusted percentage change in body weight from baseline: −1.4% with the 100 mg dose and −2% with the 300 mg dose (both Ps < .001 vs placebo).

•  • Placebo-adjusted change in systolic blood pressure from baseline: −2.24 mm Hg with the 100 mg dose and −1.62 mm Hg with the 300 mg dose.

•  • Placebo-adjusted percentage change in high-density lipoprotein cholesterol (HDL-C) from baseline: 2.6% with the 100 mg dose and 3.5% with the 300 mg dose.

•  • Placebo-adjusted percentage change in triglycerides from baseline: −6.2% with the 100 mg dose and −3.1% with the 300 mg dose.

Other Endpoint(s):

 • The overall incidence of adverse events did not differ between groups; however, the canagliflozin-treated patients experienced a higher incidence of genital fungal infections (18.7% vs 3.8% in women and 4.9% vs 1.3% in men). More patients in the canagliflozin groups also experienced hypoglycemia (28.8% vs 15.4%).

Comments: This placebo-controlled trial demonstrated improvement in HbA_1c and FPG similar to that commonly observed with other oral antidiabetic agents, along with an accompanying weight loss.

Limitations: Results only available in a meeting abstract.

Reference: Devineni D, et al, 2012^11,15

Study Design: Randomized, double-blind, placebo-controlled, multicenter study

Study Funding: Janssen Research & Development, LLC

Patients: 29 patients 18 to 65 years of age (median, 50 years) with type 2 diabetes not optimally controlled with insulin and up to 1 oral antihyperglycemic agent. Patients had to have a stable body weight with a BMI of 25 to 45 kg/m² (median, 32.3 kg/m²), FPG of 3.3 to 15 mmol/L, HbA_1c of 7% to 10.5%, and serum creatinine of less than 132.6 mcmol/L for men or less than 123.8 mcmol/L for women.

Intervention: Canagliflozin 100 mg orally once daily before the morning meal (10 patients), canagliflozin 300 mg orally twice daily before the morning and evening meals (10 patients), or placebo (9 patients) for 28 days.

Results:

Primary Endpoint(s):

•  • Change in urinary glucose excretion from baseline: +71.9 g/day with the 100 mg dose (P < .05) and +129.2 g/day with the 300 mg dose (P < .05) compared with −3.2 g/day with placebo.

•  • Change in the renal threshold for glucose excretion (24 hour) from baseline: −6.62 mmol/L with the 100 mg dose (P < .05) and −8.94 mmol/L with the 300 mg dose (P < .05) compared with +0.62 mmol/L with placebo.

•  • Change in mean 24-hour plasma glucose from baseline: −1.64 mmol/L with the 100 mg dose (P < .05) and −2.46 mmol/L with the 300 mg dose (P < .05) compared with +0.07 mmol/L with placebo.

•  • Change in FPG from baseline: −2.11 mmol/L with the 100 mg dose (P < .05) and −2.35 mmol/L with the 300 mg dose (P < .05) compared with +0.48 mmol/L with placebo.

•  • Change in HbA_1c from baseline: −0.73% with the 100 mg dose and −0.92% with the 300 mg dose (P < .05) compared with −0.19% with placebo.

•  • Change in body weight from baseline: −0.73 kg with the 100 mg dose and −1.19 kg with the 300 mg dose (P < .05) compared with +0.03 kg with placebo.

Other Endpoint(s):

•  • Symptomatic hypoglycemia occurred in 6 patients in the 100 mg group, 3 patients in the 300 mg group, and 3 patients in the placebo group. None of the hypoglycemic episodes were classified as severe or serious.

Comments: Mean baseline HbA_1c (8.3% to 8.4%) was similar across treatment groups; however, patients in the canagliflozin 100 mg group were receiving an insulin dose at baseline 2-fold higher than patients in the other 2 treatment groups. Twelve patients (41%) out of the entire study population were also receiving metformin.

Limitations: Small sample size and short duration limited the ability to make conclusions regarding the safety and efficacy of canagliflozin. This was an exploratory study; therefore, no adjustments for multiple comparisons were made.

Reference: Yale JF, et al, 2013^16,17

Study Design: Randomized, double-blind, placebo-controlled, multicenter, international study

Study Funding: Janssen Research & Development, LLC

Patients: 269 patients (60.6% men, 79.9% White, 10% Asian, 1.9% Black) with type 2 diabetes and moderate renal impairment (estimated glomerular filtration rate [GFR] of 30 to 50 mL/min/1.73 m²). Mean age was 68.5 years, mean HbA_1c was 8%, mean FPG was 9.1 mmol/L, mean BMI was 33 kg/m², and mean estimated GFR was 39.4 mL/min/1.73 m². A total of 74% were receiving insulin therapy, 31.2% were receiving a sulfonylurea, 7.4% were receiving dipeptidyl peptidase-4 inhibitors, and 1.5% were receiving biguanide.

Intervention: Oral canagliflozin 100 or 300 mg/day or placebo for 26 weeks.

Results:

Primary Endpoint(s):

•  • Change in HbA_1c from baseline: −0.33% with the 100 mg dose (P < .05 vs placebo) and −0.44% with the 300 mg dose (P < .001 vs placebo) compared with −0.03% with placebo.

Secondary Endpoint(s):

•  • Percentage of patients who achieved HbA_1c less than 7%: 27.3% with the 100 mg dose and 32.6% with the 300 mg dose compared with 17.2% with placebo.

•  • Change in FPG from baseline: −0.83 mmol/L with the 100 mg dose and −0.65 mmol/L with the 300 mg dose compared with +0.03 mmol/L with placebo.

•  • Percentage change in body weight from baseline: −1.2% with the 100 mg dose and −1.5% with the 300 mg dose compared with +0.3% with placebo.

•  • Change in systolic blood pressure from baseline: −6.1 mm Hg with the 100 mg dose and −6.4 mm Hg with the 300 mg dose compared with −0.3 mm Hg with placebo.

•  • Percentage change in triglycerides from baseline: +6.2% with the 100 mg dose and +11.9% with the 300 mg dose compared with +7.9% with placebo.

•  • Percentage change in HDL-C from baseline: +4% with the 100 mg dose and +3% with the 300 mg dose compared with +1.5% with placebo.

•  • Percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline: +6.4% with the 100 mg dose and −1% with the 300 mg dose compared with +6.3% with placebo.

Comments: Clinical study demonstrating canagliflozin efficacy and safety in patients with type 2 diabetes and moderate renal impairment. Adverse event rates were similar in the 3 groups, although canagliflozin was associated with higher rates of hypoglycemia (52.9% with canagliflozin 100 mg and 51.2% with canagliflozin 300 mg vs 36.4% with placebo), superficial genital fungal infections (3.1% and 2.4% vs 0%, respectively, in women; 1.7% and 2.1% vs 0%, respectively, in men), and osmotic diuresis– and volume-related adverse effects. Urinary tract infection (UTI) rates were higher in the canagliflozin 300 mg group (7.9%) than with either canagliflozin 100 mg (5.6%) or placebo (5.6%). Decrease in estimated GFR was −9.1% in the canagliflozin 100 mg group and −10.1% in the canagliflozin 300 mg group versus −4.5% in the placebo group. Serum urea nitrogen (BUN) increased by 12.1% in the canagliflozin 100 mg group and 12.5% in the canagliflozin 300 mg group versus 4.9% in the placebo group. Discontinuation rates related to adverse drug reactions were 4.4% in the canagliflozin 100 mg group and 2.2% in the canagliflozin 300 mg group versus 5.6% in the placebo group.

Drug: Canagliflozin vs Glimepiride

Reference: Cefalu WT, et al, 2012¹⁸

Study Design: Randomized, double-blind, active-controlled, multicenter study

Study Funding: Janssen Research & Development, LLC

Patients: 1,450 patients with type 2 diabetes inadequately controlled with metformin. Mean age was 56.2 years, mean HbA_1c was 7.8%, mean FPG was 9.2 mmol/L, and mean body weight was 86.6 kg.

Intervention: Canagliflozin 100 or 300 mg orally once daily or glimepiride at a titrated dose (mean, 5.6 mg) orally once daily for 52 weeks.

Results:

Primary Endpoint(s):

•  • Change in HbA_1c from baseline: −0.82% with the 100 mg dose and −0.93% with the 300 mg dose compared with −0.81% with glimepiride. Both doses of canagliflozin met the prespecified noninferiority margin for comparison with glimepiride; the 300 mg dose demonstrated superiority to glimepiride.

Secondary Endpoint(s):

•  • Change in FPG from baseline: −1.4 mmol/L with the 100 mg dose and −1.5 mmol/L with the 300 mg dose compared with −1 mmol/L with glimepiride.

•  • Documented rate of hypoglycemia (3.9 mmol/L or less, with or without symptoms): 5.6% with the 100 mg dose and 4.9% with the 300 mg dose compared with 34.2% with glimepiride (both Ps < .001 vs glimepiride).

•  • Percentage change in body weight from baseline: −4.2% with the 100 mg dose and −4.7% with the 300 mg dose compared with +1% with glimepiride.

•  • Change in systolic blood pressure from baseline: −3.3 mm Hg with the 100 mg dose and −4.6 mm Hg with the 300 mg dose compared with +0.2 mm Hg with glimepiride.

•  • Percentage change in triglycerides from baseline: −3.7% with the 100 mg dose and +2.3% with the 300 mg dose compared with +9.5% with glimepiride.

•  • Percentage change in HDL-C from baseline: +7.9% with the 100 mg dose and +9% with the 300 mg dose compared with +0.3% with glimepiride.

•  • Percentage change in LDL-C from baseline: +9.6% with the 100 mg dose and +14.1% with the 300 mg dose compared with +5% with glimepiride.

Other Endpoint(s): The overall incidence of adverse events did not differ between groups; however, the canagliflozin-treated patients experienced a higher incidence of genital fungal infections (14.3% with canagliflozin 100 mg and 23.8% with canagliflozin 300 mg vs 3.7% with glimepiride in women; 6.7% and 8.3% vs 1.1%, respectively, in men), UTIs (6.4% with both doses of canagliflozin vs 4.4% with glimepiride), and osmotic diuresis–related adverse events (all less than 3%).

Comments: Study demonstrated noninferiority with the 100 and 300 mg once daily dosages and superiority with the 300 mg once daily dosage relative to glimepiride, along with greater weight loss.

Limitations: Results only available in a meeting abstract.

Drug: Canagliflozin vs Sitagliptin

Reference: Gross JL, et al, 2012¹⁹

Study Design: Randomized, double-blind, active-controlled, multicenter study

Study Funding: Janssen Research & Development, LLC

Patients: 755 patients with type 2 diabetes inadequately controlled with metformin plus a sulfonylurea. Mean age was 56.7 years, mean HbA_1c was 8.1%, mean FPG was 9.3 mmol/L, and mean body weight was 88.3 kg.

Intervention: Oral canagliflozin 300 mg once daily or sitagliptin 100 mg once daily for 52 weeks.

Results:

Primary Endpoint(s):

•  • Mean change in HbA_1c from baseline: −1.03% with canagliflozin and −0.66% with sitagliptin (difference, −0.37; 95% confidence interval [CI], −0.5 to −0.25; met criteria for demonstrating the noninferiority and superiority of canagliflozin relative to sitagliptin).

Secondary Endpoint(s):

•  • Percentage of patients who achieved HbA_1c less than 7%: 47.5% with canagliflozin versus 35.3% with sitagliptin (difference, 12.3%; 95% CI, 4.9 to 19.6).

•  • Change in FPG from baseline: −1.7 mmol/L with canagliflozin versus −0.3 mmol/L with sitagliptin (difference, −1.3 mmol/L; 95% CI, −1.7 to −1; P < .001).

•  • Percentage change in body weight from baseline: −2.5% with canagliflozin versus +0.3% with sitagliptin (difference, −2.8%; 95% CI, −3.3 to −2.2; P < .001).

•  • Change in systolic blood pressure from baseline: −5.1 mm Hg with canagliflozin versus +0.9 mm Hg with sitagliptin (difference, −5.9 mm Hg; 95% CI, −7.6 to −4.2; P < .001).

•  • Percentage change in triglycerides from baseline: +9.6% with canagliflozin versus +11.9% with sitagliptin (difference, −2.3%; 95% CI, −9.8 to 5.3).

•  • Percentage change in HDL-C from baseline: +7.6% with canagliflozin versus +0.6% with sitagliptin (difference, 7%; 95% CI, 4.6 to 9.3).

•  • Percentage change in LDL-C from baseline: +11.7% with canagliflozin versus +5.2% with sitagliptin (difference, 6.4%; 95% CI, 1.7 to 11.2).

Other Endpoint(s): Overall adverse event rates were similar; however, superficial genital fungal infections were more common with canagliflozin (15.3% in the canagliflozin group vs 4.3% in the sitagliptin group in women; 9.2% vs 0.5% in men). Rates of UTIs and hypoglycemia did not differ.

Comments: Demonstrated superiority of canagliflozin 300 mg relative to sitagliptin 100 mg once daily, along with greater weight loss.

Limitations: Results reported only in a meeting abstract.

Drug: Canagliflozin vs Sitagliptin vs Placebo

Reference: Rosenstock J, et al, 2012^20-22

Study Design: Randomized, double-blind, placebo-controlled, multicenter, dose-ranging study

Study Funding: Janssen Global Services, LLC

Patients: 451 patients with type 2 diabetes inadequately controlled with metformin. Mean age was 53 years, mean HbA_1c was 7.75%, mean FPG was 162 mg/dL, and mean BMI was 31.5 kg/m².

Intervention: Oral canagliflozin 50, 100, 200, or 300 mg orally once daily; canagliflozin 300 mg orally twice daily; sitagliptin 100 mg orally once daily; or placebo for 12 weeks plus baseline metformin therapy.

Results:

Primary Endpoint(s):

•  • Mean change in HbA_1c from baseline: −0.79% with canagliflozin 50 mg, −0.76% with canagliflozin 100 mg, −0.7% with canagliflozin 200 mg, −0.92% with canagliflozin 300 mg once daily, −0.95% with canagliflozin 300 mg twice daily, and −0.74% with sitagliptin compared with −0.22% with placebo (all Ps < .001 vs placebo).

Secondary Endpoint(s):

•  • Mean change in FPG from baseline: −16.2 mg/dL with canagliflozin 50 mg, −25.2 mg/dL with canagliflozin 100 mg, −27 mg/dL with canagliflozin 200 mg, −25.2 mg/dL with canagliflozin 300 mg once daily, −23.4 mg/dL with canagliflozin 300 mg twice daily, and −12.6 mg/dL with sitagliptin compared with +3.6 mg/dL with placebo (all Ps ≤ .001 vs placebo).

•  • Mean change in body weight from baseline: −2.3% with canagliflozin 50 mg, −2.6% with canagliflozin 100 mg, −2.7% with canagliflozin 200 mg, −3.4% with canagliflozin 300 mg once daily, −3.4% with canagliflozin 300 mg twice daily, and −0.6% with sitagliptin compared with −1.1% with placebo (all canagliflozin doses, P ≤ .01 vs placebo).

•  • Mean change in overnight urinary glucose-to-creatinine ratio from baseline (mg/mg): +35.4 with canagliflozin 50 mg, +51.5 with canagliflozin 100 mg, +50.5 with canagliflozin 200 mg, +49.4 with canagliflozin 300 mg once daily, +61.6 with canagliflozin 300 mg twice daily, and −1.9 with sitagliptin compared with 1.9 with placebo (all canagliflozin doses, P ≤ .001 vs placebo).

•  • Percentage of patients who achieved HbA_1c less than 7%: 53% to 72% of patients receiving doses of canagliflozin 100 mg once daily or greater, 65% receiving sitagliptin, and 34% receiving placebo.

•  • Percentage of patients who achieved HbA_1c less than 6.5%: 27% with canagliflozin 100 mg once daily, 42% with canagliflozin 300 mg once daily, 32% with canagliflozin 300 mg twice daily, and 45% with sitagliptin compared with 13% with placebo.

Other Endpoint(s):

•  • Change in fasting serum lipids: Canagliflozin 300 mg twice daily was associated with an increase in HDL-C and LDL-C and a reduction in triglycerides; the 300 mg once-daily dose was associated with an increase in HDL-C and a reduction in triglycerides but no increase in LDL-C.

•  • Beta-cell function improved with dosages of canagliflozin 100 mg once daily and greater and with sitagliptin compared with placebo, as indirectly assessed by homeostasis model assessment-2 index of beta-cell function.

•  • Asymptomatic bacteriuria was present at baseline in 6.4% of patients randomized to canagliflozin and 6.5% randomized to sitagliptin or placebo. At 12 weeks, asymptomatic bacteriuria was present in 7.7% in the canagliflozin groups and 6.3% in the sitagliptin and placebo groups (odds ratio [OR], 1.23; 95% CI, 0.45 to 3.89). Among patients who were initially urinary culture–negative, bacteriuria was present at week 12 in 3.7% of patients treated with sitagliptin or placebo and 4.8% of patients treated with canagliflozin (P = .76).

•  • Among patients with negative vaginal cultures for Candida at baseline, cultures converted to positive at week 12 in 31% of canagliflozin-treated patients and 14% of patients treated with sitagliptin or placebo (OR, 2.8; 95% CI, 1 to 7.3). Symptomatic vulvovaginal adverse events occurred in 10% of canagliflozin-treated patients and 3% of patients treated with sitagliptin or placebo. Patients with a positive Candida culture at baseline had a much higher risk for developing symptomatic vulvovaginal adverse events (OR, 9.1; 95% CI, 2.4 to 34).

Comments: Canagliflozin was associated with changes in HbA_1c and FPG that appeared comparable with sitagliptin, along with greater weight loss.

Limitations: Study was not designed or powered to directly compare canagliflozin with sitagliptin; sitagliptin was included as an active comparator agent.

Indication: Treatment of Type 2 Diabetes Mellitus in Patients not Optimally Controlled with Diet and Exercise

Guidelines

Guideline: Standards of Medical Care in Diabetes, American Diabetes Association

Reference: American Diabetes Association, 2013¹³

Comments: Unless contraindicated, metformin is recommended as first-line therapy at the time of diagnosis in patients with type 2 diabetes mellitus. If metformin, at maximal tolerated doses, does not achieve or maintain the target HbA_1c over 3 to 6 months, a second oral agent, a GLP-1 receptor agonist, or insulin should be added. SGLT2 inhibitors were not addressed in the guidelines.

Studies

Drug: Canagliflozin vs Placebo

Reference: Stenlof K, et al, 2013^23-25

Study Design: Randomized, double-blind, placebo-controlled, multicenter, international study

Study Funding: Janssen Research & Development, LLC

Patients: 584 patients (44.2% men, 67.6% White, 14.6% Asian, 7% Black) with type 2 diabetes inadequately controlled with diet and exercise. Mean age was 55.4 years, mean duration of diabetes was 4.3 years, mean HbA_1c was 8%, mean FPG was 9.5 mmol/L, and mean BMI was 31.7 kg/m².

Intervention: Oral canagliflozin 100 or 300 mg or placebo once daily for 26 weeks following a 2-week placebo run-in period.

Results:

Primary Endpoint(s):

•  • Mean change in HbA_1c from baseline: −0.77% with the 100 mg dose, −1.03% with the 300 mg dose, and +0.14% with placebo (both Ps < .001 vs placebo).

Secondary Endpoint(s):

•  • Percentage of patients who achieved HbA_1c less than 7%: 44.5% with the 100 mg dose, 62.4% with the 300 mg dose, and 20.6% with placebo (both Ps < .001 vs placebo).

•  • Percentage of patients who achieved HbA_1c less than 6.5%: 17.8% with the 100 mg dose, 28.4% with the 300 mg dose, and 5.3% with placebo (no statistical comparison).

•  • Change in FPG from baseline: −1.5 mmol/L with the 100 mg dose, −1.9 mmol/L with the 300 mg dose, and +0.5 mmol/L with placebo (both Ps < .001 vs placebo).

•  • Change in 2-hour postprandial plasma glucose from baseline: −2.4 mmol/L with the 100 mg dose, −3.3 mmol/L with the 300 mg dose, and +0.3 mmol/L with placebo (both Ps < .001 vs placebo).

•  • Percentage change in body weight from baseline: −2.8% with the 100 mg dose, −3.9% with the 300 mg dose, and −0.6% with placebo (both Ps < .001 vs placebo).

•  • Placebo-adjusted change in systolic blood pressure from baseline: −3.7 mm Hg with the 100 mg dose and −5.4 mm Hg with the 300 mg dose (both Ps < .001 vs placebo).

•  • Placebo-adjusted percentage change in HDL-C from baseline: +6.8% with the 100 mg dose (P < .001 vs placebo) and +6.1% with the 300 mg dose (P < .01 vs placebo).

•  • Placebo-adjusted percentage change in triglycerides from baseline: −5.4% with the 100 mg dose and −10.2% with the 300 mg dose.

Other Endpoint(s):

•  • The overall incidence of adverse events was higher with canagliflozin than with placebo (61% with 100 mg and 59.9% with 300 mg vs 52.6% with placebo). Genital fungal infections, UTIs, and osmotic diuresis–related effects were more common with canagliflozin. The incidence of hypoglycemia did not differ (3.6% with canagliflozin 100 mg, 3% with canagliflozin 300 mg, and 2.6% with placebo).

•  • In a subgroup analysis of patients given a meal tolerance test, insulin secretion was increased 107 pmol/min/m² with the 100 mg dose and 119 pmol/min/m² with the 300 mg dose, and beta-cell glucose sensitivity was increased 22 pmol/min/m²/mM in both groups compared with placebo, representing an approximately 50% increase in beta-cell function.

Comments: Placebo-controlled trial demonstrating improvement in HbA_1c and FPG similar to that commonly observed with other oral antidiabetic agents, with accompanying weight loss. Power was set at 90% and was achieved. Most common adverse events were genital mycotic infections and increased urination frequency and volume.

Limitations: Slightly higher than expected discontinuation rates before week 26: 11.7%, 11.2%, and 16.5%, for canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively.

Reference: Inagaki N, et al, 2011²⁶

Study Design: Randomized, double-blind, placebo-controlled, dose-ranging, multicenter study

Study Funding: Not specified

Patients: 383 Japanese patients with type 2 diabetes. Mean age was 57 years, mean HbA_1c was 8.1%, mean FPG was 165.6 mg/dL, mean body weight was 69.4 kg, and mean BMI was 25.7 kg/m².

Intervention: Oral canagliflozin 50, 100, 200, or 300 mg or placebo once daily for 12 weeks.

Results:

Primary Endpoint(s):

•  • Change in HbA_1c from baseline: −0.61% with the 50 mg dose, −0.8% with the 100 mg dose, −0.79% with the 200 mg dose, −0.88% with the 300 mg dose, and +0.11% with placebo (all Ps < .05 vs placebo).

Secondary Endpoint(s):

•  • Change in FPG from baseline: −24.7 mg/dL with the 50 mg dose, −33.1 mg/dL with the 100 mg dose, −36.1 mg/dL with the 200 mg dose, −38.3 mg/dL with the 300 mg dose, and −3 mg/dL with placebo (all Ps < .05 vs placebo).

•  • Change in body weight from baseline: −1.98 kg with the 50 mg dose, −2.51 kg with the 100 mg dose, −2.39 kg with the 200 mg dose, −3.19 kg with the 300 mg dose, and −0.78 kg with placebo.

•  • Change in systolic blood pressure from baseline: −5.8 mm Hg with the 50 mg dose, −7.1 mm Hg with the 100 mg dose, −9.3 mm Hg with the 200 mg dose, −8.7 mm Hg with the 300 mg dose, and −1.2 mm Hg with placebo.

•  • Change in diastolic blood pressure from baseline: −2.2 mm Hg with the 50 mg dose, −3.9 mm Hg with the 100 mg dose, −5.1 mm Hg with the 200 mg dose, −4.2 mm Hg with the 300 mg dose, and −0.9 mm Hg with placebo.

Other Endpoint(s):

•  • The overall incidence of adverse events was similar among the groups.

Comments: Placebo-controlled trial in Japanese patients with type 2 diabetes that demonstrated improvement in HbA_1c and FPG similar to that commonly observed with other oral antidiabetic agents, along with accompanying weight loss.

Limitations: Results reported only in a meeting abstract.

Contraindications, Warnings, And Precautions

Contraindications

Patients with severe renal impairment (estimated GFR less than 30 mL/min/1.73 m²), with endstage renal disease, requiring dialysis, or with a history of serious hypersensitivity reaction to canagliflozin should not use this medication.¹

Warnings and Precautions

Canagliflozin causes intravascular volume contraction. Patients with impaired renal function (estimated GFR less than 60 mL/min/1.73 m²), of an advanced age, with low systolic blood pressure, and on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system are at greater risk for symptomatic hypotension.¹

Use of canagliflozin can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion or the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia.¹

Increases in serum creatinine and decreases in estimated GFR can occur after initiating canagliflozin. Patients with hypovolemia may be more susceptible to these changes.¹

The use of insulin or insulin secretagogues with canagliflozin can increase the risk of hypoglycemia.¹

Patients with a history of genital mycotic infections and uncircumcised men were more likely to develop genital mycotic infections when using canagliflozin.¹ Up to 24% of women who received canagliflozin in clinical trials developed a genital fungal infection.^17,18,19,24 Most infections were treated with topical or oral antifungals and resolved without study drug interruption.²²

Hypersensitivity reactions (eg, generalized urticaria), mild to serious in degree, generally occurred within hours to days after initiating canagliflozin treatment.¹

Dose-related increases in LDL-C occurred with canagliflozin.¹

There is no established or conclusive evidence of macrovascular risk reduction with canagliflozin or any other antidiabetic drug.¹

Canagliflozin is classified in Pregnancy Category C; there are no adequate and well-controlled studies in pregnant women. Animal data (rats) indicate that there may be an effect on renal development and maturation.¹

It is not known whether canagliflozin is excreted in human milk. It is excreted at levels 1.4 times higher than maternal plasma in rats. Therefore, it is recommended that drug therapy or breast-feeding should be discontinued.¹

Safety and effectiveness have not been established in pediatric patients younger than 18 years.¹

Adverse Reactions

Table 1 represents data from four 26-week, placebo-controlled trials (1 trial was monotherapy; 3 trials were add-on therapy). The mean age of the population was 56 years, and 2% were older than 75 years. Fifty percent of the population were men, 72% were White, 12% were Asian, and 5% were Black. Mean duration of diabetes was 7.3 years, and mean HbA_1c was 8%. A total of 20% of patients had established microvascular complications of diabetes. Baseline renal function was normal to mildly impaired. Mean duration of exposure to canagliflozin was 24 weeks.¹

Table 1.

Adverse reactions from four 26-week, placebo-controlled studies occurring in ≥ 2% of canagliflozin-treated patients¹

Adverse reactions	Canagliflozin 100 mg (n = 833)	Canagliflozin 300 mg (n = 834)	Placebo (n = 646)
Genital mycotic infections in womena	10.4%	11.4%	3.2%
UTIsb	5.9%	4.3%	4%
Increased urination	5.3%	4.6%	0.8%
Genital mycotic infections in menc	4.2%	3.7%	0.6%
Vulvovaginal pruritus	1.6%	3%	0%
Thirst	2.8%	2.3%	0.2%
Constipation	1.8%	2.3%	0.9%
Nausea	2.2%	2.3%	1.5%

^aMycotic infections in women included vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis, vulvitis, vaginal infection, and genital fungal infections. Percentages were calculated using the number of women in each group as the denominator: canagliflozin 100 mg (n = 425), canagliflozin 300 mg (n = 430), placebo (n = 312).

^bUrinary tract infections (UTIs) included UTI, cystitis, kidney infection, and urosepsis.

^cGenital mycotic infections in men included balanoposthitis, Candidabalanitis, and genital fungal infection. Percentages were calculated using the number of men in each group as the denominator: canagliflozin 100 mg (n = 408), canagliflozin 300 mg (n = 404), placebo (n = 334).

Men and women who developed genital mycotic infections while taking canagliflozin were more likely to experience recurrent infections and require appropriate treatment. Men who developed a genital mycotic infection were more likely to be uncircumcised.¹

In the 4 placebo-controlled trials, abdominal pain was also more commonly reported in patients taking canagliflozin 100 mg (1.8%) and 300 mg (1.7%) than in patients taking placebo (0.8%).¹

Canagliflozin was associated with a dose-dependent increase in serum creatinine and a concomitant decrease in estimated GFR. In the 4 placebo-controlled clinical trials, the week-6 change in estimated GFR from baseline was −3.8, −5, and −1.6 mL/min/1.73 m² for canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively. Significant renal function decline occurred the end of treatment (week 26) in 0.7%, 1.4%, and 0.5% of patients assigned to canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively.¹

In patients with moderate renal impairment (estimated GFR of 30 to less than 50 mL/min/1.73 m²) at baseline, significant renal function decline, defined as an estimated GFR 30% lower than baseline, occurred in 18%, 22.5%, and 6.9% of patients assigned to canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively. The incidence of renal-related adverse reactions was 8.9% with canagliflozin 100 mg, 9.3% with canagliflozin 300 mg, and 3.7% with placebo.¹

The occurrence of adverse reactions was evaluated in a pool of 6,177 patients in 8 placebo- and active-controlled trials. Patients received canagliflozin 100 mg (n = 3,092), canagliflozin 300 mg (n = 3,085), or a comparator (n = 3,262) once daily. The mean duration of exposure to canagliflozin was 38 weeks with 1,832 individuals exposed for more than 50 weeks. The mean age of the population was 60 years, and 5% were older than 75 years. Fifty-eight percent of the population were men, 73% were White, 16% were Asian, and 4% were Black. Mean duration of diabetes was 11 years, and mean HbA_1c was 8%. A total of 33% of patients had established microvascular complications of diabetes. Baseline renal function was normal to mildly impaired.¹ Adverse reactions in this pool occurred at a rate similar to those in Table 1. Additionally, fatigue was observed at a rate of 2.2% with canagliflozin 100 mg, 2% with canagliflozin 300 mg, and 1.7% with the comparator. Asthenia was also observed at a rate of 0.7% with canagliflozin 100 mg, 1.1% with canagliflozin 300 mg, and 0.6% with the comparator.¹

Incidence rate of acute or chronic pancreatitis from the 8 pooled trials was 2.7, 0.9, and 0.9 per 1,000 patient-years of exposure to canagliflozin 100 mg, canagliflozin 300 mg, and the comparator, respectively. The incidence rate of bone fracture was 18.7, 17.6, and 14.2 per 1,000 patient-years of exposure to canagliflozin 100 mg, canagliflozin 300 mg, and the comparator, respectively.¹

Hypersensitivity-related reactions from the 8 pooled trials occurred in 3.8%, 4.2%, and 3% of patients receiving canagliflozin 100 mg, canagliflozin 300 mg, and the comparator, respectively.¹

Canagliflozin was associated with a dose-dependent increase in the incidence of volume depletion–related adverse events such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration.¹ Table 2 shows the incidence of volume depletion–related adverse events in subgroups that had a higher incidence rate than the overall population.

Table 2.

Proportion of patients with volume depletion–related adverse events pooled from 8 clinical trials (N = 6,177)¹

Baseline characteristica	Canagliflozin 100 mg	Canagliflozin 300 mg	Comparator groupb
Overall population	2.3%	3.4%	1.5%
75 years and older	4.9%	8.7%	2.6%
Estimated GFR < 60 mL/min/1.73 m2	4.7%	8.1%	2.5%
Use of loop diuretics	3.2%	8.8%	4.7%

Note: GFR = glomular filtration rate.

^aSome patients had more than 1 risk factor.

^bPlacebo- and active-comparator groups.

In all clinical trials, hypoglycemia was defined as any event where the glucose value was less than or equal to 70 mg/dL. Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure. Hypoglycemia occurred at a higher rate when canagliflozin was coadministered with insulin or sulfonylureas.¹ Table 3 shows the incidence of hypoglycemia when canagliflozin was used as monotherapy or in combination therapy.

Table 3.

Incidence of ≥ 1 event of hypoglycemia in clinical trials¹

Drug-therapy regimen	Canagliflozin		Comparator group
Monotherapy (26 wk)	Canagliflozin 100 mg	Canagliflozin 300 mg	Placebo
Overall, n (%)	7 (3.6)	6 (3)	5 (2.6)
Metformin added (26 wk)	Canagliflozin 100 mg + metformin	Canagliflozin 300 mg + metformin	Placebo + metformin
Overall, n (%)	16 (4.3)	17 (4.6)	3 (1.6)
Severe, n (%)	1 (0.3)	1 (0.3)	0
Metformin added (52 wk)	Canagliflozin 100 mg + metformin	Canagliflozin 300 mg + metformin	Glimepiride + metformin
Overall, n (%)	27 (5.6)	24 (4.9)	165 (34.2)
Severe, n (%)	2 (0.4)	3 (0.6)	15 (3.1)
Sulfonylurea added (18 wk)	Canagliflozin 100 mg + sulfonylurea	Canagliflozin 300 mg + sulfonylurea	Placebo + sulfonylurea
Overall, n (%)	3 (4.1)	9 (12.5)	4 (5.8)
Metformin and sulfonylurea added (26 wk)	Canagliflozin 100 mg + metformin + sulfonylurea	Canagliflozin 300 mg + metformin + sulfonylurea	Placebo + metformin + sulfonylurea
Overall, n (%)	43 (27.4)	47 (30.1)	24 (15.4)
Severe, n (%)	1 (0.6)	0	1 (0.6)
Metformin and sulfonylurea added (52 wk)	—	Canagliflozin 300 mg + metformin + sulfonylurea	Sitagliptin + metformin + sulfonylurea
Overall, n (%)	—	163 (43.2)	154 (40.7)
Severe, n (%)	—	15 (4)	13 (3.4)
Metformin and pioglitazone added (26 wk)	Canagliflozin 100 mg + metformin + pioglitazone	Canagliflozin 300 mg + metformin + pioglitazone	Placebo + metformin + pioglitazone
Overall, n (%)	3 (2.7)	6 (5.3)	3 (2.6)
Insulin added (18 wk)	Canagliflozin 100 mg + insulin	Canagliflozin 300 mg + insulin	Placebo + insulin
Overall, n (%)	279 (49.3)	285 (48.6)	208 (36.8)
Severe, n (%)	10 (1.8)	16 (2.7)	14 (2.5)

Canagliflozin caused dose-related increases in mean serum potassium, magnesium, and phosphate. Transient increases in serum potassium were observed within 3 weeks after initiation of therapy in patients with moderate renal impairment. Increases in serum potassium levels of greater than 5.4 mEq/L and 15% above baseline occurred in 12.4%, 27%, and 16.1% of patients treated with canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively. An elevation greater than or equal to 6.5 mEq/L occurred in 1.1%, 2.2%, and 2.2% of patients, respectively.¹ Mean serum magnesium increases that remained elevated throughout treatment were observed within 6 weeks after initiation of therapy. In 4 placebo-controlled trials, the mean change in serum magnesium was 8.1%, 9.3%, and −0.6% for canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively. In patients with moderate renal impairment, serum magnesium increased by 9.2%, 14.8%, and 0.2% with canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively.¹ In 4 placebo-controlled trials, the mean increases in serum phosphate levels observed were 3.6%, 5.1%, and 1.5% with canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively. In patients with moderate renal impairment, serum phosphate increased by 5%, 9.3%, and 1.2% with canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively.¹

Canagliflozin can cause dose-related increases in LDL-C. In 4 pooled placebo-controlled trials, mean changes from baseline in LDL-C relative to placebo were 4.4 and 8.2 mg/dL with canagliflozin 100 and 300 mg, respectively.¹

Canagliflozin can cause dose-related increases in hemoglobin. In 4 pooled placebo-controlled trials, mean changes from baseline in hemoglobin were 0.47, 0.51 g/dL, and −0.18 with canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively.¹

Drug Interactions

Coadministration of canagliflozin with rifampin decreased canagliflozin AUC by 51%. The decrease in exposure to canagliflozin may result in decreased efficacy. If an inducer of UGT enzymes, including UGT1A9 and UGT2B4, must be coadministered with canagliflozin, consider increasing the dosage to 300 mg once daily if patients are currently tolerating canagliflozin 100 mg once daily, have an estimated GFR of greater than 60 mL/min/1.73 m², and require additional glycemic control.¹

When digoxin is coadministered with canagliflozin 300 mg, an increase of 20% in the AUC and 36% in mean peak drug concentration of digoxin was observed.¹

Recommended Monitoring

Glucose and HbA_1c should be monitored periodically throughout therapy. All patients should be monitored for hypotension and UTIs. Additionally, monitor for genital mycotic infections and treat appropriately.¹

Renal function should be assessed before initiating therapy and routinely during therapy. Patients with an estimated GFR of less than 60 mL/min/1.73 m² require more frequent monitoring. Periodically monitor serum potassium levels in patients with impaired renal function and in patients predisposed to hyperkalemia.¹

Canagliflozin may increase LDL-C; monitor and treat as appropriate.¹

Dosing

The recommended dosage of canagliflozin is 100 mg once daily taken before the first meal of the day. In patients requiring additional glycemic control and who have an estimated GFR of at least 60 mL/min/1.73 m², the dosage may be increased to 300 mg once daily.¹

In patients with moderate renal impairment (estimated GFR of 45 to less than 60 mL/min/1.73 m²), canagliflozin should be limited to 100 mg once daily. Canagliflozin should not be used in patients with severe renal impairment (estimated GFR of less than 45 mL/min/1.73 m²).¹

No dosage adjustments are necessary for patients with mild or moderate hepatic impairment. There are no data on the use of canagliflozin in patients with severe hepatic impairment; it is not recommended for use in this population.¹

In patients using an inducer of UGT (eg, rifampin, phenytoin, phenobarbital, ritonavir), the dosage may be increased to 300 mg once daily in patients requiring additional glycemic control and who have an estimated GFR of at least 60 mL/min/1.73 m².¹

Product Availability

Canagliflozin was approved by the US Food and Drug Administration in March 2013.²⁷ Canagliflozin is available as 100 and 300 mg film-coated tablets supplied in bottles of 30, 90, and 500 and blister packs of 100 containing 10 blister cards of 10 tablets each.¹

Store at 25°C (77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F).¹

DRUG SAFETY/RISK EVALUATION AND MITIGATION STRATEGY (REMS)

No REMS is required for canagliflozin.²⁷

Postmarketing Requirements

Postmarketing requirements for canagliflozin include completion of studies to evaluate pharmacokinetics, pharmacodynamics, efficacy, and safety in pediatric patients 10 to 18 years of age with type 2 diabetes mellitus.²⁷ Two randomized, double-blind, placebo-controlled trials, one evaluating the effect of canagliflozin on the incidence of major adverse cardiovascular events and the other evaluating the effect of canagliflozin on bone mineral density and markers of bone turnover in patients with type 2 diabetes mellitus, are also required.²⁷

Additionally, enhanced pharmacovigilance for canagliflozin is required; this includes surveillance, assessment and analysis, and reports of malignancy, fatal pancreatitis, hemorrhagic/necrotizing pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, serious hepatic abnormalities, and pregnancy in patients treated with canagliflozin.²⁷

Conclusion

Canagliflozin offers an oral treatment option as an adjunct to diet and exercise for patients with type 2 diabetes. Reduction in HbA_1c appears to be approximately 0.33% to 1% and is dose dependent. Canagliflozin appears to be well tolerated and exhibits similar or lower rates of hypoglycemia relative to comparator agents when used in combination therapy. Canagliflozin has been associated with an increased incidence of genital mycotic infections in men and women, UTIs, volume depletion, and changes in serum potassium levels.