Pharmacology Update
Canagliflozin Tablets (Invokana™)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The first in a new class of drugs has been approved by the FDA for the treatment of diabetes mellitus. This new class of drugs decreases the renal threshold for glucose excretion by inhibiting the sodium-glucose co-transporter 2 (SGLT2), thus increasing renal clearance of glucose. Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation and marketed by Janssen Pharmaceuticals as Invokana.
Indications
Canagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.1
Dosage
The recommended dose is 100 mg once daily taken before the first meal of the day.1 The dose may be increased to 300 mg once daily if tolerated in patients with an eGFR of 60 mL/min/1.73 m2 or greater. The dose should not exceed 100 mg daily in patients with an eGFR between 45 and 60 mL/min/1.73 m2. Canagliflozin is available as 100 mg and 300 mg tablets.
Potential Advantages
Canagliflozin provides an effective and new mechanism of action for reducing plasma glucose.
Potential Disadvantages
Canagliflozin has an adverse reaction profile that differs from currently marketed antidiabetic agents. By promoting glucose excretion, it acts as an osmotic diuretic.1 Adverse reactions include reduction in intravascular volume and hypotension. Other adverse events include increased SCr, decrease in eGFR, hyperkalemia, increases in LDL-C, serum magnesium, serum phosphate, and genital mycotic infections.
Comments
Canagliflozin lowers plasma glucose primarily by inhibiting SGLT2. Renal glucose threshold can be lowered to 70-90 mg/dL from a norm of 240 mg/dL. It also transiently inhibits intestinal SGLT1, which results in delaying intestinal glucose absorption.1,2 Canagliflozin was evaluated as monotherapy and in combination with insulin, metformin, sulfonylurea, metformin and sulfonylurea, and metformin and pioglitazone. It was also compared directly to sitagliptin and glimepiride. Subjects had type 2 diabetes inadequately controlled with diet and exercise or baseline therapy. The primary efficacy endpoint was change (difference from placebo or comparator) in HbA1c from baseline to the end of the study. Co-secondary endpoints included proportion achieving HbA1c < 7%, changes in fasting blood sugar, systolic blood pressure, body weight, and lipid profile. As monotherapy (n = 584), canagliflozin showed -0.91% (95% confidence interval [CI], -1.09, -0.73) change in HbA1c with the 100 mg and -1.16% (95% CI, -1.34, -0.99) for the 300 mg compared to placebo from baseline of approximately 8% to week 26.1,3 Percent achieving HbA1c goal of < 7% was 45% and 62% for the two doses compared to 21% for placebo. There was significant change in fasting plasma glucose, -36 m/dL and -43 mg/dL, respectively, for the two doses and 2-hour postprandial glucose (-48 mg/dL, and -64 mg/dL, respectively). There was also a 2.2% and 3.3% difference in weight loss between the two doses of canagliflozin compared to placebo. Substantial reduction in HbA1c was observed by week 12.3 In patients with HbA1c > 10%, changes in HbA1c were -2.13% and -2.56%, respectively.3 There was a modest decrease in systolic blood pressure, increase in HDL-C, and modest increase in LDL-C. For subjects inadequately controlled on metformin (up to 2000 mg/day; n = 1284), the addition of canagliflozin resulted in changes of -0.62% to -0.77% in HbA1c, respectively, from baseline to week 26.1 Similar changes (range -0.62% to -0.83%) were seen when canagliflozin was added to insulin, a sulfonylurea, metformin + sulfonylurea, and metformin + pioglitazone.1 In two separate 52-week studies, canagliflozin 300 mg/day added to metformin showed a greater lowering of HbA1c than glimepiride (6 mg to 8 mg) + metformin and was also more efficacious when added to metformin + sulfonylurea than sitagliptan (100 mg) + metformin, and sulfonylurea. Most common adverse events (vs placebo) were female genital mycotic infections (10-11% vs 3.2%) and increase in serum magnesium (8-9% vs -0.6%). The risk for hypoglycemia is significant if a sulfonylurea is part of the regimen.
Clinical Implications
Canagliflozin is the first in the class of SGLT2 inhibitors. This action lowers the threshold for glucose excretion so plasma glucose is lowered by promoting glucose excretion and osmotic diuresis. The long-term effect of polyuria and pollakiuria remains to be determined. The drug is effective in lowering HbA1c with the magnitude of reduction as monotherapy similar or less than reported with metformin monotherapy.4 According to American Diabetes Association’s multidisciplinary Professional Practice Committee, metformin is still the first-line oral therapy for type 2 diabetics.5 There are currently no comparative studies as monotherapy. The long-term safety and efficacy remain to be determined. The wholesale cost for a 30-day supply of canagliflozin (100 mg or 300 mg) is $263.
References
1. Invokana Prescribing Information. Titusville, NJ: Janssen Pharmaceuticals, Inc.; March 2013.
2. Polidori D, et al. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: Results of a randomized, placebo-controlled study. Diabetes Care 2013; Feb. 14. [Epub ahead of print.]
3. Stenlof K, 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;15:372-382.
4. Glucophage Prescribing Information. Princeton, NJ: Bristol-Myers Squibb Company; January 2009.
5. American Diabetes Association. Standards of medical care in diabetes — 2012. Diabetes Care 2012;35 (Suppl 1):S11-S63.
The first in a new class of drugs has been approved by the FDA for the treatment of diabetes mellitus. This new class of drugs decreases the renal threshold for glucose excretion by inhibiting the sodium-glucose co-transporter 2 (SGLT2), thus increasing renal clearance of glucose. Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation and marketed by Janssen Pharmaceuticals as Invokana.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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