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General Information

Invokana (canagliflozin) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor. Inhibiting SGLT2 is believed to reduce blood glucose levels by increasing the amount of glucose excreted in the urine.

Invokana is specifically indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Invokana was subsequently approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease. Invokana was approved in September of 2019 to reduce the risk of end-stage kidney disease (ESKD), worsening of kidney function, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes and diabetic kidney disease (nephropathy) with a certain amount of protein in the urine.

Invokana is supplied as tablets for oral administration. The recommended starting dose of Invokana is 100 mg once daily, taken before the first meal of the day. In patients tolerating Invokana 100 mg once daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control, the dose can be increased to 300 mg once daily.

Clinical Results

FDA Approval

The FDA approval of Invokana was based in part on a monotherapy study. Invokana was also studied in combination with metformin, sulfonylurea, metformin and sulfonylurea, metformin and a thiazolidinedione and in combination with insulin (with or without other antihyperglycemic agents). The efficacy of Invokana was compared to a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin) and a sulfonylurea (glimepiride).
Monotherapy Study
A a 26-week, double-blind, placebo-controlled study enrolled 584 patients with type 2 diabetes inadequately controlled on diet and exercise. Patients taking other antihyperglycemic agents discontinued the agent and underwent an 8-week washout followed by a 2-week, single-blind, placebo run-in period. Patients not taking oral antihyperglycemic agents entered the 2-week, single-blind, placebo run-in period directly. After the placebo run-in period, subjects were randomized to Invokana 100 mg, 300 mg, or placebo, administered once daily for 26 weeks. At the end of treatment, Invokana 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p-value <0.001 for both doses) compared to placebo. Invokana 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo. Statistically significant mean changes from baseline in systolic blood pressure relative to placebo were -3.7 mmHg and -5.4 mmHg with Invokana 100 mg and 300 mg, respectively (p<0.001 for both doses).
Efficacy Studies
Invokana compared to glimepiride, both as add-on combination with metformin
A 52-week, double-blind, active controlled study enrolled 1,450 patients with type 2 diabetes inadequately controlled on metformin monotherapy. Subjects received Invokana 100 mg or 300 mg, or glimepiride (titration allowed throughout the 52-week study to 6 or 8 mg), administered once daily as add-on therapy to metformin. Invokana 100 mg provided similar reductions in HbA1C from baseline compared to glimepiride when added to metformin therapy. Invokana 300 mg provided a greater reduction from baseline in HbA1C compared to glimepiride, and the relative treatment difference was -0.12%. Treatment with Invokana 100 mg and 300 mg daily provided greater improvements in percent body weight change, relative to glimepiride.
Invokana compared to sitagliptin, both as add-on combination therapy with metformin and sulfonylurea
A 52-week, double-blind, active-controlled study enrolled 755 patients with type 2 diabetes inadequately controlled on the combination of metformin and sulfonylurea. The subjects received Invokana 300 mg or sitagliptin 100 mg in combination with metformin and sulfonylurea. Invokana 300 mg provided greater HbA1C reduction compared to sitagliptin 100 mg when added to metformin and sulfonylurea (p<0.05).

Invokana 300 mg resulted in a mean percent change in body weight from baseline of -2.5% compared to +0.3% with sitagliptin 100 mg. A mean change in systolic blood pressure from baseline of -5.06 mmHg was observed with Invokana 300 mg compared to +0.85 mmHg with sitagliptin 100 mg.

The FDA approval of Invokana to reduce the risk of major adverse cardiovascular (CV) events was based on the CANVAS (CANagliflozin cardioVascular Assessment Study) Program which evaluated the effect of Invokana on CV risk in a broad population of more than 10,000 adults with T2D who had established CV disease (65 percent) or were at risk for cardiovascular disease with two or more risk factors (35 percent). Overall, treatment with Invokana as compared with placebo in addition to standard of care reduced the combined risk of heart attack, stroke and CV death by 14% (events occurred in 26.9 vs. 31.5 participants, respectively, per 1000 patient-years). In patients with established CV disease, treatment with Invokana reduced the combined risk of heart attack, stroke and CV death by 18% compared to placebo (events occurred in 34.1 vs. 41.3 participants, respectively, per 1000 patient-years).

Side Effects

Adverse events associated with the use of Invokana may include, but are not limited to, the following:

female genital mycotic infections
urinary tract infection
increased urination

The Invokana drug label comes with the following Black Box Warning: LOWER LIMB AMPUTATION • An approximately 2-fold increased risk of lower limb amputations associated with Invokana use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD. • Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs. • Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. • Monitor patients receiving Invokana for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

Mechanism of Action

Invokana (canagliflozin) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor. Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion.

Literature References

Stenlöf K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, Canovatchel W, Meininger G Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes, Obesity and Metabolism 2013 Apr;15(4):372-82

Rosenstock J, Aggarwal N, Polidori D, Zhao Y, Arbit D, Usiskin K, Capuano G, Canovatchel W; Canagliflozin DIA 2001 Study Group Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 2012 Jun;35(6):1232-8

Devineni D, Morrow L, Hompesch M, Skee D, Vandebosch A, Murphy J, Ways K, Schwartz S Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes, Obesity and Metabolism 2012 Jun;14(6):539-45