FDA approves first SGLT2 inhibitor for T2DM

June 15, 2013

Approval requires canagliflozin manufacturer to complete five post-marketing studies

NEW DRUG REVIEW

On March 29, 2013, FDA approved canagliflozin (Invokana, Janssen Pharmaceuticals, Inc.), a once-daily tablet indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Canagliflozin is the first drug in a new class known as sodium-glucose co-transporter 2 (SGLT2) inhibitors, which reduce the reabsorption of filtered glucose resulting in increased urinary glucose excretion. As a condition of the drug’s approval, Janssen, the manufacturer, must complete five post-marketing studies, including a cardiovascular outcomes trial; a bone safety study; a pediatric safety and efficacy study; a pediatric pharmacokinetic and pharmacodynamics study; and an enhanced pharmacovigilance program to monitor for malignancies, serious pancreatitis cases, and other adverse events. Canagliflozin should not be used by patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Efficacy: The efficacy of canagliflozin was established by nine clinical trials involving 10,285 patients with type 2 diabetes. The drug was studied both as a monotherapy and in combination with metformin, sulfonylurea, pioglitazone, and insulin. The monotherapy study was a double-blind, placebo-controlled (n=584) study lasting 26 weeks. Patients were randomly assigned to canagliflozin at doses of 100 mg or 300 mg once daily, or to placebo. Patients receiving canagliflozin achieved statistical improvement in A1c levels at the end of treatment compared to placebo (P<.001 for both doses). A greater proportion of patients taking canagliflozin achieved A1C levels less than 7%, a significant reduction in fasting plasma glucose, improved postprandial glucose, and body weight reduction. In addition, canagliflozin-treated patients had significant mean changes from baseline in systolic blood pressure compared to placebo.

The combination therapy studies included a 26-week trial of add-on combination therapy with metformin (n=1,284) and a 52-week trial comparing canagliflozin to glimepiride, both in add-on combination with metformin (n=1,450). Canagliflozin was also evaluated in an 18-week double-blind, placebo-controlled substudy in combination with sulfonylurea (n=127) and in a 26-week trial as an add-on combination therapy with metformin and sulfonylurea (n=469). In a 52-week trial, canagliflozin was compared to sitagliptin, both as add-on combination therapy with metformin and sulfonylurea (n=755), and in a 26-week trial as add-on combination therapy with metformin and pioglitazone (n=324). Canaglifozin was also studied in an 18-week trial as add-on combination therapy with insulin (with or without other antihyperglycemic agents) (n=1,718). The SGLT2 inhibitor was also studied for 26 weeks in 714 patients 55 to 80 years of age and 269 patients with renal impairments in a double-blind, placebo-controlled study.

Safety: The safety of canagliflozin was studied in both the placebo- and active-controlled trials mentioned above.  In the placebo-controlled studies the most common adverse reactions ≥ 2% in the canagliflozin-treated patients included female and male genital mycotic infections, urinary tract infections, increased urination, vulvovaginal pruritus, thirst, constipation, and nausea. In the active-controlled trials, patients experienced similar types of adverse reactions as well as fatigue, asthenia, a higher incidence of pancreatitis with the 100-mg dose, and higher incidence of bone fracture and hypersensitivity reactions. Patients 65 years of age and older have an increased risk of adverse reactions, particularly with the 300-mg dosage, related to reduced intravascular volume, which include hypotension, syncope, postural dizziness, and orthostatic hypotension. Because canagliflozin is linked to a dose-dependent increase in creatinine and a concomitant fall in GFR, patients with moderate renal impairment (eGFR to < 50 mL/min/1.73 m2) had a higher risk of renal-related adverse effects and decreases in eGFR, while experiencing less glycemic efficiency, in comparison to patients with mild renal impairment (eGFR ≥ 60 mL/min/1.73 m2) or those with no impairment.

Dosing: The recommended starting dose for canagliflozin is 100 mg, taken once daily before the first meal of the day. Patients who have mild or no renal impairment and need additional glycemic control can have their dosage increased to 300 mg. Canagliflozin is contraindicated in patients with severe renal impairment. An assessment of renal functioning is recommended before initiation of treatment and periodically during treatment. If a patient develops severe renal impairment, treatment should be discontinued. Patients who are also using a UGT enzyme inducer may require the 300-mg dosage of canagliflozin. Another antihyperglycemic agent is recommended for patients who are taking a UGT enzyme inhibitor and have moderate renal impairment.