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Phase III Study: Canagliflozin as Add-On Therapy to Metformin and Pioglitazone Lowers Blood Sugar in Diabetic Adults

Hemoglobin A1C significantly reduced versus placebo (Nov. 9)

In a phase III study, the investigational drug canagliflozin (Janssen Research & Development) substantially lowered blood glucose levels compared with placebo when used as add-on therapy in patients with type 2 diabetes who were inadequately controlled with the antihyperglycemic medications metformin and pioglitazone. The results were presented at the 4th World Congress on Controversies to Consensus in Diabetes, Obesity, and Hypertension.

Canagliflozin 100 mg or 300 mg once daily, in addition to metformin and pioglitazone, achieved statistically greater hemoglobin A1C reductions at 26 weeks compared with placebo (change from baseline: –0.89% and –1.03% vs. –0.26%, respectively; < 0.001). The overall incidence of adverse events (AEs) was generally similar across all treatment arms.

In secondary efficacy measures, both canagliflozin 100 mg and 300 mg provided reductions in body weight compared with placebo (–2.8% and –3.8% vs. –0.1%, respectively; P < 0.001) and reductions in systolic blood pressure (–5.3 mm Hg and –4.7 mm Hg vs. –1.2 mm Hg, respectively; P < 0.01 and P < 0.05). Reductions in fasting plasma glucose were consistent with the primary endpoint for canagliflozin 100 mg and 300 mg compared with placebo (–1.49 and –1.84 mmol/L vs. 0.14 mmol/L, respectively; P < 0.001).

Increases in high-density lipoprotein cholesterol were observed with canagliflozin 100 mg and 300 mg compared with placebo (7.2% [0.08 mmol/L] and 8.9% [0.10 mmol/L] vs. 2.4% [0.02 mmol/L], respectively; P < 0.05 and P < 0.001), and increases in low-density lipoprotein cholesterol were also seen (7.1% [0.08 mmol/L] and 11.3% [0.19 mmol/L] vs. –0.4% [–0.10 mmol/L], respectively). Canagliflozin also decreased triglyceride levels at the 300-mg dose (–1.7% [–0.16 mmol/L]; P < 0.01). Triglyceride levels increased at the 100-mg dose (3.1% [0.06 mmol/L]; P = NS), although placebo was associated with a higher increase (15.3% [0.10 mmol/L]).

The incidence of AEs leading to discontinuation was low and similar across treatment groups (3.5% for canagliflozin total and 5.2% for placebo). Most AEs were assessed by the investigator as mild to moderate in severity. Adverse events of genital mycotic infections and increased frequency of urination were more common with canagliflozin 100 mg and 300 mg compared with placebo in men and women; these specific adverse events were generally mild or moderate in severity and did not lead to discontinuation. Rates of urinary-tract infections and hypoglycemia were low and similar across treatment groups.

These data were included in the New Drug Application (NDA) submitted to the FDA seeking approval for the use of canagliflozin for the treatment of type 2 diabetes, announced on May 31, 2012.

Canagliflozin is an investigational sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of patients with type 2 diabetes. The kidneys of people with type 2 diabetes reabsorb greater amounts of glucose back into the body compared with nondiabetic individuals, which may contribute to elevated glucose levels. Canagliflozin blocks the reabsorption of glucose by the kidneys, thereby increasing glucose excretion and lowering blood glucose levels.

Source: Johnson & Johnson; November 9, 2012.

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