Can canagliflozin help when metformin therapy can’t control diabetes?

The authors evaluated the effectiveness and safety of canagliflozin for type 2 diabetes that could not be controlled with metformin therapy.

Metformin (Glucophage) is a recommended first-line drug therapy for type 2 diabetes that decreases glucose production in the liver, increases insulin sensitivity and enhances glucose uptake. However, the progressive nature of the disease often necessitates more intensive treatment regimens or combination therapy for patients to achieve and/or maintain glycemic (blood glucose) control. Sitagliptin (Januvia) is one such drug. Sitagliptin is a dipeptidyl peptidase-4 inhibitor that causes an increase in the release of insulin.

Canagliflozin (Invokana) is a sodium glucose co-transporter 2 inhibitor recently developed for type 2 diabetes. This drug inhibits a protein that is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this protein causes more glucose to be eliminated through the urine.

This study assessed the effectiveness and safety of canagliflozin in patients with type 2 diabetes that was inadequately controlled with metformin.

A total of 1,010 patients on metformin therapy completed the study. In period 1 (week 1 – 26) patients were randomized to receive canagliflozin 100 mg, canagliflozin 300 mg, sitagliptin 100 mg or placebo (a substance with no therapeutic effect).  In period 2 (week 27 – 52), those patients taking canagliflozin or sitagliptin continued on their treatment, but those who had been taking placebo previously were changed to sitagliptin 100 mg.

At week 26, canagliflozin 100 mg reduced HbA1c (a 3-month average measure of blood glucose) 0.62% more than placebo, and canagliflozin 300 mg reduced HbA1c 0.77% more than placebo. Sitagliptin decreased HbA1c levels 0.66% more than placebo. 45.5% of patients receiving canagliflozin 100 mg achieved HbA1c levels of less than 7% (the goal for diabetics, a level at which diabetes can be considered well-controlled) compared to 57.8% of those taking 300 mg, 29.8% of those taking placebo and 54.5% of those taking sitagliptin.

At 52 weeks, canagliflozin 100 mg did not reduce HbA1c levels more than sitagliptin, while canagliflozin 300 mg reduced HbA1c by 0.15% more than sitagliptin. At 52 weeks 54.7% of those taking canagliflozin 300 mg achieved HbA1c levels of less than 7% compared to 41.4%of those taking 100 mg and 50.6% of those taking sitagliptin. Those taking canagliflozin 300 mg were 28% more likely to achieve Hba1C levels less than 7% compared to those taking sitagliptin, while those taking canagliflozin 100 mg were 34% less likely to do so.

Those taking sitagliptin lost on average 1.2 kg over the study, compared to a loss of 3.3 kg for canagliflozin 100 mg and 3.7 kg for canagliflozin 300 mg.

The proportion of patients with documented episodes of hypoglycemia (dangerously low levels of glucose) was 6.8% for both 100 mg and 300 mg canagliflozin, 4.1% with sitagliptin and 2.7% with the group who began on placebo and then changed to sitagliptin.

The authors stated that treatment with canagliflozin improved glycemic control and reduced body weight compared with placebo over 26 weeks and with sitagliptin over 52 weeks and was generally well tolerated.

The company that developed canagliflozin, Janssen, funded the study.