Clinical Context

In the United States, canagliflozin is the first-in-class US Food and Drug Administration (FDA)–approved inhibitor of sodium glucose cotransporter 2 (SGLT2). Its mechanism of action is to lower renal resorption of glucose, thereby boosting urinary excretion of glucose, reducing plasma glucose levels, and enhancing weight loss.

In January 2013, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 10 to 5 to approve canagliflozin, based on the unmet need for new agents in the type 2 diabetes arsenal, the absence of hypoglycemia, and the potential for weight loss. The approval for canagliflozin is for use with diet and exercise, to improve glycemic control in adults with type 2 diabetes. Nine safety and efficacy trials enrolling a total of more than 10,285 patients with type 2 diabetes showed improvement in hemoglobin A1c and fasting plasma glucose levels.

Study Synopsis and Perspective

The FDA approved a novel glucose-lowering agent, canagliflozin (Invokana) for the treatment of adults with type 2 diabetes.

Canagliflozin is the first in a new class of drug, an oral inhibitor of SGLT2. Inhibition of SGLT2 reduces resorption of glucose in the kidney, resulting in increased urinary glucose excretion, with a consequent lowering of plasma glucose levels as well as weight loss.

The authorization follows a 10-to-5 vote in favor of approval of canagliflozin by the FDA's Endocrinologic and Metabolic Drugs Advisory Committee in January. The majority of panel members who supported the drug cited the unmet need for new agents to treat the growing population of patients with type 2 diabetes and canagliflozin's absence of hypoglycemia, combined with the potential for weight loss, as deciding factors.

But the panel voted 8 to 7 at the same meeting that it had concerns about the cardiovascular safety of canagliflozin, most particularly a possible elevated risk for stroke. In the end, they deemed that current data were insufficient to be certain about this risk and concluded that longer-term follow-up will be required, including completion of the Canagliflozin Cardiovascular Assessment Study (CANVAS).

CANVAS is an ongoing study performed in compliance with FDA guidance, issued in 2008, requiring cardiovascular-outcomes data for all new diabetes drugs. Final results of CANVAS are not expected until 2015.

In the announcement, the FDA listed 5 postmarketing studies for canagliflozin that the manufacturer must conduct as a condition for the drug's approval:

• A cardiovascular outcomes trial (CANVAS)
• An enhanced pharmacovigilance program to monitor for malignant tumors, serious cases of pancreatitis, and other adverse events
• A bone safety study
• A pediatric pharmacokinetic and pharmacodynamics study
• A pediatric safety and efficacy study

Clinicians should not use canagliflozin to treat patients with type 1 diabetes, those with type 2 diabetes who have increased ketones in their blood or urine, those with severe renal impairment or end-stage renal disease, or those receiving dialysis.

Vaginal yeast infection and urinary tract infection are the most common adverse events for canagliflozin. Patients may also experience dizziness or fainting, especially in the first 3 months of therapy, because canagliflozin is associated with a diuretic effect, which can reduce intravascular volume, leading to orthostatic or postural hypotension.

Others in Class: Dapagliflozin, Ipragliflozin, Empagliflozin

Canagliflozin is the first SGLT2 inhibitor to reach the market in the United States, but another drug in this class, dapagliflozin (Forxiga), is already available in Europe; it was approved there in November 2012. The FDA denied approval of dapagliflozin in January 2012 because of concerns about a cancer signal.

Canagliflozin, which has also been submitted for approval in the European Union, does not appear to share that risk, with no signal for an increase in malignant tumors in about 8000 person-years of exposure.

A third SGLT2 inhibitor, ipragliflozin, has been filed for marketing approval in Japan, and a fourth, empagliflozin, is in phase 3 trials and has just been filed for approval in the United States.

More information about the approval of canagliflozin is available on the FDA Web site.

Clinical Implications

• The FDA has approved orally administered canagliflozin to improve glycemic control in adults with type 2 diabetes, in conjunction with diet and exercise. Safety and efficacy trials showed improvement in hemoglobin A1c and fasting plasma glucose levels. However, the FDA stated that current data were insufficient to be certain about possibly elevated stroke risk.
• Contraindications to use of canagliflozin include type 1 diabetes, increased blood or urine ketones in patients with type 2 diabetes, severe renal impairment or end-stage renal disease, and dialysis. Postmarketing studies will monitor risks for cardiovascular disease, cancer, serious pancreatitis, bone conditions, and other adverse events.
• Vaginal yeast infection and urinary tract infection are the most common adverse events for canagliflozin. Patients may also experience dizziness or fainting, especially in the first 3 months of therapy. Canagliflozin is associated with a diuretic effect, which can reduce intravascular volume, leading to orthostatic or postural hypotension.

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