On March 29, the FDA approved Janssen Pharmaceuticals? canagliflozin (Invokana), making it the first SGLT-2 inhibitor approved for the treatment of type 2 diabetes in the United States. Bristol-Myers Squibb and AstraZeneca's SGLT-2 inhibitor dapagliflozin (Forxiga) has already been approved in Europe, but FDA rejection in January 2012 opened a window of opportunity for canagliflozin to secure the lucrative first-in-class status in the United States.

By targeting a glucose transporter protein in the kidney, SGLT-2 inhibitors increase the urinary excretion of glucose. This mechanism not only lowers plasma glucose but also leads to a small degree of weight loss ? an effect highly sought after by physicians and patients. Canagliflozin's approved label includes the claim that the drug is associated with a mean weight loss of about 3 percent over placebo, not bad and roughly equal to the weight loss associated with Arena and Eisai's recently approved weight-loss drug lorcaserin (Belviq). The novel mechanism is also quite distinct from other anti-diabetic drug classes and so is appropriate for combination use with just about any other anti-diabetic drug.

What's the catch? Increasing the amount of sugar in your urine comes at a cost ? an increased risk of genital urinary infections. It turns out patients are not crazy about having this particular side-effect and physicians don?t want an additional and potentially recurrent complication to treat in patients already likely to have concurrent treatment for a number of other comorbidities. Furthermore, canagliflozin's efficacy diminishes with loss of renal function: a comorbidity common in type 2 diabetics. Canagliflozin is contraindicated in patients with severe renal impairment and only the lower 100mg dose can be prescribed to patients with moderate renal impairment.

Despite some advantages over the hugely successful DPP-IV inhibitors, sales of canagliflozin are going to be restricted by side-effects and contraindications inherent to its mechanism of action. While canagliflozin's launch advantage is a massive bonus, the SGLT-2 inhibitor class on the whole lacks the wide appeal required to replicate the blockbuster success of the DPP-IV inhibitor class.

Gideon Heap is an analyst with the Pharmaview team at Decision Resources.

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