Most FDA advisors support diabetes drug canagliflozin, despite CV concerns

Miriam E Tucker

January 11, 2013

Silver Spring, MD (updated) - A US Food and Drug Administration advisory panel voted 10 to 5 in favor of approving the novel glucose-lowering agent canagliflozin (Invokana, Janssen Research & Development) for the treatment of adults with type 2 diabetes. But the FDA's Endocrinologic and Metabolic Drugs Advisory Committee also voted 8 to 7 that they had concerns about the cardiovascular safety of the agent.

Canagliflozin is an oral inhibitor of sodium glucose cotransporter 2 (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.

If approved by the FDA, canagliflozin would be the first SGLT2 inhibitor agent on the US market. In January 2012, the FDA denied approval of SGLT2 inhibitor dapagliflozin (Bristol-Myers Squibb/AstraZeneca) due to concerns about a cancer signal. However, that drug was approved in the European Union in November 2012.

Canagliflozin does not appear to share that risk, with no signal for an increase in malignancy in about 8000 person-years of exposure.

Support for the drug approval, presented by Janssen officials during the daylong meeting, included efficacy and safety data from a total of nine double-blinded phase 3 studies involving 10 285 subjects who received at least one dose of study drug. Studies investigated the drug as monotherapy, in combination with other glucose-lowering agents, and in special populations, including older patients and those with moderate renal impairment. Most studies were either 26 or 52 weeks in length.

In terms of drug efficacy, canagliflozin produced hemoglobin A1c reductions from baseline of 0.62 to 0.91 percentage points with a 100-mg dose and 0.74 to 1.16 with a dose of 300 mg.

The focus of the meeting, however, including the questions posed by the FDA to the panel, mainly involved safety, including overall cardiovascular safety and risks and benefits in the group with moderate renal impairment.

The agreed-on primary end point for the CV safety analyses was major adverse cardiovascular events plus (MACE-plus), defined as a composite end point consisting of the adjudicated events of cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina. For all the trials combined, the end point occurred in 18.9% of patients taking canagliflozin and in 20.5% of patients taking the comparator agents, for a nonsignificant hazard ratio of 0.91 (95% CI 0.68-1.21).

However, for the individual MACE-plus component of stroke, the hazard ratio was elevated, at 1.5 (95% CI 0.8-2.6). Several panel members expressed concern that there might be an elevated risk of stroke, but the numbers were too small for the individual events to allow a clear assessment.

"The stroke signal is disturbing. I'm not sure if it's real or not, although I think if it were you'd see the same thing with the other CV outcomes," said Dr Michael Proschan (National Institutes of Health, Bethesda, MD).

The sponsor also presented data from the ongoing CANVAS trial (being conducted to assess cardiovascular safety in compliance with FDA guidance issued in 2008 for all new diabetes drugs). Final results are not expected until 2015. During the first 30 days after randomization in CANVAS, there were 13 cardiovascular events in the patients on canagliflozin (0.45%) vs one on placebo (0.07%). The hazard ratio of 6.5 was not significant, due to the small number (95% CI 0.85-49.66).

Both Janssen's analysis and that of the FDA suggested that this difference was due to a lower-than-expected event rate in the placebo groups. Differences were not seen beyond 30 days.

Data from the 1085 subjects with moderate renal impairment (estimated glomerular filtration rate 30-50 mL/min/1.73 m2) also raised concern. The drug was less effective at lowering glucose in that population—as expected based on its mechanism of action. Reductions in HbA1c from baseline for this group were 0.38 and 0.47 percentage points for canagliflozin doses of 100 mg and 300 mg, respectively (p<0.001 for comparisons with both doses).

At the same time, volume-depletion events were increased in the renal-impairment group (8.5% and 5% with the 300-mg and 100-mg doses, respectively, compared with 2.6% with placebo).

Several panel members commented that those findings created an unfavorable shift in the benefit/risk ratio compared with patients with normal renal function. "There are things about use of this in the population of patients with decreased renal function that I find disconcerting. . . . I think it's quite different in them from what it is in the general population," said Dr Julia B Lewis (Vanderbilt University School of Medicine, Nashville, TN).

Another panel member suggested that canagliflozin's use be contraindicated in patients with moderate (in addition to severe) renal impairment, as was done in the EU with dapagliflozin.

Other concerns arising from the data included dose-dependent increases in LDL cholesterol, an increased risk of genital mycotic infections in both men and women, and an increased incidence of fractures.

Nonetheless, the majority of panel members who supported the drug cited the need for more effective options to treat the growing population of patients with type 2 diabetes and canagliflozin's absence of hypoglycemia combined with the potential for weight loss. However, nearly all of the committee members also expressed the need for longer-term data and for the completion of the CANVAS trial.

The FDA is expected to announce its decision by the end of March, a company spokesperson said.


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