SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel supported the approval of canagliflozin for the treatment of type 2 diabetes with caveats, including precautions about its use in patients with moderately impaired renal function and recommendations to continue to evaluate cardiovascular safety after approval.
At a meeting on Jan. 10, FDA’s Endocrinologic and Metabolic Drugs Advisory voted 10-5 to recommend approval of the selective sodium glucose cotransporter 2 (SGLT2) inhibitor for treating type 2 diabetes, based on the available safety and efficacy data on canagliflozin, which blocks the reabsorption of glucose by the kidney, increasing glucose excretion and lowering blood glucose levels.
The proposed indication is as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, taken by mouth at a dose of 100 mg or 300 mg once a day, before the first meal of the day. If approved, the drug would be the first SGLT2 inhibitor to be approved by the FDA. Primarily expressed by the kidney, SGLT2 is responsible for the majority of renal glucose reabsorption.
The manufacturer, Janssen Pharmaceuticals, submitted the results of nine phase III international studies in almost 10,300 patients with type 2 diabetes, comparing the drug with placebo or active controls, as monotherapy and as add-on therapy to other antihyperglycemic drugs; and the interim results of a cardiovascular outcomes study, required by the FDA for all new type 2 diabetes drugs. In the outcomes study, there was an imbalance in the rate of major adverse cardiovascular events (mostly strokes), with more cases among the canagliflozin-treated patients in the first 30 days, but the risk dropped after 30 days to below the threshold – a hazard ratio of 1.8 – set by the FDA as an acceptable CV risk for a new type 2 diabetes treatment.
Panelists voting on both sides noted that the risk-benefit profile was less clear-cut in patients with impaired renal function, since canagliflozin was less effective and was associated with more adverse events as renal function decreased. Those voting in favor of approval said that, although they were uncertain about the imbalance in CV events during the first 30 days of treatment, they were reassured by the available data available so far. In another vote, 8 of the 15 panel members, including several who supported approval, said they still had concerns about whether the risk had been excluded for the drug and agreed that more data were needed.
Other safety issues that panelists said should be monitored after approval included the potential long-term effects of the dose dependent increase in LDL cholesterol associated with canagliflozin treatment, and the impact of treatment on bone density and fractures. In the studies, there were more fractures among patients treated with canagliflozin – mostly low trauma upper limb fracture, but the difference was not statistically significant.
The panel chair, Dr. Abraham Thomas, the head of the division of endocrinology, diabetes, bone, and mineral disorders at Henry Ford Hospital in Detroit, voted in favor of approval, citing the "definite benefits" of the drug, but added that he, like other panelists, still had concerns regarding safety. More data are needed to determine whether the increase in adverse cardiovascular outcomes –stroke in particular – is a real issue or "a red herring," he said. Once approved, long-term follow-up of safety issues such as the effects of treatment on cardiovascular risk and bone should be evaluated in long-term registry studies, since they can be difficult to identify in clinical trials, he added.
Voting against approval, Dr. William Knowler, chief of the diabetes epidemiology and clinical research section at the Phoenix branch of the National Institute of Diabetes and Digestive and Kidney Diseases, said that he would support approval of the drug as an add-on therapy but not as an initial treatment because there were no data comparing canagliflozin to metformin, the standard initial therapy recommended by American Diabetes Association/European Association for the Study of Diabetes treatment guidelines. "I think the drug would be acceptable as add-on therapy for some patients, but for a general indication including monotherapy, I cannot recommend it," he said.
Cardiologist William Hiatt, professor of medicine at the University of Colorado, Denver, said that he voted against approval because the cardiovascular risks had not been fully evaluated and that his residual concerns about safety could be resolved once the cardiovascular outcomes study was completed.
In the phase III studies, treatment with canagliflozin resulted in significant improvements in glycemic control, based on the primary endpoint, changes in hemoglobin A1c from baseline to the end of the study, with sustained responses over 52 weeks and a large proportion of patients achieving glycemic goals, according to Janssen. Treatment in patients with renal impairment was also associated with reductions in HbA1c, which were of less magnitude than the reductions seen in patients with normal kidney function. Other favorable effects associated with canagliflozin included decreased body weight and reductions in systolic blood pressure.