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Type 2

FDA Advisory Committee Recommends Approval of Johnson & Johnson’s SGLT-2 inhibitor Invokana (canagliflozin)

On January 11, an advisory panel recommended that the FDA approve Johnson & Johnson’s SGLT-2 inhibitor, Invokana (canagliflozin). The panel voted 10-5 in favor of approving the drug for type 2 diabetes. Though the FDA does not have to follow the advisory committee’s recommendation, it typically does. A final approval decision by the FDA is expected within the next two months. As discussed in this issue’s learning curve, SGLT-2 inhibitors improve blood glucose control by causing the kidneys to excrete any excess glucose in urine.

Though the panel’s ultimate decision was to approve Invokana, its members had two main concerns that will likely influence the final approval and label (the label is all the fine print that explains which patients should or should not take the drug, the various details about how well the drug works, the risks involved in taking the drug as assessed by FDA, etc.). First, in clinical trials, Invokana did not have the same effect for patients who have completely healthy kidneys as those patients who have impaired kidney function – that means kidney problems. On average, the drug significantly lowered patients’ A1cs by 0.6-1.2% from an average baseline of 8% without any risk of hypoglycemia. However, the A1c reductions drop to just 0.3-0.4% for patients with impaired kidney function. By the end of the discussion, the panel agreed that there should be restrictions on prescribing the drug to this group of patients, since the efficacy is lower with the same or even more side effects. There was no consensus on what kidney function threshold (known as estimated glomerular filtration rate, or eGFR) should be used to determine eligibility for the drug. Should the drug be approved, we expect the final label will include at least some restriction in this regard.

The second area of heated discussion concerned the potential cardiovascular risks of Invokana. In Johnson & Johnson’s study specifically designed to examine this, a few interesting findings emerged. Although use of Invokana was associated with an overall 9% reduction in cardiovascular events compared to placebo, the risk of stroke appeared to increase with use of Invokana. Since this contrasted with the rest of the cardiovascular data, many panelists attributed this finding to chance. We assume that there will be close monitoring of strokes as well as cardiovascular disease once the drug is approved. Furthermore, the company explained that the cardiovascular benefits from taking Invokana – an increase in the “good” kind of cholesterol, called HDL cholesterol, decreases in blood pressure, improved glucose control, and decreased body weight – would compensate for any heightened adverse cardiovascular risks. Still, the stroke finding, combined with an observed increase in LDL cholesterol (the “bad” kind of cholesterol; see our learning curve on cholesterol in diaTribe #18), led panelists to ask for more cardiovascular data on Invokana to demonstrate its long-term safety.

As she has done previously, diaTribe Editor-in-Chief Kelly L. Close spoke on behalf of patients at the advisory committee meeting. Review her remarks here and slides here. Invokana is not the first SGLT-2 inhibitor that has been submitted for FDA approval; the FDA previously accepted a new drug application from AstraZeneca and Bristol-Myers Squibb for Forxiga (dapagliflozin) in March of 2011, but the FDA denied approval for Forxiga in January of 2012. After gathering additional safety data, the two companies plan to resubmit the drug for approval in the US in mid-2013. In Europe, Forxiga was approved in November 2012. With the FDA panel recommendation for Invokana, SGLT-2 inhibitors are on path to becoming available to US patients in the near future. –MN/AB