J&J diabetes drug hit by amputation risk

The CANVAS trial was supposed to provide definitive cardiovascular safety data for Janssen’s Invokana (canagliflozin) in type 2 diabetes – and while it has succeeded in this regard, investigators were concerned about an increased risk of amputation.

This is good news for Boehringer/Lilly with their rival SLGT2 Jardiance (empaglifozin).

No such issues with amputation emerged in the EMPA-REG trial which showed a cardio benefit with Jardiance in 2015, although CANVAS investigators noted that on EMPA-REG there was no systematic data collection for amputation.

Following the announcement of the trial findings, shares in J&J ticked down, while Eli Lilly’s shares rose slightly in after-hours trading.

The findings announced at the American Diabetes Association conference could affect the marketability of Invokana – and issues with the trial design and the modest improvement in cardiovascular benefit cast doubts on whether J&J will be able to include a CV benefit on the drug’s label.

Last month the FDA issued a warning over the risk, and now requires boxed warnings on Invokana.

The trial, which involved just over 10,000 patients and began in 2009 as CANVAS, had already provided enough data by 2013 to prove the SGLT2 inhibitor’s cardiac safety in line with FDA regulations, and allowed it to get a US licence.

But the trial was restarted as CANVAS-R in order to gather further data and see if Invokana can actually improve cardiac safety compared with placebo, with data from both sections pooled together.

Results showed a 14% reduction in a composite of cardiovascular death, non-fatal heart attack, or non-fatal stroke, an almost identical benefit to that seen with Jardiance.

CV death was reduced by 13%, as was all-cause mortality, and CV death, or hospitalisation for heart failure was reduced by 22% compared with placebo. However a 14% reduction in all-cause mortality did not reach statistical significance.

Also down by 40% was renal damage risk, as measured by reduction in eGFR, end stage renal disease, or renal death.

But lower extremity amputations almost doubled, leaving investigators scratching their heads.

One theory about the cause for the unexpected result is that patients were on Invokana for longer than they would be in a “real life” setting.

Patients on the trial they were often taking Invokana for nine months or more, while in real life the high cost of the drug means patients take the drug for a much shorter time period.

This means that the amputation risk does not have time to manifest itself in the real world, according to speculation on the sidelines of the conference in San Diego.

However trial investigators were keen to point out that the overall safety profile of Invokana was positive in their view – per 1,000 patients the results showed 23 fewer patients with cardio problems, 17 fewer with heart failure and 16 fewer patients with kidney problems.

This was balanced against 15 more patients per thousand with amputations, with 10 per 1,000 at the toe or forefoot and five per 1,000 above the ankle.

To make matters worse for J&J the cardio benefit results were described as “exploratory” by lead investigator Bruce Neal, of the George Institute for Global Health in Australia due to the change in the study plan half way through.

Changing the label to show the cardio benefit will therefore be “something negotiated between the regulator and the sponsor,” Neal said.