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Some physicians and their hospital-affiliated medical groups are scurrying to take patients off of the diabetes drug canagliflozin (Invokana), after results from CANVAS, the big FDA-mandated cardiovascular outcomes trial, found it the risk of lower limb amputations compared with placebo even as it also showed a cardiovascular benefit.
The findings prompted the FDA to order a for the drug on May 16, an important concern since people with diabetes are already at higher risk for amputations. Previously the agency also warned that canagliflozin and other drugs in its class -- including empagliflozin (Jardiance) and dapagliflozin (Farxiga) -- and associated adverse effects.
These safety concerns, as well as fear of litigation, have prompted a variety of policy shifts in healthcare organizations regarding canagliflozin. Already, law firms have begun advertising on TV and elsewhere for patients who have used canagliflozin and suffered amputation or ketoacidosis, presumably for class-action litigation.
In San Diego, for example, physicians in the five-hospital Sharp HealthCare system's medical groups have begun switching patients to other drugs in a "process that has been underway since the FDA warning came out," Sharp hospital spokesman John Cihomsky wrote in an email. A focus is for patients with key risk factors, such as prior amputations.
In California statewide, Kaiser Permanente had few patients among its 8.5 million enrollees taking canagliflozin, but it sent its doctors names of patients who received the drug for closer monitoring. Kaiser also suggested they discontinue the drug for patients with certain conditions, such as foot ulcers.
Some physicians said they are taking aggressive steps, even calling patients before their scheduled appointments, because of the FDA warning.
Nationally, the Veterans Health Administration does not keep canagliflozin on its formulary. A spokeswoman said in an email that if doctors want to prescribe it, "that's a decision that is made jointly by the patient and his/her care team based on the clinical needs of the patient after assessing the risks versus benefits."
The VA has compared the three drugs in the class of SGLT2 inhibitors with two other classes of diabetes drugs: DPP-4 inhibitors and sulfonylurea agents and found "no statistically significant signals" suggesting any of the drugs has a higher risk of ketoacidosis, new strokes or amputations.
"No change in practice will be proposed until sufficient evidence is available to support a change," the VA statement said.
Thus far, the amputation risk appears confined to canagliflozin. But the European Medicines Agency has indicated that for SGLT2 inhibitors.
Jessica Castles Smith, a spokesperson for canagliflozin manufacturer Janssen, said in an email that, while the amputation risk is doubled with the drug versus placebo, it remained small at 0.6 per 100 patient-years of exposure. She also stressed its benefits, including reduced risk of serious cardiovascular events including death as demonstrated in CANVAS.
Different Takes on CANVAS
The scale of that reduction, at about 0.5 events including stroke, non-fatal MI, and cardiovascular death per 100 patient-years, could be seen as more than offsetting the increase of 0.3 per 100 patient-years in amputations. But John Buse, MD, of the University of North Carolina who was an investigator in CANVAS, disputed the importance of the cardiovascular benefit. The doubled amputation risk should be taken much more seriously, he said.
"Losing a toe, or a big toe, is a big deal. You'd have to think about that two or three times before you'd accept a big toe amputation in lieu of a small heart attack," he said.
Buse added that he doesn't understand why a doctor would prescribe canagliflozin instead of empagliflozin in the first place, because with empagliflozin researchers have not found more amputations, and because another industry study, , also demonstrated a cardiovascular benefit.
No head-to-head trials have compared the three SGLT2 inhibitors.
Kenneth Mahaffey, MD, director of the Stanford Center for Clinical Research and an author of the recent CANVAS findings, acknowledged the increased risk of amputations with canagliflozin. But, he added, "We have to put the risk of amputations in perspective with the clear benefits we're seeing."
Mahaffey noted that in the trials, for every 1,000 patients treated for five years, 23 fewer patients had a cardiovascular death, a heart attack or stroke, 16 fewer patients were hospitalized for heart failure, 17 fewer patients required dialysis or required a transplant, compared with those treated with a placebo.
"Even though amputation was a significant event for patients ... both physically and psychologically, 10 of the 15 suffered toe or metatarsal (across the foot) amputations and only five had above the ankle amputations," he said.
Mahaffey said the data to date does not give any clues on why amputations are only being seen now, four years after the trials that led to the FDA's original approval for lowering glucose. Several clinical researchers said the mechanism is a mystery.
He added that the concerns are real enough, however, that he now considers switching his patients who had a prior amputation or have peripheral vascular disease to another drug, saying, "I probably would not use another SGLT2 inhibitor until we have more data. And assuming patients are already on metformin, I would try a GLP-1 (glucagon-like peptide receptor agonist) or a DPP-4 inhibitor (dipeptidyl peptidase 4), or insulin, all based on assessment of each patient," he said.
Panic Mode?
Steven Nissen, MD, chairman of cardiovascular medicine at the Cleveland Clinic, said about half of his heart disease patients also have diabetes so he prescribes diabetes drugs too. But he said he is now "uncomfortable prescribing [canagliflozin] in view of the amputation risk." He extrapolated from the recent study that one patient out of every 69 who takes it for five years will have a drug-related amputation.
The latest FDA warning and "available literature" prompted the pharmacy and therapeutics committee for the four-hospital Scripps Health system in San Diego to vote to not add canagliflozin to its inpatient formulary, committee chair Valerie Norton, MD, wrote in an email.
Some time ago, Norton, emergency room medical director at Scripps Mercy Hospital, personally saw an ED patient with diabetic ketoacidosis "felt to be a side-effect of the medication. That patient was on Invokamet [and] was pretty sick."
Paul Speckart, MD, a San Diego endocrinologist, said his five-physician practice has cleared all canagliflozin samples from its shelves and is no longer prescribing it. For the few patients who have been on the drug, they're writing prescriptions for Farxiga.
But some doctors said that taking patients off the drug en masse is an overreaction that could end up harming patients. They asked, in words to this effect, Would you rather have a heart attack or a toe amputation?
"There's a little bit of inappropriate panic going on right now" among doctors treating diabetes, said Steven Edelman, MD, a diabetes researcher at the University of California San Diego, who sees the amputation issue as overblown. "The risk is still pretty darn small, with no real explanation for the mechanism."
Edelman, founder of the non-profit organization "Taking Control of Your Diabetes," said he "respects any physician who looks at that data and says hey, there's other drugs on the market ... I'm going to switch," But he's prescribing as usual.
He added, "Bladder cancer and bone fractures have been seen with other drugs in the same class, but without the hysteria."
Edelman worries that some patients may be scared away from a drug they could benefit from, stop taking it, and don't replace it. And then, their disease gets worse.
FDA's warning has not dissuaded CVS Health, the largest pharmacy benefit manager in the nation covering 90 million insured patients, to add canagliflozin to its formulary starting in January, said spokeswoman Christine Cramer. It also removed empagliflozin.
"Many widely used drugs have black box warnings," she said, adding that the increased risk of amputations in canagliflozin "was found in only one of 12 studies of the drug, and data regarding amputations have not been collected systematically in trials of Jardiance."
Canagliflozin had $2.33 billion in U.S. sales in 2016, making it the 48th top selling drug listed by , a drug analytics company. With 4.5 million prescriptions filled in 2016, it ranked 182nd by that measure.
Michael Carome, director of Public Citizen's Health Research Group, said the amputation finding was not a surprise. His group as a "do-not-use" drug in February, 2014, shortly after it was approved. Its Worst Pills Best Pills newsletter said "canagliflozin has not been shown to offer any unique clinical benefits in comparison to several older, safer diabetes drugs. Yet it does pose serious risks that outweigh any of its benefits."
That was before the CANVAS results were released. Nevertheless, said Carome in an interview, the amputation issue "is a significant safety finding and for us, adds to our position that the drug should be avoided."