Doctors debate danger of popular diabetes drug after FDA amputation warning

Many San Diego doctors are taking their patients off of Invokana, a widely used diabetes drug, after a large industry-sponsored trial found it doubled the risk of lower limb amputations compared with those taking a placebo.

Patients are being switched to other medications even though the study’s authors say the drug’s benefits — a reduced risk of cardiovascular events including death, non-fatal heart attacks and non-fatal strokes — outweigh its risk of amputations.

The drug is prescribed for people with Type 2 diabetes. The patients in the trial  were already at high risk for heart disease and other diabetes complications including amputations.

While a number of physicians interviewed said they still prescribe the drug to lower their patients’ glucose levels, attitudes among others began to change after the U.S. Food and Drug Administration on May 16 issued what’s called a black box warning about amputations.

It urges patients taking canagliflozin, sold under the brand name Invokana, Invokamet and Invokamet XR, to contact their doctors “right away” if they notice pain or tenderness, sores, ulcers or infections in their legs or feet. About half of the amputations occurring among patients in the trial were of toes, while the rest were across the foot, at the ankle, below the knee and above the knee.

The FDA warning suggests physicians should consider factors that predispose patients to amputations, such as prior amputations, peripheral vascular disease, neuropathy and diabetic foot ulcers, before prescribing the drug. Physicians should also monitor patients for ulcers, sores, pain or tenderness “and discontinue canagliflozin if these complications occur,” the FDA said.

Physicians in the Sharp HealthCare system have begun switching patients to other drugs in a “process that has been underway since the FDA warning came out,” spokesman John Cihomsky said in an email. The focus is on patients with key risk factors, such as prior amputations, he said.

The trial also found a small increase in diabetic ketoacidosis, a potentially fatal condition if left untreated, in study participants taking canagliflozin compared with participants who took a placebo. Canagliflozin is in the same class of medication   as two other drugs, Jardiance and Farxiga. The FDA in 2015 also issued a warning about ketoacidosis in that class of medications.

The Scripps Health system’s hospital pharmacy and therapeutics committee recently voted to keep canagliflozin off of its list of drugs it uses for hospitalized patients, committee chair Dr. Valerie Norton said in an email.

Norton said that in her role as an emergency room physician at Scripps Mercy Hospital she personally saw a very sick patient with diabetic ketoacidosis, which was thought to be a side effect of taking Invokamet.

Dr. Paul Speckart, a Bankers Hill endocrinologist on staff at Scripps Mercy, said his five-physician practice has removed all canagliflozin samples from its shelves and is no longer prescribing it. For the few patients who have been on the drug, he said, they’re writing prescriptions for Farxiga, known chemically as dapagliflozin.

Lower limb amputations are a known complication in people with diabetes. According to the Centers for Disease Control and Prevention, 108,000 hospital discharges occurred in 2014 among patients with diabetes who had amputation surgery, or a rate of 5 per 1,000 diabetes patients.

The research, named CANVAS for the Canagliflozin Cardiovascular Assessment Study, began in 2009. When the third phase of the research showed benefits in lowering glucose in patients with diabetes, the FDA approved Invokana in 2013. In the recent longer look, however, CANVAS revealed a doubled amputation risk that was a surprise.

Many patients could be affected

According to one company that collects drug sales information, SymphonyHealth, 4.5 million Invokana prescriptions were filled in 2016 in the United States, with sales of $2.33 billion, making it 48th in dollar sales of all U.S. drugs that year.

The drug is sold by Janssen, a division of Johnson & Johnson, which financed the research.

Asked to respond to concerns about the drug’s doubled amputation risk, Janssen spokeswoman Jessica Castles Smith said in an email that the safety of Invokana has been demonstrated by 14 million prescriptions and controlled studies in more than 24,000 patients, and that the increased risk of amputations was 0.3 in 100 patients treated for a year or from 0.3 to 0.6.

“We are confident in the proven cardiovascular and renal safety profile of Invokana (canagliflozin) and the benefits it can bring to people living with type 2 diabetes,” she said. The drug “significantly reduced the combined risk of cardiovascular death, nonfatal myocardial infarction (heart attack) and non-fatal stroke across a broad patient population.”

Health systems taking action

Kaiser Permanente in California has an “extremely low” volume of Invokana prescriptions written for its patients, spokeswoman Jennifer Dailard said. Kaiser is giving its physicians lists of patients who have received the drug so they can be  closely monitored and suggesting the drug be discontinued for patients with certain risk factors, such as foot ulcers.

Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, said about half of his heart disease patients also have diabetes so he prescribes diabetes drugs as well. But now, he said, he is “uncomfortable prescribing (Invokana) in view of the amputation risk.” He calculated that one patient out of every 69 people who takes canagliflozin for five years will have a drug-related amputation.

That’s correct, said Dr. Kenneth Mahaffey, director of the Stanford Center for Clinical Research, one of the authors of the study findings, published June 12 in the New England Journal of Medicine.

“There absolutely is an increased risk of amputations with canagliflozin,” according to that trial, Mahaffey said. Even so, he said, “We have to put the risk of amputations in perspective with the clear benefits we’re seeing.”

In the CANVAS trial, Mahaffey noted that 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. For every 1,000 patients in the study followed for five years, 15 patients suffered an amputation, he said.

“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 study did not give any hints why amputations are only being seen now, four years after the trials that led to the FDA’s approval of Invokana.

Many doctors are now expected to watch if other drugs in the the same class — specifically the newer drugs Jardiance (empagliflozin) and Farxiga (dapagliflozin) — have similar amputation risks, although none has been shown to date.

Mahaffey said he is considering switching his patients to another drug if they have had a prior amputation or peripheral vascular disease.

What would be the next drug to use? “That’s a great question,” Mahaffey said. “I probably would not use another (drug in that class) until we have more data.”

Cardiac benefits questioned

Dr. John Buse, a diabetes researcher and chief of endocrinology at the University of North Carolina who was an investigator for the Invokana clinical trial, vociferously questioned the methodology that concluded the drug prevented major cardiac events.

He said the heart attacks noted in the study were relatively minor and most not life-threatening.

That negates the study’s findings of cardiac benefit, Buse said, predicting the FDA would never approve the drug to prevent cardiovascular events based on current data.

The doubled amputation risk should be taken much more seriously, he emphasized. “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,” Buse said.

Doctors caution against panicking

But several doctors interviewed said taking patients off the drug en masse is an overreaction that could harm patients. They asked whether a person with diabetes would 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 Dr. Steven Edelman, a diabetes researcher at UC San Diego Medical Center and the Veterans Affairs Medical Center.

He sees the amputation issue as overblown. “The risk is still pretty darn small, with no real explanation for the mechanism” that appears to be driving a higher rate of amputations, he said.

Edelman, founder of the Solana Beach non-profit “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.” He is continuing to prescribe Invokana.

“Bladder cancer and bone fractures have been seen with other drugs in the same class but without the hysteria,” he said.

Edelman worries that some patients may be scared away from a drug they could benefit from, stop taking it and not replace it. Then their disease could get worse, he said.

Dr. Georges Argoud, an endocrinologist with privileges in the Sharp and Scripps health care systems, also still prescribes Invokana because of the benefits.

“I think it’s a little bit extreme to all of a sudden decide you’re not going to use this medication,” he said.

“It’s not very often that we see amputations anymore because we’re doing a pretty good job of educating patients, physicians and emergency rooms, and being very aggressive with the management of foot ulcers. Podiatrists are doing a great job,” Argoud said.

In his three-physician practice, he said, he can’t remember the last time anyone saw a patient who had to have an amputation.

He and others noted that no trials have been done that compared Invokana head-to-head with other drugs that treat diabetes, but it’s something he said should be closely monitored by doctors and patients.

The amputation warning also did not dissuade CVS Health, the largest pharmacy benefit manager in the nation covering 90 million insured patients, to add Invokana to its standard list of covered drugs, or formulary, starting in January, spokeswoman Christine Cramer said. But CVS is removing Jardiance.

“Many widely used drugs have black box warnings,” Cramer said, adding that the increased risk of amputations in Invokana “was found in only one of 12 studies of the drug, and data regarding amputations have not been collected systematically in trials of Jardiance.”

Public Citizen says ‘do not use’

For Michael Carome, director of Public Citizen’s Health Research Group, the amputation finding was not a surprise. His group designated Invokana 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.”

Those risks included kidney injury and serious urinary tract fungal infections.

The recent amputation issue “is a significant safety finding, and for us adds to our position that the drug should be avoided,” Carome said in an interview.

Trials done before the drug was approved, he said, “were relatively short, and the main outcome they’re looking for is the effect on glucose levels.”

The Veterans Health Administration does not keep canagliflozin on its formulary, and 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.”

Health plans weigh drug’s cost

Dr. Jeffrey Sandler, a Hillcrest diabetes specialist affiliated with Scripps Mercy, suggested many decisions to discontinue the drug have to do with how much health plans and managed care groups — which have to cover the costs of patient care out of a flat per-patient rate — receive for each enrollee.

A 30-day drug supply can cost as much as $585 for a consumer without a health plan rate, discount or coupon.

“They’re very expensive drugs, so many managed care groups really don’t want to use it,” Sandler said. “On the other hand, endocrinologists and some internists do want to use it.

“For a medical group like Sharp, which oversees not just Sharp health insurance plans but Rees-Stealy (medical groups), you have to take it with a grain of salt.”

Meanwhile, attorneys are circulating ads to recruit for class-action lawsuits patients who have used Invokana if they have had leg, foot or toe amputations or ketoacidosis.

Argoud said some of his patients have become afraid of Invokana and other drugs whose harmful side effects are the subject of law firm client recruitment.

He tries to reassure them by saying: “Are you going to make decisions about your health care by looking at ads on TV, or are you going to listen to your endocrinologist, someone who has read the data and is in tune with the literature?”

With Invokana, he said, “You have a pattern of benefits that’s amazing. None of the other drugs have demonstrated in such well-done trials to reduce cardiovascular disease.” It also comes with no weight gain and no hypoglycemia, like with many of the other drugs, Argoud said.

Mahaffey said many more studies are underway, as well as more detailed analysis of the CANVAS trials. “Hopefully, we’ll have presentations and publications (about this) in the near future,” he said.

More in the series …