Studies Show Diabetes Drug Invokana Increases Amputation Risk

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People with diabetes who take a class of drugs known as sodium–glucose cotransporter 2 (SGLT2) inhibitors will now need to weigh benefits against risks after studies showed the medications significantly reduce heart problems in subjects, but, surprisingly, also increase the risk of amputation.

The results of the studies on the Johnson & Johnson drug canagliflozin, marketed under the name Invokana, confirm cardiovascular benefits not only for that particular medication, but also for others in its class. Those same results, however, call into question whether other drugs in the class also contribute to increased amputation.

“Drugs to treat diabetes have been undergoing a positive transformation in the last three or four years,” says Dr. Bruce Neal, lead investigator in the study and professor of medicine for University of New South Wales Sydney, and senior director, the George Institute for Global Health in Sydney, Australia. “It used to be we would test diabetes drugs to see if they lowered glucose levels and did not cause heart problems. Now, we test drugs and expect to see them not only lower glucose but improve cardiovascular health. It’s been extraordinary. But, now we might be finding out that there are glitches along the way.”

Neal led a team of six other academic researchers combining data from two studies, the first a clinical trial before the drug was approved by the Food and Drug Administration in 2013 and the second a post-marketing study designed to detect any cardiovascular risks from the drug. Such studies are a recent requirement of the FDA to ensure safety of new medications across a wider population than may have been tested in clinical trials for the drug’s initial approval.

The studies, one called Canagliflozin Cardiovascular Assessment Study or CANVAS, and the second CANVAS-R, looked at 10,142 type 2 diabetics, all of whom had high cardiovascular risk. The data revealed that Invokana not only reduced cardiac problems in people with type 2 diabetes but it did so significantly while also reducing kidney problems by an even bigger margin.

“The good news is that the data shows the drug reduced major cardiovascular adverse events by twenty three per 1,000 subjects over five years,” Neal says. “It reduced the chance of hospitalization for heart failure by seventeen subjects, and major renal events by sixteen subjects. These are very impressive numbers.”

The numbers are more impressive when they are conjoined with results from other research into the same kind of drug as Invokana, which is a sodium–glucose cotransporter 2 (SGLT2) inhibitor. Clinical trails on a drug from Boehringer Ingleheim/Lilly called empafloglozin and marketed under the name Jardiance showed similar cardiovascular and renal benefits to users, as did the only other drug in the class, dapagliflozin, marketed as Farxiga, from Astra Zenega Pharmaceuticals.

Neal says results of studies on the entire class of drugs suggests strongly that the entire class carries cardiovascular and renal benefits. He says that the cardiovascular and renal benefits in those drugs are not because of one ingredient in each. Rather, it appears that the overall mechanism of the drug’s joint effects on multiple factors including blood glucose, blood pressure, and kidney protection is what contributes to the benefits.

According to the European Medicines Agency (EMA) the medications act to “block a protein in the kidneys called SGLT2, which absorbs glucose back from the urine into the bloodstream as the blood is filtered in the kidneys. By blocking the action of SGLT2, these medicines cause more glucose to be lost in the urine, thereby reducing the levels of glucose in the blood.”

Neal says this action not only reduces cardiovascular and kidney problems, but also works to address the possibility of stroke.

The problem of amputations, however, as shown in the results of testing on Invokana, remains.

The data shows that amputations of the toes and forefoot—and fewer above the ankle—occurred about twice as often in subjects taking Invokana than taking placebo.

“It is unclear at the moment what the cause of the amputation is,” Neal says. “This is clearly a side effect we don’t want.”

He said more data collection, and perhaps additional clinical trials will be conducted, to determine if the increased amputation risk is the same for the entire class of drugs or not. “We’re only at the start of this process,” Neal says. “There will be more study and more papers to try and figure out what is taking place.”

When asked how to proceed with taking the drug because of this news Neal, who stresses that he is an academic researcher and not a regulator, says he would follow the advice of regulators.

That advice from the FDA has been to put a boxed warning on Invokana advising users of the drug that there is an increased amputation risk. In Europe, such warnings are on the entire class of drugs. Additionally, Invokana already includes warnings regarding increased chances of acute kidney injury and urinary tract infections from the drug.

Neal says if patients are concerned the best person to speak to is their doctor.

“Doctors don’t treat 1,000 people,” he says. “They treat 1,000 individual patients. Each person is different and needs to weigh all the factors that might affect them in deciding whether or not to use a medication.”

 

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