Johnson & Johnson’s new diabetes drug Invokana has been associated with ketoacidosis, a potentially fatal condition caused by abnormally high levels of blood acids. On the heels of a recent Safety Warning, in which the FDA cautioned patients to watch for symptoms of blood acid poisoning, the agency has now chosen to strengthen the drug’s label.
Patients who have already suffered injury intend to hold Johnson & Johnson liable for the severe complications they say were caused by Invokana. Some have even filed Invokana lawsuits, seeking compensation for medical expenses, lost wages, and pain and suffering. Along with a host of other “SGLT2 inhibitors,” Invokana has already been linked to two additional possible safety concerns. The first, identified by industry watchdog group the Institute for Safe Medication Practices, involves impaired kidney function, and a marked risk of renal failure.
The other potential risk: cardiovascular complications, including blood clots, stroke and heart attack.
Concerns regarding Invokana’s cardiovascular safety were first raised on January 10, 2013, little more than 2 months prior to the drug’s approval.
In a meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, Dr. Sidney Wolfe voiced his reservations over a series of troubling clinical trials. Wolfe, the founder of the Health Research Group, noted abnormal increases in “hemoconcentration,” the balance of red blood cells to plasma, in patients taking Invokana.
SGLT2 inhibitors like Invokana increase urine production in an attempt to flush blood glucose, at dangerously high levels in type 2 diabetes patients, from the body. But increases in urination can also be accompanied by increases in “hematocrit,” the concentration of red blood cells relative to other fluids.
The blood literally becomes thicker, increasing the risk of blood clot formation, heart attack, and stroke.
Citing early clinical trial data, Wolfe noted that Invokana’s active ingredient, canagliflozin, appeared to increase hematocrit levels far more than another SGLT2 inhibitor, dapagliflozin.
Wolfe estimated that 25% of patients prescribed Invokana would eventually experience hemoconcentrations of 47% or more, levels he called “a very dangerous range.” In fact, Wolfe pointed to one study in which a total of 13 Invokana patients suffered “cardiovascular events,” versus only one event in a placebo group.
Earlier in the meeting, FDA official Dr. Hyon Kwon noted an increased incidence of “early cardiovascular events” associated with canagliflozin in patients already at an increased risk for heart complications. Note that adults with type 2 diabetes are already at least twice as likely to suffer heart disease or stroke than people without diabetes. Kwon’s comments referred to the so-called CANVAS trial, a study involving 4,300 patients that looked specifically at Invokana’s potential cardiovascular risks.
Wolfe later remarked that these “early cardiovascular events” were “almost all thrombotic [or “ischemic”] stroke,” interruptions in the brain’s blood supply caused by blood clots.
Doctor Wolfe went so far as to question the very benefit-risk profile of canagliflozin.
He noted that Janssen Pharmaceutical was seeking Invokana’s approval based not on its ability to lower blood glucose levels, but “solely on surrogate efficacy of HbA1c lowering.”
HbA1c, or “glycated haemoglobin” is produced when haemoglobin, a protein that assists oxygen in entering cells, merges with blood glucose. Generally, lower levels of HbA1c are associated with a lower risk of diabetes complications, but the association is far from consistent. Further, HbA1c levels can only be used to estimate a patient’s average blood glucose levels over a period of weeks or months.
As Wolfe pointed out, there is little guarantee that a patient with lowered HbA1c levels will suffer fewer adverse clinical outcomes. In fact, he said: “as with all recently approved type 2 diabetes drugs, [Janssen had presented] no evidence of any improved clinical outcomes, contrary to an older diabetes drug such as metformin.”
In light of what he considered Invokana’s dubious efficacy, Dr. Wolfe concluded: “for a drug that offers a new mechanism of hemoglobin A1c lowering, devoid of any evidence of clinical benefit, the list, and I’ve only given a partial here of the serious concerns, argue strongly against approval.”
Noting the serious concerns expressed by Doctors Wolfe and Kwon, the FDA ordered Janssen Pharmaceuticals to perform a battery of follow-up studies. One clinical trial will investigate Invokana’s potential risks for cardiovascular health. But the medical community may be forced to wait until April of 2017 for the results; the agency gave Janssen four years to complete its postmarketing trials.
In the meantime, patients who have already experienced severe cardiovascular events that may be associated with Invokana have begun reviewing their legal options. Amid allegations that Janssen Pharmaceutical failed to warn the public of its type 2 diabetes drug’s potential dangers, attorneys across the country are offering consultations to current and former patients.