In May, Drug Safety News published a story about the association between treatment with the diabetic drug Invokana (canagliflozin) and an increased risk of lower limb amputation. Despite strong evidence from a number of clinical studies in the U.S. and abroad, the FDA was only willing to issue an “advisory.” After results from two clinical studies (CANVAS and CANVAS-R) became available showing a 100% higher risk of lower-extremity amputations when taking Invokana, the FDA finally required a “black box warning” on product labeling in May 2017.
More recently, medical researchers working at the University of Padova in Italy confirmed earlier findings. The most recent study, published in Lancet Diabetes and Endocrinology, was based on an analysis of safety signal reports voluntarily submitted to the FDA's adverse-event reporting system (FAERS). These reports involved other drugs of the SGLT2-inhibitor class, which includes Jardiance (empagliflozin) and Farxiga (dapagliflozin). Significantly, there has been no association found between the latter two medications and amputation risk. However, the European Medicines Agency has extended the warning to include all SGLT2-inhibitors, which the FDA has not.
The analysis looked at 66 reports of amputations associated with SGLT2-inhibitors. Among those cases, 57 – 86 percent involved patients who had been taking Invokana. Furthermore, two-thirds of those patients had no other apparent risk factors, such as nerve damage, injuries, infections and/or a previous history of amputation. Lead author Dr. Gian Paolo Fadini, an endocrinologist and metabolic disease specialist, expressed grave concerns that the data “points to an unpredictable effect of the drug.” Fadini adds, “Our data are the first to confirm the warning originated from CANVAS and tends to suggest this is not a class effect.”
Dr. Fadini's warning came with a caveat, however: “At the moment, data are not sufficiently robust to modify canagliflozin use in favor of dapagliflozin/empagliflozin. So we can only reinforce, with independent data, the boxed warning issued by the FDA and call for caution when using canagliflozin in patients with the diabetic-foot syndrome.”
SGLT2-inhibitors, or “gliflozin drugs” such as Invokana work by preventing the re-absorption of glucose by the kidneys. This allows the patient to eliminate excess blood sugar through the urine. Among the risk factors associated with these medications is ketoacidosis, a condition in which there is a dangerous drop in blood pH levels (normal blood pH is 7.4). When this occurs, high acidity of the blood can cause pyelonephritis, which can cause severe kidney damage. SGLT2-inhibitors are also linked to pancreatitis, a potentially-fatal inflammatory disease that can injure the pancreas – the source of the body's insulin. Other side effects of gliflozin drugs include urinary tract and yeast infections and hypoglycemia.
According to its most recent SEC filing, manufacturer Johnson & Johnson faces 800 lawsuits in which plaintiffs cite side effects of Invokana as the cause of action. Currently, 12 bellwether trials are scheduled for discovery (presentation of evidence) between September 1, 2017, and August 25, 2018.