Two "Potential Signals of Serious Risks/New Safety Information Identified By FAERS" Reports From 2015 Were Not Made Public By FDA Until February - March 2016
We only recently learned that the FDA has been evaluating the need for additional drug safety regulatory action as regards the controversial class of relatively new diabetes drugs known as Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors.
The following SGLT-2 inhibitors are currently approved by the FDA:
- Farxiga (dapagliflozin) tablet
- Glyxambi (empagliflozin/linagliptin) tablet
- Jardiance (empagliflozin) tablet
- Invokamet (canagliflozin/metformin HCl) tablet
- Invokana (canagliflozin) tablet
- Synjardy (empagliflozin/metformin HCl) tablets
- Xigduo XR (dapagliflozin/metformin HCl) extended release tablet
These seven diabetes medicines are currently being investigated by the FDA for the following possible "new" side effects:
Deep Vein Thrombosis (DVT)
Pulmonary Embolism (PE)
Acute Renal Injury
What led us to this recent discovery was a March 29, 2016 news report, "Possible Drug Risks Buried in Delayed FDA 'Watch Lists'", published online by Medscape (registration required).
We start with this excerpt from that Medscape investigative report:
The potential-signals list for the second quarter of 2015, the one that flagged SGLT-2 inhibitors for stroke and thromboembolic events, should have been posted on the FDA's website before September 30, 2015. Instead, it quietly appeared there on February 5, 2016, without any public notice. Concerning the issue with SGLT-2 inhibitors, the report said in its usual formulaic manner that "FDA is evaluating the need for regulatory action."
That same day, the agency posted the FAERS watch lists for the first and third quarters of 2015 as well. In total, the lists for the first 9 months of the year covered potential problems with 39 drugs or drug classes.
On March 22, the FDA finally caught up on its publication schedule when it posted the FAERS watch list for the last 3 months of 2015, which cited an additional six drugs or drug classes. SGLT-2 inhibitors popped up again, this time for acute renal injury. The refrain was the same: "FDA is evaluating the need for regulatory action."....
Strictly Confidential, No Obligation.
Next, to put the above-listed possible side effects of Invokana, Farxiga, Jardiance, and the several other SGLT2 inhibitor diabetes medicines into context, here is some more information from the "Potential Signals, Crossed Signals" section of that Medscape report:
The appearance of a drug on an FDA watch list shouldn't make anyone jump to conclusions about cause and effect. That caution applies to SGLT-2 inhibitors in the second-quarter 2015 report, particularly because other evidence doesn't point to stroke and thromboembolic events as a risk for at least one of these drugs.
A landmark study published in the New England Journal of Medicine last year demonstrated that empagliflozin offered cardiac benefits besides reducing blood glucose. In the study, called Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG), patients taking the drug had a lower relative risk for both cardiovascular mortality and all-cause mortality.
Stepping away from that aricle for a moment, the above-referenced medical journal article is "Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes" (N Engl J Med. Published September 17, 2015) (subscription required).
And here is a related September 17, 2015 Medscape piece: "Diabetes Drug Empagliflozin Cuts CV Deaths in Landmark EMPA-REG Trial" (registration required).
Now returning to the March 2016 Medscape report:
EMPA-REG, paid for by the drug's manufacturers, did not find, however, that the drug had an effect one way or the other on fatal or nonfatal strokes. Patients on empagliflozin had an overall stroke rate of 3.5% compared with 3.0% for patients receiving a placebo. The study authors said that difference was not significant.
One leading endocrinologist told Medscape Medical News that she doesn't know what to make of the stroke signal reported by the FDA in its watch list.
"The problem with these [FDA] databases is that there is no true denominator [of drug use to adverse events]," said Anne Peters, MD, a professor of medicine at the Keck School of Medicine of the University of Southern California in Los Angeles and director of its clinical diabetes program. "So we have no idea of the rates of events."
Dr Peters said it is "hard to ascertain causality" in the FDA watch list report. She noted that randomized controlled trials (RCT) for SGLT-2 inhibitors have not found an increase in strokes.
"I tend to go with RCT data in these cases, but (it's) hard to know. I have used SGLT-2 inhibitors in many, many people and never seen any of these side effects."
Dr Peters, who also writes a column for Medscape Diabetes & Endocrinology, has served as a speaker or consultant with Eli Lilly, Boehringer Ingelheim Pharmaceuticals, and AstraZeneca Pharmaceuticals, which make SGLT-2 inhibitors.
Eli Lilly, the comanufacturer of empagliflozin, told Medscape Medical News that it and Boehringer Ingelheim are aware that the FDA added the potential safety issues of stroke and thromboembolic events for SGLT-2 inhibitors to its DARRTS tracking system in 2015....
Accordingly, we will continue to monitor the medical literature for developments and watch for any forthcoming FDA action concerning the association of acute kidney / renal injury, thromboembolic events (e.g., DVTs, PEs), and/or strokes with Invokana, Farxiga, and Jardiance, as well as the other lesser-known SGLT2 inhibitor diabetes drugs.