Petition for Warning on Diabetes Drugs Denied
FDA has denied a Public Citizen petition urging the agency to require a Boxed Warning for all sodium-glucose cotransporter-2 (SGLT-2) inhibitor drugs contraindicating their use in patients with Type 1 diabetes. “There is irrefutable evidence from multiple randomized clinical trials that the SGLT-2 inhibitors canagliflozin (Janssen’s Invokana), dapagliflozin (AstraZeneca’s Farxiga), and empagliflozin (Boehringer Ingelheim’s Jardiance) — which are approved for treatment of adults with Type 2 diabetes but not Type 1 diabetes … — cause a significant increase in the incidence of life-threatening diabetic ketoacidosis (DKA) when administered to patients with Type 1 diabetes,” the petition said. The advocacy group also contended that the current off-label prescribing of these drugs to patients with Type 1 diabetes, which it said has been well documented by FDA, “is enabled by the dangerous incompleteness and submerged prominence of the warnings about the risk of DKA in the drugs’ current product labeling.”
In denying the petition, FDA concluded that the references cited, as well as other information available to the agency, do not support the addition of a contraindication on SGLT2 inhibitor drug products. The agency said that a Public Citizen-referenced meta-analysis was “problematic because results from the two phase 2 trials included in the analysis were published in nonpeer-reviewed publications for which there is minimal study-specific information available. Furthermore, DKA was adjudicated differently in each of the trials, and the meta-analysis did not account for these differences in the definition of a DKA event.” It further said that the conclusions in the meta-analysis may be unreliable because of the lack of a standardized definition of what constituted a DKA event.
Additionally, FDA took issue with the petition’s characterization of data from the agency’s Adverse Event Reporting System (FAERS). It said that the petition did not indicate whether the group reviewed individual case narratives to exclude duplicate reports or to establish an association between use of the SGLT2 inhibitor drug and the DKA event, both of which FDA did under a 2019 safety review. Furthermore, the agency said that a limitation of FAERS data is that “there is no certainty of causality such that a reported event occurred because of use of a product. Adverse event report submission to FAERS does not require that a causal relationship between a product and event be proven, and case narratives can often help determine whether the adverse event of interest is probably, possibly, or unlikely related to the product.”