Reckless Failure to Identify Dangerous Adverse Effect of New Diabetes Drugs

In December 2015, the Food and Drug Administration (FDA) required that the labeling for all members of the family of the type 2 diabetes drugs known as sodium-glucose cotransporter-2 (SGLT2) inhibitors (also commonly called “flozins”) — which we have designated as Do Not Use — be revised to include warnings about the risk of ketoacidosis, a serious, sometimes fatal condition caused by the buildup of ketones, a type of acid, in the blood.[1]

However, a paper published in the Annals of Internal Medicine on Sept. 17, 2019, revealed that incontrovertible evidence of SGLT2-inhibitor–induced ketoacidosis began accumulating more than 125 years before the first flozin drug was approved by the FDA.[2]

By August 2014, the FDA had approved three flozins: canagliflozin (INVOKANA), dapagliflozin (FARXIGA) and empagliflozin (JARDIANCE). (A fourth, ertugliflozin [STEGLATRO], was approved in December 2017.) Flozins lower blood sugar levels by causing the kidneys to dump glucose into the urine.

The FDA’s 2015 requirement for warnings about ketoacidosis was based on a review of 73 cases of ketoacidosis in patients with type 2 diabetes treated with flozins that had been reported to the agency after the approval of the first three flozins.

The September Annals paper noted that researchers in the 1880s first reported that phlorizin, a naturally occurring SGLT2 inhibitor that is the chemical precursor of today’s flozin drugs, caused high levels of glucose and ketones in the urine. The paper cited numerous subsequent studies published in medical journals throughout the past century showing that phlorizin caused ketoacidosis in dogs, cats, rabbits, rats, sheep and cows. It also described published reports from the early 1900s showing that patients with familial renal glucosuria — a genetic disorder that causes dumping of glucose in the urine and thus mimics long-term use of flozin drugs — were predisposed to ketoacidosis.

Highlighting the failure of drug companies, researchers and the FDA to recognize the overwhelming evidence that SGLT2 inhibitors cause ketoacidosis before the FDA approved flozin drugs, an accompanying editorial in the Sept. 17 issue of Annals observed the following: “The authors have compiled a disturbing tale of historical amnesia in which the neglect of 19th- and 20th-century information led to preventable adverse events in 21st-century patients. This was no secret tucked away in a dusty archive or a rare book room; it was published in top-tier medical journals of the 20th century.”[3]

Had the companies and researchers that developed the first three flozin drugs and the FDA used appropriate due diligence, they could have recognized the serious risk of ketoacidosis prior to approval of the drugs and taken appropriate steps to warn doctors and patients about this risk when the drugs were first approved.
 

References

[1] Food and Drug Administration. FDA drug safety communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. December 4, 2015. http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm. Accessed October 4, 2019.

[2] Leslie BR, Gerwin LE, Taylor SI. Sodium–glucose cotransporter-2 inhibitors: Lack of a complete history delays diagnosis. Ann Intern Med. 2019;171(6):421-426.

[3] Greene JA. Amnesia, adverse effects, and the angel of history. Ann Intern Med. 2019;171(6):434-435.