Ketoacidosis in Diabetics from SGLT2 Inhibitors

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On May 15, 2015 the FDA announced it is investigating an association between Farxiga, Jardiance, and Invokana with diabetic ketoacidosis (DKA), ketoacidosis, or ketosis.  See: “FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood”.

About a month later, Health Canada took similar action when that drug regulatory agency sent an email alert about its “Information Update – Forxiga, Invokana: Health Canada begins safety review of diabetes drugs known as SGLT2 inhibitors and risk of ketoacidosis”.

From that June 22, 2015 Health Canada MedEffect email alert we get this:

Health Canada initiated a safety review for the prescription diabetes drugs [Forxiga / Farxiga (dapagliflozin)] and [Invokana (canagliflozin)] and the risk of ketoacidosis, a serious condition that leads to high levels of blood acids called ketones. [Forxiga / Farxiga (dapagliflozin)] and [Invokana (canagliflozin)] are known as SGLT2 (sodium-glucose cotransporter-2) inhibitors and are approved in Canada for use in patients with type 2 diabetes to improve blood sugar levels, along with diet and exercise….

A preliminary search of Health Canada’s adverse reaction database identified one report of diabetic ketoacidosis involving the hospitalization of a 56-year old male taking an SGLT2 inhibitor. The patient was taking other medications at the time and further assessment will be conducted.

Health Canada will review the available information and will determine whether changes are needed in the prescribing information for this class of drugs….

Next we move from the ketoacidosis side effect linked to Invokana, Farxiga, and Jardiance to the increased risk of kidney failure which has been flagged by the Institute for Safe Medication Practices (ISMP).

From the May 6, 2015 edition of ISMP QuaterWatch, we get this information about how Invokana works as regards the kidney:

In March of 2013, the FDA approved the first drug in a new class of oral agents to lower blood sugar in patients with Type 2 diabetes. It was called [Invokana (canagliflozin)] and its mechanism of action was to inhibit a normal function of the kidney, which is to return any glucose to the blood circulation while excreting other undesirable substances. Instead, [Invokana (canagliflozin)] causes substantial amounts of sugar to be excreted in the urine. In the first year of adverse event data, we saw reports indicating serious injuries involving kidney function, and reports of serious hypersensitivity reactions. Most could have been reasonably anticipated, given the mechanism of action and pre-approval clinical trial data.

In the first year after approval, [Invokana (canagliflozin)] was launched with considerable success, reaching 426,859 outpatient prescriptions in 2014 Q2, according to data from IMS Health. In the same period we identified 457 serious adverse event reports, including 5 different adverse effects directly or indirectly related to the renal toxicity of [Invokana (canagliflozin)]. This included kidney failure or impairment ([number] = 54)….

Like Invokana, the other drugs in this new class of oral diabetes agent — such as Farxiga and Jardiance — block a key transport protein in the kidney filtration process, sodium glucose cotransporter-2 (SGLT2), thereby causing some of the circulating blood glucose to be excreted in the urine rather than returned to blood circulation.

As such, this so-called drug safety “signal” for Invokana-related kidney failure seems applicable to Farxiga (dapagliflozin) and Jardiance (empagliflozin) — as well as the other currently available SGLT2 diabetes drugs, Invokamet (canagliflozin and metformin), Xigduo XR (dapagliflozin and metformin extended-release), and Glyxambi (empagliflozin and linagliptin).

We are currently investigating potential harmful drug cases for people with Type-2 diabetes who used SGLT inhibitors and developed ketoacidosis or kidney failure, as well as when these diabetics suffer a heart attack, stroke, or heart failure.

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