Summary Safety Review - SGLT2 Inhibitors (canagliflozin, dapagliflozin, empagliflozin) - Assessing the Risk of the Body Producing High Levels of Acids in the Blood (diabetic ketoacidosis)

May 16, 2016

Product

Sodium-glucose cotransporter-2 (SGLT2) inhibitors: Invokana (canagliflozin), Forxiga (dapagliflozin), Jardiance (empagliflozin)

Potential Safety Issue

High levels of acids in the blood (diabetic ketoacidosis)

Key Messages

  • SGLT2 inhibitors are drugs that can be used on their own with diet and exercise or with other products to decrease blood sugar levels in adults with type 2 diabetes.
  • A safety review was triggered following the recent posting of a notice by the US Food and Drug Administration (FDA) about cases of acids building up in the blood, known as diabetic ketoacidosis (a potentially life-threatening event), in patients taking SGLT2 inhibitors.
  • Health Canada's safety review concluded that SGLT2 inhibitors may increase the risk of experiencing diabetic ketoacidosis and recommended to update the product information to better explain the symptoms of diabetic ketoacidosis.

Overview

Ketones are a type of waste product that the body creates when it breaks down fat to use for energy. If ketones begin to build up to toxic levels in the blood (a condition known as diabetic ketoacidosis) it can lead to symptoms such as difficulties in breathing, stomach pain, nausea and vomiting, confusion, tiredness, loss of appetite, and excessive thirst. It can lead to a coma in extreme cases. Diabetic ketoacidosis can happen to anyone with diabetes but it is more common in those with type 1 diabetes, and quite rare in people with type 2 diabetes.

A safety review was carried out by Health Canada to evaluate the risk of diabetic ketoacidosis in patients using SGLT2 inhibitors following the recent posting of a notice from the FDA about this side effect.

Use in Canada

  • SGLT2 inhibitors are drugs designed to lower blood sugar in adults with type 2 diabetes by helping remove excess sugar from the body through the urine.
  • SGLT2 inhibitors are used along with diet and exercise either alone or in combination with other specific agents that control blood sugar.
  • Three SGLT2 inhibitors are currently available in Canada: Invokana (canagliflozin), Forxiga (dapagliflozin) and Jardiance (empagliflozin). Drugs of this type first entered the Canadian market in 2014.
  • SGLT2 inhibitors should not be used (i.e. they are not indicated for use) in patients with type 1 diabetes.

Safety Review Findings

  • At the time of the review Health Canada had received 5 Canadian reports of diabetic ketoacidosis Footnote 1 (4 patients with type 2 diabetes and 1 patient with type 1 diabetes) all using Invokana.Each of these events was reported as serious and some patients were hospitalized.
  • A total of 419 international cases (310 patients with type 2 diabetes and 119 patients with type 1 diabetes) of diabetic ketoacidosis were also found in patients taking any one of the SGLT2 inhibitors. The blood sugar of patients was generally observed to be normal or mildly elevated in reports that included this information. This observation is important because the side effects of diabetic ketoacidosis can occur regardless of the patient's blood sugar level.
  • After reviewing a number of studies, it was found that type 2 diabetes patients taking SGLT2 inhibitors were more likely to experience diabetic ketoacidosis compared to those patients that were given a placebo or another type of drug that controls diabetes. In addition, in most type 2 diabetes patients, the SGLT2 inhibitors increased the levels of ketones in the blood but not enough that the patient would experience the side effects of diabetic ketoacidosis.
  • The review also noted other conditions that further increased the likelihood of experiencing diabetic ketoacidosis. These included major surgeries, serious infections, sudden serious medical illnesses, having a diet low in carbohydrates, dehydration, high alcohol consumption or having low insulin levels.
  • SGLT2 inhibitors are not indicated for use in patients with type 1 diabetes. Based on information from clinical trials, the use of SGLT2 inhibitors in these patients may further increase the risk of diabetic ketoacidosis.
  • Despite the risk of diabetic ketoacidosis, the findings show that the benefits of these products still outweigh their risks, when used as authorized.

Conclusions and Actions

  • Health Canada's safety review concluded that the evidence supported a link between the use of SGLT2 inhibitors and the risk of diabetic ketoacidosis.
  • In order to raise awareness, Health Canada will work with manufacturers to update the product information so that it better explains the symptoms that may be signs of diabetic ketoacidosis: difficulty breathing, nausea, vomiting, stomach pain, confusion, loss of appetite, feeling very thirsty and feeling unusual tiredness. If these side effects occur, patients should stop taking the drug and call their doctor or pharmacist. Health care professionals should assess patients for diabetic ketoacidosis immediately if these symptoms occur, regardless of their blood sugar level, and the SGLT2 inhibitor treatment should be discontinued.
  • A Health Product Risk Communication will also be issued to explain this side effect of using SGLT2 inhibitors.
  • Health Canada will continue to monitor safety information involving SGLT2 inhibitors, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action if and when any new health risks are identified.

Additional Information

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international adverse reaction reports and what is known about the use of this drug both in Canada and internationally.

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