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Health Groups Warn About Ketoacidosis and Diabetes Link When Taking SGLT2 Inhibitors

Christine Loughran

Last updated: November 9, 2016 9:12 pm

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SGLT2 Inhibitors are a newer class of drug meant to treat Type 2 Diabetes by stopping the absorption of glucose. The FDA warns that these drugs, including Invokana, can lead to a condition called ketoacidosis which requires hospitalization and may cause severe dehydration, coma and swelling of the brain.

Warning from the European Medicines Agency

It’s been nearly three months since the European Medicines Agency (EMA) formally warned doctors about the risks of diabetic ketoacidosis (DKA) associated with SGLT2 (sodium-glucose cotransporter-2) inhibitors, prescribed in conjunction with diet and exercise for diabetes. This was after notifying the public in June 2015 that EMA would conduct a review of this risk of ketoacidosis and diabetes for people taking SGLT2 inhibitors. 1

In a notice published in February, 2016, the EMA’s message was simple: be aware of the symptoms of diabetic ketoacidosis in people taking SGLT2 inhibitors.

This may include people whose blood sugar levels are not especially high, according to the EMA. Some cases of DKA that were found — including the life-threatening ones — were atypical, in that they occurred in patients whose glucose levels were only moderately higher than normal.

Symptoms of Diabetic Ketoacidosis

In addition to warning health care providers about the dangers of prescribing an SGLT2 inhibitor in patients with risk factors for DKA, the EMA’s warning in February also featured warnings to diabetics themselves. Patients taking Invokana or another SGLT2 inhibitor were warned to be on alert for symptoms of the condition, which may include but are not limited to:

  • Rapid weight loss.
  • Nausea or vomiting.
  • Stomach pain.
  • Excessive thirst.
  • Fast and deep breathing.
  • Confusion.
  • Unusual sleepiness or tiredness. 2

DKA occurs when the body overproduces blood acids known as ketones. In the EMA’s discovered cases of DKA in people taking SGLT2 inhibitors, the results were serious, with some patients requiring hospitalization.

In June 2015, 101 cases of diabetic ketoacidosis were reported in patients taking SGLT2 inhibitors, according to the European data processing network for suspected adverse events, EudraVigilance, as of May 19, 2015. 3

Health Canada Shares Risks of Acute Kidney Injury

In October, 2015, Health Canada released the findings of a safety review they conducted to assess the link between acute kidney injury and the use of Invokana and Forxiga (known as Farxiga in the U.S.). The agency concluded that the “evidence supported the existence of a link between the use of SGLT2 inhibitors and the risk of acute kidney injury.” At the time of their alert, Health Canada said they were working with manufacturers to adjust labeling on these products, to more strongly warn about risks kidney injury surrounding SGLT2 inhibitors for diabetes. 4

Here in the U.S., the Food and Drug Administration (FDA) first warned people about the potential dangers of SGLT2 inhibitors for diabetes leading to diabetic ketoacidosis in a Drug Safety Communication released on May 15, 2015. 5

A review of adverse events reported from March 2013 -June 6, 2014 to the FDA’s Adverse Event Reporting System (FAERS) uncovered 20 cases of DKA, ketoacidosis, and ketosis in people who took SGLT2 inhibitors for diabetes. All of these people were sent to the emergency room or required time in the hospital to treat the serious condition, and most developed DKA within two weeks of first taking an SGLT2 inhibitor.

After these and other findings, the FDA told the public they would continue to investigate reports of DKA and ketoacidosis in people being treated with SGLT2 inhibitors.

FDA and SGLT2 Inhibitor Warning

In December, 2015, the FDA published an alert that notified the public that the FDA was requiring the addition of warnings regarding DKA and severe urinary tract infections to labels on Invokana and the other SGLT2 inhibitors. In addition, the FDA notified the public it was requiring manufacturers to conduct a post-marketing study regarding reports of DKA in patients taking SGLT2 inhibitors. 6

The FDA’s review of reported adverse events also uncovered 19 cases of serious blood and kidney infections that began as urinary tract infections. All these cases were reported between March 2013 and October 2014.

The following are symptoms of urinary tract infections. Experiencing any or several of these could mean you have a UTI, which can be serious if you are currently taking an SGLT2 inhibitor:

  • A persistent, strong urge to urinate.
  • A burning sensation when urinating.
  • Producing frequent, small amounts of urine.
  • Urine that looks cloudy.
  • Urine that looks bright pink, red or cola-colored. This is a sign of blood in the urine.
  • Strong smelling urine.
  • Pelvic pain, in women, especially around the pubic bone area and in the center of the pelvis. 7

Learn more about the risks and side effects of taking SGLT2 inhibitors.

  1. Press release: “SGLT2 inhibitors: PRAC makes recommendations to minimise risk of diabetic ketoacidosis,” European Medicines Agency, February 12, 2016. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/02/news_detail_002470.jsp;
    http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SGLT2_inhibitors__20/Procedure_started/WC500187925.pdf  

  2. Press release: “SGLT2 inhibitors: PRAC makes recommendations to minimise risk of diabetic ketoacidosis,” European Medicines Agency, February 12, 2016. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/02/news_detail_002470.jsp

  3. Lisa Nainggolan, “EMA to Review Diabetic Ketoacidosis Risk With SGLT2 Inhibitors,” Medscape, June 12, 2015. http://www.medscape.com/viewarticle/846339

  4. Summary Safety Review: “Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors INVOKANA (canagliflozin) and FORXIGA (dapagliflozin) – Evaluation of a Potential Risk of Acute Kidney Injury,” Health Canada, October 16, 2015. http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/sglt2-eng.php

  5. Safety Announcement, “FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood,” U.S. Food and Drug Administration, May 15, 2015.
    http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm.  

  6. 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,” U.S. Food and Drug Administration, December 04, 2016. http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm

  7. Diseases and Conditions: Urinary tract infection (UTI), Symptoms.  MayoClinic.org. http://www.mayoclinic.org/diseases-conditions/urinary-tract-infection/basics/symptoms/CON-20037892.