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Fact Checked

Are SGLT2 Inhibitors Linked to an Increased Risk of Diabetic Ketoacidosis?

Sodium-glucose cotransporter-2 (SGLT2) inhibitors first came on to the market in April of 2013 as a new medication class to treat diabetes after clinical trial data demonstrated they were safe and effective. In 2015, the U.S. Food and Drug and Administration (FDA) issued a warning after receiving reports of higher rates of diabetic ketoacidosis (DKA) in patients taking SGLT2 inhibitors.

Researchers have set out to examine the relationship, if any, between SGLT2 inhibitors and DKA.  So what are SGLT2 inhibitors? What is diabetic ketoacidosis? And what have the researchers found? 

What are SGLT2 inhibitors?

SGLT2 inhibitors are a relatively new class of medications used to treat type 2 diabetes. SGLT2 inhibitors lower blood sugar by encouraging the kidneys to excrete sugar in the urine.

At this time, the FDA has approved the following SGLT2 inhibitors:

This medicine class is often used in combination with other diabetes medications, such as insulin or metformin.

Recent studies have found that SGLT2 inhibitors could increase the risk of a serious diabetes-related complication – diabetic ketoacidosis.

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What is Diabetic Ketoacidosis?

Diabetic ketoacidosis is a serious diabetes complication that occurs when your body does not have enough insulin to use glucose (sugar) for energy.  Instead, your body starts to burn fat, releasing ketones.  When ketones begin to build up in the blood, it becomes more acidic, hence diabetic ketoacidosis.

DKA occurs more frequently in someone with type 1 diabetes.  In this type of diabetes, the body does not make its own insulin.  While rare in someone with type 2 diabetes, DKA can still occur. 

Symptoms of diabetic ketoacidosis can come on quickly and may include:

  • Thirst or dry mouth
  • Frequent urination
  • Vomiting
  • High blood sugar levels
  • High levels of ketones in the urine
  • Fruity odor in the mouth

DKA is a very serious condition that usually requires treatment – fluid replacement, electrolyte replacement or insulin therapy – in a hospital.  If you are experiencing any of these symptoms, it is best to immediately contact your health care provider and go to your closest local emergency room.

Examining the Relationship

So what do the studies say about the potential relationship between SGLT2 inhibitors and the risk of DKA?

One recent study examined whether SGLT2 inhibitors compared to another class of diabetes medication (dipeptidyl peptidase-4 (DPP-4) inhibitors) are associated with an increased risk of DKA.  Ultimately this study suggests that SGLT2 inhibitors are associated with an almost 3-fold increased risk.  This study looked at patient profiles from seven healthcare databases from Canada and the United Kingdom.

A large recent study from the New England Journal of Medicine examined what risk exists for DKA after starting an SGLT2 inhibitor.  This study also compared SGLT2 inhibitors to DDP-4 inhibitors.  The results suggest that compared to DDP-4 inhibitors, taking SGLT2 inhibitors doubles the risk of DKA.

Another recent study from Australia looked at SGLT2 inhibitor users versus non-users and compared DKA risk.  The results showed that SGLT2 inhibitor use was associated with a small increased risk of DKA.

It is important to note that DKA, while serious, is not a common complication of diabetes, regardless of what medications are or are not used.

Takeaway

SGLT2 inhibitors are a relatively new class of medications used to treat type 2 diabetes.  In 2015, the FDA issued a warning about increased reports of DKA with SGLT2 inhibitors.  Researchers have begun examining the potential of that relationship.Three recent studies suggest that compared to DPP-4 inhibitors, SGLT2 inhibitors have an increased risk of DKA. 

Diabetic ketoacidosis, while serious, is a rare complication of type 2 diabetes.  If you have concerns, contact your primary healthcare provider to discuss what treatment options are best for you. Never discontinue any medications prescribed by your healthcare provider until you have spoken with them directly regarding your concerns. 

References:

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 website. https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious. Updated March 19, 2020. Accessed September 25, 2020.

What are my options? American Diabetes Association website. https://www.diabetes.org/diabetes/medication-management/oral-medication/what-are-my-options. Accessed September 25, 2020.

DKA (Ketoacidosis) & Ketones. American Diabetes Association website. https://www.diabetes.org/diabetes/complications/dka-ketoacidosis-ketones. Accessed September 25, 2020.

Douros A, Lix LM, Fralick M, Dell'Aniello S, Shah BR, Ronksley PE, Tremblay É, Hu N, Alessi-Severini S, Fisher A, Bugden SC, Ernst P, Filion KB. Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis : A Multicenter Cohort Study. Ann Intern Med. 2020 Sep 15;173(6):417-425. doi: 10.7326/M20-0289. Epub 2020 Jul 28. PMID: 32716707.

Fralick M, Schneeweiss S, Patorno E. Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor. N Engl J Med. 2017 Jun 8;376(23):2300-2302. doi: 10.1056/NEJMc1701990. PMID: 28591538.

Published October 1st, 2020 by Dr. Kaylea Swearingen, PharmD
Fact Checked by Chris Riley

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