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Side Effects of SGLT2 Inhibitors

Some adults with Type 2 diabetes mellitus who take SGLT2 inhibitors to help control blood sugar, along with diet and exercise, have suffered adverse reactions to these medications. In December 2015, the FDA added warnings to all SGLT2 inhibitor labels regarding the risk of diabetic ketoacidosis and serious urinary tract infections that could lead to blood or kidney infections, which are potential side effects of these medications.

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SGLT2 Inhibitors

SGLT2 inhibitors work by acting on the kidneys. SGLT2 inhibitors have also been linked with multiple kidney-related problems such as renal impairment and acute kidney injury. Serious urinary tract infections that can affect the kidneys, known as pyelonephritis, or cause blood infections, known as urosepsis, are also potential side effects.

Brand names of SGLT2 inhibitors include Invokana, Invokamet, Farxiga, Glyxambi, Jardiance, Xigduo XR and Synjardy. Each of these medications has been associated with health risks. Some people who have suffered the side effects of SGLT2 inhibitors have sought legal compensation.

Diabetic Ketoacidosis


As well as causing problems with kidneys, the U.S. Food and Drug Administration (FDA) warned in a May 2015 Safety Announcement that SGLT2 inhibitors may result in a serious condition known as diabetic ketoacidosis. Usually, this condition can occur when a diabetic’s blood-sugar levels dip below a normal range, indicating that the body does not have enough glucose (or blood sugar), the body’s preferred sustenance.

When the body lacks glucose, the body instead uses fat for fuel. The process of burning fat to fuel the body can produce a large amount of ketones, which are blood acids that can poison the body in excessive amounts. This state of excessive ketones in the body is diabetic ketoacidosis.

When diabetic ketoacidosis occurs, the sufferer can fall into a diabetic coma. The effects of ketoacidosis can be lethal if the condition is not promptly addressed. The FDA has advised that patients should “stop taking their SGLT2 inhibitor and seek medical attention immediately if they have any symptoms of ketoacidosis. …” Treatment of ketoacidosis usually requires hospitalization.

Normally, diabetic ketoacidosis is brought on by a severe imbalance of dietary glucose. However, the FDA found that many of the reported SGLT2 inhibitor-related cases of ketoacidosis occurred in patients who were euglycemic (which means they had normal blood sugar levels) or had only slightly elevated blood sugar levels at the time of their ketoacidosis.

In addition to the FDA’s findings, medical literature has also described similar development of diabetic ketoacidosis in patients taking SGLT2 inhibitors. Several studies have reported on euglycemic ketoacidosis as a potential side effect of taking the SGLT2 inhibitor canagliflozin (Invokana).

A recently published case series described nine instances wherein patients, seven with Type 1 diabetes and two with Type 2 diabetes, developed diabetic ketoacidosis after taking the same SGLT2 inhibitor drug. Three patients developed ketoacidosis for a second time after stopping and restarting the medication. Much like the cases described in the FDA’s Safety Announcement, several patients had normal or near-normal blood sugar levels, unlike what is typically observed with diabetic ketoacidosis cases.

Signs of Diabetic ketoacidosis

Diabetic ketoacidosis signs and symptoms may include:

  • Breathing difficulty

  • Abdominal pain

  • Nausea

  • Vomiting

  • Confusion

  • Unusual fatigue or sleepiness

In addition to SGLT2 inhibitor use, other risk factors for diabetic ketoacidosis may include:

  • Recent Surgery
  • Infection
  • Physical trauma
  • Pancreatitis
  • Mental distress
  • Blockage in a heart artery
  • Uncontrolled insulin

Serious Urinary Tract Infections Resulting in Blood or Kidney Infections

Also contained in the FDA Safety Announcement in December 2015 is a warning that SGLT2 inhibitors can cause serious urinary tract infections.

The urinary tract can become infected at multiple locations, affecting the bladder, the kidneys (where blood is filtered and urine is created), the ureters (which take urine from the kidneys to the bladder), or the urethra, which is the tube through which urine travels out of the bladder to be excreted from the body. A urinary tract infection (UTI) occurs when any of these areas becomes infected.

The side effects of UTIs are often so uncomfortable that many people see their doctor for a stronger, prescription treatment, such as an antibiotic.

Most times, a UTI is caused by the presence of bacteria that travels into the bladder via the urethra. However, UTIs caused by SGLT2 inhibitors may form differently. When glucose is ingested, the body filters it through the kidneys, which reabsorb some of the glucose. For people with diabetes, holding onto this additional sugar can be problematic. To combat this reuptake of sugar, SGLT2 inhibitors prevent the kidneys from retaining that extra sugar, instead taking the extra sugar out of the body via urine. This effect can increase the concentration of urinary glucose, potentially creating a more favorable environment for bacterial growth that can cause UTIs.

Symptoms of urinary tract infections may include:

  • A burning sensation during urination
  • Frequent urination
  • Feeling of urgent need to urinate
  • Pelvic pain
  • Blood in the urine
  • Fever
  • Back pain
  • Nausea or vomiting

Though SGLT2 inhibitor use has been linked to the development of UTIs, several additional risk factors include:

  • Being female
  • Sexual activity
  • Kidney stones
  • Menopause
  • Weak immune system
  • Paralysis
  • Prior kidney transplant
  • Pregnancy
  • Antibiotic use
  • Enlarged prostate

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Acute Kidney Injury

Acute kidney injury (AKI) occurs when the kidneys are suddenly damaged and begin to fail within a short period of time, often within several hours to several days. AKI treatment usually requires hospitalization. In serious cases, patients must undergo dialysis while their kidneys heal.

Signs of AKI

Signs of AKI may include:

  • Decreased urine output

  • Swollen ankles, legs and areas surrounding the eyes

  • Fatigue

  • Shortness of breath

  • Chest pain

  • Seizures

  • Confusion

  • Nausea

Sometimes AKI can happen after a major surgery, a car accident or some other incident that caused physical trauma to the abdominal region. However, in 2016, the FDA declared a link between usage of SGLT2 inhibitors containing canagliflozin (Invokana and Invokamet) or dapagliflozin (Farxiga and Xigduo XR) and acute kidney injury.

From March 2013 to October 2015, the FDA received 101 confirmed cases of AKI in patients taking medications containing canagliflozin or dapagliflozin, and stated that additional cases likely existed. The agency urged medical professionals to be watchful for AKI symptoms in patients taking SGLT2 inhibitors containing canagliflozin or dapagliflozin, and promptly discontinue these medications and treat the kidney impairment should AKI occur.

Other risk factors for AKI include:

  • Use of antimicrobial agents
  • High blood pressure
  • Being older than 65
  • Undergoing hospitalization
  • Liver disease

Stroke and Thromboembolic Events

A thromboembolism occurs when a blood clot (thrombus) forms and sometimes travels to a different part of the body and clogs a vessel. For example, a thrombus can form in a vein of a leg (known as a deep vein thrombosis or DVT) and then travel to the lungs, where it can cause a potentially fatal blockage, known as a pulmonary embolism (PE). When a thrombus clogs a brain vessel, stroke can occur. Each of these thromboembolic events can be life-challenging, and require immediate medical attention.In 2015, the FDA detected a potential signal of serious risk of stroke and thromboembolic events with the use of any of the following seven SGLT2 inhibitors: Farxiga, Glyxambi, Jardiance, Invokamet, Invokana, Synjardy and Xigduo XR. The FDA wrote on the April-June 2015 Adverse Events Reporting System webpage that the FDA was “evaluating the need for regulatory action” for stroke and thromboembolic events with these seven SGLT2 inhibitor drugs.

Signs of thromboembolism differ based upon the location of the clot, but here are several symptoms that tend to manifest across the board:

  • Chest pain
  • Rapid heart rate
  • Acute shortness of breath
  • Fainting

The following are risk factors for thromboembolism:

  • Undergoing an extended hospital stay
  • Prolonged immobility, including lower extremity paralysis
  • Major surgery
  • Advanced cancers
  • Being older than 40
  • Heart or lung failure
  • Fracture of hip, pelvis or long bones

Possible Side Effects Caused by SGLT2 Inhibitors

All SGLT2 inhibitors carry the possibility of some additional risks that may not have been seen frequently in a clinical trial setting. Since SGLT2 inhibitors are relatively new medications, the ramifications of their long-term usage may not yet be fully understood.

Patients and their doctors must remain watchful for these possible side effects.

Hypoglycemia

This condition is brought on when blood sugar dips below normal levels. Hypoglycemia may occur if a patient takes an SGLT2 inhibitor with insulin or insulin secretagogues, such as sulfonylurea.

Signs of Hypoglycemia

The signs and symptoms of hypoglycemia may include:

  • Headache

  • Irritability

  • Drowsiness

  • Hunger

  • Faster heartbeat

  • Dizziness

  • Sweating

  • Confusion

  • Jitteriness

Normally, people can often treat hypoglycemia at home by having a snack. However, in diabetics, hypoglycemia may require professional intervention.

Dehydration


This condition — marked by inadequate water and electrolytes in the body — may occur with SGLT2 inhibitor usage. The risk of dehydration may increase if a patient has low blood pressure or kidney problems, takes diuretics, follows a sodium-restricted diet, or is 65 or older.

Though mild dehydration can be treated easily by replacing lost fluids, severe dehydration can cause permanent brain damage, seizures and death, if untreated.

Signs and symptoms of dehydration may include:

  • Thirst
  • Muscle cramps
  • Headache
  • Not urinating much, or dark-colored urine
  • Dry skin
  • Irritability
  • Confusion or delirium
  • Loss of consciousness
  • Rapid heart rate

Amputations


The FDA is currently investigating whether taking canagliflozin, the active ingredient in the SGLT2 inhibitors Invokana and Invokamet, increases the risk of leg and foot amputations.10 An ongoing clinical trial found an increase in leg and foot amputations, especially toe amputations. These amputations occurred almost twice as often among patients taking canagliflozin as those taking a placebo. The European Medicines Agency (EMA) is also reviewing the data on the risk of amputations with canagliflozin, but recently extended the investigation to include all SGLT2 inhibitors.

Additional Risks

Some SGLT2 inhibitors contain language in their labeling regarding certain other side effects. These include:

  • Bladder cancer (Farxiga, Xigduo XR)
  • Changes in urination, including urgent need to urinate more often, in larger amounts or at night (Invokana, Invokamet, Farxiga)
  • Nasopharyngitis (Farxiga, Glyxambi)

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  1. FDA.gov. (2015, May 15). 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. Retrieved from http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm 

  2. U.S. Food and Drug Administration. (2015, May 15). FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. Retrieved from http://www.fda.gov/downloads/Drugs/DrugSafety/UCM446954.pdf 

  3. American Diabetes Association. (2015, March 18). DKA (Ketoacidosis) & Ketones: American Diabetes Association. Retrieved from www.diabetes.org/living-with-diabetes/complications/ketoacidosis-dka.html?referrer=https://www.google.com/ 

  4. Anne Peters et al. (2015, July 15). Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26078479 

  5. Umpierrez, G. E., & Kitabchi, A. E. (2003). Diabetic ketoacidosis: risk factors and management strategies. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15871546 

  6. U.S. Food and Drug Administration. (2015, December 4). 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. Retrieved from http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm 

  7. Whaley, J.M. et al. (2012, July 23). Targeting the kidney and glucose excretion with dapagliflozin: preclinical and clinical evidence for SGLT2 inhibition as a new option for treatment of type 2 diabetes mellitus. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422910/ 

  8. National Institute of Diabetes and Digestive and Kidney Diseases. (2016, August). Low Blood Glucose (Hypoglycemia). Retrieved from https://www.niddk.nih.gov/health-information/diabetes/preventing-diabetes-problems/low-blood-glucose-hypoglycemia 

  9. National Institutes of Health. (2015, August 29). Dehydration: MedlinePlus Medical Encyclopedia. Retrieved from https://medlineplus.gov/ency/article/000982.htm 

  10. U.S. Food and Drug Administration. (2016, May 18). FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate. Retrieved from http://www.fda.gov/Drugs/DrugSafety/ucm500965.htm