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SGLT2 Inhibitors Side Effects

People who take certain SGLT2 inhibitors to treat Type 2 diabetes are at an increased risk of having amputations. Other SGLT2 inhibitor side effects include diabetic ketoacidosis, kidney damage, and blood and kidney infections.

SGLT2 inhibitors can cause diabetic ketoacidosis and acute kidney injury. SGLT2 inhibitor side effects also include kidney and blood infections. These side effects can be fatal.

Some side effects are specific to a particular drug or active ingredient.

Invokana, Invokamet and Invokamet XR can lead to amputations. Studies link Farxiga to bladder cancer. Invokamet and Xigduo XR can cause lactic acidosis.

Invokana and Amputation

People who take Invokana, Invokamet or Invokamet XR are twice as likely to need amputations as people who take other diabetes medications.

In 2017, the U.S. Food and Drug Administration ordered Johnson & Johnson to add a black box warning to the drugs’ labels to warn people of the increased risk of amputations. The label change came four years after Johnson & Johnson first started selling Invokana to Americans.

A black box warning is the FDA’s strongest warning. The agency based its decision on results from two clinical trials: CANVAS and CANVAS-R.

The studies found leg and foot amputations roughly doubled among people taking canagliflozin.

The warnings apply only to Invokana, Invokamet and Invokamet XR. The medications contain the active ingredient canagliflozin.

“The FDA has concluded that the Type 2 diabetes medicine canagliflozin (Invokana, Invokamet, and Invokamet XR) causes an increased risk of leg and foot amputations.”

Source: U.S. Food and Drug Administration, May 2017

Farxiga and Bladder Cancer

Patients taking Farxiga are more likely to develop bladder cancer than those treated with another diabetes medication, according to clinical studies.

The FDA did not approve Farxiga at first because of a possible link to cancer and questions related to the drug’s effectiveness.

When the agency later approved Farxiga in 2014, it required the drug’s manufacturers to continue studying Farxiga to better understand its risks.

The results of these studies had not been released as of May 2018.

Diabetic Ketoacidosis

In May 2015, the FDA warned SGLT2 inhibitors may lead to diabetic ketoacidosis (DKA). DKA happens when the body produces too much acidic chemicals called ketones.

In high levels, ketones are poisonous and can cause organs to malfunction.

In December 2015, the FDA required additional warnings about DKA be added to labels of SGLT2 inhibitors.

In 2017, researchers at Brigham and Women’s Hospital in Boston examined records of 40,000 Type 2 diabetes patients.

They compared the risk of developing DKA in patients taking SGLT2 inhibitors to the risk in those taking other diabetes medications, like Januvia and Onglyza.

The researchers determined that the risk of DKA doubled with SGLT2 inhibitor use. But even with the recent research findings, DKA remains relatively rare.

“Shortly after initiation, SGLT2 inhibitors were associated with approximately twice the risk of diabetic ketoacidosis as were DPP4 inhibitors.”

Source: New England Journal of Medicine

Patients who notice symptoms of DKA should contact a doctor or emergency room immediately.

Symptoms of Diabetic Ketoacidosis
  • Aching muscles or muscle stiffness
  • Confusion
  • Difficulty breathing
  • Flushed face
  • Frequent urination or thirst that lasts for a day or more
  • Fruity-smelling breath
  • Stomach pain
  • Unusual fatigue or sleepiness
  • Vomiting and nausea

Acute Kidney Injury

In June 2016, the FDA strengthened the acute kidney injury (AKI) warning for Invokana and Farxiga. This warning also applies to Invokamet, Invokamet XR, Farxiga and Xigduo XR.

Acute kidney injury is sudden kidney failure or kidney damage.

From March 2013 to October 2015, the FDA received reports of more than 100 confirmed cases of acute kidney injury with Invokana or Farxiga use. Some of these instances required hospitalization and dialysis.

When Can Kidney Problems Occur?
Acute kidney injury happened within one month of starting the drug in about half the cases reported to the FDA.
Source: U.S. Food and Drug Administration

The FDA said it was likely more cases existed, but the agency just didn’t know about them.

Decreased blood volume and chronic kidney problems may make kidney failure more likely in some patients. Certain medications may also increase the risk.

Not all people suffering acute kidney injury experience symptoms. A doctor may have to run tests to diagnose it.

Symptoms of Acute Kidney Injury
  • Chest pain or pressure
  • Confusion
  • Fatigue or tiredness
  • Nausea
  • Seizures or coma in severe cases
  • Shortness of breath
  • Too little urine leaving the body
  • Swelling in legs and ankles and around the eyes

Kidney and Blood Infections

SGLT2 inhibitor drugs work by helping the body release excess glucose through urine. Urinary tract infections (UTIs) may be common when taking these drugs.

Kidney Injury Affected Area
Urinary tract infections caused by SGLT2 inhibitors can turn into kidney infections that can be fatal.

Antibiotics treat most UTIs. But sometimes UTIs can lead to more serious infections.

In December 2015, the FDA warned that taking SGLT2 inhibitors can increase the risk of serious infections that started as UTIs.

The agency warned of blood infections (urosepsis) and kidney infections (pyelonephritis). Both can be life-threatening.

The FDA identified 19 cases of these infections between March 2013 and October 2014. The infections started as urinary tract infections in patients taking SGLT2 inhibitors.

All 19 patients were hospitalized. A few were admitted to the intensive care unit. Some needed dialysis to treat kidney failure.

The FDA recommends patients taking SGLT2 inhibitors contact their doctor right away if they suffer UTI symptoms.

Symptoms of UTIs
  • A burning feeling when urinating
  • A need to urinate often
  • The need to urinate right away
  • Blood in the urine
  • Pain in the lower part of your stomach area (pelvis)
Symptoms of Blood Infection
  • Fever
  • Chills
  • Rapid breathing
  • Paleness
  • Heart palpitations or increased heart rate

Invokamet, Xigduo XR and Lactic Acidosis

Invokamet and Xigduo XR contain the ingredient metformin. Metformin can cause lactic acidosis.

Lactic acidosis can be fatal. It happens when too much lactic acid builds up in the blood. The body produces lactic acid when there is not enough oxygen in the body for metabolism.

The FDA requires manufacturers of Invokamet and Xigduo XR to include a black box warning for lactic acidosis in the drugs’ labels.

People taking metformin should watch out for early symptoms of lactic acidosis.

Symptoms of Lactic Acidosis
  • Abdominal or stomach discomfort
  • Decreased appetite
  • Diarrhea
  • Fast, shallow breathing
  • General feeling of discomfort
  • Muscle pain or cramping
  • Unusual sleepiness, tiredness or weakness

Please seek the advice of a medical professional before making health care decisions.

Kristin Compton
Written By Kristin Compton Writer

Kristin Compton's background is in legal studies. She worked as a paralegal before joining Drugwatch as a writer and researcher. She was also a member of the National Association of Legal Assistants. A mother and longtime patient, she has firsthand experience of the harmful effects prescription drugs can have on women and their children. Some of her qualifications include:

  • Bachelor of Arts in Legal Studies | Pre-Law from University of West Florida
  • Past employment with The Health Law Firm and Kerrigan, Estess, Rankin, McLeod & Thompson LLC
  • Personal experience battling severe food allergies, asthma and high-risk pregnancies
Edited By
Medically Reviewed By
Dr. John A. Daller
Dr. John A. Daller American Board of Surgery

13 Cited Research Articles

  1. FDA. (2016, June 14). FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). Retrieved from
  2. European Medicines Agency. (2017, February 24). SGLT2 inhibitors: information on potential risk of toe amputation to be included in prescribing information. Retrieved from
  3. FDA. (2015, May 15). FDA Drug Safety Communication: FDA warns that sglt2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. Retrieved from
  4. FDA. (2015, September 10). FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. Retrieved from
  5. FDA. (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
  6. FDA. (2016, April 8). FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. Retrieved from
  7. FDA. (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
  8. Brennan, Z. (2017, May 16). FDA Adds Boxed Warning to Janssen’s Type 2 Diabetes Drug Label. Retrieved from
  9. FDA. (2017, May 16). FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). Retrieved from
  10. European Medicines Agency. (2017, August 5). SGLT2 inhibitors (previously canagliflozin). Retrieved from
  11. Fralick, M., Schneeweiss, S. & Patorno, E. (2017, June 8). Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor. Retrieved from
  12. National Institutes of Health. (2018, April 30). Lactic acidosis. Retrieved from
  13. Creative Commons. (n.d.). University of California, San Francisco. Retrieved from
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