SGLT2 Inhibitors Side Effects

Janssen Pharmaceutical’s Invokana ushered in a new class of drugs called SGLT2 inhibitors when it won FDA approval in 2013. Hailed as a breakthrough Type 2 diabetes treatment when they first hit the market, SGLT2 inhibitors have been linked to such serious complications as raising acid levels in blood and increasing the risk for leg and foot amputations.

*Please seek the advice of a medical professional before discontinuing the use of this drug.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are intended to treat Type 2 diabetes along with diet and exercise. They have also been prescribed for off-label, or unapproved, uses including weight loss.

The active ingredients in the drugs are different gliflozin compounds.

SGLT2 inhibitors approved for use in the U.S. include:

Invokana (canagliflozin) approved in 2013

Farxiga (dapagliflozin) approved in 2014

Jardiance (empagliflozin) approved in 2016

In addition, some medications combine SGLT2 inhibitors with other diabetes drugs. These include:

Invokamet (canagliflozin and metformin)

Invokamet XR (canagliflozin and metformin extended release)

Xigduo XR (dapagliflozin and metformin extended-release)

Glyxambi (empagliflozin and linagliptin)

Synjardy (empagliflozin and metformin)

Metformin decreases glucose production in the liver while increasing the body’s ability to absorb glucose. It is often used in conjunction with insulin as well as SGLT2 inhibitors to treat Type 2 diabetes. It carries additional risks of side effects. Linagliptin works by regulating insulin levels after meals.

When first approved, SGLT2 inhibitors took a revolutionary approach to controlling blood sugar in diabetic patients. The drugs cause the body to direct excess glucose to the kidneys. From there, it is expelled through a patient’s urine.

SGLT2 Inhibitor Side Effects Range from Minor to Life-Threatening

While the way SGLT2 drugs work is unique, this can also lead to unique side effects. For example, because the drugs cause excess sugar to escape the body in urine, it can also lead to yeast infections and urinary tract infections. The drugs primarily work in the kidneys, so these drugs are not for people with weak kidney function. Some studies also show these drugs may lead to dangerous kidney infections and kidney failure.

Side effects can lead from simple annoyances such as dry mouth to more serious complications including kidney injuries.

Common SGLT2 Inhibitor Side Effect Symptoms:

  • Abdominal pain
  • Back pain
  • Constipation
  • Dry mouth
  • Fatigue
  • Increased cholesterol
  • Increased urination
  • Influenza
  • Male and female yeast infections
  • Nausea
  • Thirst
  • Urinary tract infections (UTIs)

While the majority of people taking SGLT2 inhibitors may only suffer minor side effects, a number of studies also show these drugs can cause serious and fatal side effects.

Serious SGLT2 Side Effects Include:

  • Acute kidney injury (AKI) – An abrupt decline in kidney function.
  • Blood and kidney infections resulting from serious urinary tract infections.
  • Diabetic ketoacidosis (DKA) – Too much acid in the blood.
  • Increased amputation risk of toes, feet and legs.
  • Lactic acidosis – A potentially fatal drop in oxygen levels in the blood.

The U.S. Food and Drug administration (FDA) has issued a lengthening list of safety communications, warnings and required label changes since the agency approved the first SGLT2 inhibitor for use in America in 2013.

Timeline of FDA Actions on SGLT2 Inhibitors

  • February 2013

    FDA approves Invokana for Type 2 diabetes, the first SGLT2 inhibitor approved for use in the U.S.

  • May 2015

    Warning that SGLT2 inhibitors may cause diabetic ketoacidosis (DKA), a serious condition resulting it too much acid in the blood

  • September 2015

    Strengthened warnings for Invokana and Invokamet labels related to an increased risk of bone fractures and decreased bone density

  • December 2015

    Required new warnings on SGLT2 inhibitor labels about DKA and urinary tract infections that have led to life-threatening blood and kidney infections

  • May 2016

    FDA alerted the public about an ongoing clinical trial that found an increased risk of leg and foot amputations among patients using Invokana and Invokamet

  • June 2016

    Strengthened warnings of the risk of acute kidney injury on labels for Invokana, Invokamet, Farxiga and Xigduo XR

  • May 2017

    FDA concluded Invokana and Invokamet causes an increased risk of leg and foot amputations – primarily affecting the toes

    FDA required a boxed warning — its most serious kind — added to labels for Invokana and Invokamet highlighting an increased leg and foot amputation risk

Studies Find Increased Amputation Risk with Invokana

In May 2017, the FDA mandated “black box” warnings — the agency’s most serious type — for an increased risk of leg and foot amputations added to specific SGLT2 inhibitors. The warnings applied only to canagliflozin — Invokana, Invokamet and Invokamet XR.


“[T]he FDA has concluded that the type 2 diabetes medicine canagliflozin (Invokana, Invokamet, and Invokamet XR) causes an increased risk of leg and foot amputations.”

- FDA, May 2017


The clinical trials had found leg and foot amputations roughly doubled among people taking the canagliflozin.

The two studies, called CANVAS and CANVAS-R, had not originally looked at the risk of amputations. CANVAS examined whether the drug reduced heart and blood vessel disease. CANVAS-R examined how canagliflozin affected the presence of the liver enzyme albumin in urine, an early warning sign of kidney disease.

The European trials involved more than 10,000 patients combined. In 2016, researchers began noticing significantly higher amputation rates among patients in the trials taking canagliflozin compared to those taking a placebo.

The CANVAS clinical trial showed that over a year’s time, the risk of amputation for patients was equivalent to:

  • 5.9 out of every 1,000 patients taking canagliflozin
  • 2.8 out of every 1,000 patients taking a placebo

The CANVAS-R study showed the risk of amputation for patients in the trial was:

  • 7.5 out of every 1,000 patients taking canagliflozin
  • 4.2 out of every 1,000 patients taking a placebo
 

The most common amputations were for toes or the middle of the foot. But there were also amputations of the leg both above and below the knee. Some patients had multiple amputations, including both limbs.

FDA Warns SGLT2 Use may lead to Diabetic Ketoacidosis (DKA)

In May 2015, the FDA warned that SGLT2 inhibitors may lead to a serious condition called diabetic ketoacidosis (DKA). DKA occurs when the body begins using fats as fuel rather than glucose, or sugar.

In a person with normal insulin levels, insulin aids the body in using sugar as fuel. When the body is deficient in insulin, the body cannot use sugar for fuel and it uses fat instead. Breaking down the fats causes the creation of acidic chemicals called ketones, which can build up in the body. In high levels, ketones are poisonous and can cause organs to malfunction.

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

“Our review of the [FAERS] database from March 2013 to May 2015 identified 73 cases of ketoacidosis in patients with type 1 or type 2 diabetes treated with SGLT2 inhibitors,” the FDA said in the December 2015 drug safety communication. “All patients required hospitalization or treatment in an emergency department.”

The average cost of hospitalization for diabetic ketoacidosis in the U.S. is $13,000 per patient.


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

- Researchers wrote in the New England Journal of Medicine


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 between patients taking SGLT2 inhibitors to those taking another class of diabetes drugs – DPP4 inhibitors such as Januvia and Onglyza.

The researchers noted that while the risk of the condition doubled with SGLT2 inhibitor use, DKA remains relatively rare.

And while SGLT2 inhibitors can increase the risk of DKA, they are not the main cause.

DKA is a serious condition, and patients who notice any of these symptoms should contact a doctor or emergency room immediately.

Primary causes of DKA are:

Infection

45 percent of cases

Missed or irregular insulin treatments

25 percent of cases

New diagnosis of diabetes

15 percent of cases

DKA is a serious condition, and patients who notice any of these symptoms should contact a doctor or emergency room immediately.

Symptoms of DKA include:

  • 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

FDA Strengthens Acute Kidney Injury Warning for SGLT2 Inhibitors

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

Fast Fact:

The FDA confirmed more than 100 cases of kidney injuries from SGLT2 inhibitor use in two-and- a-half-years.

“From March 2013, when canagliflozin was approved, to October 2015, FDA received reports of 101 confirmable cases of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin or dapagliflozin use,” the FDA said in a drug safety communication. “This number includes only reports submitted to FDA, so there are likely additional cases about which we are unaware.”

The FDA said that in about half the cases, AKI happened within one month of starting the drug.

Kidney injury may require hospitalization or dialysis. The FDA recommends that health care professionals consider factors that may predispose patients to kidney failure before starting them on SGLT2 inhibitors such as Invokana or Farxiga. These factors include decreased blood volume, chronic kidney problems and other medications that may increase kidney injury risk.

In some cases, AKI may not have symptoms, and health care providers may have to run tests to diagnose it.

Symptoms of AKI include:

  • 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

SGLT2 Inhibitors can Cause Serious Kidney and Blood Infections

Because SGLT2 drugs work by secreting glucose in the urine, urinary tract infections (UTIs) may be common on these drugs. Typically, UTIs may be treated with antibiotics. But sometimes UTIs can lead to more serious infections such as blood kidney infections.

In December 2015, the FDA warned that taking SGLT2 inhibitors can increase the risk of serious infections that started as UTIs. The agency had received multiple reports to its FAERS (FDA Adverse Events Reporting System) database of people developing serious infections after taking SGLT2 inhibitors.

“We also identified 19 cases of life-threatening blood infections (urosepsis) and kidney infections (pyelonephritis) that started as urinary tract infections with the SGLT2 inhibitors reported to FAERS from March 2013 through October 2014. All 19 patients were hospitalized, and a few required admission to an intensive care unit or dialysis in order to treat kidney failure,” the FDA said in its 2015 safety announcement.

The FDA recommends that patients contact a health care provider immediately if they suffer UTI symptoms.

Symptoms of UTIs include:

  • 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 include:

  • Fever
  • Chills
  • Rapid breathing
  • Paleness
  • Heart palpitations or increased heart rate

SGLT2 Inhibitor Use may Result in Lactic Acidosis

A number of SGLT2 drugs are available in combination with metformin including Invokamet and Xigduo XR. In addition to the typical side effects of SGLT2 inhibitors, these drugs also carry a black box warning for lactic acidosis, a serious condition associated with metformin.

Lactic acid is produced when oxygen levels in the body drop. When too much lactic acid builds up in the blood it results in lactic acidosis. It may lead to hypothermia, hypotension, irregular heartbeat and death.

Alcohol and drugs such as cimetidine (Tagamet), topiramate (Topamax, Qudexy), zonisamide (Zonegran) and acetazolamide (Diamox) may increase the risk of lactic acidosis.

People taking metformin, including Invokamet and Xigduo XR, should have their electrolyte levels checked one to two weeks after starting it as a precaution against lactic acidosis. People taking metformin should also 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

Author

Terry Turner is an Emmy-winning, former television journalist. He is an associate member of the American Bar Association, the ABA’s Health Law group and a member of the Alliance of Professional Health Advocates. He holds six certificates in Health Literacy for Healthcare Professionals from the Centers for Disease Control and Prevention. As a Washington-based investigative reporter, he routinely reported on health and medical policy issues before Congress, the FDA and other federal agencies. Terry received his B.A. in Media Arts from Lyon College.


Hide Sources

  1. FDA. (2016, June 14). FDA Strengthens Kidney Warnings for Diabetes Medicines Canagliflozin (Invokana, Invokamet) and Dapagliflozin (Farxiga, Xigduo XR). Retrieved from: https://www.fda.gov/downloads/drugs/drugsafety/ucm506772.pdf
  2. European Medicines Agency. (2017, February 24). SGLT2 Inhibitors: Information on Potential Risk of Toe Amputation to Be Included in Prescribing Information. Retrieved from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/02/news_detail_002699.jsp&mid=WC0b01ac058004d5c1
  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: https://www.fda.gov/downloads/drugs/drugsafety/ucm446954.pdf
  4. FDA. (2015, September 10). Invokana and Invokamet (canagliflozin): Drug Safety Communication – New Information on Bone Fracture Risk and Decreased Bone Mineral Density. Retrieved from: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm461876.htm
  5. FDA. (2015, December 4). SGLT2 Inhibitors: Drug Safety Communication – Labels to Include Warnings about too Much Acid in the Blood and Serious Urinary Tract Infections. Retrieved from: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm475553.htm
  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: https://www.fda.gov/Drugs/DrugSafety/ucm493244.htm
  7. FDA. (2016, May 18). Canagliflozin (Invokana, Invokamet): Drug Safety Communication – Clinical Trial Results Find Increased Risk of Leg and Foot Amputations. Retrieved from: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm501565.htm
  8. Brennan, Z. (2017, May 16). FDA Adds Boxed Warning to Janssen’s Type 2 Diabetes Drug Label. Retrieved from: http://www.raps.org/Regulatory-Focus/News/2017/05/16/27560/FDA-Adds-Boxed-Warning-to-Janssens-Type-2-Diabetes-Drug-Label/
  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: https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm
  10. European Medicines Agency. (2017, August 5). SGLT2 Inhibitors (Previously Canagliflozin). Retrieved from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/SGLT2_inhibitors_(previously_Canagliflozin)/human_referral_prac_000059.jsp&mid=WC0b01ac05805c516f
  11. Fralick, M., Schneeweiss, S. and Patorno, E. (2017, June 8). Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor. Retrieved from: http://www.nejm.org/doi/full/10.1056/NEJMc1701990
  12. FDA. (2016, June 14). FDA Strengthens Kidney Warnings for Diabetes Medicines Canagliflozin (Invokana, Invokamet) and Dapagliflozin (Farxiga, Xigduo XR). Retrieved from: https://www.fda.gov/downloads/drugs/drugsafety/ucm506772.pdf
  13. National Institutes of Health. (2016, December 10). Lactic Acidosis. Retrieved from: https://medlineplus.gov/ency/article/000391.htm
  14. Creative Commons. (n.d.). University of California, San Francisco. https://dtc.ucsf.edu/living-with-diabetes/complications/diabetic-ketoacidosis/
Free SGLT2 Inhibitors Case Review

Did you experience ketoacidosis after taking Invokana?
Free Case Review