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SGLT2 Inhibitors

Type 2 diabetes drugs called sodium-glucose co-transporter 2 (SGLT2) inhibitors stop glucose from reentering the blood in the kidneys. These drugs are growing in popularity because they are effective at lowering blood sugar, but the FDA issued a number of warnings linking them to serious side effects including diabetic ketoacidosis and blood and kidney infections.

SGLT2 Inhibitors - Farxiga 10mg & Invokana 300mg

Used to Treat: Type 2 diabetes

Drugs in This Class: Invokana, Invokamet, Farxiga, Xigduo, Glyxambi, Jardiance, Synjardy

FDA Safety Communications: Diabetic ketoacidosis, kidney injury, urinary tract infections, blood infections, kidney infections, increased risk of amputation

FDA Approval: Invokana, first drug in the class, 2013

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

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a newer class of Type 2 diabetes medications. The first drug in this class was Invokana (canagliflozin), first approved in 2013. After Invokana, a number of other SGLT2 inhibitors hit the market. Some also come in extended formulas and in formulas combined with metformin.

The drugs are rapidly growing in popularity. In the period between October 2014 and September 2015, doctors wrote 1.5 million prescriptions for Invokana or Farxiga (dapagliflozin), according to the FDA. Studies show they are effective in controlling excess blood glucose and lowering hemoglobin A1C — a measurement of blood sugar — in people with Type 2 diabetes. But potent blood sugar control also comes with side effects.

Beginning in December 2015, the FDA released a number of warnings linking these drugs to side effects, including some that can be fatal.  Known SGLT2  side effects range from common ones like yeast infections to more dangerous, rare problems like diabetic ketoacidosis — too much acid in the blood. Clinical studies also found more dangerous possible health risks, such as increased bladder cancer risk.

Invokana is the most popular medication in this class, but there are four other FDA-approved SGLT2 inhibitors on the market along with various combination formulas.

How Do SGLT2 Inhibitors Work?

These drugs work by preventing the kidneys from reabsorbing sugar and releasing it into the blood. The kidneys are powerful glucose filters. SGLT2 is a glucose transporter located in the proximal tubule of the kidneys. It reabsorbs 90 percent of glucose and returns it to the blood. SGLT2 inhibitors block this action of glucose reabsorption in the kidney. Instead of the glucose going back into circulation, the kidneys excrete it into urine.

A number of other Type 2 diabetes drugs affect the pancreas or insulin levels to control blood sugar. SGLT2s don’t act on insulin or the pancreas at all, and this makes SGLT2 inhibitors unique in how they work.

Diagram of How SGLT2 Inhibitors Work
Diagagram of how SGLT2 blocks the reabsorption of glucose

General SGLT2 Side Effects

The way SGLT2 drugs work is unique, but 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.

Common, Less Serious Side Effects Include:

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

Serious SGLT2 Side Effects

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. The FDA sent out safety communications warning the public about problems from diabetic ketoacidosis to increased risk of toe and foot amputation.

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. Ketones are poisonous in high levels and can cause organs to malfunction.

Symptoms of DKA include:

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

While SGLT2s can increase the risk of DKA, they are not the main cause. Studies show infection, missed or irregular insulin treatments and a new diagnosis of diabetes are the cause of diabetic ketoacidosis 40 percent, 25 percent and 15 percent of the time, respectively. The average cost of hospitalization for diabetic ketoacidosis in the U.S. is $13,000 per patient.

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

Kidney Injury

In June 2016, the FDA strengthened the acute kidney injury (AKI) warning for Invokana and Farxiga, specifically. This also applies to Ivokamet, Invokamet XR and Xigduo XR.  The FDA found more than 100 cases of acute kidney injury from March 2013 to October 2015. The agency said there may actually be more cases. Most people suffered kidney injury within one month of taking the drug.

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
Illustration of Acute Kidney Injury in Kidneys
Kidney affected by AKI

In some cases, AKI may not have symptoms, and health care providers may have to run some tests to diagnose it. 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 Invokana or Farxiga. These factors include decreased blood volume, chronic kidney problems and other medications that may increase kidney injury risk.

Blood Infection and Urinary Tract Infections (UTIs)

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 sepsis (blood infections) and kidney infections (pyelonephritis).

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

Lactic Acidosis

A number of SGLT2 drugs are available in combination with metformin. 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 acidosis occurs when too much lactic acid builds up in the blood. Alcohol and drugs such as cimetidine, topiramate, zonisamide and acetazolamide may increase the risk of lactic acidosis.

Lactic acidosis may lead to hypothermia, hypotension, irregular heartbeat and death.

Symptoms of lactic acidosis:

  • Abdominalor stomach discomfort
  • Decreased appetite
  • Diarrhea
  • Fast, shallow breathing
  • General feeling of discomfort
  • Muscle painor cramping
  • Unusual sleepiness, tiredness or weakness.

Invokana, Invokamet, Invokamet XR

Invokana 300mg pill
Invokana 300mg pill

Invokana (canagliflozin) was the first SGLT2 inhibitor approved by the FDA. Manufactured by Johnson & Johnson‘s Janssen Pharmaceuticals division, Invokana hit the market in 2013 and quickly rose in popularity. J&J also spent $19.8 million marketing the drug to doctors in 2014, according to Bloomberg.

In 2014, the FDA approved Invokamet (canagliflozin and metformin); then it approved Invokamet XR in 2016.

Unlike other SGLT2’s, the FDA also found a link between Invokana and increased toe and foot amputations. The agency released a Drug Safety Communication in May 2016 and said it was investigating. Additionally, Invokana was not tested in pregnant women, but animal studies showed irreversible kidney problems in fetuses.


  • Invokana: 100 mg and 300 mg. People with kidney issues should not take more than 100 mg daily.
  • Invokamet: 50 mg canagliflozin and 500 mg metformin. Depending on the patient’s response, the dosage of canagliflozin or metformin may be adjusted up to a maximum of 300 mg canagliflozin and 2000 mg metformin.

Drug Interactions:

  • Canagliflozin: Rifampin, digoxin
  • Metformin: Alcohol, cimetidine, topiramate, zonisamide, acetazolamide

Farxiga, Xigduo XR

Farxiga 10mg pill
Farxiga 10mg pill

Farxiga (dapagliflozin) is a pill that patients take once daily with food. Xigduo (dapagliflozin and metformin) combines the active ingredient of Farxiga with metformin. The FDA approved Farxiga in 2014, and, shortly after, it approved Xigduo XR.

The agency previously rejected Farxiga because of bladder and breast cancer concerns. It is not for treatment of Type 1 diabetes mellitus or for use in people with diabetic ketoacidosis.

Farxiga has the typical side effects of other SGLT2s, but clinical trials revealed people who take it may be five times more likely to develop bladder cancer, according to the Cancer Prevention & Treatment Fund.

In addition, research shows the drug could also promote a faster progression of bladder cancer in people who are already prone to the disease. So, people with bladder cancer should not take this drug.


  • Farxiga: 5 mg and 10 mg
  • Xigduo XR: 5 mg dapagliflozin/500 mg metformin, 5 mg/1000 mg, 10 mg/500 mg, 10 mg/1000 mg


  • Dapagliflozin: Insulin, insulin secretagogues
  • Metformin: Alcohol, cimetidine, topiramate, zonisamide, acetazolamide

Jardiance, Glyxambi and Synjardy

Jardiance (empagliflozin), approved in 2014, is an oral medication marketed and sold by Boehringer Ingelheim. Glyxambi (empagliflozin and linagliptin), approved in 2015, combines the active ingredients in Jardiance with the active ingredient in another Type 2 diabetes medicine called Tradjenta.

Tradjenta belongs to a class of medications called DPP-4 inhibitors. The FDA approved Synjardy in 2015. The drug combines empagliflozin with metformin. Like other SGLT2 inhibitors, these drugs are not for use in people with Type 1 diabetes or people with diabetic ketoacidosis. At higher dosages, animal studies showed that empagliflozin caused birth defects in rabbit fetuses and kidney and lymph node tumors in rats.


  • Jardiance: 10 mg and 25 mg
  • Glyxambi: 10 mg empagliflozin/5 mg linagliptin, 25 mg empagliflozin/5 mg linagliptin
  • Synjardy: 5 mg empagliflozin/500 mg metformin hydrochloride, 5 mg empagliflozin/1000 mg metformin hydrochloride, 12.5 mg empagliflozin/500 mg metformin hydrochloride, 12.5 mg empagliflozin/1000 mg metformin hydrochloride tablets


  • Empagliflozin: Diuretics, insulin, insulin secretagogues
  • Linagliptin: Rifampin
  • Metformin: Alcohol, cimetidine, topiramate, zonisamide, acetazolamide

SGLT2 FDA Safety Communications and Warnings

Only two years after the FDA approved Invokana, the entire SGLT2 inhibitor class of medications came under fire for serious side effects. The FDA released a number of warnings for potentially fatal side effects linked to these drugs beginning in May 2015.

  • May 2015

    The FDA issued a safety communication warning that SGLT2 drugs “may lead to ketoacidosis, a serious condition where the body produces high levels of blood acids called ketones that may require hospitalization.”

  • December 2015

    The FDA issued a safety communication notifying the public and health professionals. The agency added “warnings to the labels of a specific class of type 2 diabetes medicines called sodium-glucose cotransporter-2 (SGLT2) inhibitors about the risks of too much acid in the blood and of serious urinary tract infections. Both conditions can result in hospitalization.” FDA also warned of life-threatening blood infections that could develop from urinary tract infections linked to these drugs.

  • May 2016

    The FDA released a safety communication warning of interim “safety results from an ongoing clinical trial that found an increase in leg and foot amputations, mostly affecting the toes, in patients treated with the diabetes medicine canagliflozin (Invokana, Invokamet).”

  • June 2016

    The FDA released a safety communication informing the public that it “strengthened the existing warning about the risk of acute kidney injury for the type 2 diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). Based on recent reports, we have revised the warnings in the drug labels to include information about acute kidney injury and added recommendations to minimize this risk.”


Michelle Y. Llamas is a senior content writer and researcher for Drugwatch. She is also the host of the Drugwatch Podcast where she talks to patients, experts and advocates about drugs, medical devices and health. She uses her technical writing experience to provide easy-to-understand information on how drugs and devices work. But she also tells people what happens when products that are supposed to improve their lives can hurt them.

View Sources
  1. U.S. National Library of Medicine. (2016). JARDIANCE- empagliflozin tablet, film coated. Daily Med. Retrieved from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=faf3dd6a-9cd0-39c2-0d2e-232cb3f67565&audience=consumer#Section_5.4
  2. U.S. National Library of Medicine. (2014). FARXIGA- dapagliflozin tablet, film coated. Daily Med. Retrieved from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fc6ae30e-868b-4ac9-b69d-900922503998&audience=consumer
  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 http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm
  4. 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 http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm475553.htm
  5. 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 http://www.fda.gov/Drugs/DrugSafety/ucm500965.htm
  6. FDA. (2016, June 14). FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). Retrieved from http://www.fda.gov/Drugs/DrugSafety/ucm505860.htm
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