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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), 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

List of FDA-approved SGLT2 Inhibitors and Cost

Depending on the pharmacy and insurance plan, patients’ cost for SGLT2 inhibitors vary. Higher doses may also cost more. Medication manufacturers may also offer special savings on prescriptions, and independent companies may offer drug discount cards. But in general, here is a list of all approved SGLT2 inhibitors and a cost comparison by number of tablets. These figures are only estimates.

  • Invokana (canagliflozin), average $459 for 30 tablets
  • Invokamet (canagliflozin and metformin), average $459 for 60 tablets
  • Invokamet XR (canagliflozin and metformin extended release), average $459 for 60 tablets
  • Farxiga (dapagliflozin), about $343 for 30 tablets
  • Xigduo XR (dapagliflozin and metformin extended release), about $463 for 30 tablets
  • Jardiance (empagliflozin), about $400 for 30 tablets
  • Glyxambi (empagliflozin and linagliptin), about $562 for 30 tablets
  • Synjardy (empagliflozin and metformin), about $463 for 60 tablets

SGLT2 Side Effects

Yeast infections and urinary tract infections (UTIs) are the most common side effects of SGLT2 inhibitors , occurring in roughly four to 11 percent of people who take the drugs. UTIs should be watched for signs of more serious complications since they can in rare cases develop into serious blood or kidney infections.

Clinical trials found at least nine common side effects that occurred in at least 2 percent of patients taking SGLT2 inhibitors along with minor side effects experienced by a smaller percentage of patients.

Common, Less Serious Side Effects Include:

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

Serious Side Effects of SGLT2 Inhibitors

The FDA has required additional warnings added to some or all SGLT2 inhibitor labels on at least four occasions since first approving the drugs in 2013.

FDA warnings have highlighted risks of serious side effects of SGLT2 inhibitors including:

  • Amputation risk of toes and feet – specifically with canagliflozin
  • Diabetic ketoacidosis (DKA) – increased acid levels in the blood
  • Acute kidney injury (AKI) – sudden decrease in kidney function
  • UTIs causing serious kidney and blood infections – may require hospitalization
  • Lactic acidosis – a condition that can cause drops in blood pressure, sudden drop in body temperature, irregular heartbeat and death

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. In May 2017, the agency added a black box warning about the risk of foot and leg amputations. Additionally, Invokana was not tested in pregnant women, but animal studies showed irreversible kidney problems in fetuses.

Dosages:

  • 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.

Dosages:

  • 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

Interactions:

  • 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.

Dosages:

  • 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

Interactions:

  • 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.”

  • May 2017

    A black box warning was added to the label of Type 2 diabetes medication Invokana (canagliflozin) describing the risk of foot and leg amputations.

Author

Michelle Y. Llamas is a senior content writer. She is also the host the Drugwatch Podcast where she interviews medical experts as well as patients affected by drugs and medical devices. She has written medical and legal content for six years — including an article in The Journal of Palliative Medicine. Prior to writing for Drugwatch, she spent several years as a legal assistant for a personal injury law firm in Orlando. She obtained her Bachelor of Arts in English – Technical Communication from the University of Central Florida.


Hide 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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