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SGLT2 Inhibitors

SGLT2 inhibitors are not indicated for treatment of adults with type 1 diabetes mellitus, a metabolic disorder that also is characterized by hyperglycemia. In type 1 diabetics, however, the pancreas produces little to no insulin.

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Sodium glucose cotransporter-2 (SGLT2) inhibitors are a novel class of antihyperglycemics designed to work against SGLT2, a low-affinity, high-capacity transporter protein found in the kidney’s proximal tubules. The mechanism for SGLT2 inhibitors involves preventing the excretion of urinary glucose by reabsorbing glucose. 1 SGLT2 inhibitors discourage this reuptake of glucose in the kidney. 2

SGLT2 inhibitors are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, 3 a metabolic disorder commonly characterized by hyperglycemia (high blood sugar) and inadequate levels of insulin or insulin resistance.

Some SGLT2 inhibitors have been linked to side effects ranging from UTIs to kidney problems, amputations, bladder cancer and diabetic ketoacidosis (dka).

Using SGLT2 inhibitors for the Treatment of Type 2 Diabetes

Generally, SGLT2 inhibitors are taken orally once per day, usually before breakfast. Your doctor will prescribe the strength of the pill and tell you exactly how and when to take it. The dose may be changed if your doctor decides doing so would be more beneficial for you. 4

While taking an SGLT2 inhibitor, your doctor may advise you to check your blood sugar levels in accordance with a particular schedule. Be aware that SGLT2 inhibitors will be likely to cause your urine to test positive for glucose.

Your doctor may also order tests to check your blood sugar levels and hemoglobin A1C while taking SGLT2 inhibitors. Your doctor may periodically order these same tests, and possibly others as warranted, throughout the time you are taking SGLT2 inhibitors. Be sure to tell your doctor if you experience an adverse reaction or side effects while taking SGLT2 inhibitors. 5

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Brand Names of Popular SGLT2 Inhibitors

What Interacts with SGLT2

Three SGLT2 inhibitors approved by the FDA include canagliflozin, dapagliflozin and empagliflozin:

  • Canagliflozin is marketed under the brand name Invokana. It is manufactured by Janssen Pharmaceuticals and was approved by the FDA on March 29, 2013.

  • Dapagliflozin is marketed under the brand name Farxiga. It is manufactured by AstraZeneca and was approved by the FDA on Jan. 8, 2014.

  • Empagliflozin is marketed under the brand name Jardiance. It is distributed by Boehringer Ingelheim, marketed by both Boehringer Ingelheim and Eli Lilly, and was approved by the FDA on Aug. 1, 2014.

SGLT2 inhibitors belong to the gliflozin class of prescription medicines. The FDA has approved seven formulations of gliflozins, recommonded for use with diet and exercise to help lower blood sugar in adults with type 2 diabetes mellitus. SGLT2 inhibitors are intended to be used to help lower blood sugar by deterring the reuptake of glucose in the kidneys, preventing this glucose from reentering the bloodstream, instead causing it to be expelled from the body through urination.

SLGT2 inhibitors are available as single-active ingredient medicines but also may be combined with other diabetes medicines.

SGLT2 inhibitors may be taken alone or as a combination therapy with other antidiabetic medicines:

  • Canagliflozin and metformin is marketed under the brand name Invokamet. It is manufactured by Janssen Pharmaceuticals and the FDA approved Invokamet on Aug. 8, 2014.
  • Dapagliflozin and metformin extended-release is marketed under the brand name Xigduo XR. It is manufactured by AstraZeneca and was approved by the FDA on Oct. 29, 2014.
  • Empagliflozin and linagliptin is marketed under the brand name Glyxambi. It is distributed by Boehringer Ingelheim, marketed by both Boehringer Ingelheim and Eli Lilly, and was approved by the FDA on Jan. 30, 2015.
  • Empagliflozin and metformin is marketed under the brand name Synjardy. It is distributed by Boehringer Ingelheim, marketed by both Boehringer Ingelheim and Eli Lilly, and was approved by the FDA on Aug. 26, 2015.

SGLT2 Inhibitor Contraindications

What Interacts with SGLT2

Medicines that may adversely interact with SGLT2 inhibitors include:

  • Diuretics (water pills)

  • Rifampin

  • Phenytoin or phenobarbital

SGLT2 inhibitors are indicated for use with diet and exercise in adults with type 2 diabetes mellitus to improve control of blood sugar levels.

They are not approved for use by the FDA in people with type 1 diabetes mellitus, or for the treatment of diabetic ketoacidosis (increased ketones in the blood or urine). Also, SGLT2 inhibitors are contraindicated if you have a known allergy to SGLT2 inhibitors, severe kidney problems, or need for dialysis.

Interactions with Other Drugs

In the course of treatment with SGLT2 inhibitors, your doctor may decide to treat you with additional medicines. However, doing so may raise the risk that you could experience SGLT2 injuries due to the interactions that can occur when different drugs are taken together.

Consult your physician before taking multiple medications. Inform your physician of any medications, both prescription and over-the-counter, that you are taking. This includes nutritional supplements used for diabetes.

The FDA Investigates Diabetic Ketoacidosis Link

The U.S. Food and Drug Administration (FDA) issued a Safety Announcement regarding SGLT2 inhibitors on May 15, 2015. 6 One month later, the European Medicines Agency (EMA) announced that it had initiated an investigation into the risk of diabetic ketoacidosis with SGLT2 inhibitors. 7 In June 2015 Health Canada began a safety review of SGLT2 inhibitors and the risk side effects as well. 8 While there have been reports of SGLT2 inhibitor injuries, no recall of the drugs has been issued in the U.S. or any other country.

Between March 2013 and June 6, 2014, 20 such cases were reported through the FDA’s Adverse Event Reporting System database. All 20 required emergency room visits or hospitalization. Such cases have continued to be reported to the FDA since then, although the agency has not specified how many. 9

The EMA’s decision to investigate the risk for diabetic ketoacidosis with SGLT2 inhibitors was prompted by adverse event reports to the EMA’s EudraVigilance indicating that, as of May 19, 2015, more than 100 people who had taken SGLT2 inhibitors with type 2 diabetes suffered diabetic ketoacidosis serious enough that many of those patients required hospitalization. 10

Meanwhile, a growing body of scientific evidence regarding diabetic ketoacidosis in patients taking SGLT2 inhibitors supports the safety concerns of the FDA, EMA and Health Canada.
On December 4, 2015, the FDA safety review prompted the addition of warnings to all SGLT2 inhibitor labels regarding the risk of diabetic ketoacidosis. In addition, the FDA added warnings regarding the risk of life-threatening blood infections (urosepsis) and kidney infections (pyelonephritis) that began as urinary tract infections in people taking SGLT2 inhibitors.  11

  1. Kelsey Burr et al, “A Case Report of Ketoacidosis Associated with Canagliflozin (Invokana),” presented at the Endocrine Society 97th Annual Meeting and Expo, March 7, 2015. 

  2. Tomohide Hayami et al, Case of ketoacidosis by a sodium-glucose cotransporter 2 inhibitor in a diabetic patient with a low-carbohydrate diet,” Journal of Diabetes Investigation, Feb. 20, 2015. 

  3. Medication Guide Invokana™ (in-vo-KAHN-uh) (canagliflozin) Tablets, Reference ID 3285059, Janssen Pharmaceuticals, Inc. 2013. http://www.fda.gov/drugs/drugsafety/ucm085729.htm. Accessed June 15, 2015;
    Farxiga label: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202293s002lbl.pdf;
    Jardiance label: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204629s000lbl.pdf;
    Xigduo XR label: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205649s000lbl.pdf;
    Janumet label: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204353s002lbl.pdf;
    Glyxambi label: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206073s000lbl.pdf. 

  4. Medication Guide Invokana™ (in-vo-KAHN-uh) (canagliflozin) Tablets, Reference ID 3285059, Janssen Pharmaceuticals, Inc. 2013. http://www.fda.gov/drugs/drugsafety/ucm085729.htm. Accessed June 15, 2015. 

  5. Medication Guide Invokana™ (in-vo-KAHN-uh) (canagliflozin) Tablets, Reference ID 3285059, Janssen Pharmaceuticals, Inc. 2013. http://www.fda.gov/drugs/drugsafety/ucm085729.htm. Accessed June 15, 2015. 

  6. Safety Announcement, “FDA warns that SGLT2 Inhibitors for diabetes may result in a serious condition of too much acid in the blood,” U.S. Food and Drug Administration, May 15, 2015. 

  7. Lisa Nainggolan, “EMA to Review Diabetic Ketoacidosis Risk With SGLT2 Inhibitors,” Medscape, June 12, 2015. 

  8. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2015/53892a-eng.php 

  9. Safety Announcement, “FDA warns that SGLT2 Inhibitors for diabetes may result in a serious condition of too much acid in the blood,” U.S. Food and Drug Administration, May 15, 2015. 

  10. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/SGLT2_inhibitors/human_referral_ prac_000052.jsp&mid=WC0b01ac05805c516f 

  11. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm475553.htm