SGLT2 blockers have been linked to a number of severe side effects including diabetic ketoacidosis, severe urinary tract infection (UTI), and increased risk of amputation.
Recently, the FDA required that a black box warning will be added to prescribing information about SGLT2 inhibitors, warning of the increased risk of amputation of toes, feet, legs and other extremities.
SGLT2 inhibitors include:
- Invokana (canagliflozin) – Janssen Pharmaceuticals March 29, 2013
- Invokamet (canagliflozin and metformin) – August 8, 2014
- Farxiga (dapagliflozin) – AstraZeneca January 8, 2014
- Xigduo XR (dapagliflozin and metformin extended-release) – October 29, 2014
- Jardiance (empagliflozin) – Eli Lilly and Boehringer Ingelheim August 1, 2014
- Glyzambi (empagliflozin and sinagliptin) – January 30, 2015
- Synjardy (empagliflozin and metformin) – August 26, 2015
About SGLT2 Inhibitors
Normally, insulin produced by the pancreas is used to move glucose from the bloodstream into the cells where it can be used as energy. Excess sugar in the blood moves through the kidneys but is reabsorbed back into the bloodstream by the sodium-glucose cotransport type 2 protein.
SGLT2 Inhibitors work by blocking the SGLT2 process so that glucose is not reabsorbed by the kidneys but is excreted into the bladder where it is lost through urination. High levels of glucose in the bladder have resulted in serious effects on the kidney and bladder for some patients. In other cases, patients taking SGLT2 inhibitors have had a higher than normal rate of amputations of the extremities, particularly the toes, feet, and legs, as well as an increased risk of diabetic ketoacidosis which may be life-threatening.
SGLT2 Inhibitor Contraindications
SGLT2 Inhibitors are approved to be used along with diet and exercise for treatment of Type 2 diabetes which occurs when the pancreas is not making enough insulin or the body has become desensitized to insulin. They are not approved for use in Type 1 diabetes or in cases where the pancreas is no longer making insulin.
SGLT2 Inhibitors are not approved and should not be used in patients with diabetic ketoacidosis or those who have a history of DKA. They are also contraindicated in patients with kidney damage, who are on dialysis or who have a history of allergy to any of the gliflozin drugs.
SGLT2 Inhibitor Drug Interactions
Because the SGLT2 inhibitors work on the kidneys, medications which also affect kidney function may cause drug interactions. They may also interact with medications that affect the liver or make it harder for a diabetic to tell if they have low blood sugar or hypoglycemia.
Drug interactions with SGLT2 Inhibitors may include
- ARB blood pressure medications
- Beta blockers and calcium channel blockers
- Certain antibiotics (e.g. rifampin, quinolones)
- Anticonvulsants (e.g. phenobarbital, phenytoin)
- Other antidiabetic medications
Patients should discuss all of their medications with a health care practitioner, including over-the-counter medicines and nutritional supplements.
SGLT2 Inhibitors and Diabetic Ketoacidosis
DKA is caused by a buildup of an acidic waste product, ketones, in the bloodstream and can become life-threatening if not treated immediately.
In May of 2015, the Food and Drug Administration issued a safety warning regarding SGLT2 Inhibitor use and an increased risk of diabetic ketoacidosis (DKA). Between March 2013 and June 2014, the agency had received at least 20 reports of DKA in SGLT2 Inhibitor patients, all of which required hospitalization. During the same time period, the European Medicines Agency (EMA) reported at least 100 similar cases.
SGLT2 Inhibitors, UTI, and Kidney Damage
Increased levels of sugar in the bladder can result in the growth of bacteria, leading to a severe infection of the bladder and urinary tract (UTI). If not treated promptly, the kidneys may become infected (pyelonephritis) which may result in kidney damage and may require dialysis. In some cases, a systemic (body-wide) infection known as urosepsis may develop and become life-threatening.
In December of 2015, in addition to the warnings regarding DKA, additional warnings about an increased risk for severe urinary tract infection and kidney damage were required to be added to prescribing information.
SGLT2 Inhibitors and Amputation
Over time, high glucose levels in the bloodstream can damage the vascular system and result in an inadequate supply of oxygen and nutrients to the skin and other tissues in the extremities. Without an adequate blood supply, tissue in the extremities may become infected, gangrenous and necrotic and will ultimately require surgical removal or amputation. This particularly affects areas of the toes, feet, and legs but may also affect the hands or other distant tissues as well.
In 2016, an interim analysis of two large studies, involving canagliflozin, which showed an increased risk of amputation in patients taking SGLT2 medications prompted the FDA to issue warnings about amputation. These concerns were strengthened in 2017 when final study results confirmed that the risk may be twice that of patients not taking the medication.
In May 2017, a “black box” warning was issued for canagliflozin about amputation risk. A black box or “boxed” warning is the most severe safety alert that can be issued by the FDA and though the warning has not included other SGLT2 inhibitors in the U.S., EMA officials in Europe have included the whole category.
Brooks, M., (15 May 2015), SGLT2 inhibitor diabetes drugs may cause ketoacidosis: FDA, Medscape, accessed on 08 August 2017http://www.medscape.com/viewarticle/844754
Cefalu, W. et al, (2015), SGLT2 Inhibitors: The Latest “New Kids on the Block”!, Diabetes Care, accessed on 08 August 2017http://care.diabetesjournals.org/content/38/3/352.full
Food and Drug Administration, (15 May 2015), Drug Safety Communication: 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, accessed on 08 August 2017http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm
Food and Drug Administration, (04 December 2015), Drug Safety Communication: FDA revised labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infection, U.S. Food and Drug Administration, U.S. Food and Drug Administration, accessed on 08 August 2017http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm
Food and Drug Administration, (18 May 2016), 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, U.S. Food and Drug Administration, accessed on 08 August 2017 http://www.fda.gov/Drugs/DrugSafety/ucm500965.htm
ISMP, (06 May 2015), Questions about Canagliflozin (INVOKANA), Quarter Watch, 2., Institute for Safe Medication Practices, accessed on 08 August 2017 http://www.ismp.org/QuarterWatch/pdfs/2014Q2.pdf
Mayo Clinic, (23 October 2013). Diabetic ketoacidosis, Mayo Clinic, accessed on 08 August 2017 http://www.mayoclinic.org/diseases-conditions/diabetic-ketoacidosis/basics/definition/con-20026470
Nainggolan, Lisa, (15 April 2016), EMA Probes Link with Diabetes Drug Canagliflozin, Toe Amputation, Medscape Medical News, accessed on 08 August 2017 http://www.medscape.com/viewarticle/862009
National Library of Medicine, (2016), Invokana-canagliflozin tablet prescribing information, U.S. National Library of Medicine, accessed on 08 August 2017 http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3