SGLT2 inhibitors may help people with type 2 diabetes who already have heart disease, according to an empagliflozin study published in November 2015 in The NEJM and a canagliflozin study published in August 2017 in The NEJM. Both studies suggested the drugs may reduce the likelihood of having another heart attack, stroke, or dying from heart disease. The American Diabetes Association’s guidelines, published in January 2019 in the journal Diabetes Care, recommend SGLT2 inhibitors for people with diabetes who have been diagnosed with heart disease or who are at high risk for heart disease.
A review of 10 studies, published in January 2019 in Postgraduate Medicine, found that in people without kidney disease, taking an SGLT2 inhibitor was associated with lower levels of protein in the urine — a symptom of kidney disease — and a lower risk of developing this symptom.
But there are downfalls with SGLT2 inhibitors.
The most common side effects of SGLT2 inhibitors include genital yeast infections, flu-like symptoms and a sudden urge to urinate. SGLT2 Inhibitors May Increase Risk for Urinary Tract Infections. We know that, the incidence of urinary tract infections is about 50 perent greater in people with diabetes compared with people without diabetes. Moreover, SGLT2 inhibitors may increase the risk of genital infections.
In late August 2018, US Food and Drug Administration (FDA) issued a warning about necrotizing fasciitis of the perineum, also known as Fournier gangrene with the class of type 2 diabetes medicines called sodium-glucose cotransporter-2 (SGLT2) inhibitors. The SGLT2s affected by the warning include canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and their combinations. Fournier gangrene remains very rare, but is more common in people using sodium-glucose cotransporter (SGLT)2 inhibitors compared with other diabetes medications and has severe consequences, shows research.
Also, risk of increasing breast and bladder cancer remains a safety issue of SGLT2 (sodium glucose cotransporter type 2) inhibitors.
People have reported more than 28,100 adverse events for the four main SGLT2 drugs. Invokana has more serious adverse events than all the other drugs combined. But it was also the first drug in the class approved for sale, and it also averages more prescriptions per year.
Adverse Events Reports in FAERS
|DRUG||TIME PERIOD||TOTAL ADVERSE EVENTS||SERIOUS EVENTS||DEATHS|
|Invokana||2013 – September 2018||18,131||10,796||255|
|Farxiga||2014 – September 2018||3,923||1,119||62|
|Jardiance||2014 – September 2018||6,046||3,100||116|
|Steglatro||January 2018 – September 2018||59||7||0|
The drugs’ labels warn about common side effects such as yeast infections and nausea. The FDA has also released several Drug Safety Communications about more rare but serious side effects such as flesh-eating genital disease, lower limb amputations with Invokana, kidney problems, ketoacidosis and bone fracture risks. In addition, Farxiga may increase the risk of bladder cancer.
People who suffered serious side effects after taking the drugs have filed lawsuits against SGLT2 inhibitor manufacturers, alleging the companies knew of the dangers but failed to warn the public.
While clinical trials show the most common side effects are relatively minor, FAERS shows the most reported adverse events are more serious. The top three most-reported events in FAERS are diabetic ketoacidosis — a condition where a lack of insulin causes acid to build up in the blood— fungal infections and kidney injuries.
In 2015, the FDA released a Drug Safety Communication warning about the risk of ketoacidosis — also called diabetic ketoacidosis — and serious urinary tract infections (UTIs). The agency required drug companies to add warnings to SGLT2 medication labels.
In the same communication, the FDA warned about the risk of urinary tract infections that could turn into life-threatening blood infections (urosepsis) and kidney infections (pyelonephritis). The agency identified 19 cases of blood and kidney infections that began as urinary tract infections.
In August 2018, the FDA released a Drug Safety Communication warning that SGLT2s may cause a rare but serious genital infection called necrotizing fasciitis of the perineum — also known as Fournier’s gangrene. The disease can be life-threatening. Symptoms include tenderness, redness or swelling of the genitals and fever.
From 2014 to Sept. 30, 2018, the FDA received reports of 41 cases of bladder cancer and bladder neoplasms (possible cancerous growths) in people who took Farxiga (dapagliflozin). One person died.
In 2017, the FDA required Johnson & Johnson and Janssen Pharmaceuticals to add a black box warning to Invokana, Invokament and Invokamet XR for lower limb amputations. The agency based its decision on the results of two large, randomized, placebo-controlled trials that found amputations occurred twice as often in people who took canagliflozin versus a placebo, according to the FDA’s Drug Safety Communication.
The FDA urges people who suffer from leg or foot pain or tenderness, sores or ulcers, or infections to contact their doctor. From 2016 to Sept. 30, 2018, the agency received 236 reports of amputation in people who took Invokana. Two cases resulted in death.
In 2016, the FDA warned medications containing canagliflozin and dapagliflozin may harm kidneys. The agency required the drugs’ makers to strengthen warnings on the medication inserts.
From March 2013 to October 2015, the FDA identified 101 reported cases of kidney injury in users of canagliflozin and dapagliflozin. Some people needed to be treated in the hospital with dialysis. About half of these cases occurred within one month of starting either of the drugs.
More recent FAERS data shows people reported 1,614 cases of kidney injury with all SGLT2s from 2013 to Sept. 30, 2018 — including 54 deaths.