Gliflozin SGLT2 inhibitors, also known as sodium-glucose cotransporter-2 (SGLT2) inhibitors, are a class of diabetes mellitus medicines which includes canagliflozin, dapagliflozin, and empagliflozin. They are prescribed to adult patients with type 2 diabetes to help control their blood sugar levels, in conjunction with foot care, healthy diet, and regular exercise. These behaviors, however, may not be enough to prevent a side effect of SGLT2 inhibitors, SGLT2 amputation.

While Gliflozin SGLT2 inhibitors have been shown to be effective at managing blood sugar in the long term, they have been linked to serious side effects including increased risk of lower limb amputations and genital infections. As newer long-term studies continue to unfold, patients using gliflozin class drugs need to be aware of this growing list of potential issues.

How SGLT2 Inhibitors Work

Gliflozin, or SGLT2 inhibitors, are a popular drug class prescribed to many diabetics. Gliflozin class drugs are approved for lowering blood sugar in type 2 diabetes patients. Gliflozin works by inhibiting the SGLT2 protein in the kidneys, preventing them from reabsorbing glucose from filtered urine that the kidneys process. Glucose stays in the urine and the body eliminates it through urination.

Gliflozin is often used in conjunction with metformin, which is the primary drug used to treat type 2 diabetes patient with poor control of their blood glucose. Combination drugs of canagliflozin and metformin are marketed as Invokament and Invokament XR. In many cases, SGLT2 inhibitors assist patients with their diabetes without causing side effects. However, some patients may experience an adverse event.

SGLT2 Side Effects

Side effects of gliflozin include low blood pressure, excessive blood acidity (ketoacidosis), kidney issues, excess blood potassium, serious urinary tract infections, yeast infections, low blood sugar when used with other prescription diabetes medicine, bone breaks, and increased cholesterol.

Patients with predisposing factors such as prior amputations, peripheral vascular disease, neuropathy, and diabetic foot ulcers are at a potentially higher risk for lower limb amputation.

Common SGLT2 Side Effects

SGLT2 side effects may be subtle or minor inconveniences. For some patients, it’s difficult to link the side effect to a diabetes medicine specifically.

Stop taking canagliflozin if you experience any of the following side effects. Immediately contact a healthcare professional for emergency medical treatment if you have experienced or are experiencing any of the following while taking an SGLT2 inhibitor:

● Increased urination, particularly at night
● Increased thirst
● Constipation
● Dry mouth
● Frequent, urgent, burning, or painful urination
● Noticeable decrease in urine
● Cloudy, red, pink, or brown urine
● Strong smelling urine
● Pelvic or rectal pain
● (Women) vaginal odor, white/yellow vaginal discharge, vaginal itching
● (Men) redness, itching, or swelling of the penis, foul-smelling discharge from the penis, skin pain of the penis
● Tingling in the arms and legs
● Loss of muscle tone
● Weakness or heaviness in the legs
● Lack of energy
● Cold, gray skin
● Irregular or slow heartbeat

Serious SGLT2 Side Effects

Stop taking canagliflozin if you experience side effects. Contact a healthcare professional for emergency medical treatment if you experience any of these symptoms of diabetic ketoacidosis as these can contribute to SGLT2 amputation as well as other serious medical conditions:
● Rash
● Hives
● Itching
● Difficulty swallowing
● Swelling of the face, throat, tongue, lips, mouth, or eyes
● Hoarseness
● Nausea
● Vomiting
● Stomach-area pain
● Unusual tiredness
● Difficulty breathing

The FDA approved canagliflozin in 2013 as the first gliflozin approved for use in the U.S. for lowering blood sugar in patients who have been diagnosed with type 2 diabetes. Dapagliflozin and empagliflozin are the other two agents in the gliflozin class that has been approved by the FDA. Gliflozin has not been approved for patients with type 1 diabetes.

The Risks of SGLT2 Amputations

Though amputation as the result of SGLT2 side effects is a life-changing and often devastating end, for many it is not the end of their troubles. SGLT2 amputation carries with it the risk of serious adverse side-effects arising from the surgery.

According to a 2018 study published in The BMJ, SGLT2 inhibitors were found to significantly increase the likelihood of diabetic ketoacidosis and SGLT2 amputation. Another 2018 published in the Journal of Clinical And Translational Endocrinology of a randomized controlled trial performed with over 100 volunteers echoes this sentiment stating that among patients with a high baseline risk of amputation SGLT2 inhibitors may tip the scales in favor of SGLT2 amputation.

Following an amputation, complications can arise from infection due to amputation bone fracture, as well as decreased immune response following the surgery. The best method to prevent these and other side effects is to talk to your doctor about regulating your SGLT2 inhibitor usage in order to prevent the circumstances leading to SGLT2 amputation.

Black Box Warning: Risk for SGLT2 Amputation

In 2017, the FDA issued a Boxed Warning (Black Box Warning) for all canagliflozin pharmaceuticals marketed in the U.S. Based on data from two large clinical trials (CANVAS and CANVAS-R), the FDA concluded that canagliflozin causes an almost doubled risk of needing leg and foot amputations for patients prescribed with the drug compared to those without. Learn more about the rates of amputation in our Invokana amputation guide.

There are a number of risk factors for amputations, including diabetic neuropathy. The negative side effects of diabetic neuropathy can be mitigated with proper foot care, in addition to regular visits with a primary care physician.

Medication Guide Warning: Genital Infection Risk

In August 2018, the FDA issued an additional warning for canagliflozin, requiring that drug manufacturers include a warning about an increased risk of genital infections known as necrotizing fasciitis in the patient Medication Guide. While rare, these serious genital infections affect the genitals and the area around the genitals, and result in dead tissue that may result in losing portions of the genitals and surrounding tissue.

Also known as Fournier’s gangrene, necrotizing fasciitis may start small and worsen over time. Diabetes patients may itch their groin or genital region, and the infection may spread. Diabetes patients have reported a foul smell before visiting the emergency room to have surgical debridement and antibiotic treatment.

Drug Safety Communications: SGLT2 Diabetes Medicine

Through a series of drug safety communications, the FDA revised labels for gliflozin to include warnings about increased risks for bone fractures due to decreased bone mineral density, excessive blood acidity (ketoacidosis), and urinary tract infections. However, some diabetes patients experienced these side effects prior to being informed about the increased risk of complications.

While the FDA has issued a Black Box Warning for canagliflozin specifically, a new 2018 study (SURDIAGENE) from France found that use of diuretics in conjunction with canagliflozin might the reason for the increased risk of leg and foot amputations seen in the studies cited by the FDA. Studies show the potential risk of toe amputations is most common.

One of the authors of the study also suggested that his findings could be extended to the full gliflozin class of drugs, but stated that further studies would need to be done to draw real conclusions.

The FDA should consider the results of the SURDIAGENE study in its ongoing assessment of gliflozin SGLT2 class drugs, and conduct further studies to assess whether or not diuretics should be contraindicated with gliflozin. SGLT2 inhibitors should be monitored by a primary care physician in order to minimize the risk of SGLT2 amputation.

SGLT2 amputation is a serious public health issue. Patients taking a gliflozin class drug should consult their physicians about potential complications from diuretic co-use, as well as other side effects.

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