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About SGLT2 Inhibitors

Diabetes is not the death sentence it once was. The 21 million Americans diagnosed with the disease now have a choice of eight different classes of drugs designed to lower blood glucose. These classes include: Sulfonylureas, Biguanides, Meglitinides, Thiazolidinediones, DPP-4 inhibitors, Alpha-glucosidase inhibitors, Bile Acid Sequestrants – and, most recently, SGLT2 Inhibitors. The prescribed drug will depend upon a patient’s medical history, comorbidities, lifestyle, allergies, side effects, and other drugs being taken. The ideal patient is overweight, has high blood pressure, and requires glycemic control.

What are SGLT2 inhibitors?

On March 29, 2013, the FDA approved canagliflozin as the first Sodium-Glucose Co-Transporter 2 Inhibitor, a new class of prescription medications designed to lower blood sugar in adults with type 2 diabetes. SGLT2 is a protein that prompts sugar reabsorption in the kidney, so these inhibitors block this process and encourage the body to excrete glucose in the urine, thereby lowering blood glucose levels.

Subsequent drugs were approved through 2014, including:

  • Invokana (canagliflozin)
  • Invokamet (canagliflozin and metformin)
  • Farxiga (dapagliflozin)
  • Xigduo XR (dapagliflozin and metformin extended-release)
  • Jardiance (empagliflozin)
  • Glyxambi (empagliflozin and linagliptin)

Though the drugs are not yet approved for type 1 diabetes, doctors sometimes prescribe them off-label as a way for patients to lower insulin dosage.

Benefits of Invokana, Farxiga, Jardiance

The primary benefits of SGLT2 inhibitors are the ability to lower blood pressure and reduce levels of glycated hemoglobin in patients who cannot take metformin. Diabetes patients with higher amounts of glycated hemoglobin exhibit poorer blood glucose control that leads to cardiovascular disease, nephropathy and retinopathy, so treatment often focuses on reducing this variable. Newly diagnosed patients who take a combination of dapagliflozin and metformin also see better results than people simply taking metformin. Furthermore, many patients lose weight rapidly on these drugs because they can pass up to 300 calories of sugar through the urine each day.

Potential risks

  • Vaginal irritation and urinary tract infections in women are the most common concerns with SGLT2.
  • The oldest patients taking this class of drug may have an increased risk of bone fracture; one study published in The Lancet identified a 6 – 9.4% increased risk of fractures compared to placebos.
  • An increase in LDL cholesterol has also been observed, which warrants further investigation. A review published in the December 2013 issue of the journal Diabetes Therapy acknowledged that “Currently available information on outcomes such as stroke, heart attack, and other vascular complications is limited, but larger studies with cardiovascular end points are ongoing and will provide data in 2017 onwards.”
  • That same review mentioned a “potential relationship between SGLT2 inhibitors and neoplasia” that is currently underway. Breast and bladder cancer events were more commonly observed with dapagliflozin use, they stated. The FDA stated that there were 8 cases of breast cancer out of 4,287 patients and 7 cases of bladder cancer out of 4,310 patients, compared to 0 cases among placebo groups. Diagnosis took place within six weeks of starting treatment. The label for dapagliflozin, specifically, warns of a 0.17% incidence of bladder cancer among users.

SGLT2 inhibitors and ketoacidosis

However, even more serious SGLT2 inhibitor side effects are under investigation. On May 15, 2014, the U.S. Food and Drug Administration (FDA) issued a safety communication regarding a possible link between SGLT2 inhibitors and a potentially life-threatening condition known as ketoacidosis. When the body does not have enough insulin to use sugar for fuel, it breaks down fat instead. As fat breaks down, waste products called ketones build up in the blood and urine, which are poisonous at high concentrations.

Symptoms of ketoacidosis include:

  • Abdominal pain
  • Confusion
  • Dry skin and mouth
  • Fatigue
  • Flushed face
  • Frequent urination or thirst
  • Fruity-smelling breath
  • Headache
  • Muscle stiffness or aches
  • Nausea and vomiting
  • Rapid breathing
  • Stomach pain

If left untreated, ketoacidosis can lead to fluid buildup in the brain, heart attack, kidney failure, and death.

The FDA Adverse Event Reporting System identified 20 cases of diabetic ketoacidosis requiring hospitalization from March 2013 to June 2014. These cases were not typical because patients had type 2 diabetes and their blood sugar levels measured normal. All patients in the database had been taking the SGLT2 inhibitor for an average of two weeks.

According to Yehuda Handelsman, medical director of the Metabolic Institute of America, “Dehydration, infection, severe illnesses, not eating, a high-protein and high-fat diet, or taking less insulin can, on their own, cause ketosis. It’s not clear yet if the drugs played a role. We need more details about these cases before we rush to judgment.”

Following the FDA safety communication, regulators at the European Medicines Agency issued their own alert for diabetic ketoacidosis risks in people taking Invokana, Jardiance and other SGLT2 inhibitors sold in the EU. The press release, issued in February 2016, warns health care professionals to be on the alert for atypical presentation of ketoacidosis including normal blood sugar levels, so that the condition can be swiftly diagnosed and treated.

Who shouldn’t take SGLT2 inhibitors?

According to the American Pharmacists Association, the following patients may not be good candidates for this class of diabetes drug or would at least require increased monitoring:

  • Uncircumsized males or patients with a history of genital mycotic infections (genital infection risk)
  • Those with renal impairment or taking anti-hypertensives (hypotension and hyperkalemia risks)
  • Insulin users (hypoglycemia risk)
  • Bladder cancer patients (mortality risk) – especially for users of dapagliflozin
  • Users of loop diuretics (dehydration and hypotension risks)

More information is needed on possible SGLT2 inhibitor side effects

The pros and cons of treatment with SGLT2 inhibitors should be discussed between doctors and patients. Since the drugs are so new, more information from ongoing clinical trials will come to light in the years to follow. If some of the adverse event associations turn out to be significant, then the manufacturers of these drugs could be held liable for failing to conduct appropriate safety trials before releasing these medications to the public and for failing to warn patients of serious risks from their products’ use.

Farxiga & Invokana lawyers across the country are currently reviewing cases of people who took SGLT2 inhibitors and developed ketoacidosis or other complications. Injured patients are advised to contact an experienced drug product liability lawyer as soon as possible, since statutes of limitations in every state cut short the window of time in which an Invokana or Farxiga lawsuit can be filed.

  1. Medline Plus – Diabetic Ketoacidosis

  2. Diabetes In Control – SGLT2 Inhibitors: A New Class of Diabetes Medications

  3. FDA - FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood

  4. Endocrine Web - SGLT2 Inhibitors and Diabetic Ketoacidosis: What's Behind the FDA Warning

  5. AJMC - Benefits, Risks of SGLT2 Inhibitors Explored at Session

  6. The Lancet - Possible adverse effects of SGLT2 inhibitors on bone

  7. American Diabetes Association – What are my options?

  8. ADA – Fast Facts

  9. Diabetes Therapy - Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors: Targeting the Kidney to Improve Glycemic Control in Diabetes Mellitus

  10. American Pharmacists Association - SGLT2 inhibitors for type 2 diabetes: Clinical considerations

  11. Pharmacy Times - SGLT2 Inhibitors: A New Treatment Option for Type 2 Diabetes