(Updated Feb. 13, 2018)
Note: We are no longer taking Invokana and Invokamet cases.
Invokana belongs to a class of drugs known as sodium-glucose cotransporter-2 (SGLT2) inhibitors. These drugs lower blood sugar levels in type 2 diabetes patients, but they may also cause dangerous side effects, including diabetic ketoacidosis (DKA) and kidney problems.
Invokana can cause serious health complications, including diabetic ketoacidosis (DKA) and kidney failure.
During the drug approval process, some experts questioned the safety of Invokana and argued against approving it. There were also questions about the sufficiency of data used to approve Invokana. Although Invokana was eventually approved, questions linger about its safety and the safety of similar drugs.
Some patients have filed lawsuits against Johnson & Johnson and other drug companies, claiming they did not sufficiently warn about SGLT2 inhibitor side effects.
How Does Invokana Work?
In people with type 2 diabetes, the body does not use insulin properly. Insulin is a hormone made by the pancreas that regulates blood glucose (sugar) levels by sending sugars to cells for storage.
Invokana prevents the kidneys from reabsorbing glucose and increases renal glucose excretion, thus lowering blood glucose levels.
When glucose accumulates in the blood instead of in cells, it causes a dangerous drop in energy and gradually damages the body. SGLT2 is a naturally occurring protein in the body that helps the kidneys retrieve glucose from the blood, preventing it from disappearing through urine.
For patients with diabetes, however, this is a bad thing. Glucose needs to leave the diabetic’s body—not be reabsorbed. SGLT2 inhibitors like Invokana block the action of the SGLT2 protein. They prevent the kidneys from reabsorbing glucose and increase renal glucose excretion (sugar excretion through urine), thus lowering blood glucose levels.
Not all diabetes drugs work on the kidneys. Other diabetes drugs work on the pancreas, the muscles, the liver, and the gut.
Why Did the FDA Issue a Black Box Warning for Invokana?
In May 2017, the FDA ordered a black box warning (the highest warning it can issue) for Invokana's increased risk of foot and leg amputations. The warning was based on the results of two clinical trials which showed that patients with type 2 diabetes were twice as likely to need an amputation if they took Invokana than if they took a placebo.
The FDA reported that amputations of the toe and foot were the most common, but that leg amputations above and below the knee did occur.
What Are Some Other SGLT2 Inhibitors?
Invokana (canagliflozin; Janssen Pharmaceuticals/Johnson & Johnson), FDA-approved in 2013, was the first SGLT2 inhibitor to hit the U.S. market. It was followed by:
- Invokamet (canagliflozin and metformin; Johnson & Johnson)
- Farxiga (dapaglifozin; Bristol-Meyers Squibb and AstraZaneca)
- Xigduo XR (dapagliflozin and metformin extended-release; AstraZaneca)
- Jardiance (empagliflozin; Boehringer Ingelheim)
- Glyxambi (empagliflozin and linagliptin; Boehringer Ingelheim)
What Is Diabetic Ketoacidosis?
Diabetic ketoacidosis (DKA) is a serious diabetes complication that occurs when the body produces high levels of blood acids called ketones. Ketones are produced when cells don’t get needed energy from glucose and begin to break down fat for energy. Ketone accumulation in the blood makes it more acidic and can poison the body. DKA may cause the patient to pass out for a long period (diabetic coma) and can be fatal. Hospitalization is often required.
Invokana and Invokamet were named as drugs of concern in the FDA warning.
In May 2015, the U.S. Food and Drug Administration (FDA) warned that Invokana and other SGLT2 inhibitors may lead to DKA. It based the warning on 20 cases of DKA reported to the agency over a roughly one-year period. This is an unusually high number of cases considering that DKA most commonly occurs in patients with type 1 diabetes. All of the patients required an emergency room visit or hospitalization.
The FDA followed up with new information in December 2015, saying that SGLT2 inhibitors would now be required to carry warnings about the risk of excessive blood acids. The FDA added that the drugs would also be required to carry warnings about serious urinary tract infections. Symptoms of DKA include:
- Abdominal pain
- Difficulty breathing
- Fruity-smelling breath
What Are Some Other Health Risks of SGLT2 Inhibitors?
DKA is not the only serious side effect associated with SGLT2 inhibitors. The drugs are also linked to:
- Severe urinary tract infections
- Breast and bladder cancer
- Kidney failure
- Kidney stones
- Yeast infections
- Cardiovascular side effects
- Bone fractures
SGLT2 inhibitors are not recommended for people with impaired kidney (renal) function. This isn’t surprising, given that the drugs act on the kidneys and promote urine production. While kidney injury and impairment is mentioned in SGLT2 inhibitor prescribing information, manufacturers may not have gone far enough in warning about severe renal side effects when the drugs were first marketed. The Institute for Safe Medication Practices (ISMP) published a 2015 report identifying more than 450 Invokana adverse events, including:
- Kidney failure or impairment
- Dehydration and fluid imbalances
- Kidney stones
The ISMP raised questions about whether Invokana has been sufficiently tested, and whether its benefits outweigh its risk. It stated, “The current data are insufficient to address unanswered questions raised in the FDA reviews about whether long-term use might result in a steady decline in kidney function.”
The FDA chimed in on the issue with a June 2016 drug safety communication that said Invokana, Invokamet, Farxiga, and Xigduo XR require strengthened kidney warnings. The FDA based the new warnings on more than 100 cases of acute kidney injury, some requiring hospitalization, reported to the agency from March 2013 (when Invokana was approved) to October 2015. In about half of the cases, signs of kidney injury developed within a month of patients starting the drug. Most improved after they went off the drug. According to the FDA, signs of acute kidney injury include:
- Decreased urine
- Swelling in the legs or feet
Leg, Foot Amputations
In May 2017, the FDA ordered a black box warning (the highest warning it can issue) for Invokana's increased risk of foot and leg amputations. The warning was based on the results of two clinical trials which showed that patients with type 2 diabetes were twice as likely to need an amputation if they took Invokana than if they took a placebo. The FDA reported that amputations of the toe and foot were the most common, but that leg amputations above and below the knee did occur.
The FDA ordered a labeling change to Invokana in 2015 over the drug’s bone fracture risk. The new safety information is based on data that shows Invokana is more likely than a placebo to cause bone fractures. The data comes from a post-marketing study that the FDA ordered Janssen to conduct upon Invokana's approval.
Three case reports demonstrate a rare but potentially deadly Invokana side effect: acute pancreatitis (inflammation of the pancreas).
A Journal of Basic and Clinical Pharmacy report details a 50-year-old man who was prescribed Invokana four days prior to being admitted to the hospital complaining of malaise, weakness, abdominal pain, and vision loss. The patient stopped using Invokana and his symptoms subsided.
Another case study details a similar experience with a 33-year-old woman. The woman was admitted to the emergency room with nausea, vomiting, and severe abdominal pain. She discontinued Invokana and, like the male patient, subsequently recovered.
A third case of this kind is reported in the American Journal of Therapeutics. Invokana still does not have any pancreatitis warnings.
The FDA stated that, based on available data, it could not rule out the possibility that dapagliflozin contributes to bladder cancer and breast cancer. These findings hindered approval of Farxiga, and while it was finally granted, the FDA ordered six post-marketing studies for Farxiga.
The FDA also warned that people with active or previous cases of bladder cancer should not use Farxiga. Similar cancer risks were not found for Invokana. Dapagliflozin is also an ingredient of Xigduo XR.
There was controversy at the time of Invokana approval over what appeared to be an increase in cardiovascular events (e.g. heart attacks and strokes) among clinical trial patients, with one study showing that Invokana produced 13 CV events compared to just 1 in the placebo group.
Invokana earns Janssen roughly $1.5 billion per year.
In a vote, 8 of 15 panel members expressed concerns over data on CV risks (particularly strokes), citing data insufficiency. Despite CV concerns, the FDA panel voted 10-to-5 to approve Invokana. As part of its approval, the FDA ordered five post-marketing studies, including a cardiovascular outcomes trial.
Meanwhile, Invokana is being prescribed to hundreds of thousands of patients and is earning Janssen roughly $1.5 billion per year. All new diabetes drugs approved in the United States must be clinically evaluated for cardiovascular risk because diabetes can increase the risk of heart attack, stroke, coronary artery disease, and other CV complications.
Invokana currently has no warnings about cardiovascular side effects.