Invokana (canagliflozin) is one of several drugs that belong to a new class of Type 2 diabetes medications called sodium-glucose cotransporter 2 (SGLT2) inhibitors. Invokana and SGLT2s control blood sugar by causing excess sugar to leave the body in urine.
In March 2013, the U.S. Food and Drug Administration (FDA) approved Johnson & Johnson’s (J&J) Invokana as the first drug in its class. Then, in 2014, the FDA approved Invokamet (canagliflozin and metformin) and, in 2016, Invokamet XR (canagliflozin and metformin extended release).
The Invokana family of medications made more than $1.4 billion for J&J in 2016, according to annual reports.
Studies show the drug is effective at controlling blood sugar, but since the FDA approved the drug it has also released several safety communications and warnings.
Serious side effects of Invokana include diabetic ketoacidosis, kidney injury, urinary tract infections and cardiovascular problems.
How Invokana Works
While many drugs treat Type 2 diabetes by increasing insulin or insulin sensitivity, Invokana works by stopping the kidneys from reabsorbing glucose. It acts by inhibiting a special protein in the kidney called SGLT2 that is responsible for reabsorbing 90 percent of the glucose in the kidneys. Instead of reabsorbing the sugar, the kidneys secrete it, and it leaves the body during urination. This results in lowered levels of glucose in the blood.
Side Effects of Invokana
In clinical studies, people who took Invokana suffered a number of common side effects. Researchers gathered data from 1,667 patients with Type 2 diabetes who took Invokana for about 24 weeks. The average age was 56 years and about 2 percent were older than 75. About half of the participants were male and 72 percent of all participants were white. Certain side effects were more prevalent at the 100 mg or 300 mg dose.
Minor Side Effects
- Dehydration and thirst
- Discomfort during urination
- Increased urination
- Increased cholesterol
- Kidney problems
- Low blood sugar
- Urinary tract infections
- Yeast infections in men and women
- Vaginal itching
- Abdominal pain
Serious Side Effects
- Low blood pressure
- Kidney problems
- Hyperkalemia (high potassium)
- Urosepsis (life-threatening blood infection from a urinary tract infection)
- Pyelonephritis (kidney infection)
- Low blood sugar
- Hypersensitivity reactions
- Bone fracture
FDA Warnings and Studies
Studies and FDA safety communications link Invokana to a number of serious side effects that may be fatal. Many of these side effects also require hospitalization and intensive care or emergency treatment. These side effects include diabetic ketoacidosis (DKA), kidney injury, urinary tract infections that lead to blood infections, cardiovascular problems and acute pancreatitis.
Black Box Warning for Leg and Foot Amputation
In May 2017, the FDA added a black box warning for an increased risk of leg and foot amputations with Invokana, Invokamet and Invokamet XR. The FDA’s decision came after it reviewed the results of two large clinical trials, the Canagliflozin Cardiovascular Assessment Study (CANVAS) and A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus (CANVAS-A).
The FDA found people who took Invokana had leg and foot amputations twice as often as patients who took a placebo. Middle of the foot and toe amputations were most common, but leg amputations above and below the knee also occurred. Some patients had more than one limb amputated.
Diabetic Ketoacidosis (DKA)
In May 2015, the FDA warned that Invokana may lead to a serious condition called diabetic ketoacidosis (DKA). DKA occurs when the body cannot use sugar (glucose) as a fuel source because there is either too little or no insulin. Instead, the body breaks down fat for energy. The breakdown of fat produces ketones that can build up in the body. When these waste products build up in the blood, they become toxic.
According to the FDA warning, the agency received about 20 reports of ketoacidosis in patients treated with SGLT2 inhibitors from March 2013 to June 6, 2014. All of these patients needed to go to the hospital for treatment. Since then, the FDA said they are still receiving reports of ketoacidosis in relation to these drugs. The agency ordered manufacturers to add warnings to the drugs’ labels in December 2015.
In June 2016, the FDA strengthened the acute kidney injury (AKI) warning for Invokana. Kidney injury is a serious condition where the kidneys suddenly stop working and allow waste to build up in the body. According to the FDA, more than 100 people reported suffering kidney injury after taking Invokana or another SGLT2 drug, Farxiga, between March 2013 and October 2015. The agency says there may be more unreported cases. About half of reported cases occurred within one month of starting the drug.
In some cases, AKI may not have symptoms, and health care providers may have to run some tests to diagnose it.
Blood Infection and Urinary Tract Infections (UTIs)
In December 2015, the FDA warned that Invokana can increase the risk of serious or life-threatening blood infections (urosepsis) that started as UTIs. The agency identified 19 cases of blood infections and kidney infections (pyelonephritis) from March 2013 to October 2014.
The FDA also required Johnson & Johnson to conduct post-marketing studies and a clinical trial after initial study data showed a troubling increase in the risk of cardiovascular problems such as stroke, blood clots (thromboembolic events) and heart attacks. The Canagliflozin Cardiovascular Assessment Study (CANVAS) trial showed a 46 percent elevated risk for stroke in the first 30 days of treatment.
In 2016, the FDA said it received reports of acute pancreatitis in patients taking Invokana and other SGLT2 inhibitors. Acute pancreatitis occurs when the pancreas, the organ responsible for making insulin, becomes inflamed and swollen. It can lead to serious health problems and death if untreated. Treatment for mild cases typically involves antibiotics. For more serious cases, doctors may hospitalize patients for emergency treatment.
In its Potential Signals of Serious Risks/New Safety Information Identified by the FDA Adverse Event Reporting System (FAERS) list from April to June 2016, the agency said it was “evaluating the need for regulatory action” for acute pancreatitis for all drugs in the SGLT2 class.
One case study from 2015 by Dr. Mudit Chowdhary and colleagues was published in Therapeutics and Case Management. Dr. Chowdhary and his colleagues treated a patient who reported to the ER after experiencing vomiting, pain and nausea for two days. They concluded it was acute pancreatitis caused by Invokana.
In a second 2015 case study written by Dr. Narat Srivali and colleagues in the Journal of Basic Clinical Pharmacy, a patient developed diabetic ketoacidosis caused by acute pancreatitis after taking Invokana for four days. Doctors determined Invokana caused the problems.
Black Box Warning for Invokamet
Invokamet (canagliflozin and metformin) takes the active ingredient in Invokana and adds metformin. Because of this, the drug has a black box warning for lactic acidosis. Metformin is known to cause this condition. This happens when lactic acid builds up in the body faster than it can be removed. Symptoms include nausea, weakness, muscle pain and cramping. If the patient suspects this condition, they should go to the hospital immediately. Lactic acidosis can be fatal.
Invokana Dosages and Recommendations
The medication insert recommends a starting Invokana dose of 100 mg daily. Patients should take it before the first meal of the day. If patients do not respond to 100 mg, doctors may prescribe 300 mg a day. Patients with kidney problems should only take 100 mg a day. Invokana is not recommended in patients with serious kidney impairment.
Invokana Drug Interactions
According to the medication insert, Invokana may react with some medications. Patients should give their doctor a complete list of medications they are taking before starting treatment with Invokana.
UGT Enzyme Inducers
Taking Invokana with these drugs may decrease the effectiveness of Invokana.
Taking 300 mg Invokana with digoxin increased the digoxin concentration in the blood.
Taking Invokana with insulin may increase the risk of hypoglycemia.
SGLT2 inhibitors may work in each person differently, namely in pregnant women, nursing mothers, children and older people. These drugs are not FDA-approved for use in patients with Type 1 diabetes or people with diabetic ketoacidosis (DKA) or a history of DKA. Patients with kidney problems also should not use these drugs.
This drug has a pregnancy risk category of C. This means there are no tests or data from pregnant women and risk cannot be ruled out. But in rats, Invokana affected kidney development. These medications should only be used if the risk outweighs the benefit.
There are no tests to determine if these drugs are excreted in human breast milk, but levels of the drug were found in the milk of rats. There may be risk to the developing human kidney if babies ingest milk with traces of these drugs. Before breastfeeding, mothers should talk to their doctors.
Use in Children
The safety or effectiveness of these drugs has not been tested in children under 18.
Clinical studies show that patients 65 and older typically suffer more side effects from these medications. With Invokana, patients suffered from low blood pressure, dizziness and dehydration. The drugs were less effective in older people with poor kidney function. These drugs also caused more kidney failure in older patients. These side effects worsened for patients 75 or older.
One placebo-controlled clinical trial for Invokana involved 584 participants who had Type 2 diabetes that was not controlled with diet and exercise. The trial lasted 26 weeks. The average age was 55 years old. At the end of the trial people who took Invokana achieved a hemoglobin A1c (HbA1c) less than 7 percent.
In four studies for the safety of the drug, 1,667 patients took Invokana for about 24 weeks. Most people in the study had Type 2 diabetes for about 7 years. In the study, the most common side effects participants suffered were yeast infections and urinary tract infections. About 10 percent of women and 4 percent of men suffered from yeast infections because of the large amount of sugar in urine.
Alternatives to Invokana
People with Type 2 diabetes have numerous treatment options to discuss with their health care providers. If Invokana’s risks don’t outweigh its benefits, patients may ask their doctors if another medication will work better for them.
The most basic recommendation is eating a healthy diet that will help patients maintain healthy weight, blood pressure, cholesterol levels and blood glucose levels. Leading a lifestyle that includes exercise or regular physical activity is also highly recommended.
Some doctors may prescribe insulin shots, pumps or injectors. It’s important to take them as prescribed. All diabetes medications carry a risk of side effects, and the benefits of each medication should be greater than its risks.
In addition to SGLT2 inhibitors, types of diabetes medications include:
- DPP-4 inhibitors
- Alpha-glucosidase inhibitors
- Bile Acid Sequestrants