Actos & Bladder Cancer


Several studies have linked the diabetes drug Actos (pioglitazone) to bladder cancer. In June 2011, the FDA warned Actos users of an increased risk of bladder cancer.

Several recent studies have shown a much stronger link between Actos (pioglitazone) and bladder cancer than was indicated during clinical trials. In June 2011, the U.S. Food and Drug Administration (FDA) published a “Drug Safety Communication,” indicating that based on dose and duration of use, there exists a 40 percent increased risk of developing Actos bladder cancer.

Actos Side Effects Infographic

During clinical trials, there was an indication that it could cause bladder cancer. However, most patients and their doctors were not aware of the possible link between Actos and bladder cancer. Since that time, there have been a number of studies linking the drug to bladder cancer, including one that showed an 83 percent increased risk for bladder cancer among Actos users.

Studies Linking Actos and Bladder Cancer

Three primary studies are most cited regarding Actos bladder cancer. The foremost is a 10-year study conducted by Kaiser Permanente Northern California. Sponsored by Takeda, the manufacturer of Actos, and required by the FDA, it started in 2002 after preclinical trials indicated an increase in urinary bladder tumors in rats. A five-year interim analysis indicated a 40 percent increased risk of bladder cancer in patients who took Actos for more than 12 months. That analysis was the basis for the FDA’s 2011 label and insert requirements regarding Actos bladder cancer. In August 2014, Takeda released a statement based on the final results of the study, claiming there was no “statistically significant findings of increased risk of bladder cancer with long term use of pioglitazone.” However, the company did not release any further details. 

Unlike other warnings about severe side effects, the update was to the Warnings and Precautions section and not to the Contraindication section. There was not an update to the drug’s black-box label indicating the risk of Actos bladder cancer.

The most widely known international study researching Actos bladder cancer was a three-year study by the French Medicines Agency from 2006 to 2009 that examined 1.5 million patients. It found a statistically significant indication that patients taking pioglitazone, the active ingredient in Actos, are at a greater risk of developing bladder cancer. Researchers stated their findings were very similar to those of the KPNC study.Bladder Cancer

In June 2011, the French Medicines Agency announced that it had suspended the use of Actos. Germany quickly followed suit, except it limited suspension to all new cases. In August 2011, Takeda formally withdrew Actos from those markets. In April 2011, the American Diabetes Association published a report that reviewed adverse drug reports filed with the FDA. Researchers stated they “found a definite signal for bladder cancer associated with pioglitazone use.”

One of the most recent studies on Actos and bladder cancer was published in the May 2012 issue of the British Medical Journal. Researchers studied 115,727 patients and discovered that Actos use increased the risk of bladder cancer by 83 percent. They also revealed that the risk increases with long-term use of Actos.

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What is Bladder Cancer?

Bladder cancer is one of the most common types of cancer in the United States. According to the American Cancer Society’s latest statistics in 2015, an estimated 74,000 people received diagnoses and another 16,000 patients died from bladder cancer.  Medical professionals predict an increase in the number of bladder cancer cases in the coming years.

Cigarette smoking and chemical exposure are among the leading causes of bladder cancer, the second-most common urological cancer in adults. Bladder cancer is more common among men than women, and afflicts more Caucasians than African-Americans. It is also known for its high recurrence rate.

But for patients diagnosed with bladder cancer, the silver lining comes in the form of statistics and new medical procedures:

Bladder Cancer Statistics
About 80 percent of bladder cancer patients are diagnosed in the earliest stages.
The overall five-year survival rate is nearly 80 percent.
Innovative techniques allow an increasing number of patients to keep their bladder rather than having it removed.

Bladder Cancer Causes

Among the risk factors for bladder cancer are advanced age, chronic bladder infections and treatment with certain types of medications. Those medications include cyclophosphamide, a common chemotherapy drug, and pioglitazone, the active ingredient in the Type 2 diabetes drug Actos.

Researchers say that because the leading cause of bladder cancer is smoking, it is one of the most preventable types of cancer. Studies show that cigarette smoking raises the risk for bladder cancer fourfold.

The medical theory about bladder cancer is that it is caused by an increased concentration of toxic chemicals in urine, which exposes the bladder to those chemicals. And that, over time, this exposure causes cancer. Bladder cancer is described as a signature disease of Actos, pointing to the theory of toxic exposure being a primary cause of the disease.

Some occupations pose a stronger risk of daily exposure to workplace chemicals, which can lead to bladder cancer. Among them are:
Hairdressers Painters
Machinists Medical workers
Printers Truck drivers

There are also some lesser-known causes, including arsenic and chlorine compounds found in drinking water, and sexually transmitted diseases, such as gonorrhea and human papilloma virus (HPV).

Bladder Cancer Incidence Rates

As medical studies observed Actos users for periods of 12 months, 24 months and longer, the patients’ risk of bladder cancer increased from about 30 percent after one year to as much as 83 percent after two years.

Takeda initiated a 10-year U.S. study of the drug conducted by researchers at Kaiser Permanente. In 2014, the drug maker announced that the study “did not show any statistically significant findings of increased risk of bladder cancer with long term use of pioglitazone.” These results sharply contrast with earlier data from a 5-year interim mark of the study that showed a higher incidence of bladder cancer among patients who used the drug. The company did not release any other details of the study but promised it would make the information available at a later date. 

Among its findings:
Less than 12 months of Actos use – No significant increase
12 to 24 months – 30 percent increased risk
More than 24 months – 50 percent increased risk
More than 48 months – Greater than 50 percent increased risk

The studies consistently show the length of time patients take Actos has the strongest impact on increased risk of developing  bladder cancer. The true long-term effect of Actos will not be known until the 10-year U.S. study releases its final results.

Most At-Risk Actos Users

Lifestyle choices can put people at a greater risk for bladder cancer, even if they don’t take Actos. In the general population, the majority of bladder cancer cases develop because of cigarette use.

Actos users in the following groups are most at risk of getting bladder cancer:
Men: Incidences of bladder cancer occur more frequently in men than in women. In the Canadian study, one woman developed bladder cancer for every four men who got bladder cancer. In the general population, men are three times more likely to get bladder cancer than women.
Older than 65: The median age for Actos users who got bladder cancer was approximately 70 years old. This is similar to the general population, in which 72 percent of people who are diagnosed with bladder cancer are older than 65.
Smokers: 63 percent of Actos users who developed bladder cancer in the Canadian study were also smokers. For smokers, the increased risk of bladder cancer is already 50 percent. The carcinogens in cigarettes contribute heavily toward many types of cancer.
Obese: 59 percent of Actos users who developed bladder cancer were also obese. A person with a body mass index of more than 30 is considered obese. In the general population, obese people have a 40 percent increased risk of bladder cancer.
High glycated hemoglobin levels: The American Diabetes Association recommends people with diabetes reduce their long-term blood-sugar level to 7 percent. Of the Actos users who got bladder cancer, 52 percent of these people had a glycated hemoglobin percentage greater than 7.4 percent.
Alcohol drinkers: People who drink alcohol may be at greater risk of developing bladder cancer. Studies of the general population show a slight increase in bladder cancer associated with drinking. Six percent of Actos users who developed bladder cancer also used alcohol excessively.

Symptoms of Bladder Cancer

Symptoms of bladder cancer develop quietly in a majority of people with the disease. Hematuria, also known as bloody urine, is typically the first sign of the disease. But because this symptom is usually painless and fleeting, most patients are either unaware of it or ignore it. Although the blood could be visible, it is most often undetectable unless under a microscope.For this reason, many patients don’t learn of their diagnosis until after a urine analysis.

Other common symptoms of bladder cancer, include:

  • Frequent bladder infections
  • Frequent urination
  • Back pain
  • Painful urination

While these are less severe, they should not be ignored.

Diagnosing Bladder Cancer

Because of the stealthy nature of bladder cancer, most patients are taken by surprise by a bladder cancer diagnosis. It often comes after testing for recurrent urinary tract infections (UTIs) or during a routine medical visit.

Once tumor markers are found in the urine, doctors order a series of other tests. These include an intravenous pyelogram (IVP), the standard imaging test for bladder cancer. Through this test, physicians can view the bladder and surrounding organs for evidence of cancer. Doctors also use CT scans, MRI scans and bone scans, as well as ultrasounds, for a more complete look at the bladder.

For a closer look at the inside of the bladder, doctors may perform a bladder biopsy. This is done with a long, flexible device called a cystoscope that is inserted into the bladder through the urethra. Small tissue samples are removed for laboratory examination.

Once bladder cancer is diagnosed, oncologists will stage the cancer using the tumor, node and metastases (TNM) system. With this, medical professionals can determine the extent of the cancer and the best course of treatment.

Bladder Cancer Treatment

While surgery, either alone or in combination with other treatments, is the standard for managing bladder cancer, researchers also are finding innovative ways to treat it.

Treatment depends on the stage, or progress, of the disease.
Stage 0 through 1 treatments (non-muscle invasive):
Transurethral Resection (TUR or TURBT) – With the use of a cystoscope, surgeons are able to cauterize, or burn away, the destructive cancer cells.
Segmental cystectomy – In some early-stage patients, surgeons will remove a portion of the diseased bladder. The remaining bladder is sewn together.
Chemotherapy and immunotherapy – To ensure the cancer is killed, sometimes oncologists will order several rounds of chemotherapy or immunotherapy to impede the early-stage disease.
Stage II, III and IV treatments (muscle invasive)
Radical cystectomy – In this procedure, a surgeon removes the entire diseased bladder and replaces it with one of several urinary diversions. These include creating a new bladder from the intestines or creating a new urinary elimination system.
Chemotherapy and immunotherapy – Unless the patient is sickly or elderly, oncologists will prescribe either or both of these treatments to further destroy this spreading disease.
Clinical trials – Many oncologists will recommend that advanced-stage patients seek clinical trials for new and inventive ways to battle bladder cancer.

Despite the best efforts of medical professionals, bladder cancer is known to reoccur in most cases. For this reason, medical professionals recommend that patients have check-ups every three months for the first three years after diagnosis and then every year thereafter.

Actos Bladder Cancer Lawsuits

In June 2011 the FDA announced that it was requiring a bladder cancer warning be placed on the Actos label and insert and gave legitimacy to many former Actos users’ claims that the drug caused them to develop bladder cancer.

After the FDA announcement, the number of Actos lawsuits and inquiries about the possibility of filing a lawsuit increased. With several hundred federal cases pending, both Takeda and plaintiff attorneys filed to move all pending Actos lawsuits to one district court. On Dec. 30, 2011, the U.S. Judicial Panel on Multidistrict Litigation in Georgia consolidated all federal Actos bladder cancer lawsuits to the U.S. District Court for the Western District of Louisiana.

In April 2015, Takeda agreed to settle about 5,000 federal Actos bladder cancer lawsuits and thousands more state cases for $2.37 billion dollars.

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