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Physicians prescribe the drug Actos to regulate blood sugar levels as a treatment for Type 2 diabetes. The drug made billions for its manufacturer, Takeda Pharmaceuticals, and was the company's blockbuster drug. Unfortunately, long-term use of Actos is linked to a number of serious health complications, including bladder cancer that led to lawsuits against Takeda.

What is Actos?

Actos is an oral Type 2 diabetes drug that comes in tablet form. It is not for use in treatment of Type 1 diabetes or diabetic ketoacidosis. Typically, the dose starts at 15 or 30 mg and is taken once a day.

Some people may require a stronger dose, and doctors can increase the strength of the medicine by 15 mg increments. The maximum recommended dose of the drug is 45 mg.

  • Decreases insulin resistance and decreases the glucose made in the liver.
  • Allows the body to better dispose of excess blood sugar.
  • Makes the body’s cells more sensitive to insulin.
  • Can be used alone or with other Type 2 diabetes medicines like metformin.

Uses and Concerns

Approved by the U.S. Food and Drug Administration (FDA) in 1999, the type 2 diabetes drug Actos (pioglitazone) was one of Takeda Pharmaceuticals’ best-selling drugs. With diet and exercise, it helps control blood sugar. But, it is also a controversial drug that is linked to a number of serious side effects, including congestive heart failure, kidney disease and bladder cancer.

Eli Lilly partnered with Takeda to market the drug, and it became one of the most successful diabetes medications of all time. Before the manufacturer lost the patent on Actos in 2011, its U.S. sales were $3.58 billion in 2010. The drug’s sales made up 27 percent of the manufacturer’s revenue.

But, it is a possible side effect unique to Actos that now raises concern: bladder cancer. In August 2011, the FDA required that Takeda update the drug’s Warnings and Precautions section of the label to include a warning that use of the drug for over a year may be associated with an increased risk of bladder cancer.

In 2012, The American College of Physicians (ACP) urged newly diagnosed type 2 diabetes patients to steer away from Actos and other heavily advertised, expensive diabetes drugs in favor of tried and true methods. The group, which represents primary-care doctors, said other drugs, including metformin, are more effective and cheaper than Actos (pioglitazone.) A month of metformin costs about $14 compared to about $200 for Actos. Other drugs also come with a better safety profile.

Bladder Cancer Risk

BMJ published the latest study on pioglitazone in May 2012. This study revealed that people who take Actos for an extended period have an 83 percent higher risk of developing bladder cancer.

Before 2012, a few studies – including Takeda’s own preclinical trials – already linked the drug to bladder problems. In animal studies, male rats suffered from bladder tumors after receiving the drug.

According to the FDA, in two additional three-year studies (a liver safety study and the PROactive study) researchers noted a higher incidence of bladder cancer in patients who took Actos versus those who took other drugs. As a result of these studies, the FDA required that Takeda undertake a 10-year study of the drug’s link to bladder cancer.

The FDA will review the data once it is available to further evaluate the drug’s safety.

Bladder Cancer Symptoms
Bloody Urine Increased urge to urinate
Pain when urinating Unusual back pain

Black-Box Warning for Congestive Heart Failure

Actos has a black-box warning for congestive heart failure. TZDs are known to cause or worsen this condition. Patients with a history of heart failure should be monitored when taking Actos. This medicine is also not recommended for patients with symptomatic heart failure or stage III or IV heart failure.

Symptoms of congestive heart failure include:

  • Excessive, rapid weight gain
  • Difficulty breathing (dyspnea)
  • Fluid retention and swelling (edema)

Other Side Effects

Actos can have other side effects for users beyond bladder cancer and congestive heart failure. Other potentially dangerous ones are chronic kidney disease, lactic acidosis and bone fractures.

Chronic Kidney Disease

Researchers from Taiwan’s Kaohsiung Medical University published a study in PLoS One that found the Type 2 diabetes drug increased the risk of chronic kidney disease. The study followed 35,000 people with diabetes from 2005 to 2009. People who took Actos were four times more likely to develop kidney disease than those who did not.

Lactic Acidosis and Bone Fractures

Women who take Actos are susceptible to developing bone fractures, especially in the hands, feet, ankles and lower legs. Actos also carries a warning for the risk of developing lactic acidosis.

Lactic acidosis is a potentially fatal condition with symptoms of:
Any diabetes issues (macular edema or diabetic ketoacidosis) Fever
Heart problems or severe heart failure Trauma
Edema Fragile bones
Type 1 diabetes Active bladder cancer or a history of bladder cancer
Liver disease Pregnancy or plans to become pregnant

Liver Failure

Among patients who took Actos, there were reports of some fatal and nonfatal cases of liver failure. According to the drug’s warnings and precautions insert, there is no way to definitively prove that it does not cause liver issues.

Still, doctors should test each patient’s liver prior to prescribing the drug and monitor each patient for signs of liver damage, including:

  • Fatigue
  • Anorexia
  • Upper abdominal discomfort
  • Dark urine
  • Yellowing of the skin or eyes (jaundice)

Actos Dosage and Contraindication Information

Contraindication in the Actos Prescribing Information says Actos should not be used by patients with Class III or IV heart failure.

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Actos is taken one time each day. Doctors can decide what time of day is best. It does not have to be taken with food. A missed dose should be taken as soon as the patient remembers, but two pills should not be taken in the same day.

The drug comes in 15 mg, 30mg and 45mg doses. It also comes in combination form, and each medication comes in different doses.

People with the following conditions should not use Actos:
Congestive heart failure Edema
Hepatic (liver) effects Fractures
Bladder cancer Hypoglycemia
Macular edema Macrovascular outcomes

Alternatives to Actos

Metformin and sulfonylureas such as Glimepiride (Amaryl), Glipizide (Glucotrol), and Glyburide (DiaBeta) can be substituted for Actos. They can either be used alone or with another medication.

Other drug classes that are taken orally and may be safer substitutes include:
Repaglinide (Prandin) Works by increasing the pancreas’s insulin production
Acarbose (Precose) Works by stopping the breakdown of carbohydrates in the digestive tract so they cannot be absorbed by cells
Saxagliptin (Onglyza) Works by breaking down incretin hormones, which increases the pancreas’s insulin production and decreases the liver’s sugar production
Additional substitutes taken by injection include:
Acarbose (Precose) These drugs affect the cells in the same way that insulin does by breaking down incretin hormones, which produces more insulin and lessens the liver’s production of sugar. Liraglutide (Victoza) is an example of an insulin mimetic.
Amylin Analogues This drug affects the cells like the hormone amylin does by increasing insulin production, slowing digestion so the cells cannot absorb carbohydrates, decreasing the amount of glucose produced by the liver, and reducing appetite. There is one FDA-approved amylin analogue, pramlintide (Symlin).

Lawsuits against Takeda

Thousands of people who took the drug filed lawsuits against Takeda Pharmaceuticals and Elli Lilly after doctors diagnosed them with bladder cancer.

In the first federal trial, a Louisiana jury awarded $9 billion in punitive damages and $1.5 million in compensatory damages to Terrence Allen, a former shopkeeper from New York who said Actos caused his bladder cancer. Allen’s lawyers argued that the company “was more concerned with making money” than watching out for patient safety.

Takeda in April 2015 agreed to settle thousands of Actos bladder cancer claims for at least $2.37 billion in one of the largest pharmaceutical settlements in U.S. mass torts history. The record Actos settlement covered about 9,000 cases, meaning about $275,000 for those who sign into the settlement, which outlines guidelines to qualify for compensation. The cost of the agreement rose to $2.4 billion when at least 97 percent of cases opted to settle in September 2015.