Actos (pioglitazone) is a medication used to treat Type 2 diabetes. It is a thiazolidinedione (TZD) type medication that is similar to another antidiabetic drug, Avandia. Actos works by increasing the body’s sensitivity to insulin and by decreasing sugar stored in the liver. It can only be used by Type 2 diabetics who can still manufacture their own insulin.

Though it is effective at treating Type 2 diabetes, the FDA has warned that it may cause or increase the risk for severe or life-threatening side effects such as congestive heart failure, bladder cancer, bone fractures, ketoacidosis, and other serious complications. Thousands of lawsuits have been filed against manufacturers Takeda and Lilly due to injuries caused by Actos' use.

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What Is Actos?

Insulin is required for glucose to be used by the body’s cells as energy. Actos increases the body’s sensitivity to insulin and decreases the amount of sugar that is stored in the liver. Actos can only be used in patients who are able to make their own insulin.

What Does Actos Treat?

Actos is used to treat Type 2 diabetes. The drug cannot be used for Type 1 diabetics (insulin-dependent) whose pancreas cannot manufacture insulin. It should not be used in those with a history of ketoacidosis and is contraindicated in patients with congestive heart failure.

Who Manufactures Actos?

Actos is manufactured by Japanese pharma giant, Takeda Pharmaceutical and co-marketed with Eli Lilly, one of the largest drug companies in the U.S. It is taken once daily alone or with other antidiabetic medications such as Glucophage (metformin). At its peak, Actos was the best-selling diabetes medication in the U.S. with annual sales of over $3.85 billion.

What Is Diabetes?

Diabetes is a type of disease that impacts the body’s ability to use sugar. Because of this, typically those with a form of diabetes end up with excess glucose (sugar) in their bloodstreams. While the body does utilize glucose primarily to fuel the muscles, tissue, and the brain, too much of it, however, isn’t a good thing and can result in health problems.

There are two different types of diabetes: type 1 diabetes and type 2 diabetes.

What Is Type 1 Diabetes?

Type 1 diabetes is a type of diabetes in which the body doesn’t produce enough insulin. Insulin is what allows glucose to enter the cells, where it can be used as energy. Without enough insulin to allow the body to convert that sugar into energy for the cells, that glucose instead builds up in the bloodstream. Type 1 diabetes is also known as insulin-dependent diabetes or juvenile diabetes. This is because this type of diabetes often is first diagnosed when a patient is an adolescent. Additionally, patients with this type of diabetes are dependent on insulin medication to regulate their blood sugar levels.

What Are the Symptoms of Type 1 Diabetes?

The symptoms of type 1 diabetes can appear suddenly and may include the following:

  • Blurred vision
  • Increased hunger
  • Increased thirst
  • Bed-wetting
  • Frequently having to urinate
  • Fatigue
  • Weakness
  • Weight loss
  • Irritability
  • Mood changes

What Is Type 2 Diabetes?

Type 2 diabetes is a chronic disorder that impairs how the body processes sugar, resulting in too much sugar in the bloodstream. Type 2 diabetes used to be known as adult-onset diabetes because it typically only appeared in older adults, but with obesity now more common at younger ages, people in all age groups can develop type 2 diabetes.

What Are the Symptoms of Type 2 Diabetes?

The symptoms of type 2 diabetes include the following:

  • Increased hunger
  • Increased thirst
  • Weight loss
  • Blurred vision
  • Fatigue
  • Frequently having to urinate
  • Frequently occurring infections
  • Sores that are slow to heal
  • Numbness in the hands or feet
  • Tingling in the hands or feet
  • Darker spots on the skin, typically located in the:
    • Neck
    • Armpits

What Causes Type 2 Diabetes?

While the exact cause of type 2 diabetes isn’t known, being overweight and not being active have been linked to the disease. In type 2 diabetes, cells in the liver, muscles, and fat become insulin-resistant, meaning that they won’t take in as much insulin, which results in the cells not using as much of the sugar from the bloodstream. On top of that, the body doesn’t produce enough insulin. These two problems together prevent the body from naturally regulating glucose levels.

How Does Insulin Work?

The pancreas produces insulin whenever there’s sugar in the bloodstream. This insulin is then released into the bloodstream, where it enables the glucose in the blood to enter the cells. When the pancreas detects less sugar in the bloodstream, it releases less insulin to compensate. This is how the pancreas produces insulin in order to regulate the amount of sugar in the blood.

What Is the Difference Between Type 1 and Type 2 Diabetes?

In type 1 diabetes, the body mistakenly destroys the cells that produce insulin. This results in little to no insulin production. In type 2 diabetes, by contrast, first, the cells don’t take in as much sugar even though there is enough insulin in the bloodstream. Then, the pancreas produces even more insulin because it detects sugar in the blood. This results in insulin and sugar building up in the bloodstream. Eventually, this results in the insulin-producing cells becoming damaged and unable to produce enough insulin.

Where Does the Glucose Come From?

Glucose in the bloodstream comes from two main sources:

  • Food and drink
  • The liver

Eating and drinking too much food and drink that contains excess sugar may increase the risk of developing type 2 diabetes.

What Increases the Risk of Type 2 Diabetes?

The following factors may increase the risk of developing type 2 diabetes:

  • Being overweight
  • Being inactive
  • Fat is stored primarily around the abdomen
  • Race
  • Ethnicity
  • Family history
  • Age
  • Lipid levels in the blood
  • Pregnancy
  • PCOS
  • Prediabetes
  • Spots of darker skin (usually on the neck and armpits)

What Complications Can Occur From Diabetes?

Diabetes can cause other health complications because it can impact other organs in the body. The following are comorbidities that can occur along with type 2 diabetes:

  • Heart disease
  • Blood vessel disease
  • Nerve damage
  • Sleep apnea
  • Eye damage
  • Kidney disease
  • Hearing impairment
  • Skin diseases
  • Healing more slowly
  • Dementia

Can Type 2 Diabetes Be Prevented?

While it’s not guaranteed that you can prevent diabetes, leading a healthy lifestyle can help to reduce the risk, even for people who have a family history of type 2 diabetes. A healthy lifestyle includes:

  • Being active
  • Eating healthy food
  • Avoiding long periods of inactivity
  • Losing weight

How Is Type 2 Diabetes Treated?

Diet and exercise are important to treating type 2 diabetes and for some people can be enough to regulate blood sugar levels. For others, however, insulin and other antidiabetic medication may also be required. Insulin therapy can help to increase the supply of insulin in the body, while medication may help the cells to take in more glucose and insulin.

How Does Actos Treat Type 2 Diabetes?

Actos treats both of the problems that occur with type 2 diabetes. The medication works by decreasing the amount of sugar that is stored in the liver while simultaneously increasing the body’s sensitivity to insulin, which would enable the cells to consume more glucose from the blood.

What Are the Side Effects of Actos?

Like any other medication, Actos may have some mild side effects, including:

  • Sinusitis, headache, or symptoms of cold/flu
  • Dizziness
  • Weight gain
  • Muscle aches
  • Arm or leg pain
  • Mouth pain or tooth problems

However, Actos has also been linked to more severe, even life-threatening side effects, including:

  • Congestive heart failure
  • Heart attack
  • Bladder cancer
  • Macular edema
  • Lactic acidosis
  • Bone fracture
  • Liver disease
  • Kidney disease

What Are Actos’ Links to Congestive Heart Failure?

The antidiabetic drug, Actos (pioglitazone) has been shown to increase the risk of congestive heart failure. In 2007, the U.S. Food and Drug Administration (FDA) issued a black box warning regarding heart failure in patients who take Actos and similar medications used to treat diabetes. A black box or boxed statement warning is the most severe type of safety alert that can be issued by the FDA.

Actos’ 2007 black box warning was issued after a study published in British Medical Journal concluded that thiazolidine-type antidiabetics like Actos may nearly double the risk of congestive heart failure.  Based on this study and other information, the American Heart Association recommended that patients with a history of heart failure should not use Actos. The FDA subsequently issued a black-box warning about Actos and heart failure.

What Is Congestive Heart Failure?

Congestive heart failure occurs when the heart muscle has become weakened and is no longer able to pump blood efficiently to vital organs.  It is called “congestive” heart failure because of fluid buildup, known as pulmonary edema, which may “congest” the lungs. In addition, fluid buildup in the body may result in edema in the extremities or abdomen and may increase the chance of having a heart attack.

How Does Actos Increase the Risk of Congestive Heart Failure?

Use of Actos may cause fluid retention and increase the risk of developing congestive heart failure.  In addition, patients who already have a history of congestive heart failure may be at increased risk of worsening the condition.  In severe cases or over time, congestive heart failure may lead to myocardial infarction or heart attack.

What Are the Symptoms of Congestive Heart Failure?

The symptoms of congestive heart failure may include:

  • Shortness of breath (dyspnea)
  • Chronic coughing
  • Wheezing
  • Swelling in extremities (edema)
  • Swelling or fluid retention in the abdomen (ascites)
  • Fatigue
  • Rapid heartbeat
  • Irregular heartbeat
  • Mental confusion
  • Nausea
  • Lack of appetite

How Is Actos Linked to Heart Attack?

Certain medications, including Actos, may increase the chance of fluid retention and worsen the risk of developing heart failure.  Patients who already have a history of heart failure may be at greater risk when taking Actos. The American Heart Association has warned that Actos should not be taken by patients with certain cardiac conditions, including patients with heart failure.

What Are the Symptoms of a Heart Attack?

The symptoms of a heart attack include:

  • Pain in chest, arm, jaw, or shoulder
  • Pressure on chest
  • Sudden dizziness or fatigue
  • Cold, clammy skin or sweating
  • Anxiety or a feeling of doom
  • Palpitations or shortness of breath

How Is Actos Linked to Bladder Cancer?

Actos has been linked to an increased risk of bladder cancer. Animal studies conducted before the drug was approved for human use showed that male rats experienced a higher rate of bladder tumor formation after receiving Actos. This was confirmed in studies conducted by Takeda, manufacturer of Actos in which two studies conducted over a three-year period, showed a higher incidence of bladder cancer when compared to other drugs.

Once the results of these studies became available, the FDA required Takeda to undertake a 10-year safety study examining the increased risk of bladder cancer. The five-year interim results caused the FDA to require that Takeda add warnings regarding bladder cancer risk to Actos’ prescribing information.

The final results of the 10-year study confirmed a connection and showed bladder cancer risk may be triple when Actos is used for more than five years. Symptoms of bladder cancer may be similar to other bladder conditions but should not be ignored. Certain lifestyle choices, medical conditions, and family history may increase the chance of developing bladder cancer.

What Are the Symptoms of Bladder Cancer?

The symptoms of bladder cancer may include:

  • Painful urination
  • Increased urge to urinate
  • Blood in the urine
  • Sudden or unusual back pain

How Is Actos Linked to Macular Edema?

Actos use has been linked to an increased risk of macular edema which may contribute to blindness. Macular edema is a swelling or fluid gathering in the back of the eye or retina which may result in blurry vision. Over time, patients with macular edema may develop permanent changes in vision due to retinal damage.

Diabetics are at a higher risk of blindness than those without diabetes. Patients with diabetes should have regular eye exams to check for macular edema and retinal damage. Patients taking Actos should report the medication use to their ophthalmologist and see a physician immediately if sudden vision changes occur.

How Is Actos Linked to Lactic Acidosis?

Actos may increase the chance of developing lactic acidosis. Lactic acidosis is a medical condition in which the blood pH becomes dangerously low due to a buildup of lactic acid. Though it is rare, in certain patients it may be fatal. Diabetics are at higher than normal risk for developing lactic acidosis and Actos may increase that risk.

Elderly patients and those with hepatic or renal impairment may be at higher risk for lactic acidosis and should be closely monitored by a physician. Symptoms of lactic acidosis may vary and may worsen over time and should be reported to a healthcare provider immediately.

What Are the Symptoms of Lactic Acidosis?

The symptoms of lactic acidosis can include:

  • Nausea
  • Vomiting
  • Fatigue
  • Tiredness
  • Loss of consciousness
  • Abdominal pain
  • Muscle pain

How Is Actos Linked to Bone Fractures?

Actos may increase the risk of bone fracture, particularly in women, but also in some men. Long-term studies show that the risk may be up to three times higher than patients who did not take the medication. Actos-related bone fractures may occur due to bone loss caused by the activation of certain receptors resulting in slowed production of bone tissue. Most fractures occur after at least one year of Actos treatment and most commonly occur in the lower legs, arms, or hips

Patients who are taking the medication should have regular physical exams, including a check for bone density and other measures that show an increased risk for fractures.

How Is Actos Linked to Liver Disease?

Several cases of liver failure have been reported in patients receiving Actos. Reports include incidents of both non-fatal and fatal hepatic impairment in those using Actos. A direct cause has not been established but it is known that Actos can affect the liver’s metabolism of other medications which demonstrates a possible link.

Actos should only be used with caution in those who have an existing mild liver impairment and is not recommended in those with more advanced liver disease. Liver symptoms such as jaundice or yellowing of the skin and whites of the eyes, dark urine, light-colored feces, or unusual abdominal pain should be reported to a physician.

How Is Actos Linked to Kidney Disease?

Actos may also pose a particular risk to kidney health. A direct link between a worsened risk of kidney disease has not been fully established but a study, published in the medical journal PLoS One, showed that eight percent of study patients using Actos developed chronic kidney disease, even when the drug was given at low doses and used for less than one year. Other side effects of Actos including edema and heart failure can also put an additional burden on the kidney, contributing to kidney disease.

Patients with diabetes are at a higher than normal risk of kidney disease and should have their kidney function tested regularly. Patients taking Actos should report any symptoms of kidney or bladder problems such as inability to produce urine or unexpected swelling, to a physician right away.

Does Actos Have Negative Interactions with Other Medications?

Some people who take Actos may also have other health problems that they need medication to treat. Actos, like many other medications, can cause interactions with other drugs. These interactions can include medications that are taken over the counter. Drug interactions can sometimes be serious or even life-threatening.

Drugs that are known to interact with Actos include:

  • Warfarin/Coumadin (blood thinner) – may decrease the blood thinning effect
  • Digoxin/Lanoxin (treats congestive heart failure and arrhythmias) – may increase the toxicity of digoxin
  • Oral Contraceptives – may increase pregnancy risk
  • Fexofenadine/Allegra (antihistamine) – may increase side effects of fexofenadine and increase the risk of hypoglycemia
  • Midazolam/Versed (antianxiety) – may decrease anti-anxiety effects
  • Cimetidine/Tagamet (anti-ulcer) – may decrease the effectiveness of Actos
  • Calcium Channel Blockers (blood pressure and cardiac effects) – may increase the risk of hypertension and arrhythmia
  • Theophylline (asthma) – may increase the toxicity of theophylline, may decrease the effectiveness of Actos
  • Gemfibrozil/Lopid (cholesterol) – may increase the risk of hypoglycemia
  • Ketoconazole (anti-fungal) –may increase the risk of hypoglycemia
  • Rifampin (antiviral) – may decrease the effectiveness of Actos
  • Other anti-diabetic medications– changes in blood sugar should be closely monitored

Patients should discuss all of their medical conditions and medications that are taken with their doctor and pharmacist.

Has the FDA Warned Against Actos?

The FDA has issued warnings regarding Actos’ links to both congestive heart failure as well as bladder cancer. OIn addition, the FDA also ordered that Actos have a black box warning label, the strongest warning issued by the FDA, regarding the risks of congestive heart failure.

What Is a Black Box Warning?

A black box warning, or black label warning, is the most serious advisory that can be issued by the FDA for any medication. It is a warning to doctors and patients that the drug could have potentially fatal effects in high-risk patients.  A black box warning is printed at the top of prescribing information and is outlined in a thick, black border to be clearly seen by prescribers.

The Actos black box or boxed statement warns that Actos may increase the risk of developing congestive heart failure and states that patients who have heart failure may be at higher risk.  Patients with a history of heart problems, especially heart failure, are advised to avoid the use of Actos for treating their type 2 diabetes symptoms.

Has Actos Been Recalled?

Despite Actos’ links to life-threatening health conditions like congestive heart failure and bladder cancer, the medication is still on the market. The manufacturer has not issued a recall for the medication and while the FDA has issued warnings regarding an increased risk of conditions such as heart failure, the FDA has not ordered a recall of Actos.

Why Are People Suing Takeda?

Plaintiffs have filed lawsuits against Takeda because of injuries they sustained due to taking Actos, including congestive heart failure and bladder cancer, both of which the FDA has issued warnings about, as well as other negative health effects. In addition to injury claims by patients, in 2012, Takeda was accused of wrongdoing by one of its safety consultants. The pharmacovigilance employee claimed that the company knew about Actos’ link to several types of cancer but failed to act.

Court documents state that Takeda conducted a survey of doctors asking if a bladder cancer warning would affect their likelihood of prescribing a diabetes drug. The results suggested that Actos sales would plummet. It is speculated that Takeda knowingly postponed adequate warnings to continue making high profits.

In a 2014 trial, evidence arose that Takeda destroyed documents related to the case. Shortly before the trial began, a judge, believing the company acted in bad faith, ruled the jury must hear claims that files and documents were destroyed after employees were warned to save all pertinent information. The company admitted they were unable to find files compiled by 46 current and former employees involved with the development, marketing, and sale of the drug, including information from two of the company’s directors.

What Actos Lawsuit Settlements Have There Been?

In one of the first cases to go to court, the 2014 federal Actos lawsuit, filed in Louisiana, resulted in one of the biggest damages verdicts to date of $9 billion, when a Louisiana jury ruled Takeda Pharmaceuticals to pay a $6 billion in punitive damages and required Eli Lilly to pay $3 billion of the total damages. The damages were later reduced to a total of $38.5 million, still one of the largest settlements in drug liability to date.

Facing thousands of lawsuits in federal, state, and local courts, and having already paid millions of dollars to a handful of plaintiffs in trial cases, Takeda opted to settle nearly 9,000 cases for $2.4 billion. About 5,000 federal multi-district litigation (MDL) cases and an estimated 4,000 state and local Actos lawsuit cases were eligible for an Actos settlement.

Are There Any Actos Lawsuits?

As of 2022, all Actos lawsuits have either been dropped or settled and there is no ongoing Actos litigation.

Notwithstanding claims relating to this product, the drug/medical device remains approved by the U.S. FDA.