Thiazolidinediones: Uses, common brands, and safety info

Type 2 diabetes mellitus is a very common condition, and one that is rapidly increasing in numbers. Every 17 seconds, someone in the U.S. is diagnosed with diabetes. In the U.S., almost 11% (34 million people) of the population has diabetes. Type 2 diabetes is treated with a combination of diet, exercise, and antidiabetic drugs (oral and/or injectable). One common medication used to improve blood sugar control in patients with Type 2 diabetes is called Actos (pioglitazone). 

Actos is categorized as a thiazolidinedione (TZD) medication. Actos is the only TZD medication currently available in the U.S. It is approved by the U.S. Food and Drug Administration (FDA) and is available in both brand and generic form. Actos is sometimes prescribed alone (monotherapy) but is usually prescribed in combination with other antidiabetic agent(s), such as metformin or a sulfonylurea (such as glimepiride). In this article, we will discuss uses, side effects, warnings, and other important information about TZDs. Because there is only one TZD drug currently available, we will use the term TZD interchangeably with Actos. 

In addition to the single-ingredient product, the ingredient in Actos, pioglitazone, is available as a combination drug (in combination with another diabetes medication). For the purpose of this article, we will focus on the single-ingredient products.

Also, important to note is that two TZD drugs were taken off the market. The following TZD drugs are no longer available:

• Avandia (rosiglitazone)—and combination products Avandamet (rosiglitazone/metformin) and Avandaryl (rosiglitazone/glimepiride). Avandia was taken off the market in April 2021 by its manufacturer at the time, GlaxoSmithKline. In July 2021, Avandia was sold to Woodward Pharma.

• Rezulin (troglitazone) 

What are thiazolidinediones?

TZDs, also known as “glitazones,” are used in the treatment of Type 2 diabetes. TZDs help with blood sugar control and insulin resistance. 

Actos is the only TZD that is currently available in the U.S. It is sometimes prescribed alone, but more commonly is prescribed in addition to another diabetes medication, such as metformin. Actos is used in combination with diet and exercise. 

How do thiazolidinediones work?

Thiazolidinediones, or TZDs, help decrease blood glucose (sugar) levels by reducing insulin resistance and making the body respond to insulin. TZDs also reduce the amount of glucose produced by the liver. TZDs decrease insulin resistance by activation of receptors called peroxisome proliferator-activated receptor-gamma (PPAR-gamma) receptors, which are found in fat tissue, skeletal muscle, and the liver (hepatic tissue). 

What is insulin resistance?

According to the American Diabetes Association, people with insulin resistance need more insulin to process glucose (sugar) in the body. Over time, the pancreas cannot keep up with insulin production, and blood sugar levels increase. This can lead to prediabetes or Type 2 diabetes.

You may have heard of the term metabolic syndrome. Most people with metabolic syndrome have insulin resistance. Metabolic syndrome is a group of risk factors for heart disease. Metabolic syndrome increases the risk of developing diabetes, heart disease, and/or stroke. The risk factors of metabolic syndrome include:

• Abdominal obesity: increased waist circumference (>35 inches for women and >40 inches for men)

• High blood pressure (hypertension) of ≥130/80 mmHg

• Fasting blood glucose of ≥100 mg/dL

• High triglycerides of >150 mg/dL

• Low HDL cholesterol—the good kind of cholesterol—(<50 mg/dL for women and <40 mg/dL for men)

If a person has 3 or more of the risk factors, metabolic syndrome is diagnosed.

What are thiazolidinediones used for?

Thiazolidinedione therapy is used—along with diet and exercise—to improve glycemic control in adults with Type 2 diabetes. 

Thiazolidinediones should NOT be used in children under age 18 years, for Type 1 diabetes, or for diabetic ketoacidosis. 

Who can take thiazolidinediones?

Before taking Actos, talk to your doctor about all of the medical conditions you have and any medications you take, including prescription drugs, over-the-counter medicines, and vitamins or supplements. Only your doctor can determine if Actos is an appropriate treatment for you.

Men

Men with Type 2 diabetes, who need help with blood sugar control, may take Actos as long as they do not fall into any of the restricted categories or warnings outlined below. 

Women

Women with Type 2 diabetes, who are not pregnant or breastfeeding, and who need help with blood sugar control may take Actos as long as they do not fall into any of the restricted categories or warnings listed below. If you are pregnant, planning to become pregnant, or breastfeeding, consult your healthcare provider for medical advice. There is not enough data on Actos in pregnant women to determine the risk of fetal harm or miscarriage. Poorly controlled diabetes during pregnancy can pose an increased risk to both the mother and the unborn baby. 

It is also worth noting that Actos can induce ovulation, so there is a potential for unplanned pregnancy. Consult your healthcare provider about the need for effective birth control. 

There is no information on Actos and breastfeeding. Therefore, the prescribing information recommends that the healthcare provider consider all factors (benefits of breastfeeding, mother’s need for Actos, and potential adverse effects on the baby).  

Children 

Children should not take a TZD. The safety and efficacy of Actos in children have not been established. Also, Actos is not recommended in children due to the side effects seen in adults, such as fluid retention, heart failure, fractures, and bladder tumors. 

Seniors

In clinical studies, older adults and younger patients had similar experiences with thiazolidinedione treatment in terms of safety and efficacy. However, sample sizes were small. Consult your healthcare provider for medical advice regarding the use of Actos in older adults. 

Are thiazolidinediones safe?

Recalls/FDA safety information

• FDA Drug Safety Communication on Actos (pioglitazone), September 2016

• FDA Drug Safety Communication on Avandia (rosiglitazone), February 2011

• Rezulin recalled by FDA, March 2000

Restrictions and warnings

Actos is contraindicated (should not be used) in people with/who are:

• Allergic to pioglitazone or any ingredient in the drug

• Have established New York Heart Association (NYHA) Class III or IV heart failure

• Have symptomatic congestive heart failure

• Children 

• Type 1 diabetes

• Diabetic ketoacidosis

• Active bladder cancer

Actos has a boxed (black box) warning, which is the strongest warning required by the FDA. The warning states: 

• Thiazolidinedione therapy can cause or worsen congestive heart failure (CHF) in some patients.

• After starting Actos, and with any increase in dose, diabetic patients should be monitored closely for signs and symptoms of heart failure. These include rapid weight gain, shortness of breath, and/or swelling (edema). If heart failure develops, it should be treated and the healthcare provider should consider discontinuing Actos in the patient. 

• Actos should not be used in patients with symptomatic heart failure.

• Actos is contraindicated in patients with established New York Heart Association (NYHA) Class III or IV heart failure.

Actos should be used with caution in people with/who are:

• NYHA Class I or II heart failure

• Risk of heart failure

• Edema 

• Hepatic impairment (liver impairment)

• History of bladder cancer

• Premenopausal women who do not ovulate

Other patient information: 

• When you fill and refill your Actos prescription, you will receive a medication guide with important information about the drug. Read the guide each time you fill your prescription and ask your healthcare provider if you have any questions or concerns about your treatment with Actos. 

• Follow your doctor’s recommendations for a diabetes care plan that includes diet, exercise, and blood sugar monitoring (blood glucose and hemoglobin A1C), as well as eye care. Consult your doctor if you are sick or are having surgery, as medication requirements may change.

• Actos can cause new or worsening heart failure. If you gain weight quickly, or have swelling (especially in the lower legs), shortness of breath, or other symptoms of heart failure, contact your doctor right away or get emergency medical help if needed. People with severe heart failure or symptomatic heart failure should not take Actos.

• Actos may cause liver problems. If you have signs of liver problems such as nausea, vomiting, abdominal pain, tiredness, appetite loss, yellowing of the skin or whites of the eyes, or dark urine, stop taking Actos and get immediate medical attention.

• Actos may cause an increased risk of bladder cancer. If you have blood in the urine, pain while urinating, or new or worsening urinary urgency, contact your doctor right away. 

• When taking Actos with insulin or other medications, your risk of hypoglycemic (low blood sugar) events increases. Your healthcare provider can guide you and your family members about symptoms of hypoglycemia (such as lightheadedness, dizziness, shakiness, and hunger) and how to address them.

• Actos may result in unintended pregnancy because it can induce ovulation. Talk to your doctor about using contraception while taking Actos. 

Are thiazolidinediones controlled substances?

No, Actos is not a controlled substance.

Common thiazolidinediones side effects

The most common side effects of Actos are:

• Upper respiratory infection

• Headache 

• Muscle pain 

• Weight gain 

• Swelling 

• Fluid retention

• Flatulence

• Anemia

• Ovulation induction

Serious reactions may include:

• New or worsening congestive heart failure

• Liver toxicity

• Diabetic macular edema

• Increased risk of bladder cancer

• Fractures (in female patients)

This is not a full list of side effects. Other side effects may occur. Consult your healthcare provider for a full list of side effects. Before using Actos, talk to your doctor about what side effects to expect and how to address them. While taking Actos, report side effects to your doctor. If rare but serious side effects occur, seek medical help or emergency care if necessary.

How much do thiazolidinediones cost?

Actos is available in generic form, and most insurance companies and Medicare prescription plans cover this medication. Contact your insurance provider for up-to-date coverage information on Actos. You can always save money on your Actos prescription and refills using free SingleCare cards and coupons. For example, a standard drug of 30, 30 mg generic Actos tablets is very affordable with a SingleCare card, bringing the price down to approximately $15. Ask your pharmacist to compare prices so you can start saving today.