Thiazolidinediones

Thiazolidinediones

Also called: Glitazones

Summary

Thiazolidinediones (TZDs) are a group of antidiabetic agents that can be used along with exercise and diet to lower glucose (blood sugar) levels in patients with type 2 diabetes. These pills reduce resistance to insulin, a hormone that moves glucose from the bloodstream so the cells can use it for energy.

TZDs are taken once or twice a day. Because they do not affect the production of insulin, they are less likely to trigger episodes of low glucose (hypoglycemia), a side effect of some other antidiabetic agents. Side effects can include edema (swelling) and weight gain. Patients taking TZDs have periodic liver tests and should be monitored for possible heart problems.

The U.S. Food and Drug Administration (FDA) has approved two TZDs – pioglitazone (Actos) and rosiglitazone (Avandia) – and three combination drugs that contain a TZD. In 2007 the FDA strengthened warning labels for TZDs to add new information about risk of heart trouble.

About thiazolidinediones

Thiazolidinediones (TZDs) are a class of antidiabetic agents that can be prescribed for patients with type 2 diabetes, along with exercise and diet, to control glucose (blood sugar). These medications make cells more responsive to insulin. Insulin is a hormone produced in the pancreas that moves glucose from the bloodstream into the cells, where it is converted to energy to be used by the body. TZDs also reduce production of glucose in the liver.

Patients usually take TZDs once a day (sometimes twice). The pills do not need to be taken with a meal. It usually takes four to six weeks of TZD therapy before glucose levels are measurably affected.

TZDs are sometimes taken with other medications. Though this combination therapy can improve the effectiveness of treatment plans, it also carries the risk of increasing side effects. The major TZDs – pioglitazone (Actos) and rosiglitazone (Avandia) – may be combined with other diabetes drugs, including:

  • metformin, which is a biguanide
  • sulfonylureas
  • the newer antidiabetic agents known as DPP-4 inhibitors 
  • insulin (no longer recommended with rosiglitazone)

Some studies have shown that, in addition to lowering glucose levels, TZDs might provide other health benefits for people with type 2 diabetes. For example, some researchers have found that TZDs might help prevent Alzheimer’s disease, that they may improve cardiac blood flow, that pioglitazone might reduce the risk of a second heart attack or stroke, and that rosiglitazone might help keep arteries open in patients who have had artery-widening procedures such as balloon angioplasty. Recent research suggests that TZDs might reduce death rates in lung cancer patients who have type 2 diabetes. Scientists are studying use of TZDs in nondiabetics to treat a precancerous oral condition called leukoplakia, to possibly fight certain cancers and to possibly protect the brain during whole-brain radiation therapy.

However, there are concerns about cardiac risks of TZDs. The U.S. Food and Drug Administration (FDA) announced in August 2007 that the labeling of TZDs would be changed to add its strongest (“black box”) warning about the risk of heart failure, a condition in which the heart does not pump enough blood to meet the body’s needs. The FDA advised healthcare professionals to watch patients carefully for indicators of heart failure, including edema (swelling), shortness of breath and excessive, fast weight gain.

In November 2007 the FDA announced the boxed warning for rosiglitazone would be revised to add new information about a possible increased risk of heart attack. The agency said there was not enough evidence to show rosiglitazone was riskier than some other oral diabetes drugs. Additional research into the drug’s safety is scheduled. Earlier that year, an analysis of 42 studies indicated an increased risk of heart attack among patients taking rosiglitazone, but then another analysis found no significant increased risk of heart attack.

Like metformin, TZDs have demonstrated some effectiveness in controlling prediabetes and preventing type 2 diabetes. However, FDA has not approved them for this purpose. Some researchers have proposed using TZDs or biguanides to treat insulin resistance related to conditions such as fatty liver disease or polycystic ovarian syndrome.

In addition to edema, side effects of TZDs may include weight gain and anemia (reduced number of red blood cells). Some patients have developed macular edema, a swelling in the eye that can indicate an early stage of diabetic retinopathy. An increased incidence of bone fracture in women has been reported with TZDs. In addition, patients have periodic blood tests to monitor their liver function.

TZDs are also known as insulin sensitizers, glitazones and PPAR agonists. PPAR (peroxisome proliferator-activated receptor) agonists also include an experimental class of diabetes drugs known as glitazars.

Types and differences of thiazolidinediones

The first thiazolidinedione (TZD) approved in the United States was troglitazone (Rezulin) in 1996. However, this drug was removed from the market because it caused liver damage in some patients.

Two TZDs and several combination therapies are available in the United States:

Generic nameBrand name
pioglitazoneActos (15, 30 or 45 milligrams)
rosiglitazoneAvandia (2, 4 or 8 milligrams)
pioglitazone/glimepirideDuetact
pioglitazone/metforminACTOplus met (Competact in Europe)
rosiglitazone/glimepirideAvandaryl
rosiglitazone/metforminAvandamet

Each has advantages and disadvantages:

  • Rosiglitazone. Taken once or twice daily, with or without a meal, around the same time(s) each day, according to the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Rosiglitazone appears to increase levels of “bad” LDL cholesterol in the first months of therapy, but with continued therapy it also appears to increase “good” HDL cholesterol. Recent concerns include risk of heart failure and possibly heart attack. The maker of rosiglitazone and the U.S. Food and Drug Administration (FDA) warned in 2007 that the drug appeared to increase women’s (but not men’s) risk of bone fractures.

  • Pioglitazone. Taken once daily, with or without a meal, around the same time each day, according to the NIDDK. It raises HDL cholesterol levels, decreases triglycerides and generally has not been show to raise LDL cholesterol levels, although data from a long-term pioglitazone study did show a significant increase in LDL. It is known to interact with other medications and may, like rosiglitazone, increase risk of heart failure. The maker of pioglitazone and the FDA warned in 2007 that the drug appeared to increase risk of bone fractures in women but not men.

Avandamet combines the insulin-sensitizing effects of rosiglitazone with another antidiabetic agent, metformin, a biguanide that reduces the amount of glucose produced by the liver. Avandaryl combines rosiglitazone with glimepiride, a sulfonylurea that stimulates the pancreas to release more insulin. ACTOplus met combines pioglitazone and metformin. In 2006 the FDA approved Duetact, which combines pioglitazone and glimepiride.

TZDs under development include a compound known as MCC-555, which has had some positive results in studies on animals.

Conditions of concern with thiazolidinediones

Patients are not generally prescribed thiazolidinediones (TZDs) if they have a history of heart failure, a situation where the heart is unable to keep blood circulating properly. The most severe manifestation of this disorder is pulmonary edema (fluid in the lungs). Fluid retention – a side effect of TZDs – can make these conditions worse. The U.S. Food and Drug Administration cautions that TZDs “should not be used by people with serious or severe heart failure who have marked limits on their activity, are comfortable only at rest, or are confined to bed or a chair.”.

TZDs are not generally prescribed for patients with left ventricular dysfunction (an impaired pumping ability of the heart) or chronic renal insufficiency, a condition in which the kidneys gradually lose their ability to perform their normal functions. Liver disease may also rule out use of TZDs.

Patients who take rosiglitazone and have heart disease or are at high risk of heart attack should talk to their physician about the FDA’s revised warning about a potential increased risk for heart attack, according to the agency.

Physicians should consider the risk of fracture when prescribing TZDs to women, according to the FDA. This might be a particular concern for women who have or are at risk for osteoporosis, a common condition involving decreased bone density.

Diabetic retinopathy may be another condition of concern because some patients taking TZDs have developed macular edema.

Like other diabetes pills, TZDs are not used to treat diabetic ketoacidosis or type 1 diabetes.

Potential side effects of thiazolidinediones

Thiazolidinedione (TZDs) are not recommended for patients with heart failure or active liver disease and might be ruled out for patients with certain other heart conditions or certain kidney disorders. Because of the rare liver problems experienced by troglitazone, an earlier TZD, the U.S. Food and Drug Administration (FDA) requires that patients on TZDs have periodic enzyme testing to make sure their liver is functioning properly.

Patients should call their physician if they display any symptoms of liver disease. These include:

  • Nausea
  • Vomiting
  • Stomach pain
  • Lack of appetite
  • Fatigue
  • Yellowing of the skin or whites of the eyes (jaundice)
  • Dark-colored urine

More common side effects of using TZDs include:

  • Fluid retention and swelling (edema) in the ankles
  • Weight gain, which is largely due to fluid retention
  • Upper respiratory tract infection
  • Headache
  • Muscle aches
  • Diarrhea

Some of these side effects can be increased when TZDs are used in combination with insulin.

Patients are advised to call their physician if they develop symptoms that can indicate heart failure, including edema, shortness of breath and excessive, fast weight gain. They are advised to seek immediate medical help if they experience angina (cardiac chest pain).

Some people taking TZDs have developed macular edema. This swelling in the back of the eye can indicate an early stage of diabetic retinopathy. The FDA recommends that patients experiencing symptoms such as blurry or reduced vision contact their physician. It is important for all diabetic patients to have regular dilated pupil examinations.

Other issues to consider before taking TZDs include:

  • They can make birth control pills less effective in preventing pregnancy. Women may want to discuss other birth control options with a physician.

  • They may increase the risk of anemia, in which the blood carries less oxygen than normal. Patients with this condition may feel tired.

Drug or other interactions

Few studies have been performed to evaluate interactions of thiazolidinediones (TZDs) with other drugs. Patients should consult their physicians before taking any additional prescriptions, over-the-counter medications, nutritional supplements or herbal medications.

The maker of rosiglitazone does not recommend taking it with insulin or nitrates (a group of heart drugs) because this may increase the risk of heart problems such as angina or heart attack.

Because TZDs interact with the liver enzymes that eliminate some other drugs, it is possible for TZDs to increase the elimination of several drugs, reducing their effectiveness. These include:

  • Erythromycin (an antibiotic)
  • Calcium channel blockers
  • Cisapride (heartburn treatment)
  • Corticosteroids (a class of anti-inflammatories and immunosuppressives)
  • Cyclosporine (reduces body’s natural immunity in transplant patients)
  • Tacrolimus (anti-rejection medication used in transplant patients; topical form used for eczema)
  • Triazolam (sleep aid)
  • Trimetrexate (pneumonia drug)
  • HMG-CoA reductase inhibitors (cholesterol drugs)

The anti-fungal drug ketoconazole, used to treat conditions including yeast infections and thrush, prevents the elimination of TZDs and could lead to low glucose (blood sugar) levels, a condition known as hypoglycemia. For this reason, patients using these TZDs are especially advised to perform regular glucose monitoring.

Pregnancy use issues with thiazolidinediones

Women who use birth control pills should be aware that thiazolidinediones (TZDs) can make these oral contraceptives less effective in preventing pregnancy. In addition, premenopausal women who stopped ovulating may begin ovulating again, enabling them to conceive.

Antidiabetic agents such as TZDs generally are not used by pregnant women. During and after pregnancy, a woman’s need for insulin fluctuates. Injections of insulin are typically recommended to address these fluctuating needs and control glucose (blood sugar).

Pregnant women must maintain their proper glucose levels, as high glucose (hyperglycemia) can cause birth defects or excessive weight gain in babies. Women who are pregnant or thinking of becoming pregnant should inform their physician.

Some antidiabetic agents have been shown to pass into human breast milk. TZDs are not recommended for women who are nursing.

Child use issues with thiazolidinediones

Type 2 diabetes is becoming more common in children, but so far metformin (a biguanide) and a sulfonylurea are the only antidiabetic agents approved by the U.S. Food and Drug Administration to treat this age group. Researchers are conducting clinical studies on the pediatric use of thiazolidinediones.

Elderly use issues with thiazolidinediones

Side effects associated with antidiabetic agents such as thiazolidinediones may be more pronounced in elderly patients. This is especially true if more than one antidiabetic agent is being taken, or if the patient uses other medicines that affect glucose (blood sugar).

Questions for your doctor on TZDs

Preparing questions in advance can help patients have more meaningful discussions with their physicians regarding their conditions and treatments. Patients may wish to ask their doctor the following questions about thiazolidinediones (TZDs):

  1. Do you recommend thiazolidinediones to treat my type 2 diabetes?

  2. Which TZD or combination drug will I be prescribed?

  3. What is my dosage and frequency? How and when should I take the drug?

  4. What should I do if I forget a dose or take an extra dose?

  5. Am I likely to gain weight and have fluid retention and swelling? What other side effects might I experience from TZDs?

  6. At what point should I inform you of side effects?

  7. I’ve heard in the news about possible heart problems with TZDs – is this a serious concern for me?

  8. Should I have regular liver tests and eye exams? Will I need periodic tests of my heart?

  9. Do I have a condition, such as liver, heart, kidney or eye disease, that may rule out use of TZDs?

  10. What other treatments might be used if I have issues with TZDs?

  11. Can additional exercise and dieting reduce my need for TZDs? If so, how will this be monitored and adjusted?

  12. Can TZDs be safely used by pregnant women, nursing women, children or elders?

  13. Can TZDs help treat insulin resistance, prediabetes, cancer, Alzheimer’s disease or other conditions?
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