Thiazolidinediones, often referred to as TZDs or “glitazones,” represent a class of oral medications specifically designed to manage type 2 diabetes. These drugs work to help individuals control their blood sugar levels. They are distinct from other diabetes medications because they do not directly stimulate insulin production. Instead, their approach involves improving the body’s response to the insulin it already produces, addressing a common underlying issue in type 2 diabetes.
Mechanism of Action in the Body
Individuals with type 2 diabetes often experience insulin resistance, a condition where the body’s cells do not respond effectively to insulin. Insulin acts like a “key” that unlocks cells to allow glucose to enter and be used for energy. When cells become resistant, this “key” doesn’t work as well, leading to higher levels of glucose remaining in the bloodstream.
Thiazolidinediones address this by targeting and activating a specific protein receptor inside cells called peroxisome proliferator-activated receptor-gamma (PPAR-gamma). This receptor is found in various tissues, with a high concentration in fat cells, but it is also present in muscle and liver cells. When TZDs bind to and activate PPAR-gamma, they change the expression of certain genes involved in glucose and lipid metabolism.
Activation of PPAR-gamma makes fat, muscle, and liver cells more sensitive to insulin. This allows these cells to take up glucose from the blood more efficiently, lowering overall blood sugar levels. The drugs promote the storage of fatty acids in fat cells, which reduces the amount of free fatty acids circulating in the bloodstream. This “fatty acid steal” helps spare other insulin-sensitive tissues from the harmful metabolic effects of high free fatty acid concentrations, further improving glucose metabolism.
Available TZD Medications
Two primary thiazolidinedione medications are approved for use in managing type 2 diabetes: pioglitazone (Actos) and rosiglitazone (Avandia). These medications were introduced in the late 1990s. Pioglitazone is available in doses such as 15 mg, 30 mg, and 45 mg, while rosiglitazone is available in 2 mg, 4 mg, and 8 mg strengths.
An earlier TZD, troglitazone (Rezulin), was removed from the market due to liver toxicity concerns, which provided important context for safety monitoring. Pioglitazone and rosiglitazone are often used as part of a broader treatment plan for type 2 diabetes, sometimes as a second or third-line option. They can be prescribed alone or in combination with other diabetes medications, such as metformin or sulfonylureas, to achieve better blood sugar control.
Health Considerations and Side Effects
Thiazolidinediones are associated with several health considerations and side effects. One significant concern is fluid retention (edema), which can lead to swelling, particularly in the ankles and feet. This fluid retention can also cause or worsen congestive heart failure, a condition where the heart struggles to pump blood effectively. Due to this risk, the U.S. Food and Drug Administration (FDA) includes a black box warning regarding TZDs and heart failure.
Patients taking these medications may also experience weight gain, typically 2 to 8 pounds. This increase in weight is attributed to both fluid retention and increased fat storage. There is also an increased risk of bone fractures, particularly in women, especially postmenopausal women, due to a decrease in bone density with long-term use.
Pioglitazone has also been associated with an increased risk of bladder cancer. This risk is considered during treatment decisions. Regular monitoring for side effects is part of the treatment process.
Patient Candidacy and Medical Supervision
Determining who is a suitable candidate for TZD therapy involves a careful assessment of individual health conditions and risks. Individuals with symptomatic heart failure or a history of heart failure, particularly those with New York Heart Association (NYHA) class III or IV heart failure, generally should not take TZDs. The fluid retention associated with these medications can significantly worsen their cardiac condition.
Other conditions that may preclude TZD use include active liver disease, as a history of liver toxicity with a previous TZD (troglitazone) necessitates caution. For pioglitazone, individuals with active bladder cancer or a history of bladder cancer are advised against its use due to the increased risk. Patients at a high risk of fractures, such as those with osteoporosis or postmenopausal women, should also be carefully evaluated before starting TZD therapy.
For patients prescribed TZDs, ongoing medical supervision is important. This includes regular monitoring for signs of fluid retention, such as swelling in the ankles or sudden, unexplained weight gain. Periodic liver function tests are also performed to check for any signs of liver problems. Healthcare providers discuss the medication’s benefits and potential risks with patients, tailoring the treatment plan to their specific health needs.