Thiazolidinediones (TZDs), also known as “glitazones,” are a class of oral medications used to manage Type 2 Diabetes. These drugs function by addressing insulin resistance, a fundamental problem where the body’s cells do not respond effectively to the insulin produced by the pancreas. TZDs are prescribed to improve blood sugar control in patients whose glucose levels remain too high despite treatment with initial therapies, such as metformin, or when those first-line drugs are not tolerated.
Enhancing Insulin Sensitivity
The primary therapeutic action of TZDs is to function as insulin sensitizers by targeting a specific nuclear receptor within the body’s cells. The drugs work by activating the Peroxisome Proliferator-Activated Receptor Gamma (PPAR-gamma), which is predominantly found in adipose (fat) tissue. As a nuclear receptor, PPAR-gamma acts as a transcription factor, regulating the expression of genes involved in glucose and lipid metabolism once activated by the TZD.
This activation promotes the differentiation of new, smaller, and more insulin-sensitive fat cells, a process called adipogenesis. This encourages the uptake and storage of circulating fatty acids. By redirecting free fatty acids (FFAs) away from the bloodstream and into adipose tissue, TZDs effectively reduce the amount of fat that infiltrates muscle and liver cells. High levels of FFAs interfere with insulin signaling, so their reduction helps reverse insulin resistance in these tissues.
The net effect of this gene regulation is a substantial increase in the uptake of glucose by peripheral tissues, particularly muscle and fat, which lowers blood sugar levels. Furthermore, the activation of PPAR-gamma helps suppress the excessive glucose production that often occurs in the liver of patients with Type 2 Diabetes. This mechanism also increases the production of adiponectin, a hormone released by fat cells that further enhances the body’s sensitivity to insulin.
Current TZD Medications and Indications
The TZD class includes two main medications: pioglitazone (Actos) and rosiglitazone (Avandia). Both are approved for use alone or in combination with other common diabetes treatments, such as metformin or sulfonylureas, to achieve better glycemic control. A physician may select a TZD for a patient who has a significant degree of insulin resistance or for whom other standard combination therapies have been ineffective.
Pioglitazone is more widely used, often as a second- or third-line agent when initial glucose-lowering drugs fail to meet treatment goals. Rosiglitazone’s use is significantly more restricted due to historical safety concerns that led to regulatory scrutiny. While restrictions have been eased in some regions, it remains less commonly prescribed.
Critical Safety Considerations
A common class effect of TZDs is fluid retention, which can manifest as peripheral edema or swelling in the extremities. This retention can sometimes be severe enough to cause or worsen congestive heart failure (CHF). For this reason, TZDs are not recommended for individuals with established heart failure, particularly those classified as NYHA Class III or IV.
Another major concern is an increased risk of bone fractures, particularly observed in postmenopausal women. This risk is linked to the drug’s effect on bone metabolism, where PPAR-gamma activation may suppress the activity of osteoblasts, the cells responsible for building new bone tissue. The fractures typically occur in the arms, hands, and feet, often without major trauma.
Weight gain is also a frequent side effect, resulting from both the fluid retention and the drug’s mechanism of action, which promotes the creation of new fat cells. While the increase in fat mass is primarily concentrated in the subcutaneous fat layer, the weight increase still represents a clinical challenge for many patients.
In terms of specific drug warnings, pioglitazone carries a caution regarding a potential, though small, increased risk of bladder cancer, especially with use for longer than two years. Rosiglitazone was historically restricted due to concerns over a possible increase in the risk of myocardial infarction and other major adverse cardiovascular events.