What are thiazolidinediones, such as pioglitazone (Actos) and rosiglitazone (Avandia), used for in diabetes treatment?

Thiazolidinediones: Insulin Sensitizers for Type 2 Diabetes Management

Thiazolidinediones (TZDs) are oral antidiabetic medications that act primarily by decreasing insulin resistance in peripheral tissues and the liver, improving glycemic control in type 2 diabetes mellitus patients. 1

Mechanism of Action

• TZDs are potent agonists of peroxisome proliferator-activated receptor-gamma (PPARγ) nuclear receptors found in insulin-responsive tissues like adipose tissue, skeletal muscle, and liver 1
• Unlike sulfonylureas, TZDs are not insulin secretagogues - they require the presence of insulin to work 1
• They enhance insulin sensitivity by:
  • Decreasing insulin resistance in peripheral tissues
  • Reducing hepatic glucose output
  • Modulating transcription of insulin-responsive genes involved in glucose and lipid metabolism 1, 2

Available Medications

• Currently available TZDs in the US:
  • Pioglitazone (Actos)
  • Rosiglitazone (Avandia)
• Troglitazone, the first TZD, was withdrawn from the market due to serious liver toxicity 2

Clinical Benefits

• Effective glucose-lowering efficacy (0.5-1.4 percentage point decrease in HbA1c) 2
• More durable glycemic control compared to sulfonylureas 2
• Minimal risk of hypoglycemia when used as monotherapy 2
• Potential cardiovascular benefits with pioglitazone:
  • The PROactive trial suggested cardiovascular benefit with pioglitazone in patients with preexisting macrovascular disease 2
  • The IRIS trial showed pioglitazone reduced stroke and myocardial infarction in patients with insulin resistance 2
• Favorable effects on lipid profiles (particularly pioglitazone) 3

Important Side Effects and Risks

• Weight gain (similar to sulfonylureas) 2
• Fluid retention leading to edema 2
• Increased risk of heart failure, especially when used at higher doses or in combination with insulin 2
• Increased risk of bone fractures, particularly in women 2
• Potential bladder cancer risk with pioglitazone 2
• Rosiglitazone has been associated with increased myocardial ischemic events in some studies 2

Contraindications

TZDs are contraindicated in:

• Patients with NYHA Class III or IV heart failure 2, 4
• Patients with active liver disease or elevated liver enzymes 4
• Patients with pre-existing heart failure 4
• Patients with active bladder cancer 4

Clinical Applications

• TZDs can be used as monotherapy or in combination with:
  • Sulfonylureas
  • Metformin
  • Insulin (pioglitazone only) 1, 2
• Lower-dose therapy (e.g., pioglitazone 15-30 mg) may mitigate weight gain and edema 2
• TZDs can be used in patients with CAD but without known heart failure, with vigilant monitoring for fluid overload 2

Monitoring Recommendations

• Liver function tests at baseline, every two months for the first year, and periodically thereafter 5
• Monitor for signs of fluid retention and heart failure (rapid weight gain, edema, shortness of breath) 2, 4
• Regular assessment of cardiovascular status, especially in patients with risk factors for heart failure 4

Current Usage Patterns

Despite safety concerns that emerged in 2007, TZDs are still commonly prescribed, with approximately 8.3% of diabetes patients on a TZD according to the Diabetes Collaborative Registry 6. However, up to 40% of patients currently treated with TZDs have some evidence of heart failure and should not be candidates for this therapy 6.

TZDs represent an important class of diabetes medications that effectively improve insulin sensitivity and provide durable glycemic control, but their use requires careful patient selection and monitoring due to their potential cardiovascular risks.