Glitazones / Thiazolidinediones

Summary

Glitazones, also known as thiazolidinediones (TZDs), are a class of drugs used for the management of Type 2 diabetes. They work by activating PPAR-gamma, a nuclear receptor, to increase insulin sensitivity and peripheral glucose uptake in the body. Important side effects to know include heart failure with fluid retention, an increased risk for fractures, and weight gain.

Key Points

• Glitazones / thiazolidinediones (TZDs)
  • Drugs
    • Pioglitazone
    • Rosiglitazone
  • Mechanism
    • Activate PPAR-gamma
      • Stands for peroxisome proliferator-activated receptor gamma
        • Fibrates hit PPAR-alpha
      • It’s a nuclear receptor involved in transcription of genes
        • Delayed onset of action (several weeks)
          • This is a general principle. Drugs that work via transcriptional regulation take a while to work.
        • Increases insulin sensitivity / peripheral glucose uptake
          • Another way to think about this is decreasing insulin resistance
          • Upregulates GLUT-4
          • Since glitazones work via a transcriptional mechanism, the effects are really messy and somewhat non-specific. The big picture idea is that they increase insulin sensitivity and affect glucose / fat metabolism. Take-home is that it helps control blood sugar levels.
        • Increases levels of adiponectin (lower yield)
          • Adpionetcin is a cytokine that is secreted by fat and regulates a number of metabolic processes
  • Clinical Use
    • Type II DM (obvious)
  • Adverse Effects
    • Fluid Retention → edema → HF / weight gain
      • Contraindicated in CHF
        • May precipitate HF
      • Mechanism (paper)
        • Na+ reabsorption in PCT
        • Possibly increased vascular permeability in adipose tissue
    • Increased risk of fractures
    • Weight gain
      • Mainly secondary to fluid retention (obvious)
      • Also possibly due to increased adipocyte storage
      • This is low yield but should be obvious
    • Less risk of hypoglycemia than other drugs that increase insulin levels
      • This is a general principle. Drugs that directly increase insulin are more likely to cause hypoglycemia.
    • Hepatotoxicity
      • This was in older versions of First Aid but has since been taken out
    • Bladder cancer
      • You may see this in some texts but the data on this is really weak