Thiazolidinediones

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Chapter: Essential pharmacology : Insulin, Oral Hypoglycaemic Drugs and Glucagon

Two thiazolidinediones Rosiglitazone and Pioglitazone are available. This novel class of oral antidiabetic drugs are selective agonists for the nuclear peroxisome proliferator activated receptor γ (PPARγ) which enhances the transcription of several insulin responsive genes.


THIAZOLIDINEDIONES

 

Two thiazolidinediones Rosiglitazone and Pioglitazone are available. This novel class of oral antidiabetic drugs are selective agonists for the nuclear peroxisome proliferator activated receptor γ (PPARγ) which enhances the transcription of several insulin responsive genes. They tend to reverse insulin resistance by stimulating GLUT4 expression and translocation: entry of glucose into muscle and fat is improved. Hepatic gluconeogenesis is also suppressed. Activation of genes regulating fatty acid metabolism and lipogenesis in adipose tissue contributes to the insulin sensitizing action. Adipocyte turnover and differentiation may also be affected. Thus, fatty tissue is a major site of their action. The magnitude of blood glucose reduction is somewhat less than sulfonylureas and metformin. Improved glycaemic control results in lowering of circulating HbA1C and insulin levels in type 2 DM patients.

 

Pioglitazone lowers serum triglyceride level and raises HDL level without much change in LDL level, probably because it acts on PPARα as well. The effect of rosiglitazone on lipid profile is inconsistent.

 

Both pioglitazone and rosiglitazone are well tolerated; adverse effects are plasma volume expansion, edema, weight gain, headache, myalgia and mild anaemia. Monotherapy with glitazones is not associated with hypoglycaemic episodes. Few cases of hepatic dysfunction and some cardiovascular events have been reported; CHF may be precipitated or worsened. Monitoring of liver function is advised. They are contraindicated in liver disease and in CHF. Rosiglitazone has been found to increase the risk of fractures, especially in elderly women.

 

Rosiglitazone is metabolized by CYP2C8 while pioglitazone is metabolized by both CYP2C8 and CYP3A4. Failure of oral contraception may occur during pioglitazone therapy. Ketoconazole inhibits metabolism of pioglitazone. Drug interactions are less marked with rosiglitazone.

 

The thiazolidinediones are indicated in type 2 DM, but not in type 1 DM. They reduce blood glucose and HbA1c without increasing circulating insulin. Some patients may not respond (non-responders), especially those with low baseline insulin levels. Glitazones are primarily used to supplement sulfonylureas/metformin and in case of insulin resistance. They may also be used as monotherapy (along with diet and exercise) in mild cases. Reduction in mortality due to myocardial infarction and stroke (macrovascular complications) has been obtained in type 2 DM.

 

Several reports associating precipitation of CHF after combined use of glitazones with insulin have appeared; avoid such combinations. They should not be used during pregnancy. The Diabetes Prevention Programme (2005) has shown that glitazones have the potential to prevent type 2 DM in prediabetics.

 

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