Glitazones

Diabetes

1. Glitazones By Nishay Patel

2. How are they used? F or treatment of Type 2 diabetes 2 nd line combination therapy Pioglitazone used Competact ® ( metformin combination) Used if control of blood glucose remains or becomes inadequate (HbA1c >= 6.5%) Used as Triple therapy in exceptional circumstances (obese).

3. Mechanism of action Selective agonists for Peroxisome Proliferator -activated receptors ( γ ). The receptors are complexed with retinoid X receptors and bind to DNA. This increases the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. Need insulin to be effective

4. Actions of Glitazones Enhance insulin sensitivity in muscle and adipose tissue by causing an increase in glucose transporter expression. Reduce insulin resistance in peripheral tissues Reduce glucose production in liver by increasing adiponectin secretion . Increase adipocyte number & lipogensis . Cause an increase in PPAR γ activity and adipocyte remodelling by inducing FGF21 expression.

5. Dose and other benefits 15mg to 30mg orally once a day Takes 6-12 weeks for max effect to develop Increase in HDL cholesterol and reduction of triglyceride concentrations. Lower blood pressure and decrease vascular inflammation in vitro.

6. Contraindications and side effects Not used in people who have heart failure or who are at higher risk of fracture (elderly) Mild weight gain (1-4kg) due to increased differentiation of adipocytes and fluid retention by stimulating amiloride -sensitive Na + absorption Hypoglycaemia when used with insulin Liver failure Increased risk of bladder cancer?

7. Ahmadian et al. (2013). Nat. Med. 19, 557-566.

8. Monitoring LFT’s-Alanine transaminase (↑ 40 U/L) Look for side effects (oedema, bladder cancer, heart failure) The safety and efficacy should be reviewed after 6 months NICE criteria for continuation – HbA1c reduction of 0.5% in 6 months.

9. Other Facts T 1/2 7 hours, undergo hepatic metabolism by CYP2C subfamily TZDs are the most expensive of the oral antidiabetic agents. Acts on tissues such as liver and skeletal muscle, sensitising them to insulin action, thereby increasing glucose uptake.

10. Efficacy compared to other drugs http:// www.medscape.org/viewarticle/46679