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Diabetes Mellitus: Pharmacotherapy-TZDs!

 PHARMACOTHERAPY: THIAZOLIDINEDIONES

  • Commonly referred to as TZDs or Glitazones,Thiazolidinediones have established a role in T2DM Therapy.

Mechanism of Action:

  • TZDs are known to increase insulin sensitivity by stimulating peroxisome proliferator-activated receptor gamma (PPAR-g). Stimulation of PPAR-g results in a number of intracellular and extracellular changes including increased insulin sensitivity and decreased plasma fatty acid levels.

Pharmacokinetics:

  • The onset of TZDs is delayed for several weeks and require up ton 12 weeks before maximum effects are observed.

Therapy:

  • As monotherapy, TZDs reduce FPG levels by around 60-70mg/dL and the effect of A1c is up to 1.5% reduction.


Clinical Uses:

  • Pioglitazone and Rosiglitazone increases HDL. Pioglitazone increases HDL by 5.2mg/dL Rosiglitazone increases HDL levels by 2-4mg/dL.
  • Pioglitazone decreases serum Triglycerides by an average of 51.9mg/dL. Rosiglitazone increases serum triglycerides.
  • Pioglitazone increases LDL levels by 12.3 mg/dL. Rosiglitazone increases LDL levels by 21.3mg/dL.


Adverse Effects:

  1. Fluid retention
  2. Edema
  3. Hepatotoxicity
  4. It is known that blood volume increases approximately 10% with these agents resulting in approximately 4-5% patients developing edema.


Contraindications:

These drugs are contraindicated in pt. with;

  • in situations in which increased fluid retention is detrimental such as heart failure.
  • Insulin therapy
  • Patients with a baseline alanine aminotransferase (ALT) level greater than 2.5 times the upper limit of normal.
  • Increased rate of upper and lower limb fractures tends to occur with TZD therapy, hence patients with baseline fracture risk are contraindicated to receive TZDs.
  • Premenopausal women may begin to ovulate on TZD therapy and therefore counselling should be provided to all women capable to begin pregnant regarding this.
  • TZD is pregnancy category C drug, so proper precautions to avoid pregnancy should be used.
  •   In June 2011, the FDA alerted healthcare providers and patients that pioglitazone was found to be associated with an increased risk of bladder cancer after 1 year of therapy in ongoing epidemiological study.
  • As 2007 meta-analysis conducted by Nissen and colleagues, reported that non-significant increase in myocardial infarction with Rosiglitazone compared with other oral agents.
  • A subsequent prospective study found Rosiglitazone use to be associated with a non-significant increase in Myocardial infarction risk and non-significant reduction in stroke, but a trend towards increased cardiovascular risk in those patients with Ischemic stroke.
  • In May 2011, the FDA chose to restrict access and distribution of Rosiglitazone. It is currently only available through the Avandia-Rosiglitazone Medicines access Program for patients currently benefiting from the drug and in those who cannot achieve adequate disease management with other agents or who are not willing to use pioglitazone-containing medications after counselling with their healthcare provider.



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