Glitazones:

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Glitazones

• Are they safe?

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Background

• Enhance insulin sensitivity in the adipose
  tissue, muscle and liver cells.
• Both Rosiglitazone and pioglitazone licensed as
  mono, dual and triple therapy.
• Pioglitazone also licensed as combination therapy
  with insulin in type 2 diabetes for whom
  metformin is inappropriate.

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Glycaemic control

• As monotherapy, pioglitazone is comparable to
  both gliclazide and metformin in large studies.
• As dual therapy, not significant differences when
  compared to metformin or sulphonylurea.
• Significant improvement combined with insulin (v.
  Placebo) but four fold increase in oedema.

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Glycaemic control

• Rosiglitazone slower progression of monotherapy
  failure compared to metformin or glyburide
  (ADOPT).
• Hba1c improvement was only significant when
  compared with glyburide.
• As dual therapy it is not superior to metformin
  or SU (RECORD study).

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Glycaemic control

• When Hba1cgt9.5 inspite metforminSU, adding
  insulin produced a greater reduction than
  rosiglitazone.
• Patients poorly controlled on fixed combination
  dose of metforminrosiglitazone, required lower
  insulin doses than those on placeboinsulin,
  however rosiglitazone is not licenced for use
  with insulin in UK.

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Fluid retention and heart failure

• PROACTIVE study (group with high risk CV
  disease) serious HF was greater with
  pioglitazone than placebo.
• ADOPT incidence of HF with rosiglitazone was
  comparable with metformin but more than double
  than with glyburide.
• DREAM study significant incidence of HF with
  rosiglitazone when compared with placebo.

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Macular oedema

• It is unclear whether there is a direct
  association.
• Clinicians should be alert if patient reports
  disturbances in visual acuity.
• More often associated with concurrent peripheral
  oedema.

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Fracture

• In animals models, glitazones have been shown to
  decrease bone mineral density.
• Glitazones increase the rate of bone loss in
  women.
• ADOPT increased fracture rate in women on
  rosiglitazone compared to metformin or glyburide.

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Fractures

• Pioglitazone analysis of fracture date showed an
  increased incidence too although mean age and
  menopausal status was unknown.
• In post-menopausal women at high risk of
  fractures or with a previous fracture, specialist
  advice is recommended to use glitazones.

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Pregnancy

• Only 3 case reports of women exposed to
  glitazones in first trimester.
• All carefully monitored during pregnancy.
• The 3 cases delivered normal babies.
• Too small to draw any safety conclusions.
• Glitazones currently not advised in pregnancy.

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MI and cardiovascular disease

• PROACTIVE study 5238 high risk patients. No
  significant difference between pioglitazone and
  placebo.
• Two large meta-analysis on rosiglitazone have
  found contradictory results.
• ADOPT and DREAM studies showed comparable numbers
  in all treatment arms.

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MI and cardiovascular disease

• There is little rosiglitazone safety data.
• RECORD study to be published in 2009.
• Need for careful assessment of patients at high
  risk before starting glitazones.

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Glitazones in type 1 diabetes

• Although there was need for lower insulin doses
  in patients on pioglitazone, there was
  significant weight gain.
• Little benefit in type 1 diabetes.

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Polycystic ovaries

• No great significance over metformin and no
  trials large enough to assess effect on rates of
  pregnancy.
• Concerns on potential teratogenic effects.
• Not recommended as routine treatment.

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Non-alcoholic fatty liver disease

• Only small studies done.
• Rosiglitazone shown to reduce liver fat content.
• Significant improvement in biochemical and
  inflammatory markers but minimal effect on liver
  histology.
• No definitive data to support their use.