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The thiazolidinediones are a class of drugs which reverse the insulin resistance
seen in type 2 diabetes (1,2,3,4). There were two licensed drugs in this class,
rosiglitazone and pioglitazone. However the use of rosiglitazone is no longer
advised because the benefits of rosiglitazone no longer outweigh its risks (5).
The effect of the thiazolidinediones is
mediated by the activation of a transcription regulator called peroxisome proliferator-activated
receptor gamma (PPAR-gamma). This action modulates adipogenesis and carbohydrate
metabolism in adipocytes and skeletal muscle.
Unwanted effects of glitazones:
- clinical trials with both pioglitazone and rosiglitazone have shown no serious
hepatotoxity - however monitoring of liver function tests is advised (see
- principal unwanted effects include weight gain (about 5%, or 3.5 kg over
- water retention and leg oedema (in about 5%)
- dizziness, headache, fatigue, and hypoglycaemia (only when used in combination
with a sulphonylurea) has also been reported with both drugs in combination
- other reported effects with pioglitazone include visual disturbances, arthralgia,
impotence, flatulence, proteinuria, haematuria and with rosiglitazone, gastrointestinal
disturbances, rash, paraesthesia, dyspnoea, rash, alopecia and thrombocytopaenia
- since rosiglitazone and pioglitazone can cause fluid retention, which may
exacerbate or precipitate heart failure, these drugs should be avoided in
patients with any current, or history of heart failure - note that all patients
taking either glitazone should be monitored for features of heart failure
- macular oedema - cases of new onset and worsening macular oedema have been
reported in patients treated with rosiglitazone. It has been reported that
"in some cases, macular oedema resolved or improved following discontinuation
of therapy and in one case macular odema resolved after dose reduction "(2)
- fracture risk - a meta-analysis found that rosiglitazone and pioglitazone
approximately double the risk of fractures (site not specified) in women,
but not men (3)
- cardiovascular risk - there has been evidence from a meta-analysis concerning
the use of rosiglitazone and increased risk of myocardial infarction (4) -
for more detail see linked item
Some updated advice regarding pioglitazone (5):
- Pioglitazone is contraindicated in patients with heart failure or a history
of heart failure. Patients should be observed for signs and symptoms of heart
failure, weight gain or oedema; particularly those with reduced cardiac reserve
and when pioglitazone is used in combination with insulin
- Pioglitazone should be discontinued if any deterioration in cardiac status
- Pioglitazone is contraindicated in patients with bladder cancer or a history
of bladder cancer, or in patients with uninvestigated macroscopic haematuria.
Risk factors for bladder cancer (age, smoking history, exposure to
some occupational or chemotherapy agents or prior radiation treatment in the
pelvic region) should be assessed before initiating pioglitazone, and any
macroscopic haematuria investigated
- In light of age-related risks (especially bladder cancer, fractures and
heart failure), the balance of benefits and risks should be considered
carefully both before and during treatment in the elderly. After initiation
of pioglitazone, patients should be reviewed after three to six months to
assess adequacy of response to treatment (e.g. reduction in HbA1c)
- In patients who fail to show an adequate response, pioglitazone should be
discontinued. In light of potential risks with prolonged therapy, prescribers
should confirm at subsequent routine reviews that the benefit of pioglitazone
Rosiglitazone has been withdrawn in the UK (6):
- the European Committee on Medicinal Products for Human Use has recommended
the suspension of the marketing authorisations of the medicine across the
- the UK Commission on Human Medicines (CHM) has reviewed the available data
and has concluded that there is an increased cardiovascular risk for rosiglitazone.
It has not been possible to identify additional measures that would reduce
the cardiovascular risk or to identify a patient population in whom the benefits
continue to outweigh the risks
- CHM has therefore concluded that the benefits of rosiglitazone no longer
outweigh its risks
However note that the US Food and Drug Administration announced (7):
- The U.S. Food and Drug Administration (FDA) has determined that recent data
for rosiglitazone-containing drugs, such as Avandia, Avandamet, Avandaryl,
and generics, do not show an increased risk of heart attack compared
to the standard type 2 diabetes medicines metformin and sulfonylurea. As a
result, we are requiring removal of the prescribing and dispensing restrictions
for rosiglitazone medicines that were put in place in 2010. This decision
is based on our review of data from a large, long-term clinical trial and
is supported by a comprehensive, outside, expert re-evaluation of the data
conducted by the Duke Clinical Research Institute
Glitazones and prevention of recurrent strokes/TIAs (8):
- a systematic review concluded that "..Peroxisome proliferator-activated receptor gamma agonists probably reduce recurrent stroke and total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, and may improve insulin sensitivity and the stabilisation of carotid plaques. Their effects on adverse events are uncertain. Our conclusions should be interpreted with caution considering the small number and the quality of the included studies. Further well-designed, double-blind RCTs with large samples are required to assess the efficacy and safety of PPAR-gammaagonists in the secondary prevention of stroke and related vascular events in people with stroke or TIA. .."
- Drug and Therapeutics Bulletin (2001), 39 (9), 65-8.
- GSK (20/12/05). Reports of macular oedema in patients taking rosiglitazone.
- 1. Loke YK, et al. Long-term use of thiazolidinediones and fractures in
type 2 diabetes: a meta-analysis. CMAJ 2009;180(1).
SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction
and Death from Cardiovascular Causes. N Engl J Med. 2007
- MRHA (September 2010). Rosiglitazone.
- FDA Drug Safety Communication - Rosiglitazone (November 25th 2013)
- Liu J,
Wang LN.Peroxisome proliferator-activated receptor gamma agonists for preventing recurrent stroke and other vascular events in people with stroke or transient ischaemic attack. Cochrane Database Syst Reviews 08 October 2019.
Last edited 07/2020