Thiazolidinediones

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 menu item)
• principal unwanted effects include weight gain (about 5%, or 3.5 kg over 6 months)
• 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 therapy
• 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 occurs
  
  
• 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 is maintained.

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 European Union
• 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. .."

Reference:

1. Drug and Therapeutics Bulletin (2001), 39 (9), 65-8.
2. GSK (20/12/05). Reports of macular oedema in patients taking rosiglitazone.
3. 1. Loke YK, et al. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 2009;180(1).
4. Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med. 2007
5. MeReC Bulletin (2012);22;5
6. MRHA (September 2010). Rosiglitazone.
7. FDA Drug Safety Communication - Rosiglitazone (November 25th 2013)
8. 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.