Category:Thiazolidinediones

From Ganfyd

(Redirected from Glitazone)
Jump to: navigation, search

Easier to know as glitazones.

Contents

Actions

As well as improving insulin sensitivity in type 2 diabetic patients this class of drug act as peroxisome proliferator-activated receptor-gamma agonists, which may have particular implications in treating lipid metabolic diseases and so antagonize angiotensin II effects in vivo and in vitro and have cardiovascular antioxidant and anti-inflammatory actions. They may inhibit IGF-I and p70S6K signaling which could have implications in tumour treatment. They may also affect bone marrow and bone function.[1]. A possible neuroprotective action is under active drug development in Parkinson's disease[2].

History

Ciglitazone, the first in the class, was an analoge of clofibrate. It was found to have glucose-lowering effects but was hepato-toxic. Other thiazolidinediones were then shown to bind to a nuclear receptor protein modulating transcription of genes involved in insulin action. The class lower circulating insulin relative to plasma glucose, but do not normalise plasma glucose levels. Troglitazone managed to persist on the American market until just after safer analogues arrived at the cost of at least 90 cases of liver failure and sales of several billion dollars well after withdrawal from the British market in 1997. Rosiglitazone's market share stagnated after June 2007 after the first evidence suggesting poor cardiovascular outcomes occurred and evidence has continued to accumulate that this is likely to be the case[3]. Pioglitazone which suppresses a slightly different gene set has had more positive long term net outcome data and the comparison with rosiglitazone is now frequently used as an example of why surrogate measures of clinical effectiveness such as glucose or cholesterol control are inferior to real outcome measures such as cardiovascular morbidity when making therapeutic decisions[4]. However there are still information gaps that mean pioglitazone's clinical risk benefit ratio is not fully understood. This has lead to regulatory action by some authorities due to the risk of bladder cancer and as of mid 2011 it is unclear how much longer any drug of this class will remain on the market[5].

Side effects

Thiazolidinediones side effects include:

  • Hypoglycaemia
  • Fluid retention & oedema[6]
    • Association with heart failure induction/decompensation especially in those on insulin. Both insulin and thiazolidinediones are associated with worse diabetic mortality in heart failure[7] However cardiovascular death in those with heart failure and either pre-diabetes or diabetes treated with either rosiglitazone or pioglitazone was not increased in the larger trials with lower risk populations[8]. This has been backed up by epidemiological studies that suggested both had similar problems (if any) but studies in higher risk populations for myocardial infarction suggest rosiglitazone may not have net benefit.
  • Increased distal limb fracture risk in females- a possible mechanism for this has been postulated. [9]
    • For women with pioglitazone 0.8 fractures extra per 100 patient years, ie NNH 125 each year [10]
    • Rosiglitazone associated with increased fracture risk in woman of 1.45 fractures extra per 100 patient years compared to women on Glyburide and 1.20 fractures extra per 100 patient years compared to women on metformin ie ie NNH 69 to 83 [11][12]
    • Potentially osteoporosis[13]
  • They may suppress tissue proliferation. This could be useful with say coronary stents
  • They modulate microglia function so may be beneficial in neurodegenerative disease such as Parkinson's disease[2]
  • Rosiglitazone may have a drug specific association with increased risk of poor cardiovascular outcome
  • Induction of ovulation (may not just be in PCOS !)
  • Macular oedema[14]
  • Anaemia[15]
  • Bladder cancer had been shown to be a potential issue in rodent studies with both rosiglitazone and pioglitazone but epidemiological studies confirming this risk in man only became available in 2010[16].

References

  1. Schwartz AV. Diabetes, TZDs, and Bone: A Review of the Clinical Evidence PPAR Res. 2006:24502 pubmedcentral article http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17259663]
  2. a b Carta AR, Simuni T. Thiazolidinediones under preclinical and early clinical development for the treatment of Parkinson's disease. Expert opinion on investigational drugs. 2015 Feb; 24(2):219-27.(Link to article – subscription may be required.)
  3. Nissen SE, Wolski K. Rosiglitazone Revisited: An Updated Meta-analysis of Risk for Myocardial Infarction and Cardiovascular Mortality. Archives of internal medicine. 2010 Jun 28.(Epub ahead of print) (Link to article – subscription may be required.)
  4. Rosen CJ. Revisiting the Rosiglitazone Story -- Lessons Learned. The New England journal of medicine. 2010 Jul 21.(Epub ahead of print) (Link to article – subscription may be required.)
  5. Update on ongoing European review of pioglitazone–containing medicines EMEA accessed 10 June 2011
  6. Macfarlane DP, Fisher M. Thiazolidinediones in patients with diabetes mellitus and heart failure : implications of emerging data. Am J Cardiovasc Drugs. 2006;6(5):297-304.
  7. Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J, et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 2007 doi: 10.1136/bmj.39314.620174.80
  8. Lago RM, Singh PP,Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. The Lancet 2007; 370:1129-1136
  9. Schwartz AV. Diabetes, TZDs, and Bone: A Review of the Clinical Evidence PPAR Res. 2006:24502 Pubmedcentral article [1]
  10. FDA Medwatch report FDA approved Dear Doctor letter
  11. FDA warning
  12. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. The New England journal of medicine 2006;355:2427-43. (Direct link – subscription may be required.)
  13. Grey A. Skeletal consequences of thiazolidinedione therapy. . 2007 Sep 28.(Epub ahead of print) (Link to article – subscription may be required.)
  14. Fong DS, Contreras R. Glitazone use associated with diabetic macular edema. American journal of ophthalmology. 2009 Apr; 147(4):583-586.e1.(Link to article – subscription may be required.)
  15. Berria R, Glass L, Mahankali A, Miyazaki Y, Monroy A, De Filippis E, Cusi K, Cersosimo E, Defronzo RA, Gastaldelli A. Reduction in Hematocrit and Hemoglobin Following Pioglitazone Treatment is not Hemodilutional in Type II Diabetes Mellitus. Clin Pharmacol Ther. 2007.
  16. Risque de cancer de la vessie chez les personnes diabétiques traitées par pioglitazone en France : une étude de cohorte sur les données du SNIIRAM et du PMSI Caisse nationale de l’assurance maladie, Paris, France. Rapport final du 7/06/2011 accessed 10 June 2011

Pages in category "Thiazolidinediones"

The following 3 pages are in this category, out of 3 total.

P

R

T

Personal tools