Rapid Response

Thiazolidinediones and Clinical Diabetes Management: New Challenges for the Fall of 2007

Authors: NA


Three thiazolidinediones (TZDs) have been introduced into clinical use in the United States. These compounds are nuclear transcription activators that affect dozens of different genes. Due to the unique coactivator and corepressor proteins that associate and dissociate with the PPAR-gamma protein/TZD complex, no two of these compounds should be expected to have exactly the same pattern of gene activation or suppression.1–3 Troglitazone was withdrawn from the market due to what appears to have been a unique idiosyncratic end stage liver disease that was not observed with pioglitazone or rosiglitazone. The event rate for this fatal hepatotoxicity was approximately 1:35,000 exposed patients.4 Based upon the fact that two safer TZDs were available, the FDA suggested that troglitazone be withdrawn from the market. In an open-labeled conversion study conducted after the withdrawal of troglitazone, subjects were randomly converted from troglitazone to either rosiglitazone or pioglitazone.5 No difference was noted in hemoglobin A1c depending on which TZD was used. However, the conversion from troglitazone to pioglitazone was associated with more than a 15% fall in LDL concentration, while converting from troglitazone to rosiglitazone caused little change in LDL concentration.

This content is limited to qualifying members.

Existing members, please login first.

If you have an existing account please login now to access this article or view your purchase options.

Purchase only this article ($15)

Create a free account, then purchase this article to download or access it online for 24 hours.

Purchase an SMJ online subscription ($75)

Create a free account, then purchase a subscription to get complete access to all articles for a full year.

Purchase a membership plan (fees vary)

Premium members can access all articles plus recieve many more benefits. View all membership plans and benefit packages.


1. Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism.Endocr Rev 1999;20:649–688.
2. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: Opening the x-files. Science 2001;294:1866–1870.
3. Berger JP, Petro AE, Macnaul KL, et al. Distinct properties and advantages of a novel paroxisome proliferator-activated protein γ selective modulator. Mol Endocrinol 2003;17:662–676.
4. Troglitazone: Presentation to Advisory Committee. Available at:http://www.fda.gov/ohrms/dockets/ac/00/slides/3615s1a/sld016.htm.
5. Kahn M, St. Peter JV, Xue J. Prospective, Randomized Comparison of the Metabolic effects of Pioglitazone or Rosiglitazone in Patients With Type 2 Diabetes Who Were Previously Treated With Troglitazone. Diabetes Care 2002;25:708–711.
6. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–2471.
7. Psaty BM, Furberg CD. Rosiglitazone and Cardiovascular Risk. N Engl J Med 2007;356:2522–2524.
8. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes–an interim analysis. N Engl J Med 2007; 357:28–38.
9. Psaty BM, Furberg CD. The record on rosiglitazone and the risk of myocardial infarction.. N Engl J Med 2007;357:67–69.
10. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685–696.
11. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–1289.
12. PROactive Study Executive Committee and Data and Safety Monitoring Committee. PROactive study. Lancet 2006;367:982.
13. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998;316:823–828.
14. Goldberg R, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005;28:1547–1554.
17. Brooks MM, Frye RL, Genuth S, et al. Hypotheses, design, and methods for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Am J Cardiol2006;97(Suppl):9G–19G.