Skip to main content
SpringerLink
Log in

The Role of Thiazolidinediones in the Treatment of Patients with Type 2 Diabetes Mellitus

  • Leading Article
  • Published:
Treatments in Endocrinology

Abstract

Diabetes mellitus is a significant and growing health concern worldwide. Unfortunately, type 2 diabetes mellitus is generally under-managed, and this may explain the increasing prevalence of diabetic complications throughout the world. The introduction of newer classes of antihyperglycemic agents should enhance the ability of clinicians to achieve optimal blood glucose control.

One recent addition to the pharmacologic armamentarium is the thiazolidinedione class. The main effect of thiazolidinediones is amelioration of insulin resistance. These agents may also preserve β-cell function, although evidence in favor of this effect is still inconclusive. The mechanism of action of thiazolidinediones is not completely understood. Similarly, the current state of knowledge cannot explain the differences in the lipid effects of pioglitazone and rosiglitazone.

Thiazolidinediones are commonly used as add-on therapy for those requiring large daily doses of insulin therapy, or in addition to sulfonylurea agents and metformin for those reluctant to start insulin therapy. The potential role of thiazolidinediones as first-line therapy is now emerging. It is possible that in certain subgroups, particularly patients with renal failure, elderly individuals or those with corticosteroid-induced diabetes mellitus, the use of thiazolidinediones as a first-line therapy is justifiable. However, the lack of a long-term safety record, and the cost, would limit the widespread acceptance of this class of agents as first-line therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Table IV
Table V

Similar content being viewed by others

References

  1. American Diabetes Association. Diabetes 1996 Vital Statistics. Alexandria (VA): American Diabetes Association,1996

    Google Scholar 

  2. King H,Aubert RE, Herman WH. Global burden of diabetes, 1995–2025. Diabetes Care 1998; 21: 1414–31

    Article  PubMed  CAS  Google Scholar 

  3. Beckles GLA, Engelgau MM, Narayan KMV, et al. Population-based assessment of the level of care among adults with diabetes in the U.S. Diabetes Care 1998; 21: 1432–8

    Article  PubMed  CAS  Google Scholar 

  4. American Diabetes Association. Clinical practice recommendations 2001. Diabetes Care 2001; 24Suppl. 1: S1–133

    Google Scholar 

  5. American Diabetes Association. Complete guide to diabetes. Alexandria (VA): American Diabetes Association, 1997

    Google Scholar 

  6. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977–86

    Article  Google Scholar 

  7. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995; 28: 103–17

    Article  PubMed  CAS  Google Scholar 

  8. U. K.Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53

    Article  Google Scholar 

  9. Mooradian AD, Chehade J. Implications of the UK Prospective Diabetes Study: questions answered and issues remaining. Drugs Aging 2000; 16: 159–64

    Article  PubMed  CAS  Google Scholar 

  10. Turner RC, Call CA, Frighi V, et al. The UKPDS Group: glycemic control with diet, sulfonylurea, metformin, or insulin in patients with multiple therapies (UKPDS 49). JAMA 1999; 281: 2005–12

    Article  PubMed  CAS  Google Scholar 

  11. Holman RR. Assessing the potential for alpha-glucosidase inhibitors in prediabetic states. Diabetes Res Clin Pract 1998; 40 Suppl.: S21–5

    Article  PubMed  CAS  Google Scholar 

  12. Anonymous. Consensus Development Conference on Insulin Resistance. Nov 5,6, 1997. American Diabetes Association. Diabetes Care. 1998; 21: 310-4

  13. Haffner SM, D’Agostino Jr R, Mykkanen L. Insulin sensitivity in subjects with type 2 diabetes: relationship to cardiovascular risk factors: the Insulin Resistance Atherosclerosis Study. Diabetes Care 1999; 22: 562–8

    Article  PubMed  CAS  Google Scholar 

  14. Turner NC, Clapham JC. Insulin resistance, impaired glucose tolerance and non-insulin-dependent diabetes, pathologic mechanism and treatment: current status and therapeutic possibilities. Prog Drug Res 1998; 51: 33–94

    Article  PubMed  CAS  Google Scholar 

  15. DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 1988 Jun; 37(6): 667–87

    PubMed  CAS  Google Scholar 

  16. Mooradian AD, Thurman JE. Drug therapy of postprandial hyperglycemia. Drugs 1999; 57: 19–29

    Article  PubMed  CAS  Google Scholar 

  17. Robertson R, Porte Jr D. The glucose receptor: a defective mechanism in diabetes mellitus distinct from the beta adrenergic receptor. J Clin Invest 1973; 52: 870–6

    Article  PubMed  CAS  Google Scholar 

  18. DeFronzo RZ, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM: a balanced overview. Diabetes Care 1992; 15(3): 318–68

    Article  PubMed  CAS  Google Scholar 

  19. Gerich J. Address the insulin secretion defect: a logical first-line approach. Metabolism 2000; 49Suppl. 2: 12–6

    Article  PubMed  CAS  Google Scholar 

  20. Bak H, Moller N, Schmitz O, et al. In vivo action and muscle glycogen synthase activity in type II (noninsulin dependent) diabetes mellitus: Effects of diet treatment. Diabetologia 1992; 35: 777–84

    PubMed  CAS  Google Scholar 

  21. Beck-Nielsen H, Pedersen O, Lindskov H. Normalization of the insulin sensitivity and the cellular insulin binding during treatment of obese diabetics for one year. Acta Endocrinol (Copenh) 1979; 90: 103–12

    CAS  Google Scholar 

  22. Freidenberg G, Reichart D, Olefsky J, et al. Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin dependent diabetes mellitus: effect of weight loss. J Clin Invest 1988; 82: 1398–406

    Article  PubMed  CAS  Google Scholar 

  23. Weyer C, Bogardus C, Mott DM, et al. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999; 104: 787–94

    Article  PubMed  CAS  Google Scholar 

  24. Boyko EJ, Fujimoto WY, Leonetti DL, et al. Visceral adiposity and risk of type 2 diabetes: a prospective study among Japanese Americans. Diabetes Care 2000; 23: 465–71

    Article  PubMed  CAS  Google Scholar 

  25. Campbell S, Mooradian AD. Diabetes mellitus. In: Bressler R, Katz MD, editors. Geriatric pharmacy. New York: McGraw Hill, Inc., 1993: 409–25

    Google Scholar 

  26. Chehade JM, Mooradian AD. A rational approach to drug therapy of type 2 diabetes mellitus. Drugs 2000; 60: 95–113

    Article  PubMed  CAS  Google Scholar 

  27. Lebovitz HE. Alpha-glucosidase inhibitors. Endocrinol Metab Clin North Am 1997; 26: 539–51

    Article  PubMed  CAS  Google Scholar 

  28. Bailey CJ, Turner RC. Metformin. New Engl J Med 1996; 334: 574–9

    Article  PubMed  CAS  Google Scholar 

  29. Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 1996; 45: 1661–9

    Article  PubMed  CAS  Google Scholar 

  30. Steppan CM, Baily ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature 2001; 409: 292–3

    Article  Google Scholar 

  31. Burant CF, Sreenan S, Hirano Kl, et al. Troglitazone action is independent of adipose tissue. J. Clin. Invest 1997; 100: 2900–8

    Article  PubMed  CAS  Google Scholar 

  32. Steppan CM, Brown EJ, Wright CM, et al. A family of tissue-specific resistin like molecules. Proc. Nat’l. Acad. Sci. (USA) 2001; 98: 502–6

    Article  CAS  Google Scholar 

  33. Willson TM, Brown PJ, Sternbach DD, et al. The PPARS: From orphan receptors to drug discovery. J Med Chem 2000; 43: 527–50

    Article  PubMed  CAS  Google Scholar 

  34. Thampy GK, Haas MJ, Mooradian AD. Troglitazone stimulates acetyl-CoA carboxylase activity through a posttranslational mechanism. Life Sci. 2000, in press

  35. Wang M, Wise SC, Leff T, et al. Troglitazone, an antidiabetic agent, inhibits cholesterol biosynthesis through a mechanism independent of peroxisome proliferator activated receptor γ. Diabetes 1999; 48: 254–60

    Article  PubMed  CAS  Google Scholar 

  36. Fukui Y, Masui S, Osada S, et al. A new thiazolidinedione, NG-2100, which is a weak PPAR-gamma activator, exhibits potent antidiabetic effects and increases uncoupling protein 1 in white adipose tissue of KKAY obese mice. Diabetes 2000; 49: 759–67

    Article  PubMed  CAS  Google Scholar 

  37. Edelstein SL, Knowler WC, Bain RP, et al. Predictors of progression from impaired glucose tolerance to NIDDM: An analysis of six prospective studies. Diabetes 1997; 46: 701–10

    Article  PubMed  CAS  Google Scholar 

  38. Cavaghan MK, Ehrmann DA, Byrne MM, et al. Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance. J Clin Invest 1997; 100: 530–7

    Article  PubMed  CAS  Google Scholar 

  39. Sreenan S, Keck S, Fuller T, et al. Effects of troglitazone on substrate storage and utilization in insulin-resistant rats. Am J Physiol 1999; 276: E1119–29

    PubMed  CAS  Google Scholar 

  40. Finegood DT, McArthur MD, Kojwang D, et al. Beta cell mass dynamics in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death. Diabetes 2001; 50: 1021–9

    Article  PubMed  CAS  Google Scholar 

  41. Diabetes Prevention Program NIH. NIDDK home page. Press release. Available from URL: http:Wwww.niddk.nih.gov [Accessed 2001 Aug 21]

  42. Sak Y, Grill VE. A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and -cell oxidation through a process likely coupled to fatty acid oxidation. Endocrinology 1990; 127: 1580–9

    Article  Google Scholar 

  43. Martin G, Schoonjans K, Shaels B, et al. PPAR γ activators improve glucose homeostasis by stimulating fatty acid uptake in the adipocytes. Atherosclerosis 1998; 137: 575–80

    Article  Google Scholar 

  44. Li AC, Brown KK, Silvestre MJ, et al. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 2000; 106: 523–31

    Article  PubMed  CAS  Google Scholar 

  45. Koshiyama H, Shimono D, Kuwamura N, et al. Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 2001; 86: 3452–6

    Article  PubMed  CAS  Google Scholar 

  46. Minamikawa J, Tanabe S, Yamauchi M, et al. Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 1998; 83: 1818–20

    Article  PubMed  CAS  Google Scholar 

  47. Takagi T, Akasaka T, Yamamuro A, et al. Troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non-insulin dependent diabetes mellitus: a serial intravascular ultrasound study. J Am Coll Cardiol 2000; 36: 1529–35

    Article  PubMed  CAS  Google Scholar 

  48. Ogihara T, Rakugi H, Ikegami H, et al. Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives. Am J Hypertension 1995; 8: 3160–320

    Article  Google Scholar 

  49. Yoshimoto T, Naruse M, Nishikawa M, et al. Antihypertensive and vasculo-and renoprotective effects of pioglitazone in genetically obese diabetic rats. Am J Physiol 1997; 272: E989–96

    PubMed  CAS  Google Scholar 

  50. Kruszynska YT, Yu JG, Olefsky JM, et al. Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects. Diabetes 2000; 49: 633–9

    Article  PubMed  CAS  Google Scholar 

  51. Kato K, Satoh H, Endo Y, et al. Thiazolidinediones down-regulate plasminogen activator inhibitor type 1 expression in human vascular endothelial cells: a possible role for PPAR gamma in endothelial function. Biochem Biophys Res Commun 1999; 258: 431–5

    Article  PubMed  CAS  Google Scholar 

  52. Camp HS, Li O, Wise SC, et al. Differential activation of peroxisome proliferator-activated receptor gamma by troglitazone and rosiglitazone. Diabetes 2000; 49: 539–47

    Article  PubMed  CAS  Google Scholar 

  53. Walker AB, Naderali EK, Chattington PD, et al. Differential vasoactive effects of the insulin sensitizers rosiglitazone (BRL49653) and troglitazone on human small arteries in vitro. Diabetes 1998; 47: 810–4

    Article  PubMed  CAS  Google Scholar 

  54. Ishizuka T, Itaya S, Wada H, et al. Differential effect of antidiabetic thiazolidine-diones troglitazone and pioglitazone on human platelet aggregation mechanism. Diabetes 1998; 47: 1494–500

    Article  PubMed  CAS  Google Scholar 

  55. Aronoff S, Rosenblatt S, Braithwaite S, et al. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 2000; 23: 1605–11

    Article  PubMed  CAS  Google Scholar 

  56. Fonseca V, Rosenstock J, Patwardhan R, et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus. A randomized controlled trial. JAMA 2000; 283: 1695–702

    Article  PubMed  CAS  Google Scholar 

  57. Raskin P, Rappaport EB, Cole ST, et al. Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in patients with type II diabetes. Diabetologia 2000; 43: 278–84

    Article  PubMed  CAS  Google Scholar 

  58. Phillips LS, Grunberger G, Miller E, et al. For the Rosiglitazone Clinical Trials Study Group. Once- a nd twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care 2001; 24: 308–15

    Article  PubMed  CAS  Google Scholar 

  59. Lebovitz HE, Dole JF, Patwardhan R, et al. Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 2001; 86: 280–8

    Article  PubMed  CAS  Google Scholar 

  60. Scherbaum W, Goke B, For the German Pioglitazone Study Group. The effect of pioglitazone vs. acarbose on the lipid profile in patients with type 2 diabetes [abstract]. Diabetes 2001; 50Suppl. 2: A454

    Google Scholar 

  61. Prince MJ, Zagar AJ, Robertson KE. Effect of pioglitazone on HDL-c, a cardiovascular risk factor in type 2 diabetes [abstract]. Diabetes 2001; 50Suppl. 2: A128

    Google Scholar 

  62. Davidson PC, Sabbah HT, Steed RD, et al. Pioglitazone versus rosiglsitazone therapy in randomized follow up in patients previously treated with troglitazone [abstract]. Diabetes 2001; 50Suppl. 2: A109

    Google Scholar 

  63. King AB, Armstrong D. Comparison of the glucose and lipid effect of rosiglitazone (Ros) and pioglitazone (Pio) following conversion from troglitazone (Tro) treatment [abstract]. Diabetes 2001; 50Suppl. 2: A120

    Google Scholar 

  64. King AB. A comparison in a clinical setting of the efficacy and side effects of three thiazolidinediones [letter]. Diabetes Care 2000; 23: 557

    Article  PubMed  CAS  Google Scholar 

  65. Gegick CG, Altheimer MD. Comparison of effects of thiazolidinediones on cardiovascular risk factors: observations from a clinical practice. Endocrine Pract 2001; 7: 162–9

    CAS  Google Scholar 

  66. Howard BV, Robbins DC, Sievers ML, et al. LDL Cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL: The Strong Heart Study. Arterioscler Thromb Vasc Biol. 2000; 20: 830–5

    Article  PubMed  CAS  Google Scholar 

  67. Castelli WP. Cholesterol and lipids in the risk of coronary artery disease-the Framingham Heart Study. Can J Cardiol 1988; 4Suppl. A: 5A–10

    PubMed  Google Scholar 

  68. King AB, Armstrong D. Characteristics of the patients who gain weight while on pioglitazone treatment [abstract]. Diabetes 2001; 50Suppl. 2: A120

    Google Scholar 

  69. Rezulin (troglitazone) Package Insert. Ann Arbor (MI): Parke Davis, Jun 1999

  70. Al-Salman J, Heider A, Kemp DG, et al. Hepatocellular injury in a patient receiving rosiglitazone: a case report. Ann Intern Med 2000; 132: 121–4

    PubMed  CAS  Google Scholar 

  71. Mooradian AD. Rosiglitazone: a viewpoint. Drugs Aging 1999; 57: 931

    Google Scholar 

Download references

Acknowledgements

The authors thank Mr Christopher G. Perkin for his editorial assistance. This work was supported by an unrestricted educational grant from Eli Lilly Co. and Takeda Co. The authors have received honoraria from Eli Lilly Co. and Takeda Co. for speaking engagements.

Author information

Authors and Affiliations

  1. Division of Endocrinology, Saint Louis University School of Medicine, 1402 South Grand Blvd., St Louis, Missouri, 63104, USA

    Arshag D. Mooradian, Joe Chehade & Jerome E. Thurman

Authors
  1. Arshag D. Mooradian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joe Chehade
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jerome E. Thurman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arshag D. Mooradian.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mooradian, A.D., Chehade, J. & Thurman, J.E. The Role of Thiazolidinediones in the Treatment of Patients with Type 2 Diabetes Mellitus. Mol Diag Ther 1, 13–20 (2002). https://doi.org/10.2165/00024677-200201010-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00024677-200201010-00002

Keywords

Search

Navigation