Drugs

, Volume 54, Issue 1, pp 89–101 | Cite as

Troglitazone

  • Caroline M. Spencer
  • Anthony Markham
Adis New Drug Profile

Summary

  • ▴ Troglitazone decreases insulin resistance (improves insulin sensitivity), which results in reduced plasma glucose and insulin levels in patients with non-insulin-dependent diabetes mellitus (NIDDM).

  • ▴ Risk factors for cardiovascular disease such as elevated proinsulin and triglyceride levels are also reduced by troglitazone.

  • ▴ In clinical trials, troglitazone 200 to 800mg daily (alone or in combination with other oral antidiabetic agents or insulin) reduced plasma or serum glucose levels and glycosylated haemoglobin compared with both baseline and placebo in patients with NIDDM refractory to other oral antidiabetic agents (usually sulphonylureas).

  • ▴ Troglitazone was generally well tolerated in clinical trials. In patients in the US, the incidence of adverse events in troglitazone recipients was similar to that in placebo recipients.

Keywords

Glibenclamide Proinsulin Troglitazone Glyburide Dependent Diabetes Mellitus 

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References

  1. 1.
    Lehmann JM, Moore LB, Smith-Oliver TA, et al. An anti-diabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ). J Biol Chem 1995; 270(22): 12953–6PubMedCrossRefGoogle Scholar
  2. 2.
    Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 1996 Dec; 45: 1661–9PubMedCrossRefGoogle Scholar
  3. 3.
    Park K-S, Abrams-Carter L, Mudaliar S, et al. Troglitazone effects on gene expression in human skeletal muscle involve regulation of PPARγ [abstract no. 0085]. Diabetes 1997; 46 Suppl. 1:22AGoogle Scholar
  4. 4.
    Fujiwara T, Yoshioka S, Yoshioka T, et al. Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes 1988 Nov; 37: 1549–58PubMedCrossRefGoogle Scholar
  5. 5.
    Tafuri SR. Troglitzone enhances differentiation, basal glucose uptake, and Glut1 protein levels in 3T3-L1 adipocytes. Endocrinology 1996; 137(11): 4706–12PubMedCrossRefGoogle Scholar
  6. 6.
    Yano Y, Sumida Y, Tsuchihasi K, et al. Long-term treatment with troglitazone increases translocation of GLUT4 in insulin-stimulated adipocytes from aging Sprague-Dawley(SD) rats [abstract no. 318]. Diabetes 1996 May; 45 Suppl. 2: 87AGoogle Scholar
  7. 7.
    Park K, Abrams L, Nikoulina S, et al. Effect of troglitazone on glucose transport and glycogen synthase activity in human skeletal muscle cultures from obese non-diabetic and NIDDM subjects [abstract no. 342]. Diabetes 1996 May; 45 Suppl. 2: 93AGoogle Scholar
  8. 8.
    Ciaraldi TP, Huber-Knudsen K, Hickman M, et al. Regulation of glucose transport in cultured muscle cells by novel hypoglycemic agents. Metabolism 1995 Aug; 44: 976–81PubMedCrossRefGoogle Scholar
  9. 9.
    Eckel J, Müller H, Niggemann J, et al. Troglitazone-induced insulin sensitizing in cardiac muscle of diabetic ZDF-rats correlates to inhibition and redistribution of membrane-associated PKC [abstract no. 0575]. Diabetes 1997; 46 Suppl. 1: 149AGoogle Scholar
  10. 10.
    Okuno A, Tamemoto H, Tobe K, et al. The promotive effect of troglitazone, an insulin sensitizer, on differentiation of the adiopose tissues in Zucker fatty rats [abstract no. 0329]. Diabetes 1997; 46 Suppl. 1:84AGoogle Scholar
  11. 11.
    Ciaraldi TP, Gilmore A, Olefsky JM, et al. In vitro studies on the action of CS-045, a new antidiabetic agent. Metabolism 1990 Oct; 39: 1056–62PubMedCrossRefGoogle Scholar
  12. 12.
    Neschen S, Noe C, Roden M, et al. Troglitazone acutely inhibits insulin-stimulated glycogenesis in isolated rat skeletal muscle [abstract no. 254]. Diabetologia 1996 Aug; 39 Suppl. 1: A69Google Scholar
  13. 13.
    Fujiwara T, Okuno A, Yoshioka S, et al. Suppression of hepatic gluconeogenesis in long-term troglitazone treated diabetic KK and C57BL/KsJ-db/db mice. Metabolism 1995 Apr; 44: 486–90PubMedCrossRefGoogle Scholar
  14. 14.
    Fulgencio J-P, Kohl C, Girard J, et al. Troglitazone inhibits fatty acid oxidation and esterification, and gluconeogenesis in isolated hepatocytes from starved rats. Diabetes 1996 Nov; 45: 1556–62PubMedCrossRefGoogle Scholar
  15. 15.
    Murano K, Inoue Y, Emoto M, et al. CS-045, a new oral antidiabetic agent, stimulates fructose-2,6-bisphosphate production in rat hepatocytes. Eur J Pharmacol 1994 Mar 21; 254: 257–62PubMedCrossRefGoogle Scholar
  16. 16.
    Kellerer M, Kroder G, Tippmer S, et al. Troglitazone prevents glucose-induced insulin resistance of insulin receptor in rat-1 fibroblasts. Diabetes 1994 Mar; 43: 447–53PubMedCrossRefGoogle Scholar
  17. 17.
    Fujiwara T, Wada M, Fukuda K, et al. Characterization of CS-045, a new oral antidiabetic agent, II. Effects on glycemic control and pancreatic islet structure at a late stage of the diabetic syndrome in C57BL/KsJ-db/db mice. Metabolism 1991 Nov; 40: 1213–8PubMedCrossRefGoogle Scholar
  18. 18.
    Inoue Y, Tanigawa K, Nakamura S, et al. Lack of effect of CS-045, a new antidiabetic agent, on insulin secretion in the remnant pancreas after 90% pancreatectomy in rats. Diabetes Res Clin Pract 1995 Jan; 27: 19–26PubMedCrossRefGoogle Scholar
  19. 19.
    Niwa K, Horikoshi H, Kanno T. Troglitazone (CS-045) potentiates glucose-induced biphasic insulin secretion in the absence of potentiation of Ca2+ signaling in rat pancreatic islets. Biomed Res 1995 Oct; 16: 345–51Google Scholar
  20. 20.
    Masuda K, Okamoto Y, Tsuura Y, et al. Effects of troglitazone (CS-045) on insulin secretion in isolated rat pancreatic islets and HIT cells: an insulinotropic mechanism distinct from glibenclamide. Diabetologia 1995 Jan; 38: 24–30PubMedCrossRefGoogle Scholar
  21. 21.
    Suter SL, Nolan JJ, Wallace P, et al. Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care 1992 Feb; 15: 193–203PubMedCrossRefGoogle Scholar
  22. 22.
    Kumar S, Boulton AJM, Beck-Nielsen H, et al. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Diabetologia 1996 Jun; 39: 701–9PubMedCrossRefGoogle Scholar
  23. 23.
    Valiquett T, Balagtas C, Whitcomb R. Troglitazone dose-response study in patients with NIDDM [abstract no. 406]. Diabetes 1995 May; 44 Suppl. 1: 109AGoogle Scholar
  24. 24.
    Norris R, Valiquett T, Balagtas C. Comparison of troglitazone (CI991) dosing regimens and placebo in the treatment of patients with NIDDM [abstract no. 187]. Diabetes 1993 May; 42 Suppl. 1: 59AGoogle Scholar
  25. 25.
    Hansen AP. Effects of troglitazone, a thiazolidinedione, in elderly non-insulin-dependent diabetic patients [abstract no. 775]. Diabetologia 1995; 38 Suppl. 1: A200Google Scholar
  26. 26.
    Troglitazone Study Group. The metabolic effects of troglitazone in non-insulin dependent diabetes (NIDDM) [abstract no. 0573]. Diabetes 1997; 46 Suppl. 1: 149AGoogle Scholar
  27. 27.
    Ghazzi MN, Perez JE, Antonucci TK, et al. Cardiac and glycemic benefits of troglitazone treatment in NIDDM. Diabetes 1997 Mar; 46: 433–9PubMedCrossRefGoogle Scholar
  28. 28.
    Iwamoto Y, Kosaka K, Kuzuya T, et al. Effect of combination therapy of troglitazone and sulphonylureas in patients with type 2 diabetes who were poorly controlled by sulphonylurea therapy alone. Diabetic Med 1996 Apr; 13: 365–70PubMedCrossRefGoogle Scholar
  29. 29.
    Iwamoto Y, Kosaka K, Kuzuya T, et al. Effects of troglitazone. A new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. Diabetes Care 1996 Feb; 19: 151–6PubMedCrossRefGoogle Scholar
  30. 30.
    Fukuda T, Nakano O, Amano M, et al. A clinical study of a new hypoglycemic agent, troglitazone, in type 2 diabetes patients who are unsatisfactorily-controlled with insulin [in Japanese]. Rinsho Iyaku 1995; 11(10): 2055–62Google Scholar
  31. 31.
    Kuzuya T, Iwamoto Y, Kosaka K, et al. An early phase II clinical trial of a new oral hypoglycemic drug, CS-045, in patients with non-insulin dependent diabetes mellitus [in Japanese]. Rinsho Iyaku 1993; 9 Suppl. 3: 3–18Google Scholar
  32. 32.
    Iwamoto Y, Kuzuya T, Matsuda A, et al. Effect of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NIDDM. Diabetes Care 1991 Nov; 14: 1083–6PubMedCrossRefGoogle Scholar
  33. 33.
    Antonucci T, Whitcomb R, McLain R, et al. Impaired glucose tolerance is normalized by treatment with the thiazolidinedione troglitazone. Diabetes Care 1997 Feb; 20(2): 188–93PubMedCrossRefGoogle Scholar
  34. 34.
    Nolan JJ, Ludvik B, Beerdsen P, et al. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994 Nov 3; 331: 1188–93PubMedCrossRefGoogle Scholar
  35. 35.
    US approval for troglitazone. Scrip 1997 Feb 7 (2204): 17Google Scholar
  36. 36.
    Foot EA, Williams ZV, Mohamed-Ali V, et al. Troglitazone but not glibenclamide reduces proinsulin-like molecules, risk factors for cardiovascular disease, in NIDDM patients [abstract no. 256]. Diabetologia 1996 Aug; 39 Suppl. 1: A69Google Scholar
  37. 37.
    Prigeon RL, Porte Jr D. Effect of troglitazone on proinsulin and insulin levels in persons with non-insulin dependent diabetes mellitus [abstract no. 1207]. Diabetes 1996 May; 45 Suppl. 2: 323AGoogle Scholar
  38. 38.
    Cominacini L, Garbin U, Pastorino AM, et al. Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells. Diabetologia 1997; 40: 165–72PubMedCrossRefGoogle Scholar
  39. 39.
    Cominacini L, Garbin U, Fratta Pasini A, et al. Troglitazone increases the resistance of LDL to oxidation in healthy volunteers [abstract no. 885]. Diabetologia 1996 Aug; 39 Suppl. 1: A233CrossRefGoogle Scholar
  40. 40.
    Akanuma Y, Kosaka K, Kuzuya T, et al. Long-term study of a new oral hypoglycemic agent CS-045 in patients with non-insulin dependent diabetes mellitus [in Japanese]. Rinsho Iyaku 1993; 9 Suppl. 3: 127–49Google Scholar
  41. 41.
    Yamada N, Akanuma Y, Murase T, et al. Clinical evaluation of a new oral hypoglycemic drug CS-045 in patients with non-insulin dependent diabetes mellitus accompanying hypertriglyceridemia [in Japanese]. Rinsho Iyaku 1993; 9 Suppl. 3: 165–78Google Scholar
  42. 42.
    Valiquett T, Huang S, Whitcomb R. Effects of troglitazone monotherapy in patients with NIDDM: a 6-month multicenter study [abstract no. 0168]. Diabetes 1997; 46 Suppl. 1: 43AGoogle Scholar
  43. 43.
    Law RE, Meehan WP, Xi X-P, et al. Troglitazone inhibits vascular smooth muscle cell growth and intimai hyperplasia. J Clin Invest 1996 Oct 15; 98: 1897–905PubMedCrossRefGoogle Scholar
  44. 44.
    Morikang E, Benson SC, Kurtz TW, et al. Effects of thiazolidinediones on growth and differentiation of human aorta and coronary myocytes. Am J Hypertens 1997; 10: 440–6PubMedGoogle Scholar
  45. 45.
    Dominguez LJ, Ofenstein JP, Sowers JR. Metformin and troglitazone decrease mitochondrial metabolism in vascular smooth muscle cells in contrast to insulin’s effects [abstract no. P3-857]. 10th ICE 1996 Jun 12; l2: 969Google Scholar
  46. 46.
    Goud C, Webb RC. The insulin-sensitizing agent CS-045 inhibits contraction of rat vascular smooth muscle [abstract]. Hypertension 1995 Sep; 26: 553Google Scholar
  47. 47.
    Walker A, Chattington P, Buckingham R, et al. Differential vasoactive effects of the insulin-sensitizers BRL 49653 and troglitazone on human resistance arteries in vitro [abstract no. 525]. Diabetes 1996 May; 45 Suppl. 2: 143AGoogle Scholar
  48. 48.
    Ren J, Dominguez LJ, Sowers JR, et al. Troglitazone attenuates high-glucose-induced abnormalities in relaxation and intracellular calcium in rat ventricular myocytes. Diabetes 1996 Dec; 45: 1822–5PubMedCrossRefGoogle Scholar
  49. 49.
    Fonseca V, Reynolds T, Hemphill D, et al. Effect of troglitazone on fibrinolysis and coagulation [abstract no. 0366]. Diabetes 1997; 46 Suppl. 1: 93AGoogle Scholar
  50. 50.
    Driscoll J, Ghazzi M, Perez J, et al. A 96-week follow-up on cardiac safety in patients with type II diabetes treated with troglitazone [abstract no. 0574]. Diabetes 1997; 46 Suppl. 1: 149AGoogle Scholar
  51. 51.
    Ogihara T, Rakugi H, Ikegami H, et al. Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives. Am J Hypertens 1995 Mar; 8: 316–20PubMedCrossRefGoogle Scholar
  52. 52.
    Shibata H, Nii S, Kobayashi M, et al. Phase I study of a new hypoglycemic agent CS-045 in healthy volunteers. Safety and pharmacokinetics in single administration [in Japanese]. Rinsho Iyaku 1993; 9(7): 1503–18Google Scholar
  53. 53.
    Shibata H, Nii S, Kobayashi M, et al. Phase I study of a new hypoglycemic agent CS-045 in healthy volunteers. Safety and pharmacokinetics in repeated administration [in Japanese]. Rinsho Iyaku 1993; 9(7): 1519–37Google Scholar
  54. 54.
    Yamanouchi T, Shinohara T, Tagaya T, et al. Pharmacokinetics study of a new oral hypoglycemic agent CS-045 in patients with non-insulin dependent diabetes mellitus [in Japanese]. Rinsho Iyaku 1995; 11(11): 2325–39Google Scholar
  55. 55.
    Parke-Davis. Rezulin™ (troglitazone) tablets. Prescribing information. Morris Plains, New Jersey, USA: Parke-Davis, 1997Google Scholar
  56. 56.
    Loi CM, Vassos AB, Randinitis EJ, et al. Pharmacokinetics of troglitazone in healthy subjects and in patients with type II diabetes mellitus [abstract no. PI-87]. Clin Pharmacol Ther 1997; 61(2): 159Google Scholar
  57. 57.
    Young MA, Williams ZV, Eastmond R. Similar pharmacokinetics of troglitazone in young and elderly subjects [abstract no. 882]. Diabetologia 1996 Aug; 39 Suppl. 1: A233Google Scholar
  58. 58.
    Shibukawa A, Sawada T, Nakao C, et al. High-performance frontal analysis for the study of protein binding of troglitazone (CS-045) in albumin solution and in human plasma. J Chromatogr A 1995 Apr 21; 697: 337–43PubMedCrossRefGoogle Scholar
  59. 59.
    Kawai K, Kawasaki-Tokui Y, Odaka T, et al. Disposition and metabolism of the new oral antidiabetic drug troglitazone in rats, mice and dogs. Arzneimittel Forschung 1997; 47(I): 356–8PubMedGoogle Scholar
  60. 60.
    Young MA, Robinson CE, Devoy MAB, et al. The influence of food on the pharmacokinetics of GR92132X, a thiazolidinedione, in healthy subjects [abstract]. Br J Clin Pharmacol 1994 May; 37: 482PGoogle Scholar
  61. 61.
    Püchler K, Sasahara K, Witte PU, et al. Lack of pharmacokinetic interaction between troglitazone and glibenclamide in NIDDM patients [abstract no. 880]. Diabetologia 1996 Aug; 39 Suppl. 1: A232Google Scholar
  62. 62.
    Kosaka K, Kuzuya T, Akanuma Y, et al. Clinical evaluation of a new oral hypoglycemic drug CS-045 in patients with non-insulin dependent diabetes mellitus poorly controlled by sulfonylureas. A double-blind, placebo-controlled study [in Japanese]. Rinsho Iyaku 1993; 9 Suppl. 3: 95–126Google Scholar
  63. 63.
    Akanuma Y, Kosaka K, Kuzuya T, et al. Clinical evaluation of a new oral hypoglycemic agent CS-045 in patients with non-insulin dependent diabetes mellitus poorly controlled by sulfonylureas. A dose-finding study by dose increasing method [in Japanese]. Rinsho Iyaku 1993; 9 Suppl. 3: 39–60Google Scholar
  64. 64.
    Akanuma Y, Kosaka K, Toyoda T, et al. Clinical evaluation of a new oral hypoglycaemic agent CS-045 in combination with insulin [poster]. Presented at the 56th Annual Scientific Sessions of the American Diabetes Association; 1996 Jun 8–11; San Francisco (CA)Google Scholar
  65. 65.
    Kosaka K, Toyota T, Kuzuya T, et al. Clinical evaluation of a new hypoglycemic agent CS-045 in combination with insulin. Igaku Ayumi 1996; 179(12-13): 951–79Google Scholar
  66. 66.
    Foot EA, Patel J, Williams ZV, et al. Improved metabolic control by addition of troglitazone to glibenclamide therapy in non-insulin-dependent diabetics [abstract no. 168]. Diabetologia 1995 Aug; 38 Suppl. 1: A44Google Scholar
  67. 67.
    Raskin P, Graveline JF. Efficacy of troglitazone in combination with insulin in NIDDM [abstract no. 0170]. Diabetes 1997; 46 Suppl. 1:44ACrossRefGoogle Scholar
  68. 68.
    Sankyo/Parke-Davis troglitazone post-approval interaction studies urged; narrow, type II diabetes indication wins unanimous approval recommendation. FDC Pink 1996 Dec 16; 58: 3–5Google Scholar
  69. 69.
    Ghazzi M, Mitchell-Radke L, Venable T, et al. Troglitazone improves glycemic control in patients with type II diabetes who are not optimally controlled on sulfonylurea [abstract no. 0169]. Diabetes 1997; 46 Suppl. 1: 44ACrossRefGoogle Scholar
  70. 70.
    Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic efects of troglitazone and metformin in NIDDM [abstract no. 0134]. Diabetes 1997; 46 Suppl. 1: 34ACrossRefGoogle Scholar
  71. 71.
    Kuzuya T, Iwamoto Y, Kosaka K, et al. A pilot clinical trial of a new oral hypoglycemic agent, CS-045, in patients with non-insulin dependent diabetes mellitus. Diabetes Res Clin Pract 1991 Mar; 11: 147–54PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1997

Authors and Affiliations

  • Caroline M. Spencer
    • 1
  • Anthony Markham
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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