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Combined Thiazolidinedione-Insulin Therapy

Should We Be Concerned About Safety?

  • Current Opinion
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Abstract

Thiazolidinediones, also called glitazones, are insulin sensitisers that act as agonists of the peroxisome proliferator-activated receptors-gamma (PPARγ). After the withdrawal of troglitazone due to hepatotoxicity, only pioglitazone and rosiglitazone can be used for treating patients with type 2 diabetes mellitus, either as monotherapy or in combination with metformin or with sulphonylureas (or glinides). The combination of glitazones with insulin is also appealing, as it allows improvement of glycaemic control while decreasing the daily insulin requirement. Insulin dosage has to be adjusted regularly to avoid hypoglycaemic episodes. However, some concerns have been raised about such combined glitazone-insulin therapy because it may favour weight gain due to both enhanced adipogenesis and fluid retention. Such adverse effects are commonly observed in all diabetic individuals receiving glitazones, whatever the mode of use, but they appear to be exacerbated in insulin-treated patients. Body fat gain is a major drawback of treatment with adipogenic compounds such as glitazones. However, some evidence suggests that the fat is redistributed in a favourable direction, that is, from visceral to subcutaneous depots, although no long-term follow-up is yet available. An estimated 2–5% of patients receiving glitazone monotherapy and 5–15% receiving concomitant insulin therapy experience peripheral oedema. Some anecdotal cases of pulmonary oedema have also been reported, especially in insulin-treated patients, although the actual incidence of this complication is unknown. All glitazones increase the intravascular volume by approximately 6–7% in a dose-dependent manner. Rather than a direct effect on cardiac or renal function, fluid retention and tissue oedema seem to be part of a vascular ‘leak’ syndrome. Such a phenomenon may have greater consequences in patients with type 2 diabetes treated with insulin because such patients are usually older, have had the disease long-term and have worse cardiac or renal function. Additionally, glitazones may potentiate the renal effects of insulin on sodium and water retention. Regardless of the mechanism, it is conceivable that additional fluid retention caused by glitazones may alter the already precarious volume status in patients with underlying cardiac or renal dysfunction, thus leading to oedema and congestive heart failure. Thus, it is prudent to either avoid glitazones or use them cautiously in individuals with impaired cardiac function. Further studies are clearly needed to define the mechanisms of fluid retention associated with glitazone use and to determine the safety of cautious use of these new insulin sensitisers in insulin-treated patients with type 2 diabetes.

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References

  1. Scheen AJ, Lefebvre PJ. Pathophysiology of type 2 diabetes. In: Kuhlmann J, Puls W, editors. Handbook of experimental pharmacology, oral antidiabetics. Berlin: Springer Verlag, 1996: 7–42

    Google Scholar 

  2. Scheen AJ, Lefebvre PJ. Insulin resistance versus insulin deficiency: which one comes first? The old question revisited. In: Di Mario U, Leonetti F, Pugliese G, et al., editors. Diabetes in the new millennium. New York: Wiley & Sons, 2000: 101–13

    Google Scholar 

  3. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 2003; 46: 3–19

    Article  PubMed  CAS  Google Scholar 

  4. Turner RC, Cull CA, Frighi V, et al. Glycaemic control with diet, sulfonylurea, metformin or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999; 281: 2005–12

    Article  PubMed  CAS  Google Scholar 

  5. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care 2003; 26 Suppl. 1: S33–50

    Google Scholar 

  6. Scheen AJ. Drug treatment of non-insulin-dependent diabetes mellitus in the 1990s: achievements and future developments. Drugs 1997; 54: 355–68

    Article  PubMed  CAS  Google Scholar 

  7. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999; 131: 281–303

    PubMed  CAS  Google Scholar 

  8. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002; 287: 360–72

    Article  PubMed  CAS  Google Scholar 

  9. Scheen AJ, Lefebvre PJ. Treatment of diabetes mellitus. In: Sirtori C, editor. Clinical pharmacology. London: McGraw Hill, 2000: 685–98

    Google Scholar 

  10. Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes. Diabetes Rev 1995; 3: 308–34

    Google Scholar 

  11. Scheen AJ. Insulin therapy in the treatment of NIDDM. International Diabetes Federation Bulletin 1996; 41: 16–8

    Google Scholar 

  12. Herman LS. Optimising therapy for insulin-treated type 2 diabetes mellitus. Drugs Aging 2000; 17: 283–94

    Article  Google Scholar 

  13. European Diabetes Policy Group. A desktop guide to type 2 diabetes mellitus. Diabet Med 1999; 16: 716–30

    Google Scholar 

  14. Lebovitz HE. Stepwise and combination drug therapy for the treatment of NIDDM. Diabetes Care 1994; 17: 1542–4

    PubMed  CAS  Google Scholar 

  15. Scheen AJ, Lefebvre PJ. Oral antidiabetic drugs: a guide to selection. Drugs 1998; 55: 225–36

    Article  PubMed  CAS  Google Scholar 

  16. Buse J. Combining insulin and oral agents. Am J Med 2000; 108Suppl. 6A: 23S–32S

    Article  PubMed  CAS  Google Scholar 

  17. Yki-Jarvinen H. Combination therapies with insulin in type 2 diabetes. Diabetes Care 2001; 24: 758–67

    Article  PubMed  CAS  Google Scholar 

  18. Garber AJ. Benefits of combination therapy of insulin and oral hypoglycaemic agents. Arch Intern Med 2003; 163: 1781–2

    Article  PubMed  CAS  Google Scholar 

  19. Yki-Jarvinen H, Ryysy L, Nikkila K, et al. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus: a randomized, controlled trial. Ann Intern Med 1999; 130: 389–96

    PubMed  CAS  Google Scholar 

  20. Makimattila S, Nikkila K, Yki-Jarvinen H. Causes of weight gain during insulin therapy with and without metformin in patients with type II diabetes mellitus. Diabetologia 1999; 42: 406–12

    Article  PubMed  CAS  Google Scholar 

  21. 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 

  22. Day C. Thiazolidinediones: a new class of antidiabetic drugs. Diabet Med 1999; 16: 179–92

    Article  PubMed  CAS  Google Scholar 

  23. Mudalar S, Henry RR. New oral therapies for type 2 diabetes mellitus: the glitazones or insulin sensitizers. Annu Rev Med 2001; 52: 239–57

    Article  Google Scholar 

  24. Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 2001; 70: 341–67

    Article  PubMed  CAS  Google Scholar 

  25. Stumvoll M, Haring HU. Glitazones: clinical effects and molecular mechanisms. Ann Med 2002; 34: 217–24

    PubMed  CAS  Google Scholar 

  26. Spencer CM, Markham A. Troglitazone. Drugs 1997; 54: 89–101

    Article  PubMed  CAS  Google Scholar 

  27. Scheen AJ, Lefebvre PJ. Troglitazone: antihyperglycemic activity and potential role in the treatment of type 2 diabetes. Diabetes Care 1999; 22: 1568–77

    Article  PubMed  CAS  Google Scholar 

  28. Gale EA. Lessons from the glitazones: a story of drug development. Lancet 2001; 357: 1870–5

    Article  PubMed  CAS  Google Scholar 

  29. Scheen AJ. Hepatotoxicity with thiazolidinediones: is it a class effect? Drug Saf 2001; 24(12): 873–88

    Article  PubMed  CAS  Google Scholar 

  30. Gillies PS, Dunn CJ. Pioglitazone. Drugs 2000; 60: 333–43

    Article  PubMed  CAS  Google Scholar 

  31. Schatz H, Massi-Benedetti M, editors. Pioglitazone: from discovery to clinical practice. Exp Clin Endocrinol Diabetes 2000; 108Suppl. 2: S221–80

    Google Scholar 

  32. Chilcott J, Tappenden P, Lloyd Jones M, et al. A systematic review of the clinical effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus. Clin Ther 2001; 23: 1792–823

    Article  PubMed  CAS  Google Scholar 

  33. Balfour JA, Plosker GL. Rosiglitazone. Drugs 1999; 57: 921–30

    Article  PubMed  CAS  Google Scholar 

  34. Malinowski JM, Bolesta S. Rosiglitazone in the treatment of type 2 diabetes mellitus: a critical review. Clin Ther 2000; 22: 1151–68

    Article  PubMed  CAS  Google Scholar 

  35. Wagstaff AJ, Goa KL. Rosiglitazone: a review of its use in the management of type 2 diabetes mellitus. Drugs 2002; 62: 1805–37

    Article  PubMed  CAS  Google Scholar 

  36. Braunstein S. New developments in type 2 diabetes mellitus: combination therapy with a thiazolidinedione. Clin Ther 2003; 25: 1895–917

    Article  PubMed  CAS  Google Scholar 

  37. Diamant M, Heine RJ. Thiazolidinediones in type 2 diabetes mellitus. Current clinical evidence. Drugs 2003; 63: 1373–405

    Article  PubMed  CAS  Google Scholar 

  38. Yu JG, Kruszynska YT, Mulford MI, et al. A comparison of troglitazone and metformin on insulin requirements in euglycemic intensively insulin-treated type 2 diabetic patients. Diabetes 1999; 48: 2414–21

    Article  PubMed  CAS  Google Scholar 

  39. Campbell IA. Antidiabetic drugs present and future: will improving insulin resistance benefit cardiovascular risk in type 2 diabetes mellitus? Drugs 2000; 60: 1017–28

    Article  PubMed  CAS  Google Scholar 

  40. Fujiwara T, Horikoshi H. Troglitazone and related compounds: therapeutic potential beyond diabetes. Life Sci 2000; 67: 2405–16

    Article  PubMed  CAS  Google Scholar 

  41. Parulkar AA, Pendergrass ML, Granda-Ayala R, et al. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med 2001; 134: 61–71

    PubMed  CAS  Google Scholar 

  42. Martens FM, Visseren FL, Lemay J, et al. Metabolic and additional vascular effects of thiazolidinediones. Drugs 2002; 62: 1463–80

    Article  PubMed  CAS  Google Scholar 

  43. Ovalle F, Fernando OB. Thiazolidinediones: a review of their benefits and risks. South Med J 2002; 95: 1188–94

    PubMed  Google Scholar 

  44. Wang CH, Weisel RD, Liu PP, et al. Glitazones and heart failure: critical appraisal for the clinician. Circulation 2003; 107: 1350–4

    Article  PubMed  Google Scholar 

  45. McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 2001; 86: 713–8

    Article  PubMed  CAS  Google Scholar 

  46. Wheatcroft SB, Williams IL, Shah AM, et al. Pathophysiological implications of insulin resistance on vascular endothelial function. Diabet Med 2003; 20: 255–68

    Article  PubMed  CAS  Google Scholar 

  47. Olansky L, Marchetti A, Lau H. Multicenter retrospective assessment of thiazolidinedione monotherapy and combination therapy in patients with type 2 diabetes: comparative subgroup analyses of glycemic control and blood lipid levels. Clin Ther 2003; 25: B64–80

    Article  PubMed  CAS  Google Scholar 

  48. Schwartz S, Raskin P, Fonseca V, et al. Effect of troglitazone in insulin treated patients with type 2 diabetes. N Engl J Med 1998; 338: 861–6

    Article  PubMed  CAS  Google Scholar 

  49. Leiter L, Ross S, Halle J-P, et al. Efficacy and safety of troglitazone in type 2 diabetic patients inadequately controlled on insulin therapy [abstract]. Diabetes 1999; 48Suppl. 1: A115

    Google Scholar 

  50. Buse J, Gumbiner B, Mathias NP, et al. for the Troglitazone Insulin Study Group. Troglitazone use in insulin-treated type 2 diabetic patients. Diabetes Care 1998; 21: 1455–61

    Article  PubMed  CAS  Google Scholar 

  51. Rosenstock J, Einhorn D, Hershon K, et al. and the Pioglitazone 014 Study Group. Efficacy and safety of pioglitazone in type 2 diabetes: a randomised, placebo-controlled study in patients receiving stable insulin therapy. Int J Clin Pract 2002; 56: 251–7

    PubMed  CAS  Google Scholar 

  52. Raskin P, Rendell M, Riddle MC, et al. for the Rosiglitazone Clinical Trials Study Group. A randomised trial of rosiglitazone therapy in patients with inadequately controlled insulin treated type 2 diabetes. Diabetes Care 2001; 24: 1226–32

    Article  PubMed  CAS  Google Scholar 

  53. Davidson J, Perez A, Popovici C, et al. Addition of pioglitazone to stable insulin therapy in poorly controlled patients with type 2 diabetes: results of a double-blind, multicenter, randomized study [abstract]. Diabetes 2003; 52Suppl. 1: A445

    Google Scholar 

  54. Raz I, Stranks S, Filipczak R, et al. In inadequately controlled patients with type 2 diabetes, biphasic insulin aspart 30 combined with pioglitazone provides better glycemic control than biphasic insulin aspart 30 monotherapy or pioglitazone/sulfonylurea combination [abstract]. Diabetes 2003; 52Suppl. 1: A453–4

    Google Scholar 

  55. Buch HN, Baskar V, Barton DM, et al. Combination of insulin and thiazolidinedione therapy in massively obese patients with type 2 diabetes. Diabet Med 2002; 19: 572–4

    Article  PubMed  CAS  Google Scholar 

  56. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care 2003; 26: 1902–12

    Article  PubMed  CAS  Google Scholar 

  57. Scheen AJ. Obesity and diabetes. In: Kopelman PG, editor. The management of obesity and related disorders. London: Martin Dunitz, 2001: 11–44

    Google Scholar 

  58. Montague CT, O’Rahilly S. The perils of portliness: causes and consequences of visceral adiposity. Diabetes 2000; 49: 883–8

    Article  PubMed  CAS  Google Scholar 

  59. Scheen AJ. Current management strategies for coexisting diabetes mellitus and obesity. Drugs 2003; 63: 1165–84

    Article  PubMed  CAS  Google Scholar 

  60. Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998; 47: 507–14

    Article  PubMed  CAS  Google Scholar 

  61. Scheen AJ. Glitazones et prise de poids. Ann Endocrinol 2002; 63: 1S41–4

    CAS  Google Scholar 

  62. Larsen TM, Toubro S, Astrup A. PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy? Int J Obes Relat Metab Disord 2003; 27: 147–61

    Article  PubMed  CAS  Google Scholar 

  63. Shimizu H, Tsuchiya T, Sato N, et al. Troglitazone reduces plasma leptin concentrations but increases hunger in NIDDM patients. Diabetes Care 1998; 21: 1470–4

    Article  PubMed  CAS  Google Scholar 

  64. Kelly IE, Han TS, Walsh K, et al. Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care 1999; 22: 288–93

    Article  PubMed  CAS  Google Scholar 

  65. Mori Y, Murakawa Y, Okada K, et al. Effect of troglitazone on body fat distribution in type 2 diabetic patients. Diabetes Care 1999; 22: 908–12

    Article  PubMed  CAS  Google Scholar 

  66. Kawai T, Takei I, Oguma Y, et al. Effects of troglitazone on fat distribution in the treatment of male type 2 diabetes. Metabolism 1999; 48: 1102–7

    Article  PubMed  CAS  Google Scholar 

  67. Akazawa S, Sun F, Ito M, et al. Efficacy of troglitazone on body fat distribution in type 2 diabetes. Diabetes Care 2000; 23: 1067–71

    Article  PubMed  CAS  Google Scholar 

  68. Katoh S, Hata S, Matsushima M, et al. Troglitazone prevents the rise in visceral adiposity and improves fatty liver associated with sulfonylurea therapy: a randomized controlled trial. Metabolism 2001; 50: 414–7

    Article  PubMed  CAS  Google Scholar 

  69. de Souza CJ. Eckhardt M, Gagen K, et al. Effects of pioglitazone on adipose tissue remodelling within the setting of obesity and insulin resistance. Diabetes 2001; 50: 1863–71

    Article  PubMed  Google Scholar 

  70. Nakamura T, Funahashi T, Yamashita S, et al. Thiazolidinedione derivative improves fat distribution and multiple risk factors in subjects with visceral fat accumulation: double-blind placebo-controlled trial. Diabetes Res Clin Pract 2001; 54: 181–90

    Article  PubMed  CAS  Google Scholar 

  71. Miyazaki Y, Mahankali A, Matsuda M, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002; 87: 2784–91

    Article  PubMed  CAS  Google Scholar 

  72. Carey DG, Cowin GJ, Galloway GJ, et al. Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients. Obes Res 2002; 10: 1008–15

    Article  PubMed  CAS  Google Scholar 

  73. Shadid S, Jensen MD. Effects of pioglitazone versus diet and exercise on metabolic health and fat distribution in upper body obesity. Diabetes Care 2003; 26: 3148–52

    Article  PubMed  CAS  Google Scholar 

  74. Virtanen KA, Hallsten K, Parkkola R, et al. Differential effects of rosiglitazone and metformin on adipose tissue distribution and glucose uptake in type 2 diabetic subjects. Diabetes 2003; 52: 283–90

    Article  PubMed  CAS  Google Scholar 

  75. Sewter CP, Blows F, Vidal-Puig A, et al. Regional differences in the response of human pre-adipocytes to PPPARgamma and RXRalpha agonists. Diabetes 2002; 51: 718–23

    Article  PubMed  CAS  Google Scholar 

  76. Adams M, Montague CT, Prins JB, et al. Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation. J Clin Invest 1997; 100: 3149–53

    Article  PubMed  CAS  Google Scholar 

  77. King AB, Armstrong D. Characteristics of the patients who gain weight while on pioglitazone treatment [abstract]. Diabetes 2001; 50Suppl. 1: A120

    Google Scholar 

  78. Nichols GA, Erbey JR, Hillier TA, et al. Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors. Diabetes Care 2001; 23: 1614–9

    Article  Google Scholar 

  79. Bell DSH. Heart failure: the frequent, forgotten, and often fatal complication of diabetes. Diabetes Care 2003; 26: 2433–41

    Article  PubMed  Google Scholar 

  80. Bauters C, Lamblin N, McFadden EP, et al. Influence of diabetes mellitus on heart failure risk and outcomes. Cardiovasc Diabetol 2003; 2: 1–16

    Article  PubMed  Google Scholar 

  81. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham Study. Am J Cardiol 1974; 34: 29–34

    Article  PubMed  CAS  Google Scholar 

  82. Kennedy FP. Do thiazolidinediones cause congestive heart failure? Mayo Clin Proc 2003; 78: 1076–7

    Article  PubMed  CAS  Google Scholar 

  83. Ogawa S, Takeuchi K, Ito S. Plasma BNP levels in the treatment of type 2 diabetes with pioglitazone. J Clin Endocrinol Metab 2003; 88: 3993–6

    Article  PubMed  CAS  Google Scholar 

  84. El Muayed M, Lavis VR, Safi HJ, et al. Use of glitazones in cardiac patients: case for B-type natriuretic peptide monitoring? Am J Cardiol 2004; 93: 600–2

    Article  PubMed  CAS  Google Scholar 

  85. Paolisso G, De Riu S, Marrazzo G, et al. Insulin resistance and hyperinsulinemia in patients with chronic congestive heart failure. Metabolism 1991; 40: 972–7

    Article  PubMed  CAS  Google Scholar 

  86. Swan JW, Walton C, Godsland IF, et al. Insulin resistance in chronic heart failure. Eur Heart J 1994; 15: 1528–32

    PubMed  CAS  Google Scholar 

  87. Coats AJ, Anker SD. Insulin resistance in chronic heart failure. J Cardiovasc Pharmacol 2000; 35Suppl. 4: S9–14

    Article  PubMed  CAS  Google Scholar 

  88. Swan JW, Anker SD, Walton C, et al. Insulin resistance in chronic heart failure: relation to severity and etiology of heart failure. J Am Coll Cardiol 1997; 30: 527–32

    Article  PubMed  CAS  Google Scholar 

  89. Suskin N, McKelvie RS, Burns RJ, et al. Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure. Eur Heart J 2000; 21: 1368–75

    Article  PubMed  CAS  Google Scholar 

  90. Amato L, Paolisso G, Cacciatore F, et al. Congestive heart failure predicts the development of non-insulin-dependent diabetes mellitus in the elderly. The Osservatorio Geriatrico Regione Campania Group. Diabetes Metab 1997; 23: 213–8

    PubMed  CAS  Google Scholar 

  91. Tenenbaum A, Motro M, Fisman EZ, et al. Functional class in patients with heart failure is associated with the development of diabetes. Am J Med 2003; 114: 271–5

    Article  PubMed  Google Scholar 

  92. Solang L, Malmberg K, Ryden L. Diabetes mellitus and congestive heart failure: further knowledge needed. Eur Heart J 1999; 20: 789–95

    Article  PubMed  CAS  Google Scholar 

  93. Norhammar A, Malmberg K. Heart failure and glucose abnormalities: an increasing combination with poor functional capacity and outcome. Eur Heart J 2000; 21: 1293–4

    Article  PubMed  CAS  Google Scholar 

  94. Grundy SM. Higher incidence of new-onset diabetes in patients with heart failure. Am J Med 2003; 114: 331–2

    Article  PubMed  Google Scholar 

  95. Bishop-Bailey D. Peroxisome proliferator-activated receptors in the cardiovascular system. Br J Pharmacol 2000; 129: 823–34

    Article  PubMed  CAS  Google Scholar 

  96. Viberti GC. Rosiglitazone: potential beneficial impact on cardiovascular disease. Int J Clin Pract 2003; 57: 128–34

    PubMed  CAS  Google Scholar 

  97. Wooltorton E. Rosiglitazone (Avandia) and pioglitazone (Actos) and heart failure [letter]. CMAJ 2002; 166: 219

    PubMed  Google Scholar 

  98. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure. A consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004; 27: 256–63

    Article  PubMed  CAS  Google Scholar 

  99. Young MM, Squassante L, Wemer J, et al. Troglitazone has no effect on red cell mass or other erythropoietic parameters. Eur J Clin Pharmacol 1999; 55: 101–4

    Article  PubMed  CAS  Google Scholar 

  100. McMorran M. Rosiglitazone (Avandia): hepatic, cardiac and hematological reactions. CMAJ 2001; 165: 82–3

    PubMed  CAS  Google Scholar 

  101. Gorson DM. Significant weight gain with Rezulin therapy [letter]. Arch Intern Med 1999; 159: 99

    Article  PubMed  CAS  Google Scholar 

  102. Bell DSH. Unilateral edema due to a thiazolidinedione [letter]. Diabetes Care 2003; 26: 2700

    Article  PubMed  Google Scholar 

  103. Hirsch IB, Kelly J, Cooper S. Pulmonary edema associated with troglitazone therapy [letter]. Arch Intern Med 1999; 159: 1811

    Article  PubMed  CAS  Google Scholar 

  104. Inoue K, Sano H. Troglitazone-induced pulmonary edema. Arch Intern Med 2000; 160: 871–2

    Article  PubMed  CAS  Google Scholar 

  105. Thomas ML, Lloyd SJ. Pulmonary edema associated with rosiglitazone and troglitazone. Ann Pharmacother 2001; 35: 123–4

    Article  PubMed  CAS  Google Scholar 

  106. Kermani A, Garg A. Thiazolidinedione-associated congestive heart failure and pulmonary edema. Mayo Clin Proc 2003; 78: 1088–91

    Article  PubMed  CAS  Google Scholar 

  107. Eckland D, Urquhart R, Edwards GC, et al. Cardiac safety of pioglitazone in comparison with metformin and gliclazide [abstract]. Diabetologia 2003; 46Suppl. 2: A291

    Google Scholar 

  108. Rosak C, Standl E, Stammer H, et al. Rosiglitazone is effective and safe in clinical practice [abstract]. Diabetologia 2003; 46Suppl. 2: A291–2

    Google Scholar 

  109. King KA, Levi VE. Prevalence of edema in patients receiving combination therapy with insulin and thiazolidinedione. Am J Health Syst Pharm 2004; 61: 390–3

    PubMed  Google Scholar 

  110. DeFronzo RA. The effect of insulin on renal sodium metabolism: a review with clinical implications. Diabetologia 1981; 21: 779–84

    Article  Google Scholar 

  111. Stenvinkel P, Bolinder J, Alvestrand A. Effects of insulin on renal haemodynamics and the proximal and distal tubular sodium handling in healthy subjects. Diabetologia 1992; 35: 1042–8

    Article  PubMed  CAS  Google Scholar 

  112. Muscelli E, Natali A, Bianchi S, et al. Effect of insulin on renal sodium and uric acid handling in essential hypertension. Am J Hypertens 1996; 9: 746–52

    Article  PubMed  CAS  Google Scholar 

  113. Takeda Pharmaceuticals America. Actos® (pioglitazone hydrochloride) tablets, prescribing information [online]. Available from URL: http://www.actos.com/pi.pdf [Accessed 2004 Aug 31]

  114. GlaxoSmithKline. Avandia® (rosiglitazone maleate) tablets, prescribing information [online] Available from URL: http://us-gsk.com/products/assets/us_avandia.pdf [Accessed 2004 Aug 31]

  115. Cheng AY, Fantus IG. Thiazolidinedione-induced congestive heart failure. Ann Pharmacother 2004, 38: 817–20

    Article  PubMed  Google Scholar 

  116. Singh N. Rosiglitazone and heart failure: long-term vigilance. J Cardiovasc Pharmacol Ther 2004; 9: 21–5

    Article  PubMed  Google Scholar 

  117. Benbow A, Stewart M, Yeoman G. Thiazolidinediones for type 2 diabetes: all glitazones may exacerbate heart failure [letter]. BMJ 2001; 322: 236

    Article  PubMed  CAS  Google Scholar 

  118. Niemeyer NV, Janney LM. Thiazolidinedione-induced edema. Pharmacotherapy 2002; 22: 924–9

    Article  PubMed  Google Scholar 

  119. Masoudi FA, Wang Y, Inzucchi SE, et al. Metformin and thiazolidinedione use in medicare patients with heart failure. JAMA 2003; 290: 81–5

    Article  PubMed  CAS  Google Scholar 

  120. United States Food and Drug Administration hearing on pioglitazone. Available from URL: http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3507t2.rtf [Accessed 1999 May 18]

  121. Delea TE, Edelsberg JS, Hagiwara M, et al. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study. Diabetes Care 2003; 26: 2983–9

    Article  PubMed  CAS  Google Scholar 

  122. Tang WHW, Francis GS, Hoogwerf BJ, et al. Fluid retention after initiation of thiazolidinedione therapy in diabetic patients with established chronic heart failure. J Am Coll Cardiol 2003; 41: 1394–8

    Article  PubMed  CAS  Google Scholar 

  123. Malone RM, DeWalt DA, Pignone MP, et al. Is the tolerability of long-term thiazolidinedione therapy overstated? [letter]. J Am Coll Cardiol 2003; 42: 1334–5

    Article  PubMed  Google Scholar 

  124. Mayfield R, McLean D, Crook D, et al. CS-045 toxicity to the cynomolgus monkeys by repeated oral administration for 52 weeks. J Clin Ther Med 1993; 9Suppl. 3: 317–41

    Google Scholar 

  125. Yamamoto K, Ohli R, Lee RT, et al. Peroxisome proliferator-activated receptor-gamma activators inhibit cardiac hypertrophy in cardiac monocytes. Circulation 2001; 104: 1670–5

    Article  PubMed  CAS  Google Scholar 

  126. Yue T, Chen J, Bao W, et al. In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone. Circulation 2001; 104: 2588–94

    Article  CAS  Google Scholar 

  127. Kawabata H, Ishikawa K. Cardioprotection with pioglitazone is abolished by nitric oxide synthase inhibitor in ischemic rabbit hearts: comparison of the effects of pioglitazone and metformin. Diabetes Metab Res Rev 2003; 19: 299–305

    Article  PubMed  CAS  Google Scholar 

  128. Ghazzi MN, Perez JE, Antonucci TK, et al. the Troglitazone Study Group. Cardiac and glycemic benefits of troglitazone treatment in NIDDM. Diabetes 1997; 46: 433–9

    Article  PubMed  CAS  Google Scholar 

  129. St John Sutton M, Rendall M, Dandona P, et al. A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care 2002; 25: 2058–64

    Article  PubMed  Google Scholar 

  130. Haffner SM, Greenberg AS, Weston WM, et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002; 106: 679–84

    Article  PubMed  CAS  Google Scholar 

  131. Koshiyama H, Shimono D, Kuwamura N, et al. 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 

  132. Ogino K, Furuse Y, Uchida K, et al. Troglitazone improves cardiac function in patients with congestive heart failure. Cardiovasc Drugs Ther 2002; 16: 215–20

    Article  PubMed  CAS  Google Scholar 

  133. Mizushige K, Tsuji T, Noma T. Pioglitazone: cardiovascular effects in prediabetic patients. Cardiovasc Drug Rev 2002; 20: 329–40

    Article  PubMed  CAS  Google Scholar 

  134. Idris I, Gray S, Donnelly R. Rosiglitazone and pulmonary oedema: an acute dose-dependent effect on human endothelialcell permeability. Diabetologia 2003; 46: 288–90

    PubMed  CAS  Google Scholar 

  135. Fukunaga Y, Itoh H, Doi K, et al. Thiazolidinediones, peroxisome proliferator-activated receptor-gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides. Atherosclerosis 2001; 158: 113–9

    Article  PubMed  CAS  Google Scholar 

  136. Emoto M, Anno T, Sato Y, et al. Troglitazone treatment increases plasma vascular endothelial growth factor in diabetic patients and its mRNA in 3T3-L1 adipocytes. Diabetes 2001; 50: 1166–70

    Article  PubMed  CAS  Google Scholar 

  137. Baba T, Shimada K, Neugenhauer S, et al. The oral insulin sensitizer, thiazolidinedione, increases plasma vascular endothelial growth factor in type 2 diabetic patients [letter]. Diabetes Care 2001; 24: 953–4

    Article  PubMed  CAS  Google Scholar 

  138. Manley HJ, Allcock NM. Thiazolidinedione safety and efficacy in ambulatory patients receiving hemodialysis. Pharmacotherapy 2003; 23: 861–5

    Article  PubMed  CAS  Google Scholar 

  139. Graham DJ, Drinkard CR, Shatin D. Incidence of idiopathic acute liver failure and hospitalised liver injury in patients treated with troglitazone. Am J Gastroenterol 2003; 98: 175–9

    Article  PubMed  CAS  Google Scholar 

  140. Tolman KG. Thiazolidinedione hepatotoxicity: a class effect? Int J Clin Pract Suppl 2000; 113: 29–34

    PubMed  CAS  Google Scholar 

  141. Van Gaal L, Scheen AJ. Are all glitazones the same? Diabetes Metab Res Rev 2002; 18: S1–4

    Article  PubMed  CAS  Google Scholar 

  142. Scheen AJ, Luyckx FH. Liver disease in obesity. Best Pract Res Clin Endocrinol Metab 2002; 16: 703–16

    Article  PubMed  CAS  Google Scholar 

  143. Jick SS, Stender M, Myers MW. Frequency of liver disease in type 2 diabetic patients treated with oral antidiabetic agents. Diabetes Care 1999; 22: 2067–71

    Article  PubMed  CAS  Google Scholar 

  144. Belcher G, Matthews DR. Safety and tolerability of pioglitazone. Exp Clin Endocrinol Diabetes 2000; 108Suppl. 2: S267–73

    Article  Google Scholar 

  145. Belcher G, Lambert C, Edwards GC, et al. Results of liver safety testing in 3713 type 2 diabetic patients treated for one year in double blind controlled trials with pioglitazone, metformin or gliclazide [abstract]. Diabetologia 2003; 4Suppl. 2: A291

    Google Scholar 

  146. Lebovitz HE, Kreider M, Freed MI. Evaluation of liver function in type 2 diabetic patients during clinical trials: evidence that rosiglitazone does not cause hepatic dysfunction. Diabetes Care 2002; 25: 815–21

    Article  PubMed  CAS  Google Scholar 

  147. Mayerson AB, Hundal RS, Dufour S, et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 2002; 51: 797–802

    Article  PubMed  CAS  Google Scholar 

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  1. Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Sart Tilman (B35), B4000, Liége 1, Belgium

    André J. Scheen

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Scheen, A.J. Combined Thiazolidinedione-Insulin Therapy. Drug-Safety 27, 841–856 (2004). https://doi.org/10.2165/00002018-200427120-00002

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