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Impact of thiazolidenediones on serum lipoprotein levels

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Abstract

The thiazolidinediones, acting through peroxisome proliferator-activated receptor γ (PPARγ), affect multiple areas of metabolism. Of increasing importance is the recognition that these agents affect lipoprotein metabolism and cause changes in serum lipid and lipoprotein levels. All three thiazolidinediones, including troglitazone (which was withdrawn in the year 2000), rosiglitazone, and pioglitazone, tend to increase highdensity lipoprotein (HDL) cholesterol, increase the size/decrease the density of low-density lipoprotein (LDL) particles, and raise the level of lipoprotein(a). In addition, troglitazone and pioglitazone, but not rosiglitazone, lower triglyceride levels modestly, thereby further contributing to increases in LDL and HDL size. The mechanism for these effects is still being clarified, but may involve enhancement of triglyceride clearance (in the case of pioglitazone), alteration of apolipoprotein C-III levels, reduction of hepatic lipase, and increase in ATP binding cassette A1 (ABCA1) activity. The clinical implications of these effects need further exploration.

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References and Recommended Reading

  1. Reynolds K, Goldberg RB: Thiazolidinediones: beyond glycemic control. Treat Endocrinol 2006, 5:25–36.

    Article  PubMed  Google Scholar 

  2. Ikeda H, Taketomi S, Sugiyama Y, et al.: Effects of pioglitazone on glucose and lipid metabolism in normal and insulin resistant animals. Arzneimittelforschung 1990, 40:156–162.

    PubMed  CAS  Google Scholar 

  3. van Wijk JP, de Koning EJ, Martens EP, et al.: Thiazolidinediones and blood lipids in type 2 diabetes. Arterioscler Thromb Vasc Biol 2003, 23:1744–1749.

    Article  PubMed  Google Scholar 

  4. Chiquette E, Ramirez G, Defronzo R: A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch Intern Med 2004, 164:2097–2104.

    Article  PubMed  CAS  Google Scholar 

  5. Goldberg RB, Capuzzi D: Lipid disorders in type 1 and type 2 diabetes. Clin Lab Med 2001, 21:147–172.

    PubMed  CAS  Google Scholar 

  6. Schwartz S, Raskin P, Fonseca V, et al.: Effect of troglitazone in insulin-treated patients with type II diabetes mellitus. Troglitazone and Exogenous Insulin Study Group. N Engl J Med 1998, 338:861–866.

    Article  PubMed  CAS  Google Scholar 

  7. Horton ES, Whitehouse F, Ghazzi MN, et al.: Troglitazone in combination with sulfonylurea restores glycemic control in patients with type 2 diabetes. The Troglitazone Study Group. Diabetes Care 1998, 21:1462–1469.

    Article  PubMed  CAS  Google Scholar 

  8. Yale JF, Valiquett TR, Ghazzi MN, et al.: The effect of a thiazolidinedione drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus poorly controlled with sulfonylurea and metformin. A multicenter, randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001, 134:737–745.

    PubMed  CAS  Google Scholar 

  9. Gomez-Perez FJ, Aguilar-Salinas CA, Vazquez-Chavez C, et al.: Further insight on the hypoglycemic and nonhypoglycemic effects of troglitazone 400 or 600 mg/d: effects on the very-low-density and high-density lipoprotein particle distribution. Metabolism 2002, 51:44–51.

    Article  PubMed  CAS  Google Scholar 

  10. Chu NV, Kong AP, Kim DD, et al.: Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care 2002, 25:542–549.

    Article  PubMed  CAS  Google Scholar 

  11. Kerenyi Z, Samer H, James R, et al.: Combination therapy with rosiglitazone and glibenclamide compared with upward titration of glibenclamide alone in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2004, 63:213–223.

    Article  PubMed  CAS  Google Scholar 

  12. Derosa G, Cicero AF, Gaddi A, et al.: A comparison of the effects of pioglitazone and rosiglitazone combined with glimepiride on prothrombotic state in type 2 diabetic patients with the metabolic syndrome. Diabetes Res Clin Pract 2005, 69:5–13.

    Article  PubMed  CAS  Google Scholar 

  13. Khan M, Xu Y, Edwards G, et al.: Effects of pioglitazone on the components of diabetic dyslipidaemia: results of double-blind, multicentre, randomised studies. Int J Clin Pract 2004, 58:907–912.

    Article  PubMed  CAS  Google Scholar 

  14. Tan MH, Johns D, Strand J, et al.: Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control, and lipid profiles in patients with Type 2 diabetes. Diabet Med 2004, 21:859–866.

    Article  PubMed  CAS  Google Scholar 

  15. Betteridge DJ, Verges B: Long-term effects on lipids and lipoproteins of pioglitazone versus gliclazide addition to metformin and pioglitazone versus metformin addition to sulphonylurea in the treatment of type 2 diabetes. Diabetologia 2005, 48:2477–2481.

    Article  PubMed  CAS  Google Scholar 

  16. Charbonnel BH, Matthews DR, Schernthaner G, et al.: A longterm comparison of pioglitazone and gliclazide in patients with Type 2 diabetes mellitus: a randomized, double-blind, parallelgroup comparison trial. Diabet Med 2005, 22:399–405.

    Article  PubMed  CAS  Google Scholar 

  17. Hanefeld M, Brunetti P, Schernthaner GH, et al.: One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes. Diabetes Care 2004, 27:141–147.

    Article  PubMed  CAS  Google Scholar 

  18. Dormandy JA, Charbonnel B, Eckland DJ, et al.: Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglit Azone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005, 366:1279–1289.

    Article  PubMed  CAS  Google Scholar 

  19. Szapary PO, Bloedon LT, Samaha FF, et al.: Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome. Arterioscler Thromb Vasc Biol 2006, 26:182–188.

    Article  PubMed  CAS  Google Scholar 

  20. Samaha FF, Szapary PO, Iqbal N, et al.: Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome. Arterioscler Thromb Vasc Biol 2006, 26:624–630.

    Article  PubMed  CAS  Google Scholar 

  21. Goldberg RB, 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.

    Article  PubMed  CAS  Google Scholar 

  22. King AB: A comparison in a clinical setting of the efficacy and side effects of three thiazolidinediones. Diabetes Care 2000, 23:557.

    Article  PubMed  CAS  Google Scholar 

  23. van Wijk JP, de Koning EJ, Castro Cabezas M, et al.: Rosiglitazone improves postprandial triglyceride and free fatty acid metabolism in type 2 diabetes. Diabetes Care 2005, 28:844–849.

    Article  PubMed  Google Scholar 

  24. Majali KA, Cooper MB, Staels B, et al.: The effect of sensitisation to insulin with pioglitazone on fasting and postprandial lipid metabolism, lipoprotein modification by lipases, and lipid transfer activities in type 2 diabetic patients. Diabetologia 2006, 49:527–537.

    Article  PubMed  CAS  Google Scholar 

  25. Deeg MA, Goldberg RB, Buse JB, et al.: The comparative effect of pioglitazone and rosiglitazone on lipoprotein subfractions in patients with type 2 diabetes and dyslipidemia [abstract]. Paper presented at American Diabetes Association 65th Scientific Sessions 2005; A960.

  26. Tan GD, Fielding BA, Currie JM, et al.: The effects of rosiglitazone on fatty acid and triglyceride metabolism in type 2 diabetes. Diabetologia 2005, 48:83–95.

    Article  PubMed  CAS  Google Scholar 

  27. Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, et al.: PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J 1996, 15:5336–5348.

    PubMed  CAS  Google Scholar 

  28. Kobayashi J, Nagashima I, Hikita M, et al.: Effect of troglitazone on plasma lipid metabolism and lipoprotein lipase. Br J Clin Pharmacol 1999, 47:433–439.

    Article  PubMed  CAS  Google Scholar 

  29. Nagashima K, Lopez C, Donovan D, et al.: Effects of the PPARgamma agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus. J Clin Invest 2005, 115:1323–1332.

    Article  PubMed  CAS  Google Scholar 

  30. von Eynatten M, Schneider JG, Humpert PM, et al.: Decreased plasma lipoprotein lipase in hypoadiponectinemia: an association independent of systemic inflammation and insulin resistance. Diabetes Care 2004, 27:2925–2929.

    Article  Google Scholar 

  31. Robinson AC, Jeffs JA, Gray RG, et al.: Metabolic effects of Troglitazone in patients with diet-controlled type 2 diabetes. Eur J Clin Invest 2004, 34:29–36.

    Article  PubMed  CAS  Google Scholar 

  32. Carpentier A, Taghibiglou C, Leung N, et al.: Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster. J Biol Chem 2002, 277:28795–2802.

    Article  PubMed  CAS  Google Scholar 

  33. Lewis GF, Uffelman K, Naples M, et al.: Intestinal lipoprotein overproduction, a newly recognized component of insulin resistance, is ameliorated by the insulin sensitizer rosiglitazone: studies in the fructose-fed Syrian golden hamster. Endocrinology 2005, 146:247–255.

    Article  PubMed  CAS  Google Scholar 

  34. Schadinger SE, Bucher NL, Schreiber BM, et al.: PPARgamma2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes. Am J Physiol Endocrinol Metab 2005, 288:E1195-E1205.

    Article  PubMed  CAS  Google Scholar 

  35. Hirano T, Yoshino G, Kazumi T: Troglitazone and small low-density lipoprotein in type 2 diabetes. Ann Intern Med 1998, 129:162–163.

    PubMed  CAS  Google Scholar 

  36. Tack CJ, Smits P, Demacker PN, et al.: Troglitazone decreases the proportion of small, dense LDL and increases the resistance of LDL to oxidation in obese subjects. Diabetes Care 1998, 21:796–799.

    Article  PubMed  CAS  Google Scholar 

  37. Cominacini L, Young MM, Capriati A, et al.: Troglitazone increases the resistance of low density lipoprotein to oxidation in healthy volunteers. Diabetologia 1997, 40:1211–1218.

    Article  PubMed  CAS  Google Scholar 

  38. Sobal G, Menzel EJ, Sinzinger H: Troglitazone inhibits long-term glycation and oxidation of low-density lipoprotein. J Cardiovasc Pharmacol 2005, 46:672–680.

    Article  PubMed  CAS  Google Scholar 

  39. Iida KT, Kawakami Y, Suzuki M, et al.: Effect of thiazolidinediones and metformin on LDL oxidation and aortic endothelium relaxation in diabetic GK rats. Physiol Endocrinol Metab 2003, 284:E1125-E1130.

    CAS  Google Scholar 

  40. Lawrence JM, Reid J, Taylor GJ, et al.: Favorable effects of pioglitazone and metformin compared with gliclazide on lipoprotein subfractions in overweight patients with early type 2 diabetes. Diabetes Care 2004, 27:41–46.

    Article  PubMed  CAS  Google Scholar 

  41. Perez A, Khan M, Johnson T, et al.: Pioglitazone plus a sulphonylurea or metformin is associated with increased lipoprotein particle size in patients with type 2 diabetes. Vasc Dis Res 2004, 1:44–50.

    Article  Google Scholar 

  42. Winkler K, Konrad T, Fullert S, et al.: Pioglitazone reduces atherogenic dense LDL particles in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study. Diabetes Care 2003, 26:2588–2594.

    Article  PubMed  CAS  Google Scholar 

  43. Freed MI, Ratner R, Marcovina SM, et al.: Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in type 2 diabetes mellitus. Am J Cardiol 2002, 90:947–952.

    Article  PubMed  CAS  Google Scholar 

  44. Lewis GF, Murdoch S, Uffelman K, et al.: Hepatic lipase mRNA, protein, and plasma enzyme activity is increased in the insulin-resistant, fructose-fed Syrian golden hamster and is partially normalized by the insulin sensitizer rosiglitazone. Diabetes 2004, 53:2893–2900.

    Article  PubMed  CAS  Google Scholar 

  45. Schneider JG, von Eynatten M, Schiekofer S, et al.: Low plasma adiponectin levels are associated with increased hepatic lipase activity in vivo. Diabetes Care 2005, 28:2181–2186.

    Article  PubMed  CAS  Google Scholar 

  46. Ovalle F, Bell DS: Effect of thiazolidinediones on high-density lipoprotein subfractions. Endocr Pract 2002, 8:102–104.

    PubMed  Google Scholar 

  47. Carreon-Torres E, Juarez-Meavepena M, Cardoso-Saldana G, et al.: Pioglitazone increases the fractional catabolic and production rates of high-density lipoproteins apo AI in the New Zealand White Rabbit. Atherosclerosis 2005, 181:233–240.

    Article  PubMed  CAS  Google Scholar 

  48. Ko SH, Song KH, Ahn YB, et al.: The effect of rosiglitazone on serum lipoprotein(a) levels in Korean patients with type 2 diabetes mellitus. Metabolism 2003, 52(6):731–4.

    Article  PubMed  CAS  Google Scholar 

  49. Tack CJ, Smits P, DeMacker PN, et al.: Effect of troglitazone on lipoprotein(a) levels in obese subjects. Diabetes Care 1999, 22:1752–1753.

    Article  PubMed  CAS  Google Scholar 

  50. Nagai Y, Abe T, Nomura G: Does pioglitazone, like troglitazone, increase serum levels of lipoprotein(a) in diabetic patients? Diabetes Care 2001, 24:408–409.

    Article  PubMed  CAS  Google Scholar 

  51. Lewin AJ, Kipnes MS, Meneghini LF, et al.: Simvastatin/Thiazolidinedione Study Group: Effects of simvastatin on the lipid profile and attainment of low-density lipoprotein cholesterol goals when added to thiazolidinedione therapy in patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, placebo-controlled trial. Clin Ther 2004, 26:379–389.

    Article  PubMed  CAS  Google Scholar 

  52. Kahn M, Berhanu P, Perez A, et al.: Effects of pioglitazone in combination with stable statin therapy on lipid levels in subjects with type 2 diabetes and dyslipidemia after treatment conversion from rosiglitazone: results from an open label study [abstract]. American Diabetes Association 65th Scientific Sessions 2005, A553.

  53. Alsheikh-Ali AA, Karas RH: Adverse events with concomitant use of simvastatin or atorvastatin and thiazolidinediones. Am J Cardiol 2004, 93:1417–1418.

    Article  PubMed  CAS  Google Scholar 

  54. Seber S, Ucak S, Basat O, et al.: The effect of dual PPAR alpha/gamma stimulation with combination of rosiglitazone and fenofibrate on metabolic parameters in type 2 diabetic patients. Diabetes Res Clin Pract 2006, 71:52–58.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Ronald B. Goldberg MD.

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Goldberg, R.B. Impact of thiazolidenediones on serum lipoprotein levels. Curr Atheroscler Rep 8, 397–404 (2006). https://doi.org/10.1007/s11883-006-0037-5

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