American Journal of Cardiovascular Drugs

, Volume 5, Issue 3, pp 201–209 | Cite as

Cardiovascular Risk Factors Associated with Insulin Resistance

Effects of Oral Antidiabetic Agents
Review Article

Abstract

Patients with type 2 diabetes mellitus have a greater risk of cardiovascular disease than nondiabetic individuals. These patients are often insulin resistant and have an associated clustering of risk factors that contribute to cardiovascular disease. The risk factors include dyslipidemia, hypertension, altered hemostasis, and chronic inflammation. A primary objective in the management of type 2 diabetes mellitus is normalization of blood glucose levels; however, some of the oral drugs used to control blood glucose levels have significant effects on these risk factors. In this article, we review the current data involving the modification of these cardiovascular risk factors by the biguanide (metformin), the thiazolidinediones (troglitazone, rosiglitazone, and pioglitazone), the α-glucosidase inhibitors (miglitol, acarbose), and the insulin secretagogs (glyburide [glibenclamide], glipizide, chlorpropamide, tolbutamide, tolazamide, glimepiride, repaglinide, and nateglinide). Generally, the thiazolidinediones improve hemostasis and endothelial function and reduce blood pressure, while having variable effects on dyslipidemia. Metformin improves dyslipidemia and altered hemostasis and decreases plasma C-reactive protein levels with little or no effect on blood pressure. Data on the effects of the α-glucosidase inhibitors and insulin secretagogs are sparse; however, these drugs appear to have little or no effect on cardiovascular risk factors.

References

  1. 1.
    Haffner SM, Lehto S, Rönnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 329: 229–34.CrossRefGoogle Scholar
  2. 2.
    Goldstein BJ. Insulin resistance as the core defect in type 2 diabetes mellitus. Am J Cardiol 2002; 90 (5A): 3G–10G.PubMedCrossRefGoogle Scholar
  3. 3.
    American Diabetes Association. Consensus development conference on insulin resistance. Diabetes Care 1998 Feb; 21 (2): 310–4.Google Scholar
  4. 4.
    Davidson MB. Clinical implications of insulin resistance syndromes. Am J Med 1995; 99: 420–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Pyörälä M, Miettinen H, Laakso M, et al. Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Circulation 1998; 98: 398–404.PubMedCrossRefGoogle Scholar
  6. 6.
    Dandona P, Aljada A, Mohanty P. The anti-inflammatory and potential anti-atherogenic effect of insulin: a new paradigm. Diabetologia 2002; 45: 924–30.PubMedCrossRefGoogle Scholar
  7. 7.
    Pannacciulli N, DeMitrio V, Marino R, et al. Effect of glucose tolerance status on PAI-1 plasma levels in overweight and obese subjects. Obes Res 2002 Aug; 10 (8): 717–25.PubMedCrossRefGoogle Scholar
  8. 8.
    Meigs JB, Mittleman MA, Nathan DM, et al. Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. JAMA 2000; 283: 221–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Vinik AI, Erbas T, Park TS, et al. Platelet dysfunction in type 2 diabetes. Diabetes Care 2001 Aug; 24 (8): 1476–85.PubMedCrossRefGoogle Scholar
  10. 10.
    Reusch JEB. Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome. Am J Cardiol 2002; 90 (5A): 19G–26G.PubMedCrossRefGoogle Scholar
  11. 11.
    Reaven GM, Chen YDI, Jeppesen J, et al. Insulin resistance and hyperinsulinemia in individuals with small, dense, low-density lipoprotein particles. J Clin Invest 1993 Jul; 92: 141–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002; 287: 2570–81.PubMedCrossRefGoogle Scholar
  13. 13.
    Steinberg D, Parthasarathy S, Carew TE, et al. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989; 320: 915–24.PubMedCrossRefGoogle Scholar
  14. 14.
    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: Rosiglitazone Study 108 Investigators. Am J Cardiol 2002 Nov; 90: 947–52.PubMedCrossRefGoogle Scholar
  15. 15.
    Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: an update [published erratum appears in Hypertension 2001 May; 37 (5): 1350]. Hypertension 2001; 37: 1053–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Simonson DC. Etiology and prevalence of hypertension in diabetic patients. Diabetes Care 1988 Nov–Dec; 11 (10): 821–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Supiano MA, Hogikyan RV, Morrow LA, et al. Hypertension and insulin resistance: role of sympathetic nervous system activity. Am J Physiol 1992 Nov; 263 (5 Pt 1): E935–942.PubMedGoogle Scholar
  18. 18.
    Festa A, D’Agostino R, Howard G, et al. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000; 102: 42–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Ceriello A, Bortolotti N, Motz E, et al. Meal-induced oxidative stress and low-density lipoprotein oxidation in diabetes: the possible role of hyperglycemia. Metabolism 1999 Dec; 48 (12): 1503–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Temelkova-Kurktschiev T, Siegert G, Bergmann S, et al. Subclinical inflammation is strongly related to insulin resistance but not to impaired insulin secretion in a high risk population for diabetics. Metabolism 2002 Jun; 51 (6): 743–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Dandona P, Aljada A, Mohanty P, et al. Insulin inhibits intranuclear factor κB and stimulates IκB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 2001; 86: 3257–65.PubMedCrossRefGoogle Scholar
  22. 22.
    Charles MA, Eschwège E, Grandmottet P, et al., on behalf of the BIGPRO 1.2 Study Group. Treatment with metformin of non-diabetic men with hypertension, hypertriglyceridaemia and central fat distribution: the BIGPRO 1.2 trial. Diabetes Metab Res Rev 2000 Jan–Feb; 16: 2–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects: a study of two ethnic groups. Diabetes Care 1993 Apr; 16 (4): 653–5.CrossRefGoogle Scholar
  24. 24.
    Grant PJ. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care 1996 Jan; 19 (1): 64–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Ehrmann DA, Schneider DJ, Sobel BE, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997 Jul; 82: 2108–16.PubMedCrossRefGoogle Scholar
  26. 26.
    Fonseca VA, Reynolds T, Hemphill D, et al. Effect of troglitazone on fibrinolysis and activated coagulation in patients with non-insulin-dependent diabetes mellitus. J Diabetes Complications 1998; 12: 181–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Panahloo A, Mohamed-Ali V, Andrés C. Effect of insulin versus sulfonylurea therapy on cardiovascular risk factors and fibrinolysis in type II diabetes. Metabolism 1998 Jun; 47 (6): 637–43.PubMedCrossRefGoogle Scholar
  28. 28.
    Kato K, Yamada D, Midorikawa S, et al. Improvement by the insulin-sensitizing agent, troglitazone, of abnormal fibrinolysis in type 2 diabetes mellitus. Metabolism 2000 May; 49 (5): 662–5.PubMedCrossRefGoogle Scholar
  29. 29.
    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 PPARγ in endothelial cells. Biochem Biophys Res Commun 1999 May; 258 (2): 431–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Giugliano D, DeRosa N, DiMarco G, et al. Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care 1993 Oct; 16 (10): 1387–90.PubMedCrossRefGoogle Scholar
  31. 31.
    Marbury T, Huang W, Strange P, et al. Repaglinide versus glyburide: a one year comparison trial. Diabetes Res Clin Pract 1999 Mar; 43 (3): 155–66.PubMedCrossRefGoogle Scholar
  32. 32.
    Scott R, Lintott CJ, Zimmet P, et al. Will acarbose improve the metabolic abnormalities of insulin-resistant type 2 diabetes mellitus? Diabetes Res Clin Pract 1999 Mar; 43 (3): 179–85.PubMedCrossRefGoogle Scholar
  33. 33.
    Bayraktar M, Van Thiel DH, Adalar N. A comparison of acarbose versus metformin as an adjuvant therapy in sulfonylurea-treated NIDDM patients. Diabetes Care 1996 Mar; 19 (3): 252–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Hanefeld M, Fischer S, Schulze J, et al. Therapeutic potential of acarbose as first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care 1991 Aug; 14 (8): 732–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Ishizuka T, Itaya S, Wada H, et al. Differential effect of the antidiabetic thiazolidinediones troglitazone and pioglitazone on human platelet aggregation mechanism. Diabetes 1998 Sep; 47 (9): 1494–500.PubMedCrossRefGoogle Scholar
  36. 36.
    Klaff LJ, Kernoff L, Vinik AI, et al. Sulfonylureas and platelet function. Am J Med 1981; 70 (3): 627–30.PubMedCrossRefGoogle Scholar
  37. 37.
    DeBellis R, Novoa E, Dol B, et al. Changes in platelet aggregation caused by glyburide in diabetic patients. Clin Ther 1984; 6 (3): 335–43.Google Scholar
  38. 38.
    Siluk D, Kaliszan R, Haber P, et al. Antiaggregatory activity of hypoglycaemic sulphonylureas. Diabetologia 2002 Jul; 45: 1034–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Robinson AC, Burke J, Robinson S, et al. The effects of metformin on glycemic control and serum lipids in insulin-treated NIDDM patients with suboptimal metabolic control. Diabetes Care 1998 May; 21 (5): 701–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Palumbo PJ. Metformin: effects on cardiovascular risk factors in patients with non-insulin-dependent diabetes mellitus. J Diabetes Complications 1998 Mar–Apr; 12 (2): 110–19.PubMedCrossRefGoogle Scholar
  41. 41.
    Fanghanel G, Sánchez-Reyes L, Trujillo C, et al. Metformin’s effects on glucose and lipid metabolism in patients with secondary failure to sulfonylureas. Diabetes Care 1996 Nov; 19 (11): 1185–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Amador-Licona N, Guízar-Mendoza J, Vargas E, et al. The short-term effect of a switch from glibenclamide to metformin on blood pressure and microalbuminuria in patients with type 2 diabetes mellitus. Arch Med Res 2000 Nov–Dec; 31 (6): 571–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Khan MA, St Peter JV, Xue JL. A 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 Apr; 25 (4): 708–11.PubMedCrossRefGoogle Scholar
  44. 44.
    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. Diabetes Care 2000 Nov; 23 (11): 1605–11.PubMedCrossRefGoogle Scholar
  45. 45.
    Rosenstock J, Einhorn D, Hershon K, et al. Efficacy and safety of pioglitazone in type 2 diabetes: a randomized, placebo-controlled study in patients receiving stable insulin therapy: the Pioglitazone 014 Study Group. Int J Clin Pract 2002 May; 56 (4): 251–7.PubMedGoogle Scholar
  46. 46.
    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 Mar; 43 (3): 278–84.PubMedCrossRefGoogle Scholar
  47. 47.
    Lebovitz HE, Dole JF, Patwardhan R, et al. Rosiglitazone monotherapy is effective in patients with type 2 diabetes: the Rosiglitazone Clinical Trials Study Group. [published erratum appears in J Clin Endocrinol Metab 2001 Apr; 86 (4): 1659]. J Clin Endocrinol Metab 2001; 86: 280–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Agardh C-D, Björgell P, Nilsson-Ehle P. The effects of tolbutamide on lipoproteins, lipoprotein lipase and hormone-sensitive lipase. Diabetes Res Clin Pract 1999 Nov; 46: 99–108.PubMedCrossRefGoogle Scholar
  49. 49.
    Coniff RF, Shapiro JA, Seaton TB, et al. Multicenter, placebo-controlled trial comparing acarbose (BAYg 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. Am J Med 1995 May; 98: 443–51.PubMedCrossRefGoogle Scholar
  50. 50.
    Marre M, Van Gaal L, Usadel KH, et al. Nateglinide improves glycemic control when added to metformin monotherapy: results of a randomized trial with type 2 diabetes patients. Diabetes Obes Metab 2002 May; 4 (3): 177–86.PubMedCrossRefGoogle Scholar
  51. 51.
    Kawamura T, Egusa G, Fujikawa R, et al. Effect of acarbose on glycemic control and lipid metabolism in patients with non-insulin-dependent diabetes mellitus. Curr Ther Res 1998; 59 (2): 97–106.CrossRefGoogle Scholar
  52. 52.
    Kelley DE, Bidot P, Freedman Z, et al. Efficacy and safety of acarbose in insulin-treated patients with type 2 diabetes. Diabetes Care 1998 Dec; 21 (12): 2056–61.PubMedCrossRefGoogle Scholar
  53. 53.
    Hoffmann J, Spengler M. Efficacy of 24-week monotherapy with acarbose, metformin, or placebo in dietary-treated NIDDM patients: the Essen-II Study. Am J Med 1997; 103: 483–90.PubMedCrossRefGoogle Scholar
  54. 54.
    Johnston PS, Feig PU, Coniff RF, et al. Chronic treatment of African-American type 2 diabetic patients with α-glucosidase inhibition. Diabetes Care 1998 Mar; 21 (3): 416–22.PubMedCrossRefGoogle Scholar
  55. 55.
    Chan JCN, Chan KA, Ho LLT, et al. An Asian multicenter clinical trial to assess the efficacy and tolerability of acarbose compared with placebo in type 2 diabetic patients previously treated with diet: the Asian Acarbose Study Group. Diabetes Care 1998 Jul; 21 (7): 1058–61.PubMedCrossRefGoogle Scholar
  56. 56.
    Lam KSL, Tiu SC, Tsang MW, et al. Acarbose in NIDDM patients with poor control on conventional oral agents. Diabetes Care 1998 Jul; 21 (7): 1154–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Escobar-Jiménez F, Barajas C, DeLeiva A, et al. Efficacy and tolerability of miglitol in the treatment of patients with non-insulin-dependent diabetes mellitus. Curr Ther Res 1995; 56 (3): 258–68.CrossRefGoogle Scholar
  58. 58.
    Chu NV, Kong AP, Kim DD, et al. Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes [published erratum appears in Diabetes Care 2002 May; 25 (5): 947]. Diabetes Care 2002 Mar; 25 (3): 542–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Tack CJJ, Smits P, Demacker PNM, et al. Troglitazone decreases the proportion of small, dense LDL and increases the resistance of LDL to oxidation in obese subjects. Diabetes Care 1998 May; 21 (5): 796–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Cominacini L, Young MM, Capriati S, et al. Troglitazone increases the resistance of low density lipoprotein to oxidation in healthy volunteers. Diabetologia 1997 Oct; 40 (10): 1211–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Snorgaard O, Kober L, Carlsen J. The effect of metformin on blood pressure and metabolism in nondiabetic hypertensive patients. J Intern Med 1997 Nov; 242 (5): 407–12.PubMedCrossRefGoogle Scholar
  62. 62.
    United Kingdom Prospective Diabetes Study Group. UKPDS28: a randomized trial of efficacy of early addition of metformin in sulfonylurea-treated type 2 diabetes. Diabetes Care 1998; 21 (1): 87–92.CrossRefGoogle Scholar
  63. 63.
    DeFronzo RA, Goodman AM, on behalf of The Multicenter Metformin Study Group. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1995 Aug; 333 (9): 541–9.PubMedCrossRefGoogle Scholar
  64. 64.
    St John Sutton M, Rendell 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 Nov; 25 (11): 2058–64.CrossRefGoogle Scholar
  65. 65.
    Hirose H, Kawai T, Yamamoto Y, et al. Effects of pioglitazone on metabolic parameters, body fat distribution, and serum adiponectin levels in Japanese male patients with type 2 diabetes. Metabolism 2002 Mar; 51 (3): 314–7.PubMedCrossRefGoogle Scholar
  66. 66.
    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 (3): 316–20.PubMedCrossRefGoogle Scholar
  67. 67.
    Sung BH, Izzo Jr JL, Dandona P, et al. Vasodilatory effects of troglitazone improve blood pressure at rest and during mental stress in type 2 diabetes mellitus. Hypertension 1999; 34: 83–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Levy J, Vandenberg M, Grunberger G. Insulin versus glipizide treatment in patients with non-insulin-dependent diabetes mellitus: effects on blood pressure and glucose tolerance. Am J Hypertens 1995 May; 8: 445–53.PubMedCrossRefGoogle Scholar
  69. 69.
    Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol 2001 Apr; 37 (5): 1344–50.PubMedCrossRefGoogle Scholar
  70. 70.
    Mohanty P, Aljada A, Ghanim H, et al. Rosiglitazone improves vascular reactivity, inhibits reactive oxygen species (ROS) generation, reduces p47phox subunit expression in mononuclear cells (MNC) and reduces C reactive protein (CRP) and monocyte chemotactic protein-1 (MCP-1): evidence of a potent anti-inflammatory effect [abstract no. 276-OR]. Diabetes 2001; 50 (Suppl. 2): A68.Google Scholar
  71. 71.
    Caballero AE, Saouaf R, Lim SC, et al. The effects of troglitazone, an insulin-sensitizing agent, on the endothelial function in early and late type 2 diabetes: a placebo-controlled randomized clinical trial. Metabolism 2003; Feb; 52 (2): 173–80.PubMedCrossRefGoogle Scholar
  72. 72.
    Pavlović D, Kocić R, Kocić G, et al. Effect of four-week metformin treatment on plasma and erythrocyte antioxidative defense enzymes in newly diagnosed obese patients with type 2 diabetes. Diabetes Obes Metab 2000; 2 (4): 251–6.PubMedCrossRefGoogle Scholar
  73. 73.
    Ghanim H, Garg R, Aljada A, et al. Suppression of nuclear factor-κB by troglitazone: evidence for an anti-inflammatory effect and a potential antiatheros-clerotic effect in the obese. J Clin Endocrinol Metab 2001; 86: 1306–12.PubMedCrossRefGoogle Scholar
  74. 74.
    May JM, Qu ZC. Troglitazone protects human erythrocytes from oxidant damage. Antioxid Redox Signal 2000; 2 (2): 243–50.PubMedCrossRefGoogle Scholar
  75. 75.
    Ryysy L, Yki-Järvinen H. Improvement of glycemic control by 1 year of insulin therapy leads to a sustained decrease in sE-selectin concentrations in type 2 diabetics. Diabetes Care 2001 Mar; 24: 549–54.PubMedCrossRefGoogle Scholar
  76. 76.
    Tankova T, Koev D, Dakovska L, et al. The effect of repaglinide on insulin secretion and oxidative stress in type 2 diabetic patients. Diabetes Res Clin Pract 2003; 59: 43–9.PubMedCrossRefGoogle Scholar
  77. 77.
    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 Aug; 106: 679–84.PubMedCrossRefGoogle Scholar
  78. 78.
    Yudkin JS, Panahloo A, Stehouwer C, et al. The influence of improved glycaemic control with insulin and sulphonylureas on acute phase and endothelial markers in type II diabetic subjects. Diabetologia 2000 Sep; 43 (9): 1099–106.PubMedCrossRefGoogle Scholar
  79. 79.
    Lindahl B, Nilsson TK, Jansson JH, et al. Improved fibrinolysis by intense lifestyle intervention: a randomized trial in subjects with impaired glucose tolerance. J Intern Med 1999 Jul; 246: 105–12.PubMedCrossRefGoogle Scholar
  80. 80.
    Marfella R, Acampora R, Verrazzo G, et al. Metformin improves hemodynamic and Theological responses to L-arginine in NIDDM patients. Diabetes Care 1996 Sep; 19 (9): 934–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Ceriello A, Taboga C, Tonutti L, et al. Post-meal coagulation activation in diabetes mellitus: the effect of acarbose. Diabetologia 1996 Apr; 39 (4): 469–73.PubMedCrossRefGoogle Scholar
  82. 82.
    Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med 2002; 137: 25–33.PubMedGoogle Scholar
  83. 83.
    Velazquez EM, Mendoza SG, Wang P, et al. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with polycystic ovary syndrome. Metabolism 1997 Apr; 46 (4): 454–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Ovalle F, Bell DSH. Troglitazone’s effect on lipoprotein (a) levels [letter]. Diabetes Care 1999 May; 22: 859–60.PubMedCrossRefGoogle Scholar
  85. 85.
    Nagai Y, Abe T, Nomura G. Does pioglitazone, like troglitazone, increase serum levels of lipoprotein(a) in diabetic patients [letter]. Diabetes Care 2001 Feb; 24 (2): 408–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Gaboury CL, Simonson DC, Seely EW, et al. Relation of pressor responsiveness to angiotensin II and insulin resistance in hypertension. J Clin Invest 1994 Dec; 94 (6): 2295–300.PubMedCrossRefGoogle Scholar
  87. 87.
    Steinberg HO, Brechtel G, Johnson A, et al. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest 1994 Sep; 94 (3): 1172–9.PubMedCrossRefGoogle Scholar
  88. 88.
    UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317 (12): 703–13.CrossRefGoogle Scholar
  89. 89.
    Howes LG, Sundaresan P, Lykos D. Cardiovascular effects of oral hypoglycaemic drugs. Clin Exp Pharmacol Physiol 1996 Mar; 23 (3): 201–6.PubMedCrossRefGoogle Scholar
  90. 90.
    Blackman DJ, Morris-Thurgood JA, Atherton JJ, et al. Endothelium-derived nitric oxide contributes to the regulation of venous tone in humans. Circulation 2000 Jan 18; 101 (2): 165–70.PubMedCrossRefGoogle Scholar
  91. 91.
    Cardillo C, Kilcoyne CM, Cannon III RO, et al. Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo. Hypertension 2000 Jun; 35 (6): 1237–41.PubMedCrossRefGoogle Scholar
  92. 92.
    Mather K, Anderson TJ, Verma S. Insulin action in the vasculature: physiology and pathophysiology. J Vasc Res 2001 Sep–Oct; 38 (5): 415–22.PubMedCrossRefGoogle Scholar
  93. 93.
    Diamanti-Kandarakis E, Spina G, Kouli C, et al. Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effects of metformin therapy. J Clin Endocrinol Metab 2001; 86: 4666–73.PubMedCrossRefGoogle Scholar
  94. 94.
    Viberti G, Kahn SE, Greene DA, et al. A diabetes outcome progression trial (ADOPT): an international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes. Diabetes Care 2002 Oct; 25 (10): 1737–43.PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.University of Texas — Pan AmericanEdinburgUSA
  2. 2.The University of Texas at AustinTexasUSA
  3. 3.Tulane University Health Sciences CenterNew OrleansUSA

Personalised recommendations