Diabetes Care, Vol 16, Issue 4 621-629, Copyright © 1993 by American Diabetes Association

ARTICLES

Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups

DK Nagi and JS Yudkin
Academic Unit of Diabetes and Endocrinology, Whittington Hospital, London, United Kingdom.

OBJECTIVE--To investigate the effects of metformin on glycemic control, insulin resistance, and risk factors for cardiovascular disease in NIDDM subjects from two ethnic groups (Caucasian and Asian) with different risks of cardiovascular disease. RESEARCH DESIGN AND METHODS--A total of 27 subjects with NIDDM (17 Caucasian, 10 Asian) were given metformin and placebo each for a 12-wk period in a randomized, double-blind, placebo-controlled crossover study, and the dose was increased after 1 and 6 wk, up to a maximum of 850 mg three times a day. Insulin resistance, glycemic control, and cardiovascular risk factors were assessed before and after each treatment phase. The end of 12 wk of metformin treatment was compared with the end of 12 wk of placebo treatment. RESULTS--Metformin treatment was associated with significant improvement in FPG at 6 and 12 wk (mean difference at 12 wk, -3.08 mM, 95% CI -4.12 to -2.04 mM, P < 0.0001) and MCR of glucose (median difference 0.40 ml.kg-1.min-1, interquartile range -0.10 to 1.30 ml.kg-1.min-1, P = 0.036). beta-cell function calculated by HOMA also improved significantly (median difference 14%, interquartile range 7 to 23%, P < 0.001). Total triglyceride (median difference -0.2 mM, interquartile range -0.6 to 0.1 mM, P = 0.034), total cholesterol (mean difference -0.52 mM, 95% CI -0.83 to -0.22 mM, P = 0.002), and LDL cholesterol (mean difference -0.40 mM, 95% CI -0.64 to -0.16 mM, P = 0.002) fell significantly on metformin treatment, whereas no significant changes were observed in HDL cholesterol. PAI-1 activity fell significantly (mean difference -5.3 AU/ml, 95% CI -8.2 to -2.4 AU/ml, P = 0.001), but plasma fibrinogen concentrations and platelet function, spontaneous or agonist induced, were unaffected. UAE was lower on metformin treatment (median difference -2.4 micrograms/min, interquartile range -4.4 to -0.2 micrograms/min, P = 0.004), but metformin had no significant effect on BP. The effects of metformin on glycemic control and cardiovascular risk factors were generally similar in the two ethnic groups. CONCLUSIONS--These findings indicate that metformin treatment improves glycemic control, and lowers insulin resistance and risk factors for cardiovascular disease, including PAI-1, and may therefore be useful in the long-term management of NIDDM subjects who have a high risk of cardiovascular disease.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. S Lund, L. Tarnow, C. D A Stehouwer, C. G Schalkwijk, T. Teerlink, J. Gram, K. Winther, M. Frandsen, U. M Smidt, O. Pedersen, et al. Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes Eur. J. Endocrinol., May 1, 2008; 158(5): 631 - 641. [Abstract] [Full Text] [PDF]

				E. Bonora, S. Kiechl, J. Willeit, F. Oberhollenzer, G. Egger, J. B. Meigs, R. C. Bonadonna, and M. Muggeo Insulin Resistance as Estimated by Homeostasis Model Assessment Predicts Incident Symptomatic Cardiovascular Disease in Caucasian Subjects From the General Population: The Bruneck Study Diabetes Care, February 1, 2007; 30(2): 318 - 324. [Abstract] [Full Text] [PDF]

				E. Diamanti-Kandarakis, T. Paterakis, K. Alexandraki, C. Piperi, A. Aessopos, I. Katsikis, N. Katsilambros, G. Kreatsas, and D. Panidis Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin Hum. Reprod., June 1, 2006; 21(6): 1426 - 1431. [Abstract] [Full Text] [PDF]

				A. Festa, K. Williams, R. P. Tracy, L. E. Wagenknecht, and S. M. Haffner Progression of Plasminogen Activator Inhibitor-1 and Fibrinogen Levels in Relation to Incident Type 2 Diabetes Circulation, April 11, 2006; 113(14): 1753 - 1759. [Abstract] [Full Text] [PDF]

				S. Schwartz, V. Fonseca, B. Berner, M. Cramer, Y.-K. Chiang, and A. Lewin Efficacy, Tolerability, and Safety of a Novel Once-Daily Extended-Release Metformin in Patients With Type 2 Diabetes Diabetes Care, April 1, 2006; 29(4): 759 - 764. [Abstract] [Full Text] [PDF]

				K. Isoda, J. L. Young, A. Zirlik, L. A. MacFarlane, N. Tsuboi, N. Gerdes, U. Schonbeck, and P. Libby Metformin Inhibits Proinflammatory Responses and Nuclear Factor-{kappa}B in Human Vascular Wall Cells Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 611 - 617. [Abstract] [Full Text] [PDF]

				B. Kimmel and S. E. Inzucchi Oral Agents for Type 2 Diabetes: An Update Clin. Diabetes, April 1, 2005; 23(2): 64 - 76. [Abstract] [Full Text] [PDF]

				A. E. Caballero, A. Delgado, C. A. Aguilar-Salinas, A. N. Herrera, J. L. Castillo, T. Cabrera, F. J. Gomez-Perez, and J. A. Rull The Differential Effects of Metformin on Markers of Endothelial Activation and Inflammation in Subjects with Impaired Glucose Tolerance: A Placebo-Controlled, Randomized Clinical Trial J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3943 - 3948. [Abstract] [Full Text] [PDF]

				S. Mudaliar Intense Management of Diabetes Mellitus: Role of Glucose Control and Antiplatelet Agents J. Clin. Pharmacol., April 1, 2004; 44(4): 414 - 422. [Abstract] [Full Text] [PDF]

				S. R. Salpeter, E. Greyber, G. A. Pasternak, and E. E. Salpeter Risk of Fatal and Nonfatal Lactic Acidosis With Metformin Use in Type 2 Diabetes Mellitus: Systematic Review and Meta-analysis Arch Intern Med, November 24, 2003; 163(21): 2594 - 2602. [Abstract] [Full Text] [PDF]

				C. A. Eagleson, A. B. Bellows, K. Hu, M. B. Gingrich, and J. C. Marshall Obese Patients with Polycystic Ovary Syndrome: Evidence that Metformin Does Not Restore Sensitivity of the Gonadotropin-Releasing Hormone Pulse Generator to Inhibition by Ovarian Steroids J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5158 - 5162. [Abstract] [Full Text] [PDF]

				B. E. Sobel, D. J. Taatjes, and D. J. Schneider Intramural Plasminogen Activator Inhibitor Type-1 and Coronary Atherosclerosis Arterioscler. Thromb. Vasc. Biol., November 1, 2003; 23(11): 1979 - 1989. [Abstract] [Full Text] [PDF]

				S. J. McNulty, E. Ur, and G. Williams A Randomized Trial of Sibutramine in the Management of Obese Type 2 Diabetic Patients Treated With Metformin Diabetes Care, January 1, 2003; 26(1): 125 - 131. [Abstract] [Full Text] [PDF]

				M. G. Wulffele, A. Kooy, P. Lehert, D. Bets, J. C. Ogterop, B. Borger van der Burg, A. J.M. Donker, and C. D.A. Stehouwer Combination of Insulin and Metformin in the Treatment of Type 2 Diabetes Diabetes Care, December 1, 2002; 25(12): 2133 - 2140. [Abstract] [Full Text] [PDF]

				C. Kluft and J. Jespersen Review: Diabetes as a procoagulant condition The British Journal of Diabetes & Vascular Disease, September 1, 2002; 2(5): 358 - 362. [Abstract] [PDF]

				D. Kirpichnikov, S. I. McFarlane, and J. R. Sowers Metformin: An Update Ann Intern Med, July 2, 2002; 137(1): 25 - 33. [Abstract] [Full Text] [PDF]

				A. Festa, R. D'Agostino Jr, R. P. Tracy, and S. M. Haffner Elevated Levels of Acute-Phase Proteins and Plasminogen Activator Inhibitor-1 Predict the Development of Type 2 Diabetes: The Insulin Resistance Atherosclerosis Study Diabetes, April 1, 2002; 51(4): 1131 - 1137. [Abstract] [Full Text] [PDF]

				B. Molavi, N. Rasouli, and J. L. Mehta Peroxisome Proliferator-Activated Receptor Ligands as Antiatherogenic Agents: Panacea or Another Pandora's Box? Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2002; 7(1): 1 - 8. [Abstract] [PDF]

				N. V. Chu, A. P. S. Kong, D. D. Kim, D. Armstrong, S. Baxi, R. Deutsch, M. Caulfield, S. R. Mudaliar, R. Reitz, R. R. Henry, et al. Differential Effects of Metformin and Troglitazone on Cardiovascular Risk Factors in Patients With Type 2 Diabetes Diabetes Care, March 1, 2002; 25(3): 542 - 549. [Abstract] [Full Text] [PDF]

				S. E. Inzucchi Oral Antihyperglycemic Therapy for Type 2 Diabetes: Scientific Review JAMA, January 16, 2002; 287(3): 360 - 372. [Abstract] [Full Text] [PDF]

				K. F. Standeven, R. A.S. Ariens, P. Whitaker, A. E. Ashcroft, J. W. Weisel, and P. J. Grant The Effect of Dimethylbiguanide on Thrombin Activity, FXIII Activation, Fibrin Polymerization, and Fibrin Clot Formation Diabetes, January 1, 2002; 51(1): 189 - 197. [Abstract] [Full Text] [PDF]

				W. Bagg, C. Ferri, G. Desideri, G. Gamble, P. Ockelford, and G. D. Braatvedt The Influences of Obesity and Glycemic Control on Endothelial Activation in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5491 - 5497. [Abstract] [Full Text] [PDF]

				A. A. Parulkar, M. L. Pendergrass, R. Granda-Ayala, T. R. Lee, and V. A. Fonseca Nonhypoglycemic Effects of Thiazolidinediones Ann Intern Med, January 2, 2001; 134(1): 61 - 71. [Abstract] [Full Text] [PDF]

				S. Matthaei, M. Stumvoll, M. Kellerer, and H.-U. Häring Pathophysiology and Pharmacological Treatment of Insulin Resistance Endocr. Rev., December 1, 2000; 21(6): 585 - 618. [Abstract] [Full Text]

				V. A. Fonseca Risk Factors for Coronary Heart Disease in Diabetes Ann Intern Med, July 18, 2000; 133(2): 154 - 156. [Full Text] [PDF]

				J. B. Meigs, M. A. Mittleman, D. M. Nathan, G. H. Tofler, D. E. Singer, P. M. Murphy-Sheehy, I. Lipinska, R. B. D'Agostino, and P. W. F. Wilson Hyperinsulinemia, Hyperglycemia, and Impaired Hemostasis: The Framingham Offspring Study JAMA, January 12, 2000; 283(2): 221 - 228. [Abstract] [Full Text] [PDF]

				L. Ciotta, V. De Leo, F. Galvani, A. La Marca, and A. Cianci Endocrine and metabolic effects of octreotide, a somatostatin analogue, in lean PCOS patients with either hyperinsulinaemia or lean normoinsulinaemia Hum. Reprod., December 1, 1999; 14(12): 2951 - 2958. [Abstract] [Full Text] [PDF]

				R. A. DeFronzo Pharmacologic Therapy for Type 2 Diabetes Mellitus Ann Intern Med, August 17, 1999; 131(4): 281 - 303. [Abstract] [Full Text] [PDF]

				J. E. Nestler and D. J. Jakubowicz Lean Women with Polycystic Ovary Syndrome Respond to Insulin Reduction with Decreases in Ovarian P450c17{alpha} Activity and Serum Androgens J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 4075 - 4079. [Abstract] [Full Text] [PDF]

				J. E. Nestler and D. J. Jakubowicz Decreases in Ovarian Cytochrome P450c17{alpha} Activity and Serum Free Testosterone after Reduction of Insulin Secretion in Polycystic Ovary Syndrome N. Engl. J. Med., August 29, 1996; 335(9): 617 - 623. [Abstract] [Full Text] [PDF]

				T. A. Kotchen Attenuation of Hypertension by Insulin-Sensitizing Agents Hypertension, August 1, 1996; 28(2): 219 - 223. [Full Text]

				C. J. Bailey and R. C. Turner Metformin N. Engl. J. Med., February 29, 1996; 334(9): 574 - 579. [Full Text] [PDF]

				R. A. DeFronzo, A. M. Goodman, and The Multicenter Metformin Study Group Efficacy of Metformin in Patients with Non-Insulin-Dependent Diabetes Mellitus N. Engl. J. Med., August 31, 1995; 333(9): 541 - 549. [Abstract] [Full Text] [PDF]

				B. Saulie, J. White, and R. K. Campbell Pharmacy Update: Metformin in the Treatment of Non-Insulin-Dependent Diabetes Mellitus The Diabetes Educator, January 1, 1995; 21(5): 441 - 445. [PDF]