Effect of Rosiglitazone Treatment on Nontraditional Markers of Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus

Background—Markers of systemic inflammation (eg, C-reactive protein [CRP] and interleukin-6 [IL-6]) have been proposed to be “nontraditional” risk factors for cardiovascular disease in patients with type 2 diabetes mellitus. Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of atherosclerotic plaque rupture, which raises the possibility of the use of MMP-9 levels as a marker for future myocardial infarction or unstable angina. In vitro and animal studies suggest that thiazolidinediones can reduce the expression of these markers. The purpose of this analysis was to determine whether rosiglitazone alters serum concentrations of CRP, IL-6, MMP-9, and white blood cell count (WBC) and to examine the relationship of these effects with demographic and disease variables. Methods and Results—CRP, IL-6, MMP-9, and WBC were analyzed from stored frozen serum samples obtained from patients with type 2 diabetes who completed a 26-week randomized, double-blind, placebo-controlled study. After 26 weeks of rosiglitazone treatment, the percentage reductions in mean CRP, MMP-9, and WBC levels were statistically significant compared with baseline and placebo (P <0.01). The percentage reduction in mean IL-6 was small and similar in the rosiglitazone and placebo groups. The change in each inflammatory marker from baseline to week 26 was significantly correlated (P <0.05) with each of the other markers, as well as with the homeostasis model assessment estimate of insulin resistance. Conclusions—Rosiglitazone reduces serum levels of MMP-9 and the proinflammatory marker CRP in patients with type 2 diabetes, which indicates potentially beneficial effects on overall cardiovascular risk.

[1]  L. Niskanen,et al.  Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in Type 2 (non-insulin-dependent) diabetic and non-diabetic subjects , 1993, Diabetologia.

[2]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[3]  Jennifer Tuepker Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. , 2003, Circulation.

[4]  S. Haffner,et al.  Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. , 2002, Diabetes.

[5]  S. Mudaliar,et al.  Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. , 2002, Diabetes care.

[6]  H. M. Lee,et al.  Evidence of increased matrix metalloproteinase-9 concentration in patients following cardiopulmonary bypass. , 2001, The journal of extra-corporeal technology.

[7]  W. Bao,et al.  In Vivo Myocardial Protection From Ischemia/Reperfusion Injury by the Peroxisome Proliferator–Activated Receptor-&ggr; Agonist Rosiglitazone , 2001, Circulation.

[8]  J. Manson,et al.  C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. , 2001, JAMA.

[9]  N Rifai,et al.  Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. , 2001, JAMA.

[10]  H. Koshiyama,et al.  Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. , 2001, The Journal of clinical endocrinology and metabolism.

[11]  Y. Oka,et al.  Troglitazone treatment increases plasma vascular endothelial growth factor in diabetic patients and its mRNA in 3T3-L1 adipocytes. , 2001, Diabetes.

[12]  L Wood,et al.  Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. , 2001, American journal of physiology. Endocrinology and metabolism.

[13]  S. Grundy,et al.  Effect of Hydroxymethyl Glutaryl Coenzyme A Reductase Inhibitor Therapy on High Sensitive C-Reactive Protein Levels , 2001, Circulation.

[14]  S. Haffner,et al.  Do interventions to reduce coronary heart disease reduce the incidence of type 2 diabetes? A possible role for inflammatory factors. , 2001, Circulation.

[15]  P W Macfarlane,et al.  Pravastatin and the Development of Diabetes Mellitus: Evidence for a Protective Treatment Effect in the West of Scotland Coronary Prevention Study , 2001, Circulation.

[16]  H. Mabuchi,et al.  Circulating Matrix Metalloproteinases and Their Inhibitors in Premature Coronary Atherosclerosis , 2001, Clinical chemistry and laboratory medicine.

[17]  A. Naylor,et al.  Plasma MMP-9 - a marker of carotid plaque instability. , 2001, European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery.

[18]  H. Lebovitz,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Rosiglitazone Monotherapy Is Effective in Patients with Type 2 Diabetes , 1999 .

[19]  B. Staels,et al.  Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. , 2000, Biochemical pharmacology.

[20]  A. Folsom,et al.  Nontraditional Risk Factors for Coronary Heart Disease Incidence among Persons with Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study , 2000, Annals of Internal Medicine.

[21]  S. Haffner,et al.  Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). , 2000, Circulation.

[22]  U. Boelsterli,et al.  Down-regulation by troglitazone of hepatic tumor necrosis factor-alpha and interleukin-6 mRNA expression in a murine model of non-insulin-dependent diabetes. , 2000, Biochemical pharmacology.

[23]  P. Ridker,et al.  C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. , 2000, The New England journal of medicine.

[24]  Sillanaukee,et al.  Association of serum sialic acid and MMP‐9 with lipids and inflammatory markers , 2000, European journal of clinical investigation.

[25]  P. Libby,et al.  Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. , 1998, Circulation research.

[26]  T. Ueno,et al.  Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. , 1998, Journal of the American College of Cardiology.

[27]  K. Anderson,et al.  White blood cell count and cardiovascular disease. Insights from the Framingham Study. , 1992, JAMA.

[28]  W. Kannel,et al.  Diabetes and cardiovascular disease. The Framingham study. , 1979, JAMA.