Clinical trials of therapy with fibric

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1 Pathophysiology/Complications O R I G I N A L A R T I C L E Beneficial Effects of Fenofibrate to Improve Endothelial Dysfunction and Raise Adiponectin Levels in Patients With Primary Hypertriglyceridemia KWANG KON KOH, MD, PHD, FACC, FAHA 1 SEUNG HWAN HAN, MD 1 MICHAEL J. QUON, MD, PHD 3 2 JEONG YEAL AHN, MD EAK KYUN SHIN, MD 1 OBJECTIVE Improvement in endothelial function is predicted to improve insulin sensitivity, and this may be one mechanism by which fenofibrate decreases the incidence of coronary heart disease. We hypothesize fenofibrate improves endothelial function by enhancing insulin sensitivity. RESEARCH DESIGN AND METHODS We administered placebo or fenofibrate 200 mg daily for 8 weeks to 46 patients with primary hypertriglyceridemia (24 had metabolic syndrome). This study was randomized, double blind, placebo controlled, and crossover in design. RESULTS Compared with placebo, fenofibrate decreased total cholesterol, non-hdl cholesterol, apolipoprotein B, and triglycerides and increased HDL cholesterol and apolipoprotein A-I (all P 0.001) while tending to decrease LDL cholesterol (P 0.069). Fenofibrate significantly improved percent flow-mediated dilator response to hyperemia by 48 5% (P 0.001) and lowered plasma levels of high-sensitivity C-reactive protein (hscrp) relative to baseline measurements from 0.80 to 0.70 mg/l (P 0.001) and fibrinogen levels by 16 3% (P 0.001). Compared with placebo, fenofibrate therapy significantly increased plasma levels of adiponectin by 14 5% (P 0.008) and increased insulin sensitivity (assessed by quantitative insulin sensitivity check index [QUICKI]) by 6 2% (P 0.048). There were significant correlations between percent changes in adiponectin levels and percent changes in flowmediated dilation (r 0.401, P 0.006), hscrp (r 0.443, P 0.002), or QUICKI (r 0.292, P 0.049). Multivariate regression analysis showed that only changes in adiponectin levels persisted as an independent predictor of changes in flow-mediated dilation (r 0.504, P 0.013). Overall, we observed similar results in 24 patients with metabolic syndrome. CONCLUSIONS Fenofibrate therapy significantly improved percent flow-mediated dilator response to hyperemia, reduced inflammation marker levels, increased adiponectin levels, and improved insulin sensitivity in hypertriglyceridemic or metabolic syndrome patients. Diabetes Care 28: , 2005 From the 1 Division of Cardiology, Gachon Medical School, Incheon, Korea; the 2 Division of Laboratory Medicine, Gachon Medical School, Incheon, Korea; and the 3 Diabetes Unit, Laboratory of Clinical Investigation, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland. Address correspondence and reprint requests to Kwang Kon Koh, MD, PhD, FACC, FAHA, Professor of Medicine, Director, Vascular Medicine and Atherosclerosis Unit, Division of Cardiology, Gil Heart Center, Gachon Medical School, 1198 Kuwol-dong, Namdong-gu, Incheon, Korea kwangk@ghil. com. Received for publication 9 December 2004 and accepted in revised form 16 February Abbreviations: hscrp, high-sensitivity C-reactive protein; PPAR, peroxisome proliferator activated receptor; QUICKI, quantitative insulin sensitivity check index. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Clinical trials of therapy with fibric acid derivatives demonstrate an improvement in cardiovascular end points and coronary stenosis (1). Peroxisome proliferator activated receptors (PPARs) are nuclear receptors activated by fatty acids and derivatives. PPAR mediates the hypolipidemic action of fibrates and is highly expressed in tissues such as heart, where it stimulates the -oxidative degradation of fatty acids. PPAR controls plasma levels of cholesterol and triglycerides, which constitute major risk factors for coronary heart disease. Furthermore, experimental studies have shown that PPAR regulates the expression of key proteins involved in all stages of atherogenesis such as vascular inflammation, suggesting that PPAR exerts direct antiatherogenic actions at the level of the vascular wall (2). These direct vascular effects of fibrates may contribute to the cardiovascular event reduction and explain the clinical benefit in these clinical trials. The endothelial dysfunction associated with metabolic syndrome and other insulin-resistant states are characterized by impaired nitric oxide (NO) release from endothelium (3). Thus, improvement in endothelial function is predicted to improve insulin sensitivity, and this may be one mechanism by which fenofibrate decreases the incidence of coronary heart disease. Excess body fat is frequently associated with dyslipidemia, metabolic syndrome, and atherosclerotic vascular diseases (4). Adiponectin is one of a number of proteins secreted by adipose cells that may couple regulation of insulin sensitivity with energy metabolism and serve to link obesity with insulin resistance (5). Decreased plasma adiponectin levels are observed in patients with diabetes and patients with coronary artery disease (4). Thus, decreased levels of adiponectin may also play a key role in the development of insulin resistance. In addition, adiponectin also possesses DIABETES CARE, VOLUME 28, NUMBER 6, JUNE

2 Metabolic effects of fenofibrate antiatherogenic properties. For example, adiponectin stimulates production of NO (6). However, to date, there are no published studies that have investigated the effects of fenofibrate on adiponectin and insulin sensitivity in patients with hypertriglyceridemia. Therefore, we investigated the vascular and metabolic effects of fenofibrate in patients with hypertriglyceridemia. RESEARCH DESIGN AND METHODS This study was randomized, double blind, placebo controlled, and crossover in design. None had diabetes, were smokers, or had previous angina. We excluded patients with moderate or severe hypertension, nephrotic syndrome, hypothyroidism, coronary artery disease, or peripheral vascular disease. No patient had taken any cholesterol-lowering agent, hormone replacement therapy, or antioxidant vitamin supplements during the preceding 2 months. We administered placebo or micronized fenofibrate 200 mg daily to 46 patients with primary hypertriglyceridemia ( 150 mg/dl) for 8 weeks, with the second treatment period initiated upon completion of the first treatment period (without washout phase). A research nurse counted pills at the end of treatment to monitor compliance. Baseline total cholesterol, triglyceride, LDL cholesterol, HDL cholesterol, non-hdl cholesterol, apolipoprotein B, and apolipoprotein A-I levels were 236 8, , 133 8, 44 1, 192 7, 132 4, and mg/dl, respectively. The mean age was 57 1 years, and 18 (39%) were men. Mean BMI was kg/m 2. Ten of 46 patients were mildly hypertensive. No additional medications, including antihypertensive drugs, aspirin, or nonsteroidal antiinflammatory drugs, were allowed during the study period to avoid other drugs effects. Twenty-four of 46 patients had metabolic syndrome according to the definition of National Cholesterol Education Program Adult Treatment Panel III (7). The study was approved by the Gil Hospital Institute Review Board, and all participants gave written informed consent. Laboratory assays Blood samples for laboratory assays were obtained at 8:00 A.M. following an overnight fast before and at the end of each treatment period. Placebo or fenofibrate was taken at 7:00 P.M. following meals. These samples were immediately coded so that investigators performing laboratory assays were blinded to subject identity or study sequence. Assays for lipids, glucose, and plasma adiponectin were performed in duplicate by enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN) and assays for highsensitivity C-reactive protein (hscrp) levels by latex agglutination (CRP-Latex (II); Denka-Seiken, Tokyo, Japan). Assays for plasma insulin levels were performed in duplicate by immunoradiometric assay (Insulin-Riabead II; Abbott Japan, Tokyo, Japan). All samples from the same patient (batch samples) were measured in blinded pairs on the same enzyme-linked immunosorbent assay kit to minimize run-to-run variability. The interassay and intra-assay coefficients of variation (CVs) were 6%. Quantitative insulin sensitivity check index (QUICKI), a surrogate index of insulin sensitivity, was calculated as follows (insulin is expressed in U/ml and glucose in mg/dl): QUICKI 1/[log- (insulin) log(glucose)] (8). Vascular studies Imaging studies of the right brachial artery were performed using an ATL HDI 3000 ultrasound machine (Bothell, WA) equipped with a 10-MHz linear-array transducer and lower-arm occlusion technique, based on a previously published technique (9,10). All images were transmitted to a personal computer via ethernet with DICOM (digital imaging and communication in medicine) format and then saved on the hard disk of a personal computer in bitmap format. Arterial diameters were measured with Image Tool for Windows version 2.0 (University of Texas Health Science Center, San Antonio, TX). Measurements were performed by investigators blinded to the subject s identity and medication status. Measurements of maximum diameter and percent flow-mediated dilation were made in 10 studies selected at random. The inter- and intraobserver variability for repeated measurement of maximum diameter were and mm, respectively. The inter- and intraobserver variability for repeated measurement of percent flow-mediated dilation were and %, respectively. Statistical analysis Data are expressed as means SE or median (range 25 75%). After testing data for normality, we used Student s paired t or Wilcoxon signed rank test to compare the relative changes in values in response to placebo and fenofibrate treatments, as reported in Tables 1 and 2. We did not incorporate a washout period between placebo and fenofibrate treatments based on our previous study (9). However, to assess the possibility of a carryover effect from the initial treatment periods to the next treatment period, we compared the percent changes of 1) the first treatment placebo and the second treatment placebo with 2) the first treatment fenofibrate and the second treatment fenofibrate relative to baseline values by using Student s unpaired t or Mann-Whitney rank sum test. No significant differences were found in the above two comparisons. In other words, there were no detectable carryover effects. Pearson or Spearman correlation coefficient analysis was used to assess associations between measured parameters. We calculated that 30 subjects would provide 80% power for detecting an absolute increase of 1.5% in flowmediated dilation of the brachial artery between placebo and fenofibrate, with 0.05 based on our previous studies (9 11). The comparison of endotheliumdependent dilation between placebo and fenofibrate was prospectively designated as the primary end point of the study. All other comparisons were considered secondary. A value of P 0.05 was considered to be statistically significant. RESULTS Effects of therapies on lipids and vasomotor function There were no significant differences in BMI between placebo and fenofibrate, and BMI was unchanged by either therapy. Compared with placebo, fenofibrate significantly changed lipoprotein levels. As expected, fenofibrate decreased total cholesterol, non-hdl cholesterol, apolipoprotein B, and triglycerides and increased HDL cholesterol and apolipoprotein A-I (all P 0.001; Table 1) and tended to decrease LDL cholesterol (P 0.069). Fenofibrate significantly im DIABETES CARE, VOLUME 28, NUMBER 6, JUNE 2005

3 Koh and Associates Table 1 Effects of fenofibrate in 46 hypertryglyceridemic patients Variables Placebo Fenofibrate Percent changes BMI (kg/m 2 ) (2.75) (2.75) Lipids (mg/dl) Total cholesterol (50) (35)* 11 2 (15)* Triglycerides (105) (59)* 47 4 (28)* LDL cholesterol (52) (34) 1 6 (39) Apolipoprotein B (28) (22)* 21 3 (18)* HDL cholesterol 45 1 (9) 55 2 (12)* 25 4 (24)* Apolipoprotein A-I (20) (28)* 9 2 (13)* Non-HDL cholesterol (48) (36)* 19 3 (18)* Vasomotor function Brachial artery diameter (mm) Basal (0.45) (0.42) 0 1 (7) Hyperemia (0.46) (0.45) 2 1 (7) Basal (0.45) (0.44) 0 1 (8) Nitroglycerin (0.50) (0.50) 2 1 (7) Flow-mediated dilation (%) (1.30) (1.29)* 48 5 (34)* Nitroglycerin dilation (%) (3.05) (3.57) 7 3 (23) Fibrinogen (mg/dl) (72) (61)* 16 3 (21)* CRP (mg/l) 0.80 ( ) 0.70 ( )* (233)* Insulin resistance ADP ( g/ml) 3.21 ( ) 3.54 ( ) 14 5 (37) Insulin ( U/ml) (2.24) (2.99) 1 11 (75) Glucose (mg/dl) 89 4 (26) 88 3 (23) 1 3 (19) QUICKI (0.072) (0.069) 6 2 (14) Data are means SE (SD) or median (25th 75th percentile). *P vs. placebo, P 0.01, P After testing data for normality, we used Student s paired t or Wilcoxon signed rank test to compare the relative changes in values in response to placebo and fenofibrate treatments. Non-HDL cholesterol total cholesterol HDL cholesterol. QUICKI 1/ log(insulin) log(glucose) (8). proved the percent flow-mediated dilator response to hyperemia by 48 5% (P 0.001; Fig. 1, Table 1). However, the brachial artery dilator response to nitroglycerin was not significantly changed (P 0.169). Of interest, there was a siginificant inverse correlation between the flowmediated dilation following placebo and the percent change in flow-mediated dilation following fenofibrate (r 0.745, P ). Following fenofibrate therapy, improvement in flow-mediated dilation inversely correlated with changes in total cholesterol levels (r and P 0.029), LDL cholesterol levels (r and P 0.041), and non-hdl cholesterol levels (r 0.389, P 0.008). However, changes in flow-mediated dilation were not significantly correlated with changes in triglyceride levels (r and P 0.229) and HDL cholesterol levels (r 0.244, P 0.102). Effects of therapies on adiponectin and insulin resistance There were inverse correlations between BMI and baseline plasma adiponectin levels (r 0.283, P 0.057). There were significant correlations between baseline adiponectin levels and baseline triglycerides (r 0.331, P 0.025), HDL cholesterol (r 0.339, P 0.021), insulin (r 0.337, P 0.022), or QUICKI (r 0.391, P 0.007). Compared with placebo, fenofibrate therapy significantly increased plasma levels of adiponectin by 14 5% (P 0.008; Fig. 1). Fenofibrate therapy did not significantly change fasting insulin and glucose levels. However, compared with placebo, fenofibrate therapy significantly increased QUICKI by 6 2% (P 0.048). There were correlations between percent changes in adiponectin levels and percent changes in flow-mediated dilation (r 0.401, P 0.006), hscrp (r 0.443, P 0.002), QUICKI (r 0.292, P 0.049), or insulin (r 0.273, P 0.067). The relationship between changes in flow-mediated dilation and changes in adiponectin levels was also investigated in a multivariate setting with other predictors (glucose, HDL cholesterol, triglycerides, and BMI). Only changes in adiponectin levels persisted as an independent predictor of changes in flow-mediated dilation (r 0.504, P 0.013). Effects of therapies on hscrp and fibrinogen Compared with placebo, fenofibrate significantly lowered plasma levels of hscrp from 0.80 to 0.70 mg/l (P 0.001) and fibrinogen levels by 16 3% (P 0.001). Effects of therapies in patients with metabolic syndrome We analyzed 24 patients with metabolic syndrome, as reported in Table 2. Overall, compared with the effects of fenofibrate in 46 hypertriglyceridemic patients, we observed similar results in 24 patients with metabolic syndrome. Compared with placebo, fenofibrate significantly changed lipoprotein and fibrinogen levels and significantly improved the percent flowmediated dilator response to hyperemia by 47 6% (P 0.001; Table 2). Compared with placebo, fenofibrate therapy significantly increased plasma levels of adiponectin by 12 6% (P 0.021). Fenofibrate therapy did not significantly change fasting insulin and glucose levels. DIABETES CARE, VOLUME 28, NUMBER 6, JUNE

4 Metabolic effects of fenofibrate Table 2 Effects of fenofibrate in 24 patients with metabolic syndrome among 46 hypertryglyceridemic patients Variables Placebo Fenofibrate Percent changes Age (years) 58 2 (42 74) Sex (men:women) 10:14 BMI (kg/m 2 ) (2.84) (2.82) Lipids (mg/dl) Total cholesterol (42) (35) 5 3 (16) Triglycerides (90) (59)* 51 5 (24)* LDL cholesterol (43) (30) 20 9 (44) Apolipoprotein B (25) (20)* 12 4 (21)* HDL cholesterol 42 2 (9) 52 3 (13)* 24 5 (23)* Apolipoprotein A-I (21) (31) 9 3 (14) Non-HDL cholesterol (37) (31) 12 4 (19) Vasomotor function Brachial artery diameter (mm) Basal (0.47) (0.34) 1 2 (9) Hyperemia (0.48) (0.37) 2 2 (9) Basal (0.47) (0.39) 1 2 (10) Nitroglycerin (0.49) (0.46) 2 2 (9) Flow-mediated dilation (%) (1.42) (1.44)* 47 6 (31)* Nitroglycerin dilation (%) (3.36) (3.07) 5 5 (24) Fibrinogen (mg/dl) (51) (56)* 17 3 (16)* CRP (mg/l) 0.75 ( ) 0.80 ( ) (314) Insulin resistance ADP ( g/ml) 3.35 ( ) 3.55 ( ) 12 6 (30) Insulin ( U/ml) (2.44) (3.47) (51) Glucose (mg/dl) 95 7 (32) 95 6 (28) 2 3 (17) QUICKI (0.057) (0.072) 6 3 (13) Data are expressed as means SE (SD) or median (25th 75th percentile). *P 0.001, P 0.01, P 0.05 vs. placebo. After testing data for normality, we used Student s paired t or Wilcoxon signed rank test to compare the relative changes in values in response to placebo and fenofibrate treatments. Non-HDL cholesterol total cholesterol HDL cholesterol. QUICKI 1/ log(insulin) log(glucose) (8). However, compared with placebo, fenofibrate therapy significantly increased QUICKI by 6 3% (P 0.026). Fenofibrate therapy did not significantly reduce hscrp levels (P 0.092). CONCLUSIONS We observed that fenofibrate therapy significantly improved the percent flow-mediated dilator response to hyperemia, reduced levels of inflammation markers, increased adiponectin levels, and improved insulin sensitivity in hypertriglyceridemic patients. Several studies (12,13) have examined the effect of fibrates on vasomotor function. In the current study, we observed that fenofibrate significantly improved the percent flow-mediated dilator response to hyperemia consistent with other studies (12,13). Plausible mechanisms underlying improvement of flowmediated dilation following fenofibrate include changes of lipoproteins. In support of this speculation, we observed significant correlations between the improvement in flow-mediated dilation and the changes in total cholesterol, LDL cholesterol, and non-hdl cholesterol levels. Niacin treatment increases HDL cholesterol levels, improves flow-mediated dilation, and increases endothelial NO synthase expression in patients, suggesting that HDL-mediated increases in endothelial NO synthase expression and activity may contribute to the observed enhancement in vasorelaxation (14). In the current study, we observed that fenofibrate treatment increased HDL cholesterol levels and improved flow-mediated dilation; however, we did not observe a significant correlation between the improvement in flow-mediated dilation and the changes in HDL cholesterol. We also observed that fenofibrate therapy caused a small, but statistically significant, decrease in hscrp levels, consistent with the findings of others (12). When evaluating the physiological relevance of this finding, it may be important to consider that our subjects were patients with primary hypertriglyceridemia without coronary artery disease or other risk factors who had relatively low pretreatment hscrp levels (median 0.8 mg/l), and, thus, the reduction of absolute levels of hscrp by fenofibrate, while statistically significant, is small. Moreover, it is important to note that in our study, multiple independent markers (including triglyceride levels, adiponectin levels, and QUICKI) all changed in a manner that is consistent with improved insulin sensitivity. This reinforces and supports our hypothesis that these factors are linked by pathophysiological mechanisms. Nevertheless, conclusive demonstration of the clinical relevance of these small, but statistically significant, changes will require a prospectively designed large-scale clinical trial that is beyond the scope of the present study. Fenofibrate therapy resulted in significant elevation of adiponectin levels and increased insulin sensitivity (assessed by QUICKI). QUICKI is a reliable surrogate index for insulin sensitivity that has an especially excellent correlation with the reference standard glucose clamp method 1422 DIABETES CARE, VOLUME 28, NUMBER 6, JUNE 2005

5 Koh and Associates Figure 1 Compared with placebo, fenofibrate significantly improved the percent flow-mediated dilator response to hyperemia (A) and increased plasma levels of adiponectin (B). Mean values are identified by open circles. in insulin-resistant subjects with type 2 diabetes or obesity (r 0.9 in subjects with these diseases) (8). In addition, test characteristics of QUICKI including CV (CV 0.05) and discriminant ratio are significantly better than other simple surrogate indexes and comparable with those of the glucose clamp (15). In a number of relevant clinical conditions, including type 2 diabetes, gestational diabetes, and hypertension, QUICKI can appropriately follow changes in insulin sensitivity after various therapeutic interventions when compared directly with glucose clamp results (15,16). Moreover, a large meta-analysis of insulin-resistant subjects demonstrated that QUICKI is among the best surrogate indexes in terms of predictive power for the onset of diabetes (17). Of particular relevance to this study, decreasing values for QUICKI are also a reliable predictor of increased carotid intima-media thickness (18). Since changes in insulin sensitivity were a secondary outcome for this study, our data on improved insulin sensitivity should be regarded as pilot data for a more focused study on insulin sensitivity. The present study is the first report demonstrating that fenofibrate therapy increases adiponectin levels. Adiponectin is an adipose-derived factor that augments and mimics metabolic actions of insulin. Adiponectin can directly stimulate NO production from endothelium via activation of AMP-activated protein kinase (6). Therefore, increasing adiponectin levels would be predicted to improve both insulin sensitivity and endothelial function by multiple mechanisms. Regulation of metabolic homeostasis and hemodynamic homeostasis may be coupled by vascular actions of insulin to stimulate production of NO (6). Thus, improvements in endothelial function may increase insulin sensitivity, while increased insulin sensitivity may improve endothelial function (3). On the other hand, there may be additional mechanisms for fenofibrate therapy to improve insulin sensitivity that are independent of endothelial function. PPAR activators improve insulin sensitivity and reduce adiposity in rodent models (19). Effects of fenofibrate therapy to increase adiponectin levels may mediate, in part, improved insulin sensitivity supported by significant correlations shown in the present study. Fenofibrate therapy for 2 months treatment increased adiponectin levels without a change in body weight. This raises the possibility that drug therapy is directly altering adiponectin levels independent of adiposity. Thus, it is possible that increased adiponectin levels are contributing to improvement in insulin sensitivity rather than simply reflecting a change in adiposity. Metabolic syndrome is associated with atherosclerotic disease. Obesity is one of the most important contributors to cardiovascular disease. Adipose tissue secretes various bioactive molecules that may directly contribute to the development of obesity-related diseases (20). Dysregulation of adipocyte-derived endocrine factors caused by overnutrition may directly participate in the development of atherosclerosis. Adiponectin may couple regulation of insulin sensitivity with energy metabolism, serve to link obesity with insulin resistance, and possess antiatherogenic properties. In the present study, more than half (57%) of subjects were overweight. Furthermore, compared with the effects of fenofibrate in 46 hypertriglyceridemic patients, we observed similar results in a subgroup of 24 patients with the metabolic syndrome. Thus, our study has implications for the treatment of patients with the metabolic syndrome. Of interest, we observed significant correlations between the degree of changes in adiponectin levels and flow-mediated dilation, insulin levels, QUICKI, or hscrp levels following fenofibrate therapy. Thus, our findings are consistent with those of Ouchi et al. (21), who demonstrated that plasma hscrp levels were negatively correlated with plasma adiponectin levels in male coronary artery disease patients. Our multivariate regression analysis demonstrated that only changes in adiponectin levels persisted as an independent predictor of changes in flowmediated dilation (r 0.504, P 0.013). In conclusion, fenofibrate therapy significantly improved percent flowmediated dilator response to hyperemia, reduced levels of inflammation markers, increased adiponectin levels, and improved insulin sensitivity in hypertriglyceridemic patients with or without metabolic syndrome. The effects of fenofibrate treatment to improve endothelial function and insulin sensitivity and to suppress inflammatory markers relevant to cardiovascular disease are likely to have important beneficial health consequences in patients with hypertriglyceridemia or the metabolic syndrome. Acknowledgments We greatly appreciate the critical review and comments of Myron A. Waclawiw, PhD (Office of Biostatistics Research, National Heart, Lung, and Blood Institute, Rockville, MD). We will present our study in part as abstracts in the 54th Annual Scientific Session of the American College of DIABETES CARE, VOLUME 28, NUMBER 6, JUNE

6 Metabolic effects of fenofibrate Cardiology, Orlando, Florida, 6 9 March References 1. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J: Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High- Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 341: , Barbier O, Torra IP, Duguay Y, Blanquart C, Fruchart JC, Glineur C, Staels B: Pleiotropic actions of peroxisome proliferatoractivated receptors in lipid metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol 22: , Vincent MA, Montagnani M, Quon MJ: Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium. Curr Diab Rep 3: , Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Funahashi T, Matsuzawa Y, the Osaka CAD Study Group: Coronary artery disease: association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 23: 85 89, Heilbronn LK, Smith SR, Ravussin E: The insulin-sensitizing role of the fat derived hormone adiponectin. Curr Pharm Des 9: , Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ: Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 278: , National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106: , Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ: Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85: , Koh KK, Ahn JY, Han SH, Kim DS, Jin DK, Kim HS, Shin MS, Ahn TH, Choi IS, Shin EK: Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients. J Am Coll Cardiol 42: , Koh KK, Quon MJ, Han SH, Chung W-J, Ahn JY, Seo Y-H, Kang MH, Ahn TH, Choi IS, Shin EK: Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients. Circulation 110: , Koh KK, Son JW, Ahn JY, Jin DK, Kim HS, Choi YM, Kim DS, Jeong EM, Park GS, Choi IS, Shin EK: Comparative effects of diet and statin on nitric oxide bioactivity and matrix metalloproteinases in hypercholesterolemic patients with coronary artery disease. Arterioscler Thromb Vasc Biol 22:E19 E23, Evans M, Anderson RA, Graham J, Ellis GR, Morris K, Davies S, Jackson SK, Lewis MJ, Frenneaux MP, Rees A: Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus. Circulation 101: , Marchesi S, Lupattelli G, Lombardini R, Roscini AR, Siepi D, Vaudo G, Pirro M, Sinzinger H, Schillaci G, Mannarino E: Effects of fenofibrate on endothelial function and cell adhesion molecules during post-prandial lipemia in hypertriglyceridemia. J Clin Pharm Ther 28: , Kuvin JT, Ramet ME, Patel AR, Pandian NG, Mendelsohn ME, Karas RH: A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: enhanced vasorelaxation and increased endothelial nitric oxide synthase expression. Am Heart J 144: , Mather KJ, Hunt AE, Steinberg HO, Paradisi G, Hook G, Katz A, Quon MJ, Baron AD: Repeatability characteristics of simple indices of insulin resistance: implications for research applications. J Clin Endocrinol Metab 86: , Katsuki A, Sumida Y, Gabazza EC, Murashima S, Urakawa H, Morioka K, Kitagawa N, Tanaka T, Araki-Sasaki R, Hori Y, Nakatani K, Yano Y, Adachi Y: QUICKI is useful for following improvements in insulin sensitivity after therapy in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 87: , Hanley AJ, Williams K, Gonzalez C, D Agostino RB Jr, Wagenknecht LE, Stern MP, Haffner SM, the San Antonio Heart Study, the Mexico City Diabetes Study, the Insulin Resistance Atherosclerosis Study: Prediction of type 2 diabetes using simple measures of insulin resistance: combined results from the San Antonio Heart Study, the Mexico City Diabetes Study, and the Insulin Resistance Atherosclerosis Study. Diabetes 52: , Rajala U, Laakso M, Paivansalo M, Pelkonen O, Suramo I, Keinanen-Kiukaanniemi S: Low insulin sensitivity measured by both quantitative insulin sensitivity check index and homeostasis model assessment method as a risk factor of increased intima-media thickness of the carotid artery. J Clin Endocrinol Metab 87: , Guerre-Millo M, Gervois P, Raspe E, Madsen L, Poulain P, Derudas B, Herbert JM, Winegar DA, Willson TM, Fruchart JC, Berge RK, Staels B: Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 275: , Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259:87 91, Ouchi N, Kihara S, Funahashi T, Nakamura T, Nishida M, Kumada M, Okamoto Y, Ohashi K, Nagaretani H, Kishida K, Nishizawa H, Maeda N, Kobayashi H, Hiraoka H, Matsuzawa Y: Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation 107: , DIABETES CARE, VOLUME 28, NUMBER 6, JUNE 2005