- Email: [email protected]
Effects of rosiglitazone on endothelial function, C-reactive protein, and components of the metabolic syndrome in nondiabetic patients with the metabolic syndrome
Effects of Rosiglitazone on Endothelial Function, C-Reactive Protein, and Components of the Metabolic Syndrome in Nondiabetic Patients With the Metabolic Syndrome Tzung-Dau Wang, MD, PhD, Wen-Jone Chen, MD, PhD, Jong-Wei Lin, Ming-Fong Chen, MD, PhD, and Yuan-Teh Lee, MD, PhD Fifty nondiabetic patients who met a modified National Cholesterol Education Program definition for the metabolic syndrome were randomized to receive either rosiglitazone (4 mg/day; n ⴝ 25) or placebo (n ⴝ 25) for 8 weeks. Compared with those receiving placebo, patients in the rosiglitazone group achieved significant reductions in fasting plasma insulin levels (ⴚ40%), homeostasis model assessment indexes (ⴚ45%), systolic and diastolic blood pressures, and high-sensitivity C-reactive protein levels (ⴚ31%). There were no changes in fasting plasma glucose with either treatment. Although rosiglitazone treatment greatly increased plasma levels of low-density lipoprotein cholesterol (18%) and apolipoprotein B (16%), it significantly improved both endotheliumdependent flow-mediated vasodilation (p <0.001) and endothelium-independent nitroglycerin-induced vasodilation (p ⴝ 0.01) of the right brachial artery. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:362–365)
osiglitazone is a thiazolidinedione developed to reduce insulin resistance in patients with type 2 R diabetes. One recent study demonstrated that rosigli1
tazone improved insulin sensitivity in nondiabetic insulin-resistant subjects without causing hypoglycemia.2 Although thiazolidinediones can reduce insulin resistance, there is no clear evidence that they will reduce the risk for coronary heart disease (CHD). Nevertheless, in vitro and animal studies suggest that thiazolidinediones have beneficial effects on the endothelium and vascular inflammation,3,4 both of which play important roles in the pathogenesis of atherosclerosis. Assessment of endothelial function by measuring flow-mediated dilation (FMD) of the brachial artery is currently being regarded as a potential tool for predicting CHD risks.5 Studies regarding the effects of troglitazone on endothelium-dependent FMD of the brachial artery in insulin-resistant subjects have shown inconsistent results,3,6 whereas no human studies evaluating the effects of rosiglitazone on FMD From the Departments of Internal Medicine and Emergency Medicine, Division of Cardiology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Dr. Lee’s address is: Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, 7,Chung-Shan South Road, Taipei 100, Taiwan. E-mail: [email protected]. Manuscript received July 10, 2003; revised manuscript received and accepted October 2, 2003.
362
©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 February 1, 2004
BS,
have been reported. It has been demonstrated that treatment with rosiglitazone significantly reduces Creactive protein (CRP) levels in patients with type 2 diabetes.7 However, there are few data regarding the effects of rosiglitazone on CRP levels in nondiabetic subjects with the insulin-resistant metabolic syndrome. In the present, randomized, double-blind, placebo-controlled study, we assessed the efficacy of rosiglitazone on both endothelium-dependent FMD and CRP as surrogate indicators of future CHD, and on components of the metabolic syndrome in nondiabetic patients with the metabolic syndrome. •••
Patients were recruited from the clinics at the National Taiwan University Hospital without restrictions to gender or socioeconomic status. The presence of metabolic syndrome was determined by criteria defined by the National Cholesterol Education Program Adult Treatment Panel III,8 which were modified to the World Health Organization proposed waist circumference cut points for Asians.9 Subjects were required to have ⱖ3 of the following criteria: (1) waist circumference of ⬎90 cm in men and ⬎80 cm in women; (2) serum triglycerides of ⱖ150 mg/dl; (3) high-density lipoprotein (HDL) cholesterol levels ⬍40 mg/dl in men and ⬍50 mg/dl in women; (4) impaired fasting glucose of 110 to 125 mg/dl; or (5) blood pressure of ⱖ130/85 mm Hg or treated hypertension. The major exclusion criteria were acute coronary events, stroke, or coronary revascularization within the preceding 3 months; diabetes mellitus according to the criteria of the American Diabetes Association; overt liver disease; chronic renal failure; hypothyroidism; myopathy; alcohol or drug abuse; several other significant diseases; or use of other lipidlowering therapy, immunosuppressants, erythromycin, and hormone replacement therapy. All subjects gave written informed consent and the study was approved by the ethics committee of the National Taiwan University Hospital. Eligible patients were instructed to adhere to the American Heart Association step 1 diet throughout the study and underwent an 8-week run-in period during which previous lipid-lowering therapy was discontinued. After the run-in phase, patients were then randomized to receive either rosiglitazone (4 mg/day; n ⫽ 25) or matching placebo (n ⫽ 25) for the 8-week double-blind phase. Patients were seen at the screening visit (i.e., before the 8-week run-in period), 1 week before randomization (baseline laboratory and vascu0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.10.022
glucose (mmol/L)/22.5 . The coefficients of variation were ⬍5% for evRosiglitazone Placebo ery type of measurement. Characteristics (n ⫽ 25) (n ⫽ 25) p Value Endothelium-dependent flow-mediated vasodilation in response to reAge (yrs) 59.0 ⫾ 14.8 60.0 ⫾ 11.6 0.749 Men 15 (60%) 14 (56%) 0.777 active hyperemia and endothelium25.2 ⫾ 3.4 25.6 ⫾ 3.0 0.746 Body mass index (kg/m2) independent, nitroglycerin-induced Waist circumference (cm) 89 ⫾ 7 88 ⫾ 8 0.820 vasodilation were evaluated in the Coronary heart disease 5 (20%) 5 (20%) 1.000 right brachial artery 1 week before Systemic hypertension 19 (76%) 18 (72%) 0.750 Diabetes mellitus 0 (0%) 0 (0%) 1.000 randomization and after 8 weeks of Current smoker 2 (8%) 3 (12%) 0.641 active treatment. Ultrasound meaBlood pressure (mm Hg) surements were obtained using a Systolic 138 ⫾ 25 136 ⫾ 18 0.389 high-resolution ultrasound machine Diastolic 81 ⫾ 14 80 ⫾ 10 0.885 (Hewlett-Packard 5500, Palo Alto, Fasting glucose (mg/dl) 101 ⫾ 16 98 ⫾ 15 0.435 Fasting insulin (IU/ml) 9.5 (7.7–22.9) 9.2 (5.4–29.7) 0.355 California) equipped with an L11-3 HOMA index 2.9 (1.9–5.7) 2.6 (1.3–5.7) 0.333 linear array transducer. Arterial diPlasma lipids ameters were measured at rest, durTotal cholesterol (mg/dl) 234 ⫾ 28 232 ⫾ 28 0.497 ing reactive hyperemia, again at rest Triglycerides (mg/dl) 249 ⫾ 113 239 ⫾ 59 0.727 LDL cholesterol (mg/dl) 135 ⫾ 27 140 ⫾ 29 0.892 (after vessel recovery), and after adHDL cholesterol (mg/dl) 36 ⫾ 6 38 ⫾ 9 0.346 ministration of 0.6 mg of sublingual Non-HDL cholesterol (mg/dl) 202 ⫾ 28 191 ⫾ 23 0.174 nitroglycerin. Reactive hyperemia Total cholesterol/HDL cholesterol 6.56 ⫾ 1.60 6.32 ⫾ 0.94 0.199 was induced by inflation of a pneuApolipoprotein A1 (mg/dl) 114 ⫾ 42 116 ⫾ 27 0.761 matic cuff on the upper arm to suApolipoprotein B (mg/dl) 96 ⫾ 21 99 ⫾ 24 0.754 LDL cholesterol/apolipoprotein B 1.45 ⫾ 0.40 1.40 ⫾ 0.72 0.363 prasystolic pressure, followed by High-sensitivity CRP (mg/dl) 0.22 (0.13–0.62) 0.19 (0.08–0.52) 0.530 cuff deflation after 4.5 minutes. The Vessel size (mm) 4.4 ⫾ 0.4 4.4 ⫾ 0.5 0.342 brachial artery was scanned in longiFlow-mediated vasodilation (%) 6.2 (3.9–8.8) 6.7 (4.5–10.7) 0.240 tudinal sections 2 to 8 cm above the Nitroglycerin-induced vasodilation (%) 12.2 (7.5–15.1) 13.8 (8.1–16.9) 0.285 elbow, and the arterial diameter was Values are expressed as mean ⫾ SD or median (interquartile range). measured on B-mode images using ultrasonic calipers. The end-diastolic arterial diameter was measured from lar studies), at entry (randomization), and at 4 and 8 1 media-adventitia interface to the other at the clearest weeks of treatment. At week 8, physical examinations, section 3 times at baseline, every 20 seconds after laboratory assessments, and vascular studies were reactive hyperemia, and after administration of nitroglycerin. The maximum vessel diameter was defined repeated. Blood pressure was measured 3 times in the right as the average of the 3 consecutive maximum diamarm of seated subjects with a standard mercury sphyg- eter measurements after hyperemia and nitroglycerin, momanometer after a 5-minute rest. The last 2 read- respectively. Vasodilation was then calculated as the ings were averaged for this analysis. Two fasting percent change in diameter compared with baseline. In blood samples were obtained at baseline 7 days apart our laboratory, measurements were obtained by 1 exand at the end of the 8-week drug-therapy phase perienced operator, who was blinded to the medica(weeks 7.5 and 8). Venous blood samples were placed tion studied, in a temperature-controlled room (21°C in tubes containing ethylenediaminetetraacetic acid to 24°C) at the same time of day in patients who fasted and were centrifuged within 30 minutes at 2,000 rpm overnight. The intraobserver variation was 1.5%. for 10 minutes. Plasma was then separated and stored Medications were discontinued on the morning of the at ⫺70°C until analysis. Levels of total cholesterol, visit, and nitrates were withheld for 24 hours before total triglycerides, low-density lipoprotein (LDL) cho- studies. Data were analyzed by nonparametric methods to lesterol and HDL cholesterol were assayed by routine laboratory techniques using the methods of the Lipid avoid assumptions about the distribution of measured Research Clinics, as reported previously.10 If plasma variables. Comparisons between groups were made triglycerides were ⱖ400 mg/dl, LDL cholesterol was using the Mann-Whitney U statistic test. Differences assessed by a direct method.10 Concentrations of apo- between baseline and post-treatment values were anlipoproteins A1 and B were measured by turbidmetric alyzed using the Wilcoxon signed-rank test. Mannimmunoassay using commercial kits (Sigma, St. Whitney analysis was used for comparing percent Louis, Missouri). High-sensitivity CRP was assayed changes between baseline and post-treatment values in by rate nephelometry (Dade Behring, Newark, Dela- patients receiving rosiglitazone versus those receiving ware). Insulin concentrations were determined in du- placebo. Distribution of continuous variables in plicate using a commercially available immunosor- groups are expressed as mean ⫾ SD or median (inbent kit (Immuno-Biologic Laboratories, Hamburg, terquartile range), when appropriate. A p value ⬍0.05 Germany). The marker of insulin resistance, the ho- was considered statistically significant. Baseline characteristics of the 50 patients enrolled meostasis model assessment (HOMA) index,11 was defined as fasting plasma insulin (U/ml) ⫻ fasting in the study are listed in Table 1. Despite mean fasting TABLE 1 Baseline Characteristics of Participants
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TABLE 2 Changes in Various Parameters in Rosiglitazone and Placebo Groups Characteristics Systolic blood pressure (mm Hg) Baseline Study end p Value Diastolic blood pressure (mm Hg) Baseline Study end p Value Body mass index (kg/m2) Baseline Study end p Value Waist circumference (cm) Baseline Study end p Value Fasting glucose (mg/dl) Baseline Study end p Value Fasting insulin (IU/ml) Baseline Study end p Value HOMA index Baseline Study end p Value Total cholesterol (mg/dl) Baseline Study end p Value Triglycerides (mg/dl) Baseline Study end p Value LDL cholesterol (mg/dl) Baseline Study end p Value HDL cholesterol (mg/dl) Baseline Study end p Value Non-HDL cholesterol (mg/dl) Baseline Study end p Value Total cholesterol/HDL cholesterol Baseline Study end p Value Apolipoprotein A1 (mg/dl) Baseline Study end p Value Apolipoprotein B (mg/dl) Baseline Study end p Value LDL cholesterol/apolipoprotein B Baseline Study end p Value High-sensitivity CRP (mg/dl) Baseline Study end p Value
Rosiglitazone (n ⫽ 25)
Placebo (n ⫽ 25)
p Value
138 ⫾ 25 128 ⫾ 15 0.001
136 ⫾ 18 137 ⫾ 19 0.597
0.002
81 ⫾ 14 74 ⫾ 11 0.014
80 ⫾ 10 79 ⫾ 12 0.442
0.080
25.2 ⫾ 3.4 25.3 ⫾ 3.4 0.285
25.6 ⫾ 3.0 25.6 ⫾ 2.9 0.317
0.957
89 ⫾ 7 90 ⫾ 6 0.439
88 ⫾ 8 88 ⫾ 7 0.257
0.894
101 ⫾ 16 99 ⫾ 15 0.383
98 ⫾ 15 97 ⫾ 17 0.696
0.370
9.5 (7.7–22.9) 6.1 (4.1–7.7) 0.002 2.9 (1.9–5.7) 1.5 (1.2–2.2) 0.002
9.2 (5.4–19.7) 10.1 (4.9–18.4) 0.765
0.016
2.6 (1.3–5.7) 2.4 (0.8–4.7) 0.374
0.039
234 ⫾ 28 256 ⫾ 36 0.002
232 ⫾ 28 227 ⫾ 24 0.773
0.014
249 ⫾ 113 227 ⫾ 107 0.563
239 ⫾ 59 228 ⫾ 46 0.415
0.717
135 ⫾ 27 155 ⫾ 24 0.001
140 ⫾ 29 135 ⫾ 23 0.339
0.025
36 ⫾ 6 38 ⫾ 9 0.021
38 ⫾ 9 38 ⫾ 13 0.204
0.032
202 ⫾ 28 226 ⫾ 39 0.008
191 ⫾ 23 185 ⫾ 23 0.977
0.011
6.56 ⫾ 1.60 6.77 ⫾ 1.80 0.367
6.32 ⫾ 0.94 6.28 ⫾ 1.04 0.887
0.174
114 ⫾ 42 112 ⫾ 28 0.825
116 ⫾ 27 117 ⫾ 29 0.744
0.530
96 ⫾ 21 109 ⫾ 22 0.006
99 ⫾ 24 99 ⫾ 23 0.981
0.012
1.45 ⫾ 0.40 1.40 ⫾ 0.45 0.309
1.40 ⫾ 0.72 1.39 ⫾ 0.68 0.695
0.766
0.22 (0.13–0.62) 0.11 (0.04–0.40) 0.002
0.19 (0.08–0.52) 0.18 (0.09–0.45) 0.201
0.035
364 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 93
plasma glucose levels in this study being similar to those of the 2,946 Chinese controls, the mean fasting insulin levels and HOMA indexes were significantly higher than those of the controls (insulin 5.2 IU/ml; HOMA, 1.32).12 The 2 groups showed similar use of various classes of drugs at baseline and during the treatment periods (data not shown). There were no dropouts from the study and no serious adverse events. Safety screening biochemistry (including creatine phosphokinase and transaminases) did not change significantly during the study. Table 2 shows the effects of both rosiglitazone and placebo on various parameters. At the end of the 8-week treatment, patients in the rosiglitazone group achieved significant reductions in fasting plasma insulin levels (⫺40%), HOMA indexes (⫺45%), systolic and diastolic blood pressures (⫺7% and ⫺9%, respectively), and high-sensitivity CRP levels (⫺31%). There was no change in fasting plasma glucose with either treatment. Although rosiglitazone treatment greatly increased plasma levels of LDL cholesterol (18%), non-HDL cholesterol (12%), and apolipoprotein B (16%), it significantly improved both FMD and nitroglycerin-induced vasodilation of the right brachial artery. The beneficial effect of rosiglitazone on FMD remained statistically significant after adjustment for age, gender, body mass index, conventional risk factors, and plasma HDL cholesterol, LDL cholesterol, insulin, and CRP levels in multivariate analysis models (data not shown). •••
In this study, we demonstrated, for the first time, that in nondiabetic patients with the metabolic syndrome, 8-week treatment with rosiglitazone (despite its association with untoward changes in lipoprotein metabolism) greatly increased both endothelium-dependent and -independent vascular reactivity, and reduced blood pressure, fasting insulin, the HOMA index, and CRP levels without causing significant changes in fasting glucose levels. Whether these advantages of rosiglitazone treatment could translate into clinical benefits in terms of CHD morbidity and mortality awaits further investi-
FEBRUARY 1, 2004
TABLE 2 (Continued) Characteristic
Rosiglitazone (n ⫽ 25)
Placebo (n ⫽ 25)
Vessel size (mm) Baseline 4.4 ⫾ 0.4 4.4 ⫾ 0.5 Study end 4.4 ⫾ 0.4 4.4 ⫾ 0.4 p Value 0.236 0.284 Flow-mediated vasodilation (%) Baseline 6.2 (3.9–8.8) 6.7 (4.5–10.7) Study end 12.6 (10.3–15.9) 6.8 (4.2–9.7) p Value ⬍0.001 0.381 Nitroglycerin-induced vasodilation (%) Baseline 12.2 (7.5–15.1) 13.8 (8.1–16.9) Study end 15.8 (12.7–18.9) 14.3 (9.8–18.4) p Value 0.010 0.370 Values are expressed mean ⫾ SD or median (interquartile range).
gation. Given that treatment with rosiglitazone is associated with a worsening of lipid profiles, combination therapy with rosiglitazone plus statins may be an ideal therapeutic option for nondiabetic patients with the metabolic syndrome.1 The average fasting insulin levels and HOMA indexes of our patients are higher than the top quartile values of each factor (8.8 and 2.46 IU/ml, respectively) in a Chinese population-based study.12 This finding indicates that our patients were insulin resistant, although they were selected by the clinical criteria of the metabolic syndrome.8 The magnitude of improvement in the HOMA indexes seen with rosiglitazone in these nondiabetic insulin-resistant patients was similar to those observed in diabetic patients receiving rosiglitazone.13,14 Insulin resistance has been associated with high-normal blood pressure.15 Likewise, our results showed that rosiglitazone significantly lowered both systolic and diastolic blood pressures in nondiabetic patients with the metabolic syndrome. This finding is consistent with recent studies that showed the effectiveness of thiazolidinediones in reducing blood pressures in hypertensive patients.2,16 The observation that 8-week treatment of rosiglitazone significantly increased plasma levels of LDL cholesterol and non-HDL cholesterol is correlated with the magnitude and timing of changes previously reported in long-term rosiglitazone monotherapy studies in diabetic patients.14,17 It has been shown that 8-week treatment with rosiglitazone in diabetic patients resulted in a shift in LDL phenotype from dense to the less atherogenic, large buoyant subfractions.17 Although we did not measure levels of small dense LDL, the LDL cholesterol/apolipoprotein B ratio did not increase with rosiglitazone treatment in this study.
p Value
This finding suggests that the increase in LDL cholesterol was primarily due to increases in LDL particles rather than increases in LDL particle size.18 Further detailed studies are needed to address this issue.
0.347 1. Ginsberg HN. Treatment for patients with the meta-
bolic syndrome. Am J Cardiol 2003;91(suppl):29E– 39E. 2. Raji A, Williams GH, Seely EW, Simonson DC, Bekins SA. Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients. Diabetes Care 2003;26:172–178. 0.083 3. Martens FM, Visseren FL, Lemay J, de Koning EJ, Rabelink TJ. Metabolic and additional vascular effects of thiazolidinediones. Drugs 2002;62:1463–1480. 4. Fukunaga Y, Itoh H, Doi K, Tanaka T, Yamashita J, Chun TH, Inoue M, Masatsugu K, Sawada N, Saito T, et al. Thiazolidinediones, peroxisome proliferator-activated receptor gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides. Atherosclerosis 2001;158:113–119. 5. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, et al, International Brachial Artery Reactivity Task Force. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery. J Am Coll Cardiol 2002;39:257–265. 6. Tack CJ, Ong MK, Lutterman JA, Smits P. Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance: effects of troglitazone. Diabetologia 1998;41:569 –576. 7. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002;106:679 –684. 8. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the 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). JAMA 2001;285:2486 –2497. 9. World Health Organization. The Asia-Pacific perspective: redefining obesity and its treatment. Geneva: WHO, 2000. 10. Wang TD, Chen WJ, Chien KL, Su SSY, Hsu HC, Chen MF, Liau CS, Lee YT. Efficacy of cholesterol levels and ratios in predicting future coronary heart disease in a Chinese population. Am J Cardiol 2001;88:737–743. 11. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–419. 12. Chien KL, Lee YT, Sung FC, Hsu HC, Su TC, Lin RS. Hyperinsulinemia and related atherosclerotic risk factors in the population at cardiovascular risk: a community-based study. Clin Chem 1999;45:838 –846. 13. Lebovitz HE, Dole JF, Patwardhan R, Rappaport EB, Freed MI. Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 2001;86:280 –288. 14. Phillips LS, Grunberger G, Miller E, Patwardhan R, Rappaport EF, Salzman A. Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care 2001;24:308 –315. 15. Reusch JEB. Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome. Am J Cardiol 2002;90(suppl):19G–26G. 16. Fullert S, Schneider F, Haak E, Rau H, Badenhoop K, Lubben G, Usadel KH, Konrad T. Effects of pioglitazone in non-diabetic patients with arterial hypertension: a double-blind, placebo-controlled study. J Clin Endocrinol Metab 2002; 87:5503–5506. 17. Freed MI, Ratner R, Marcovina SM, Kreider MM, Biswas N, Cohen BR, Brunzell JD, and the Rosiglitazone Study 108 Investigators. 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. 18. Griffin BA, Furlonger N, Iversen A. Plasma apolipoprotein (b) to LDL cholesterol ratio as a marker of small, dense LDL. Ann Clin Biochem 2000;37: 537–539.
0.015
BRIEF REPORTS
365
osiglitazone is a thiazolidinedione developed to reduce insulin resistance in patients with type 2 R diabetes. One recent study demonstrated that rosigli1
tazone improved insulin sensitivity in nondiabetic insulin-resistant subjects without causing hypoglycemia.2 Although thiazolidinediones can reduce insulin resistance, there is no clear evidence that they will reduce the risk for coronary heart disease (CHD). Nevertheless, in vitro and animal studies suggest that thiazolidinediones have beneficial effects on the endothelium and vascular inflammation,3,4 both of which play important roles in the pathogenesis of atherosclerosis. Assessment of endothelial function by measuring flow-mediated dilation (FMD) of the brachial artery is currently being regarded as a potential tool for predicting CHD risks.5 Studies regarding the effects of troglitazone on endothelium-dependent FMD of the brachial artery in insulin-resistant subjects have shown inconsistent results,3,6 whereas no human studies evaluating the effects of rosiglitazone on FMD From the Departments of Internal Medicine and Emergency Medicine, Division of Cardiology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Dr. Lee’s address is: Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, 7,Chung-Shan South Road, Taipei 100, Taiwan. E-mail: [email protected]. Manuscript received July 10, 2003; revised manuscript received and accepted October 2, 2003.
362
©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 February 1, 2004
BS,
have been reported. It has been demonstrated that treatment with rosiglitazone significantly reduces Creactive protein (CRP) levels in patients with type 2 diabetes.7 However, there are few data regarding the effects of rosiglitazone on CRP levels in nondiabetic subjects with the insulin-resistant metabolic syndrome. In the present, randomized, double-blind, placebo-controlled study, we assessed the efficacy of rosiglitazone on both endothelium-dependent FMD and CRP as surrogate indicators of future CHD, and on components of the metabolic syndrome in nondiabetic patients with the metabolic syndrome. •••
Patients were recruited from the clinics at the National Taiwan University Hospital without restrictions to gender or socioeconomic status. The presence of metabolic syndrome was determined by criteria defined by the National Cholesterol Education Program Adult Treatment Panel III,8 which were modified to the World Health Organization proposed waist circumference cut points for Asians.9 Subjects were required to have ⱖ3 of the following criteria: (1) waist circumference of ⬎90 cm in men and ⬎80 cm in women; (2) serum triglycerides of ⱖ150 mg/dl; (3) high-density lipoprotein (HDL) cholesterol levels ⬍40 mg/dl in men and ⬍50 mg/dl in women; (4) impaired fasting glucose of 110 to 125 mg/dl; or (5) blood pressure of ⱖ130/85 mm Hg or treated hypertension. The major exclusion criteria were acute coronary events, stroke, or coronary revascularization within the preceding 3 months; diabetes mellitus according to the criteria of the American Diabetes Association; overt liver disease; chronic renal failure; hypothyroidism; myopathy; alcohol or drug abuse; several other significant diseases; or use of other lipidlowering therapy, immunosuppressants, erythromycin, and hormone replacement therapy. All subjects gave written informed consent and the study was approved by the ethics committee of the National Taiwan University Hospital. Eligible patients were instructed to adhere to the American Heart Association step 1 diet throughout the study and underwent an 8-week run-in period during which previous lipid-lowering therapy was discontinued. After the run-in phase, patients were then randomized to receive either rosiglitazone (4 mg/day; n ⫽ 25) or matching placebo (n ⫽ 25) for the 8-week double-blind phase. Patients were seen at the screening visit (i.e., before the 8-week run-in period), 1 week before randomization (baseline laboratory and vascu0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.10.022
glucose (mmol/L)/22.5 . The coefficients of variation were ⬍5% for evRosiglitazone Placebo ery type of measurement. Characteristics (n ⫽ 25) (n ⫽ 25) p Value Endothelium-dependent flow-mediated vasodilation in response to reAge (yrs) 59.0 ⫾ 14.8 60.0 ⫾ 11.6 0.749 Men 15 (60%) 14 (56%) 0.777 active hyperemia and endothelium25.2 ⫾ 3.4 25.6 ⫾ 3.0 0.746 Body mass index (kg/m2) independent, nitroglycerin-induced Waist circumference (cm) 89 ⫾ 7 88 ⫾ 8 0.820 vasodilation were evaluated in the Coronary heart disease 5 (20%) 5 (20%) 1.000 right brachial artery 1 week before Systemic hypertension 19 (76%) 18 (72%) 0.750 Diabetes mellitus 0 (0%) 0 (0%) 1.000 randomization and after 8 weeks of Current smoker 2 (8%) 3 (12%) 0.641 active treatment. Ultrasound meaBlood pressure (mm Hg) surements were obtained using a Systolic 138 ⫾ 25 136 ⫾ 18 0.389 high-resolution ultrasound machine Diastolic 81 ⫾ 14 80 ⫾ 10 0.885 (Hewlett-Packard 5500, Palo Alto, Fasting glucose (mg/dl) 101 ⫾ 16 98 ⫾ 15 0.435 Fasting insulin (IU/ml) 9.5 (7.7–22.9) 9.2 (5.4–29.7) 0.355 California) equipped with an L11-3 HOMA index 2.9 (1.9–5.7) 2.6 (1.3–5.7) 0.333 linear array transducer. Arterial diPlasma lipids ameters were measured at rest, durTotal cholesterol (mg/dl) 234 ⫾ 28 232 ⫾ 28 0.497 ing reactive hyperemia, again at rest Triglycerides (mg/dl) 249 ⫾ 113 239 ⫾ 59 0.727 LDL cholesterol (mg/dl) 135 ⫾ 27 140 ⫾ 29 0.892 (after vessel recovery), and after adHDL cholesterol (mg/dl) 36 ⫾ 6 38 ⫾ 9 0.346 ministration of 0.6 mg of sublingual Non-HDL cholesterol (mg/dl) 202 ⫾ 28 191 ⫾ 23 0.174 nitroglycerin. Reactive hyperemia Total cholesterol/HDL cholesterol 6.56 ⫾ 1.60 6.32 ⫾ 0.94 0.199 was induced by inflation of a pneuApolipoprotein A1 (mg/dl) 114 ⫾ 42 116 ⫾ 27 0.761 matic cuff on the upper arm to suApolipoprotein B (mg/dl) 96 ⫾ 21 99 ⫾ 24 0.754 LDL cholesterol/apolipoprotein B 1.45 ⫾ 0.40 1.40 ⫾ 0.72 0.363 prasystolic pressure, followed by High-sensitivity CRP (mg/dl) 0.22 (0.13–0.62) 0.19 (0.08–0.52) 0.530 cuff deflation after 4.5 minutes. The Vessel size (mm) 4.4 ⫾ 0.4 4.4 ⫾ 0.5 0.342 brachial artery was scanned in longiFlow-mediated vasodilation (%) 6.2 (3.9–8.8) 6.7 (4.5–10.7) 0.240 tudinal sections 2 to 8 cm above the Nitroglycerin-induced vasodilation (%) 12.2 (7.5–15.1) 13.8 (8.1–16.9) 0.285 elbow, and the arterial diameter was Values are expressed as mean ⫾ SD or median (interquartile range). measured on B-mode images using ultrasonic calipers. The end-diastolic arterial diameter was measured from lar studies), at entry (randomization), and at 4 and 8 1 media-adventitia interface to the other at the clearest weeks of treatment. At week 8, physical examinations, section 3 times at baseline, every 20 seconds after laboratory assessments, and vascular studies were reactive hyperemia, and after administration of nitroglycerin. The maximum vessel diameter was defined repeated. Blood pressure was measured 3 times in the right as the average of the 3 consecutive maximum diamarm of seated subjects with a standard mercury sphyg- eter measurements after hyperemia and nitroglycerin, momanometer after a 5-minute rest. The last 2 read- respectively. Vasodilation was then calculated as the ings were averaged for this analysis. Two fasting percent change in diameter compared with baseline. In blood samples were obtained at baseline 7 days apart our laboratory, measurements were obtained by 1 exand at the end of the 8-week drug-therapy phase perienced operator, who was blinded to the medica(weeks 7.5 and 8). Venous blood samples were placed tion studied, in a temperature-controlled room (21°C in tubes containing ethylenediaminetetraacetic acid to 24°C) at the same time of day in patients who fasted and were centrifuged within 30 minutes at 2,000 rpm overnight. The intraobserver variation was 1.5%. for 10 minutes. Plasma was then separated and stored Medications were discontinued on the morning of the at ⫺70°C until analysis. Levels of total cholesterol, visit, and nitrates were withheld for 24 hours before total triglycerides, low-density lipoprotein (LDL) cho- studies. Data were analyzed by nonparametric methods to lesterol and HDL cholesterol were assayed by routine laboratory techniques using the methods of the Lipid avoid assumptions about the distribution of measured Research Clinics, as reported previously.10 If plasma variables. Comparisons between groups were made triglycerides were ⱖ400 mg/dl, LDL cholesterol was using the Mann-Whitney U statistic test. Differences assessed by a direct method.10 Concentrations of apo- between baseline and post-treatment values were anlipoproteins A1 and B were measured by turbidmetric alyzed using the Wilcoxon signed-rank test. Mannimmunoassay using commercial kits (Sigma, St. Whitney analysis was used for comparing percent Louis, Missouri). High-sensitivity CRP was assayed changes between baseline and post-treatment values in by rate nephelometry (Dade Behring, Newark, Dela- patients receiving rosiglitazone versus those receiving ware). Insulin concentrations were determined in du- placebo. Distribution of continuous variables in plicate using a commercially available immunosor- groups are expressed as mean ⫾ SD or median (inbent kit (Immuno-Biologic Laboratories, Hamburg, terquartile range), when appropriate. A p value ⬍0.05 Germany). The marker of insulin resistance, the ho- was considered statistically significant. Baseline characteristics of the 50 patients enrolled meostasis model assessment (HOMA) index,11 was defined as fasting plasma insulin (U/ml) ⫻ fasting in the study are listed in Table 1. Despite mean fasting TABLE 1 Baseline Characteristics of Participants
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TABLE 2 Changes in Various Parameters in Rosiglitazone and Placebo Groups Characteristics Systolic blood pressure (mm Hg) Baseline Study end p Value Diastolic blood pressure (mm Hg) Baseline Study end p Value Body mass index (kg/m2) Baseline Study end p Value Waist circumference (cm) Baseline Study end p Value Fasting glucose (mg/dl) Baseline Study end p Value Fasting insulin (IU/ml) Baseline Study end p Value HOMA index Baseline Study end p Value Total cholesterol (mg/dl) Baseline Study end p Value Triglycerides (mg/dl) Baseline Study end p Value LDL cholesterol (mg/dl) Baseline Study end p Value HDL cholesterol (mg/dl) Baseline Study end p Value Non-HDL cholesterol (mg/dl) Baseline Study end p Value Total cholesterol/HDL cholesterol Baseline Study end p Value Apolipoprotein A1 (mg/dl) Baseline Study end p Value Apolipoprotein B (mg/dl) Baseline Study end p Value LDL cholesterol/apolipoprotein B Baseline Study end p Value High-sensitivity CRP (mg/dl) Baseline Study end p Value
Rosiglitazone (n ⫽ 25)
Placebo (n ⫽ 25)
p Value
138 ⫾ 25 128 ⫾ 15 0.001
136 ⫾ 18 137 ⫾ 19 0.597
0.002
81 ⫾ 14 74 ⫾ 11 0.014
80 ⫾ 10 79 ⫾ 12 0.442
0.080
25.2 ⫾ 3.4 25.3 ⫾ 3.4 0.285
25.6 ⫾ 3.0 25.6 ⫾ 2.9 0.317
0.957
89 ⫾ 7 90 ⫾ 6 0.439
88 ⫾ 8 88 ⫾ 7 0.257
0.894
101 ⫾ 16 99 ⫾ 15 0.383
98 ⫾ 15 97 ⫾ 17 0.696
0.370
9.5 (7.7–22.9) 6.1 (4.1–7.7) 0.002 2.9 (1.9–5.7) 1.5 (1.2–2.2) 0.002
9.2 (5.4–19.7) 10.1 (4.9–18.4) 0.765
0.016
2.6 (1.3–5.7) 2.4 (0.8–4.7) 0.374
0.039
234 ⫾ 28 256 ⫾ 36 0.002
232 ⫾ 28 227 ⫾ 24 0.773
0.014
249 ⫾ 113 227 ⫾ 107 0.563
239 ⫾ 59 228 ⫾ 46 0.415
0.717
135 ⫾ 27 155 ⫾ 24 0.001
140 ⫾ 29 135 ⫾ 23 0.339
0.025
36 ⫾ 6 38 ⫾ 9 0.021
38 ⫾ 9 38 ⫾ 13 0.204
0.032
202 ⫾ 28 226 ⫾ 39 0.008
191 ⫾ 23 185 ⫾ 23 0.977
0.011
6.56 ⫾ 1.60 6.77 ⫾ 1.80 0.367
6.32 ⫾ 0.94 6.28 ⫾ 1.04 0.887
0.174
114 ⫾ 42 112 ⫾ 28 0.825
116 ⫾ 27 117 ⫾ 29 0.744
0.530
96 ⫾ 21 109 ⫾ 22 0.006
99 ⫾ 24 99 ⫾ 23 0.981
0.012
1.45 ⫾ 0.40 1.40 ⫾ 0.45 0.309
1.40 ⫾ 0.72 1.39 ⫾ 0.68 0.695
0.766
0.22 (0.13–0.62) 0.11 (0.04–0.40) 0.002
0.19 (0.08–0.52) 0.18 (0.09–0.45) 0.201
0.035
364 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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plasma glucose levels in this study being similar to those of the 2,946 Chinese controls, the mean fasting insulin levels and HOMA indexes were significantly higher than those of the controls (insulin 5.2 IU/ml; HOMA, 1.32).12 The 2 groups showed similar use of various classes of drugs at baseline and during the treatment periods (data not shown). There were no dropouts from the study and no serious adverse events. Safety screening biochemistry (including creatine phosphokinase and transaminases) did not change significantly during the study. Table 2 shows the effects of both rosiglitazone and placebo on various parameters. At the end of the 8-week treatment, patients in the rosiglitazone group achieved significant reductions in fasting plasma insulin levels (⫺40%), HOMA indexes (⫺45%), systolic and diastolic blood pressures (⫺7% and ⫺9%, respectively), and high-sensitivity CRP levels (⫺31%). There was no change in fasting plasma glucose with either treatment. Although rosiglitazone treatment greatly increased plasma levels of LDL cholesterol (18%), non-HDL cholesterol (12%), and apolipoprotein B (16%), it significantly improved both FMD and nitroglycerin-induced vasodilation of the right brachial artery. The beneficial effect of rosiglitazone on FMD remained statistically significant after adjustment for age, gender, body mass index, conventional risk factors, and plasma HDL cholesterol, LDL cholesterol, insulin, and CRP levels in multivariate analysis models (data not shown). •••
In this study, we demonstrated, for the first time, that in nondiabetic patients with the metabolic syndrome, 8-week treatment with rosiglitazone (despite its association with untoward changes in lipoprotein metabolism) greatly increased both endothelium-dependent and -independent vascular reactivity, and reduced blood pressure, fasting insulin, the HOMA index, and CRP levels without causing significant changes in fasting glucose levels. Whether these advantages of rosiglitazone treatment could translate into clinical benefits in terms of CHD morbidity and mortality awaits further investi-
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TABLE 2 (Continued) Characteristic
Rosiglitazone (n ⫽ 25)
Placebo (n ⫽ 25)
Vessel size (mm) Baseline 4.4 ⫾ 0.4 4.4 ⫾ 0.5 Study end 4.4 ⫾ 0.4 4.4 ⫾ 0.4 p Value 0.236 0.284 Flow-mediated vasodilation (%) Baseline 6.2 (3.9–8.8) 6.7 (4.5–10.7) Study end 12.6 (10.3–15.9) 6.8 (4.2–9.7) p Value ⬍0.001 0.381 Nitroglycerin-induced vasodilation (%) Baseline 12.2 (7.5–15.1) 13.8 (8.1–16.9) Study end 15.8 (12.7–18.9) 14.3 (9.8–18.4) p Value 0.010 0.370 Values are expressed mean ⫾ SD or median (interquartile range).
gation. Given that treatment with rosiglitazone is associated with a worsening of lipid profiles, combination therapy with rosiglitazone plus statins may be an ideal therapeutic option for nondiabetic patients with the metabolic syndrome.1 The average fasting insulin levels and HOMA indexes of our patients are higher than the top quartile values of each factor (8.8 and 2.46 IU/ml, respectively) in a Chinese population-based study.12 This finding indicates that our patients were insulin resistant, although they were selected by the clinical criteria of the metabolic syndrome.8 The magnitude of improvement in the HOMA indexes seen with rosiglitazone in these nondiabetic insulin-resistant patients was similar to those observed in diabetic patients receiving rosiglitazone.13,14 Insulin resistance has been associated with high-normal blood pressure.15 Likewise, our results showed that rosiglitazone significantly lowered both systolic and diastolic blood pressures in nondiabetic patients with the metabolic syndrome. This finding is consistent with recent studies that showed the effectiveness of thiazolidinediones in reducing blood pressures in hypertensive patients.2,16 The observation that 8-week treatment of rosiglitazone significantly increased plasma levels of LDL cholesterol and non-HDL cholesterol is correlated with the magnitude and timing of changes previously reported in long-term rosiglitazone monotherapy studies in diabetic patients.14,17 It has been shown that 8-week treatment with rosiglitazone in diabetic patients resulted in a shift in LDL phenotype from dense to the less atherogenic, large buoyant subfractions.17 Although we did not measure levels of small dense LDL, the LDL cholesterol/apolipoprotein B ratio did not increase with rosiglitazone treatment in this study.
p Value
This finding suggests that the increase in LDL cholesterol was primarily due to increases in LDL particles rather than increases in LDL particle size.18 Further detailed studies are needed to address this issue.
0.347 1. Ginsberg HN. Treatment for patients with the meta-
bolic syndrome. Am J Cardiol 2003;91(suppl):29E– 39E. 2. Raji A, Williams GH, Seely EW, Simonson DC, Bekins SA. Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients. Diabetes Care 2003;26:172–178. 0.083 3. Martens FM, Visseren FL, Lemay J, de Koning EJ, Rabelink TJ. Metabolic and additional vascular effects of thiazolidinediones. Drugs 2002;62:1463–1480. 4. Fukunaga Y, Itoh H, Doi K, Tanaka T, Yamashita J, Chun TH, Inoue M, Masatsugu K, Sawada N, Saito T, et al. Thiazolidinediones, peroxisome proliferator-activated receptor gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides. Atherosclerosis 2001;158:113–119. 5. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, et al, International Brachial Artery Reactivity Task Force. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery. J Am Coll Cardiol 2002;39:257–265. 6. Tack CJ, Ong MK, Lutterman JA, Smits P. Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance: effects of troglitazone. Diabetologia 1998;41:569 –576. 7. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002;106:679 –684. 8. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the 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). JAMA 2001;285:2486 –2497. 9. World Health Organization. The Asia-Pacific perspective: redefining obesity and its treatment. Geneva: WHO, 2000. 10. Wang TD, Chen WJ, Chien KL, Su SSY, Hsu HC, Chen MF, Liau CS, Lee YT. Efficacy of cholesterol levels and ratios in predicting future coronary heart disease in a Chinese population. Am J Cardiol 2001;88:737–743. 11. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–419. 12. Chien KL, Lee YT, Sung FC, Hsu HC, Su TC, Lin RS. Hyperinsulinemia and related atherosclerotic risk factors in the population at cardiovascular risk: a community-based study. Clin Chem 1999;45:838 –846. 13. Lebovitz HE, Dole JF, Patwardhan R, Rappaport EB, Freed MI. Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 2001;86:280 –288. 14. Phillips LS, Grunberger G, Miller E, Patwardhan R, Rappaport EF, Salzman A. Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care 2001;24:308 –315. 15. Reusch JEB. Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome. Am J Cardiol 2002;90(suppl):19G–26G. 16. Fullert S, Schneider F, Haak E, Rau H, Badenhoop K, Lubben G, Usadel KH, Konrad T. Effects of pioglitazone in non-diabetic patients with arterial hypertension: a double-blind, placebo-controlled study. J Clin Endocrinol Metab 2002; 87:5503–5506. 17. Freed MI, Ratner R, Marcovina SM, Kreider MM, Biswas N, Cohen BR, Brunzell JD, and the Rosiglitazone Study 108 Investigators. 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. 18. Griffin BA, Furlonger N, Iversen A. Plasma apolipoprotein (b) to LDL cholesterol ratio as a marker of small, dense LDL. Ann Clin Biochem 2000;37: 537–539.
0.015
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