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The Effect of Statin Therapy on Endothelial Function in Type 2 Diabetes Without Manifest Cardiovascular Disease

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The Effect of Statin Therapy on Endothelial Function in Type 2 Diabetes Without Manifest Cardiovascular Disease Pathophysiology/Complications ORIGINAL ARTICLE The Effect of Statin Therapy on Endothelial Function in Type 2 Diabetes Without Manifest Cardiovascular Disease 1 4 EDITH D. BEISHUIZEN, MD J. CAREL M. VAN DER VIJVER, MD, PHD oxide overproduction and thus decreased 1 1 JOUKE T. TAMSMA, MD, PHD A. EDO MEINDERS, MD, PHD NO availability (3). Regarding insulin, its 2 1 J. WOUTER JUKEMA, MD, PHD MENNO V. HUISMAN, MD, PHD 3 vasodilatory capacity is at least in part NO MARCEL A. VAN DE REE, MD, PHD dependent (4,5), thus explaining how in- sulin resistance might be related to endo- thelial dysfunction. Flow-mediated dilation (FMD) of the brachial artery is a noninvasive technique OBJECTIVE — Cardiovascular disease (CVD) is the most important cause of mortality in patients with type 2 diabetes and is preceded by endothelial dysfunction. Flow-mediated dilation for measuring endothelial function. FMD (FMD) is a noninvasive technique for measuring endothelial dysfunction. We aimed to deter- of the brachial artery has been shown to mine the effect of long-term statin therapy versus placebo on FMD in patients with type 2 be the result of endothelium-derived NO diabetes without manifest CVD. release (6) and is related to coronary va- soreactivity (7). FMD has proven to be RESEARCH DESIGN AND METHODS — A randomized, placebo-controlled, double- predictive for the presence of coronary ar- blind trial was performed with 250 type 2 diabetic patients. Patients were given 0.4 mg ceriv- tery disease (8,9), for future cardiovascu- astatin or placebo daily. In August 2001, when cerivastatin was withdrawn from the market, the lar events (10–12), and for postoperative 0.4 mg cerivastatin was replaced by 20 mg simvastatin, without deblinding the study. The primary end point was the change in FMD, measured by B-mode ultrasound, after 2 years. cardiovascular events (13) in high-risk populations. Improvement in FMD pre- RESULTS — Determinants of baseline FMD were diabetes duration, common carotid intima- dicts a favorable cardiovascular outcome media thickness, and brachial artery diameter. FMD at baseline was 1.51% in the placebo group in postmenopausal hypertensive women and 1.66% in the statin group and did not change significantly after 2 years. (2). However, in patients at lower risk, FMD was not independently associated CONCLUSIONS — The 2-year statin therapy had no effect on FMD in type 2 diabetes. with outcome (14). FMD is impaired in Statin-induced improvement of cardiovascular risk in patients with type 2 diabetes may be patients with type 2 diabetes with re- mediated through mechanisms other than increased nitric oxide availability. ported FMD values of 4.47–12.3% in Diabetes Care 28:1668–1674, 2005 control subjects vs. 2.96–6.1% in type 2 diabetic patients in cross-sectional studies (15–22). Hydroxymethylglutaryl-CoA reduc- ardiovascular disease (CVD) is the ulation, and diminishes vascular smooth tase inhibitors (statins) have been shown most important cause of mortality in muscle cell proliferation and migration. to reverse endothelial dysfunction in hy- patients with type 2 diabetes (1). Type 2 diabetes is associated with endo- C percholesterolemic nondiabetic patients, Endothelial dysfunction precedes the de- thelial dysfunction; the underlying mech- velopment of atherosclerotic plaques and anisms are complex and related to possibly through upregulation of endo- is believed to be reversible (2). Nitric ox- hyperglycemia (sorbitol, hexosamine, thelial NO synthase expression (23–25), ide (NO) is a key molecule in this process. protein kinase C, and advanced glycation resulting in increased NO production. It modulates blood flow and vascular per- end product pathways) and insulin resis- Statins also inhibit superoxide produc- meability, limits inflammation and coag- tance, resulting in mitochondrial super- tion (25), thereby reducing NO break- down. The net effect is an increase in NO ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● availability, theoretically within days after From the 1Department of General Internal Medicine, Leiden University Medical Center, Leiden, the Neth- starting statin therapy. This may explain 2 erlands; the Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; the the rapid improvement in endothelial 3Department of Internal Medicine, Diakonessenhuis, Utrecht, the Netherlands; and the 4Department of Internal Medicine, Leyenburg Hospital, the Hague, the Netherlands. dysfunction observed in several studies in Address correspondence and reprint requests to E.D. Beishuizen, Department of General Internal Med- nondiabetic subjects (26). In patients icine, C1-R41, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, Netherlands. E-mail: with type 2 diabetes, the results of studies [email protected]. with short-term statin therapy are, how- Received for publication 2 December 2004 and accepted in revised form 10 April 2005. Abbreviations: CCA, common carotid artery; CVD, cardiovascular disease; FMD, flow-mediated dila- ever, contradictory with respect to FMD. tion; IMT, intima-media thickness; NMD, nitroglycerin-mediated dilation. We therefore conducted a randomized, A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion placebo-controlled trial to evaluate the ef- factors for many substances. fect of 2 years of statin therapy on endo- © 2005 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 thelial function in patients with type 2 marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. diabetes without CVD. 1668 DIABETES CARE, VOLUME 28, NUMBER 7, JULY 2005 Beishuizen and Associates RESEARCH DESIGN AND Table 1—Baseline characteristics METHODS — The study design and baseline characteristics of the original pa- Placebo Statin tient population have been described n 79 103 elsewhere (27). Briefly, 250 patients aged Male sex 38 (48) 52 (51) 30–80 years, without CVD and with type Age (years) 59 Ϯ 10 59 Ϯ 11 2 diabetes for Ն1 year, were included in Race this randomized, double-blind clinical White 60 (76) 72 (70) trial. Patients were given 0.4 mg ceriva- Indo-Asian 10 (13) 21 (20) statin (Bayer, Mijdrecht, the Netherlands) Other 9 (11) 10 (10) or placebo daily for 2 years. After the BMI (kg/m2) 31.2 Ϯ 6.0 30.5 Ϯ 5.4 withdrawal of cerivastatin from the mar- Waist-to-hip ratio 1.00 Ϯ 0.09 0.98 Ϯ 0.08 ket, the 0.4-mg cerivastatin dose was re- Current smoker 19 (24) 27 (26) placed by 20 mg simvastatin (Merck Hypertension 46 (58) 49 (48) Sharp & Dome, Haarlem, the Nether- Diabetes duration (years) 9 Ϯ 88Ϯ 7 lands) without deblinding the study. Insulin use 45 (57) 51 (50) Only patients who completed the study A1C (%) 7.68 Ϯ 1.31 7.50 Ϯ 0.98 were included in the present analysis. Microalbuminuria* 12 (15) 21 (20) There were no significant differences in CCA IMT (mm) 0.780 Ϯ 0.129 0.763 Ϯ 0.124 demographic or lipid parameters between Ϯ Ͼ Ͼ the full cohort (n ϭ 250) and the patients Data are means SD or n (%). *Defined for men as 2.5 g/mol creatine and for women as 3.5 g/mol creatine. in this study (n ϭ 182), except for race, since more whites than nonwhites com- pleted the study (data not shown). Eligi- During the study, all measurements were every beat during a 5-min period. After ble patients gave their written informed performed by the same two certified ul- a 10-min rest, another 15 R-wave– consent. The study was performed at the trasonographers. triggered beats were stored. Subse- Leyenburg Hospital, the Hague. The study Fasting subjects were examined in the quently, two puffs of nitroglycerin (0.8 was approved by the hospital’s medical supine position. Heart rate was continu- mg) spray were given sublingually, upon ethics committee. ously monitored by three-lead electrocar- which R-wave–frozen images were again The primary end point of the study diogram. Mean common carotid intima- recorded for every beat during a 5-min was the change in FMD between baseline media thickness (IMT) was measured as period. and 24 months. Secondary end points reported earlier (27). Briefly, the left and Lumen diameter (D) was defined as were the change in absolute diameter right distal 1.0 cm of the common carotid the distance between the media- Ϫ (Dmax D), the time to peak (tmax), the arteries, near and far walls, were exam- adventitia interfaces of far and near wall. change in nitroglycerin-mediated dilation ined longitudinally in the angle resulting Using an automated contour detection (NMD), and the FMD-to-NMD ratio. in an optimal and maximal IMT (while system, D was measured semiautomati- Comparisons between standard measure- avoiding plaques). For each segment, cally by placing a cursor on the media- ments for FMD at 1 min after cuff defla- three R-wave triggered images were adventitia interfaces. FMD was defined as tion and for NMD at 3, 4, or 5 min after stored. Mean IMT was measured when the percentage increase in brachial artery nitroglycerin administration and real possible over the entire 1 cm of the vessel diameter within 30–120 s after ischemia Ϫ maximum values obtained by beat-to- segment. Mean common carotid artery ([Dmax D]/D). NMD is defined as the beat analysis were analyzed as exploratory (CCA) IMT was obtained by averaging the percentage increase within 5 min after end points. mean IMTs of the far and near wall, both nitroglycerin. Patients returned to the study site left and right. Earlier studies in our institute re- after a 12-h fast at 3, 6, 12, 18, and 24 For FMD, the right arm was placed in ported reliability coefficients of 99, 99, months when blinded lipid and safety extension in the elbow, hand in supina- and 67% for baseline diameter, peak di- measurements (creatine kinase and ala- tion, with wrist and elbow supported by ameter, and FMD, respectively (28).
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