0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(2):740–747 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2003-031116 The Effects of Atorvastatin on Endothelial Function in Diabetic Patients and Subjects at Risk for Type 2 Diabetes PANAYIOTIS A. ECONOMIDES, ANTONELLA CASELLI, ELIZABETH TIANI, LALITA KHAODHIAR, EDWARD S. HORTON, AND ARISTIDIS VEVES Joslin Diabetes Center (P.A.E., E.T., E.S.H.) and Microcirculation Laboratory (A.C., L.K., A.V.), Beth Israel Deaconess Downloaded from https://academic.oup.com/jcem/article/89/2/740/2840787 by guest on 28 September 2021 Medical Center, Harvard Medical School, Boston Massachusetts 02215 We have investigated the effect of atorvastatin on the endo- risk group, there was a decrease in the C-reactive protein thelial function of patients with diabetes and subjects at risk [median (25–75 percentile), 0.12 mg/dl (0.07–0.27 mg/dl) at exit for type 2 diabetes in a 12-wk, prospective, randomized, visit vs. 0.24 mg/dl (0.07–0.35 mg/dl) at baseline; P < 0.05] and placebo-controlled, double-blind clinical trial. The flow- TNF␣ [median (25–75 percentile), 2.6 pg/ml (1.8–4.1 pg/ml) at mediated dilation (FMD; endothelium dependent) and nitro- exit visit vs. 4.4 pg/ml (3.6–6.0 pg/ml) at baseline; P < 0.05] in glycerin-induced dilation (endothelium independent) in the the atorvastatin-treated patients, whereas in the diabetes brachial artery and the vascular reactivity at the forearm skin group, a decrease in endothelin-1 (mean ؎ SD, 0.97 ؎ 0.29 pg/ml were measured. FMD improved in the atorvastatin-treated, at exit visit vs. 1.19 ؎ 0.42 pg/ml at baseline; P < 0.05) and at-risk subjects [median (25–75 percentile), 7.2% (2.9–9.6%) at plasminogen activator inhibitor-1 [median (25–75 percentile), exit visit vs. 6.6% (2.9–9.5%) at baseline; P < 0.05]. A similar 18 ng/ml (9–24 ng/ml) at exit visit vs. 27 ng/ml (7–41 ng/ml) at improvement of FMD was found in atorvastatin-treated dia- baseline; P < 0.05] were observed. We conclude that atorva- betic patients [median (25–75 percentile), 5.6 (3.9–7.9) at exit statin improves endothelial function and decreases levels of No changes were markers of endothelial activation and inflammation. (J Clin .[0.07 ؍ visit vs. 4.2 (3.2–7.2) at baseline; P observed in nitroglycerin-induced dilation and the microcir- Endocrinol Metab 89: 740–747, 2004) culation reactivity measurements in either group. In the at- NDOTHELIAL FUNCTION IS abnormal in both the nitric oxide synthase expression and nitric oxide production, E macro- and microcirculation in subjects with type 1 or antiinflammatory action and effects on thrombosis, and fa- type 2 diabetes mellitus (1–3). Furthermore, endothelial func- vorable effects on plaque architecture and stability (9–11). tion is impaired in healthy subjects who are at risk of de- Thus, it is currently accepted that statins have pleiotropic veloping type 2 diabetes by virtue of having one or both properties that may contribute to the observed reduction in parents with type 2 diabetes, with or without impaired glu- cardiovascular disease (12). cose tolerance (3, 4). In addition, subjects at risk of devel- Direct action on the endothelial cell has emerged as one of oping diabetes have increased levels of inflammatory cyto- the most prominent mechanisms through which statins may kines and biochemical markers of endothelial dysfunction exert their beneficial effects (13, 14). Therefore, if this hy- suggesting that inflammation and endothelial dysfunction pothesis is correct, it would be expected that treatment with may be contributing factors to the development of diabetes statins should improve the impaired endothelial function (3, 5, 6). when it is impaired in conditions such as diabetes or the Statins have been shown to lower serum cholesterol levels prediabetic stage, even under conditions of normolipidemia. markedly and reduce cardiovascular morbidity and mortal- The main objective of this study was to study the effect of ity (7). Although it was initially thought that the reduction atorvastatin, one of the most powerful statins in providing in cardiovascular disease was solely related to their lipid- total cholesterol, LDL, and triglyceride reduction, on the lowering capacity, over the last few years, it has been rec- endothelial function of the micro- and macrocirculation. To ognized that statins may additionally act through mecha- this end, we have conducted a double-blind, randomized, nisms that are independent of low-density lipoprotein (LDL) placebo-controlled clinical trial that included subjects with cholesterol lowering to provide a 30% relative risk reduction impaired endothelial function divided into one group of of major coronary events (8). Several such mechanisms have healthy subjects at risk of developing diabetes and one group been proposed, including the up-regulation of endothelial of patients with type 1 or 2 diabetes. Abbreviations: CRP, C-reactive protein; cv, coefficient of variation; Subjects and Methods FMD, flow-mediated dilation; HDL, high-density lipoprotein; LDL, low- density lipoprotein; PAI, plasma activator inhibitor; tPA, tissue plas- Subjects minogen activator. A total of 77 subjects were included in the study. Subjects were JCEM is published monthly by The Endocrine Society (http://www. enrolled if they were between the ages of 21 and 80 yr and at risk for type endo-society.org), the foremost professional society serving the en- 2 diabetes (either having a first-degree relative with type 2 diabetes and docrine community. normal glucose tolerance or impaired glucose tolerance defined as a 2-h 740 Economides et al. • Effect of Atorvastatin in Diabetes J Clin Endocrinol Metab, February 2004, 89(2):740–747 741 blood glucose value between 140–199 mg/dl during a 75-g oral glucose Endothelium-independent vasodilation in the macrocirculation was as- tolerance test) or had type 1 or type 2 diabetes. Diabetes was defined sessed by studying brachial artery diameter changes 5 min after the according to the recommendations of the American Diabetes Associa- administration of 400 ␮g of sublingual nitroglycerine (nitroglycerine- tion Expert Committee on the Classification and Diagnosis of Diabetes induced dilation). This test was performed 15 min after the reactive (15). hyperemia test and after obtaining a new baseline reading. To avoid confounding factors known to affect endothelial function After the baseline clinical and laboratory evaluations, participants in and/or glucose metabolism, the following exclusion criteria were ap- all three groups were randomized to either 20 mg atorvastatin treatment plied: treatment with lipid-lowering drugs during the previous 3 or corresponding placebo. The randomization procedure was carried months, cardiac arrhythmia, congestive heart failure, uncontrolled hy- out in a double-blind fashion, and the codes were kept masked until the pertension, recent stroke, chronic renal disease, macroalbuminuria (ex- end of the study. pressed as albumin to creatinine ratio Ͼ 300 ␮g/mg), severe dyslipi- Participants were asked to return for the exit visit after a 12-wk demia (triglycerides Ͼ 600 mg/dl or cholesterol Ͼ 300 mg/dl), or any treatment period. The diabetic patients were also asked to continue with other serious chronic disease requiring active treatment. Subjects were their same diabetes medications and dosages and were encouraged to also excluded if they were on any of the following medications: continue with their usual meal plan and physical activity level. In case glucocorticoids, antineoplastic agents, psychoactive agents, and problems with diabetes control were encountered, any modification to bronchodilators. the diabetes management was recorded. During the exit visit, blood tests Downloaded from https://academic.oup.com/jcem/article/89/2/740/2840787 by guest on 28 September 2021 The protocol was approved by the ethics committee or institutional for glycosylated hemoglobin, glucose, biochemical markers of inflam- review board at each center, and all participants gave written informed mation, and endothelial function were taken, and the vascular reactivity consent. Volunteers for the study were recruited through local adver- in the micro- and macrocirculation was measured. tisement at the Joslin Diabetes Center and the Beth Israel Deaconess Medical Center in Boston. Data analysis Methods The Minitab statistical package (Minitab Inc., State College, PA) for personal computers was used for the statistical analysis. A two-tailed Volunteers attended the Joslin Diabetes Center Clinical Research comparison was assumed. The analyses were performed using a paired Center to undergo the clinical and laboratory evaluations. A general t test for parametrically distributed data and the Wilcoxon matched-pair physical examination was performed by a study physician. Subjects signed rank test for nonparametrically distributed data to compare were studied at all visits after an overnight fast. Participants were asked baseline data and changes in all variables at the end of the study within not to take their diabetes medications (sulfonylureas or metformin) for each group. The t test was used to compare the baseline characteristics 12 h before any of the studies, and those participants taking insulin were asked to omit the rapid-acting insulin the morning of each visit. TABLE 1. Baseline characteristics of the studied subjects Plasma glucose, total serum cholesterol, LDL cholesterol, high- density lipoprotein (HDL) cholesterol, triglycerides, liver function tests, At risk of type 2 Diabetic electrolytes, blood urea nitrogen, and creatinine were measured using diabetes patients the Synchron CX analyzer (Beckman/Coulter, Brea, CA). Routine uri- Total patients (no.) 37 40 nalysis was also performed. The glycosylated hemoglobin (normal Age (yr) 49 Ϯ 12 53 Ϯ 13 range, 4–6%) was determined in whole blood using ion-exchange HPLC Males (%) 20 (54%) 23 (58%) (Tosoh 2.2, Tokyo, Japan).