Efonidipine Simultaneously Improves Blood Pressure, Endothelial Function, and Metabolic Parameters in Nondiabetic Patients With Hypertension KWANG KON KOH, MD 1 MICHAEL J. QUON, MD, PHD 2 SANG JIN LEE, MD 1 SEUNG HWAN HAN, MD 1 JEONG YEAL AHN, MD 3 JEONG-A KIM, PHD 2 WOOK-JIN CHUNG, MD 1 YONGHEE LEE, PHD 4 EAK KYUN SHIN, MD 1 H ypertension is characterized by en- dothelial dysfunction and fre- quently clusters with metabolic disorders that are characterized by insulin resistance (1,2). These comorbidities may be explained, in part, by reciprocal rela- tionships between endothelial dysfunc- tion and insulin resistance (1). By contrast with calcium channel blockers (CCBs), treatment of hypertension with -block- ers and diuretics is associated with a higher risk of type 2 diabetes (3). This advantage of CCBs may relate to specific mechanisms that target the vicious syn- ergy between endothelial dysfunction and insulin resistance. CCBs activate nitric ox- ide (NO) synthase in vitro and enhance NO production in vivo (4). This may im- pact on the roles of adiponectin, leptin, and resistin to influence metabolic sig- nals, inflammation, and atherosclerosis (5–7). Efonidipine hydrochloride is a 1,4- dihydropyridine–type CCB with long- lasting vasodilator actions and little reflex tachycardia (8). Efonidipine im- proves endothelial function in patients with hypertension when compared with doses of nifedipine that result in com- parable decreases in mean blood pres- sure (9). Therefore, we hypothesized that efonidipine therapy may simulta- neously improve endothelial dysfunc- tion, adipocytokine profiles, and other metabolic parameters in nondiabetic patients with hypertension. RESEARCH DESIGN AND METHODS — We evaluated effects of efonidipine in a randomized, double- blind, placebo-controlled, crossover study. Thirty-nine hypertensive patients (systolic blood pressure [SBP] 180 mmHg and diastolic blood pressure [DBP] 110 mmHg) were considered el- igible for this study. We excluded patients with severe hypertension, unstable an- gina, acute myocardial infarction, or renal insufficiency. None of our subjects were diabetic (based on history or criteria ac- cording to the Report of the Expert Com- mittee on the Diagnosis and Classification of Diabetes Mellitus [10]) or smokers. To minimize acute side effects, during an ini- tial run-in period, study medication was titrated from 40 to 80 mg efonidipine up- wards over a 2-week period if no hypo- tension (SBP  100 mmHg) or hypertension (SBP 140 mmHg) was noted. After the run-in period, all patients underwent a 3-week washout period. At the end of the washout period, partici- pants were randomly assigned to either 40 – 80 mg efonidipine or placebo daily during 8 weeks. Patients were then crossed over to the second treatment arm on completion of the first treatment arm (without washout phase). The Green Cross Pharmaceutical company (Yongin, Korea) provided the identical placebo (purchased by investigators). One patient suffered from facial flushing and was withdrawn. Thus, data from 38 patients were analyzed. This study was approved by the Gil Hospital Institute Review Board. Blood samples were obtained at 8:00 A.M. following an overnight fast be- fore and after each treatment period. Assays for plasma insulin, malondialde- hyde, adiponectin, leptin, and resistin were performed in duplicate by immu- noradiometric assay or by enzyme- linked immunosorbent assay as previously described (11–13). Quanti- tative insulin sensitivity check index (QUICKI) was calculated as described (14). Imaging studies of the right bra- chial artery were performed by ultra- sound as described (11–13). Data are expressed as means  SEM or median (range 25–75%). We used paired Student’s t test or Wilcoxon’s signed-rank test to compare relative changes in response to treatment. Pear- son’s or Spearman’s correlation coeffi- cient analysis was used to assess associations between parameters. We cal- culated that 30 subjects would provide 80% power for detecting an absolute in- crease of 1.5% in flow-mediated dila- tion of the brachial artery between placebo and efonidipine, with = 0.05 (15). A value of P  0.05 was considered to represent statistical significance. RESULTS — The mean age of our sub- jects was 46  2 years, and the male: female proportion was 21:17. Baseline characteristics are reported in Table 1. No carryover effects were found (data are not shown). ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1 Department of Cardiology, Gil Heart Center, Gachon Medical School, Incheon, Korea; the 2 Diabetes Unit, Laboratory of Clinical Investigation, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland; the 3 Department of Cardiology, Laboratory Medicine, Gachon Medical School, Incheon, Korea; and the 4 Department of Statistics, Ewha Womans University, Seoul, Korea. Address correspondence and reprint requests to Kwang Kon Koh, MD, Professor of Medicine, Department of Cardiology, Gil Heart Center, Gachon Medical School, 1198 Kuwol-dong, Namdong-gu, Incheon, Korea 405-760. E-mail: kwangk@gilhospital.com. Received for publication 5 November 2006 and accepted in revised form 18 February 2007. Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-2267. Abbreviations: CCB, calcium channel blocker; DBP, diastolic blood pressure; SBP, systolic blood pres- sure; QUICKI, quantitative insulin sensitivity check index. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. © 2007 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. Emerging Treatments and Technologies B R I E F R E P O R T DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1605