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Efonidipine Simultaneously Improves Blood Pressure, Endothelial Function, and Metabolic Parameters in Nondiabetic Patients with Hypertension

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Efonidipine Simultaneously Improves Blood Pressure, Endothelial Function, and Metabolic Parameters in Nondiabetic Patients with Hypertension Emerging Treatments and Technologies BRIEF REPORT Efonidipine Simultaneously Improves Blood Pressure, Endothelial Function, and Metabolic Parameters in Nondiabetic Patients With Hypertension 1 2 KWANG KON KOH, MD JEONG-A KIM, PHD underwent a 3-week washout period. At 2 1 MICHAEL J. QUON, MD, PHD WOOK-JIN CHUNG, MD the end of the washout period, partici- 1 4 SANG JIN LEE, MD YONGHEE LEE, PHD pants were randomly assigned to either 1 1 SEUNG HWAN HAN, MD EAK KYUN SHIN, MD 3 40–80 mg efonidipine or placebo daily JEONG YEAL AHN, MD during 8 weeks. Patients were then crossed over to the second treatment arm on completion of the first treatment arm ypertension is characterized by en- sure (9). Therefore, we hypothesized (without washout phase). The Green dothelial dysfunction and fre- that efonidipine therapy may simulta- Cross Pharmaceutical company (Yongin, H quently clusters with metabolic neously improve endothelial dysfunc- Korea) provided the identical placebo disorders that are characterized by insulin tion, adipocytokine profiles, and other (purchased by investigators). One patient resistance (1,2). These comorbidities may metabolic parameters in nondiabetic suffered from facial flushing and was be explained, in part, by reciprocal rela- patients with hypertension. withdrawn. Thus, data from 38 patients tionships between endothelial dysfunc- were analyzed. This study was approved tion and insulin resistance (1). By contrast RESEARCH DESIGN AND by the Gil Hospital Institute Review with calcium channel blockers (CCBs), METHODS — We evaluated effects of Board. treatment of hypertension with ␤-block- efonidipine in a randomized, double- Blood samples were obtained at ers and diuretics is associated with a blind, placebo-controlled, crossover 8:00 A.M. following an overnight fast be- higher risk of type 2 diabetes (3). This study. Thirty-nine hypertensive patients fore and after each treatment period. advantage of CCBs may relate to specific (systolic blood pressure [SBP] Ͻ180 Assays for plasma insulin, malondialde- mechanisms that target the vicious syn- mmHg and diastolic blood pressure hyde, adiponectin, leptin, and resistin ergy between endothelial dysfunction and [DBP] Ͻ110 mmHg) were considered el- were performed in duplicate by immu- insulin resistance. CCBs activate nitric ox- igible for this study. We excluded patients noradiometric assay or by enzyme- ide (NO) synthase in vitro and enhance with severe hypertension, unstable an- linked immunosorbent assay as NO production in vivo (4). This may im- gina, acute myocardial infarction, or renal previously described (11–13). Quanti- pact on the roles of adiponectin, leptin, insufficiency. None of our subjects were tative insulin sensitivity check index and resistin to influence metabolic sig- diabetic (based on history or criteria ac- (QUICKI) was calculated as described nals, inflammation, and atherosclerosis cording to the Report of the Expert Com- (14). Imaging studies of the right bra- (5–7). mittee on the Diagnosis and Classification chial artery were performed by ultra- Efonidipine hydrochloride is a 1,4- of Diabetes Mellitus [10]) or smokers. To sound as described (11–13). dihydropyridine–type CCB with long- minimize acute side effects, during an ini- Data are expressed as means Ϯ SEM lasting vasodilator actions and little tial run-in period, study medication was or median (range 25–75%). We used reflex tachycardia (8). Efonidipine im- titrated from 40 to 80 mg efonidipine up- paired Student’s t test or Wilcoxon’s proves endothelial function in patients wards over a 2-week period if no hypo- signed-rank test to compare relative with hypertension when compared with tension (SBP Ͻ100 mmHg) or changes in response to treatment. Pear- doses of nifedipine that result in com- hypertension (SBP Ͼ140 mmHg) was son’s or Spearman’s correlation coeffi- parable decreases in mean blood pres- noted. After the run-in period, all patients cient analysis was used to assess ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● associations between parameters. We cal- From the 1Department of Cardiology, Gil Heart Center, Gachon Medical School, Incheon, Korea; the culated that 30 subjects would provide 2Diabetes Unit, Laboratory of Clinical Investigation, National Center for Complementary and Alternative 80% power for detecting an absolute in- Medicine, National Institutes of Health, Bethesda, Maryland; the 3Department of Cardiology, Laboratory crease of Ն1.5% in flow-mediated dila- 4 Medicine, Gachon Medical School, Incheon, Korea; and the Department of Statistics, Ewha Womans tion of the brachial artery between University, Seoul, Korea. ␣ϭ Address correspondence and reprint requests to Kwang Kon Koh, MD, Professor of Medicine, Department placebo and efonidipine, with 0.05 of Cardiology, Gil Heart Center, Gachon Medical School, 1198 Kuwol-dong, Namdong-gu, Incheon, Korea (15). A value of P Ͻ 0.05 was considered 405-760. E-mail: [email protected]. to represent statistical significance. 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- RESULTS — The mean age of our sub- sure; QUICKI, quantitative insulin sensitivity check index. jects was 46 Ϯ 2 years, and the male: A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion female proportion was 21:17. Baseline factors for many substances. characteristics are reported in Table 1. No © 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 carryover effects were found (data are not marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. shown). DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 1605 Vascular and metabolic effects of efonidipine Table 1—Effects of efonidipine in 38 patients with hypertension Percentage Variables Baseline Placebo Efonidipine changes BMI (kg/m2) 24.7 Ϯ 0.5 24.7 Ϯ 0.5 24.6 Ϯ 0.5 0.4 Ϯ 0.3 (2.0) Heart rate (bpm) 86 Ϯ 282Ϯ 2 (12) 84 Ϯ 2 (13) 4 Ϯ 3 (16) SBP (mmHg) 155 Ϯ 2 148 Ϯ 2 (15) 134 Ϯ 2 (14)* Ϫ9 Ϯ 1 (8) DBP (mmHg) 95 Ϯ 191Ϯ 1 (9) 83 Ϯ 2 (9)* Ϫ9 Ϯ 1 (8) Lipids (mg/dl) Total cholesterol 186 Ϯ 4 183 Ϯ 5 (31) 187 Ϯ 5 (29) 3 Ϯ 2 (12) Triglycerides 162 Ϯ 19 157 Ϯ 18 (112) 155 Ϯ 16 (101) 15 Ϯ 9 (54) LDL cholesterol 105 Ϯ 4 102 Ϯ 4 (22) 106 Ϯ 4 (25) 5 Ϯ 3 (16) HDL cholesterol 49 Ϯ 353Ϯ 3 (20) 50 Ϯ 2 (14) Ϫ3 Ϯ 3 (21) Vasomotor function Flow-mediated dilation (%) 4.28 Ϯ 0.22 5.42 Ϯ 0.26 (1.58) 6.20 Ϯ 0.25 (1.52)* 21 Ϯ 7 (41) Nitroglycerin dilation (%) 13.87 Ϯ 0.70 14.62 Ϯ 0.68 (4.21) 14.84 Ϯ 0.80 (4.90) 2 Ϯ 4 (23) Malondialdehyde (␮mol/l) 1.20 Ϯ 0.04 1.22 Ϯ 0.04 (0.25) 1.12 Ϯ 0.05 (0.31)† Ϫ8 Ϯ 3 (18) C-reactive protein (mg/l) 0.80 (0.50–1.40) 0.85 (0.40–1.40) 0.65 (0.50–1.30) 25 Ϯ 18 (109) Insulin resistance Adiponectin (␮g/ml) 4.3 Ϯ 0.6 4.2 Ϯ 0.6 (3.7) 4.6 Ϯ 0.6 (3.9)† 15 Ϯ 4 (23) Insulin (␮U/ml) 7.33 (4.89–12.05) 7.63 (4.91–11.25) 6.78 (4.50–9.20) 3 Ϯ 8 (52) Glucose (mg/dl) 103 Ϯ 2 102 Ϯ 2 (12) 100 Ϯ 2 (15) Ϫ2 Ϯ 2 (10) QUICKI 0.360 Ϯ 0.010 0.351 Ϯ 0.006 (0.039) 0.359 Ϯ 0.007 (0.040) 3 Ϯ 2 (13) Leptin (ng/ml) 5.2 Ϯ 0.6 5.2 Ϯ 0.6 (3.6) 4.7 Ϯ 0.5 (3.3)† Ϫ12 Ϯ 4 (26) Resistin (ng/ml) 7.66 (5.81–10.34) 7.76 (5.83–10.41) 8.12 (5.31–9.99)* Ϫ1 Ϯ 6 (39) Data are expressed as means Ϯ SEM (SD) or median (25–75th percentile). *P Ͻ 0.001 vs. placebo. †P Ͻ 0.05 vs. placebo. QUICKI ϭ 1/͓log (insulin) ϩ log (glucose)͔ (ref. 14). When compared with placebo, efo- adiponectin and HDL cholesterol levels function in patients with hypertension (9) nidipine therapy reduced SBP and DBP by (r ϭ 0.434, P ϭ 0.006) and QUICKI (r ϭ when compared with nifedipine. Finally, 9 Ϯ 1% (P Ͻ 0.001) and 9 Ϯ 1% (P Ͻ 0.379, P ϭ 0.019) following efonidipine urinary excretion of 8-hydroxy-2Ј- 0.001), respectively. When compared therapy. In a multiple regression model, deoxyguanosine and serum malondialde- with placebo, efonidipine improved flow- percentage changes in adiponectin levels hyde–modified LDL are both decreased mediated dilator response to hyperemia following efonidipine therapy persisted as by efonidipine, but not nifedipine, ther- by 21 Ϯ 7% (P Ͻ 0.001) and reduced an independent predictor of percentage apy. Although we did not directly com- plasma malondialdehyde levels by 8 Ϯ changes in HDL cholesterol levels (␤ϭ pare efonidipine with other CCBs in the 3% (P ϭ 0.011). 0.459, P ϭ 0.006) and QUICKI (␤ϭ current study, it will be of interest to do so There were positive correlations be- 0.467, P ϭ 0.067). in future studies. tween baseline adiponectin and HDL cho- Following efonidipine therapy, im- Potential mechanisms for CCBs to in- lesterol levels (r ϭ 0.533, P Ͻ 0.001), as provement in flow-mediated dilation was fluence insulin sensitivity may relate to well as between baseline BMI and baseline correlated with percentage changes in their ability to target the vicious synergy adiponectin (r ϭϪ0.507, P ϭ 0.001) or plasma levels of malondialdehyde (r ϭ between endothelial dysfunction and in- leptin (r ϭ 0.508, P ϭ 0.001) levels.
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