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Published online March 10, 2007
Diabetes Care 30:1605-1607, 2007
DOI: 10.2337/dc06-2267
© 2007 by the American Diabetes Association
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Emerging Treatments and Technologies
Brief Report

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

Kwang Kon Koh, MD1, Michael J. Quon, MD, PHD2, Sang Jin Lee, MD1, Seung Hwan Han, MD1, Jeong Yeal Ahn, MD3, Jeong-a Kim, PHD2, Wook-Jin Chung, MD1, Yonghee Lee, PHD4 and Eak Kyun Shin, MD1

1 Department of Cardiology, Gil Heart Center, Gachon Medical School, Incheon, Korea
2 Diabetes Unit, Laboratory of Clinical Investigation, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland
3 Department of Cardiology, Laboratory Medicine, Gachon Medical School, Incheon, Korea
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{at}gilhospital.com

Abbreviations: CCB, calcium channel blocker • DBP, diastolic blood pressure • SBP, systolic blood pressure • QUICKI, quantitative insulin sensitivity check index


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
Hypertension is characterized by endothelial dysfunction and frequently clusters with metabolic disorders that are characterized by insulin resistance (1,2). These comorbidities may be explained, in part, by reciprocal relationships between endothelial dysfunction and insulin resistance (1). By contrast with calcium channel blockers (CCBs), treatment of hypertension with ß-blockers 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 synergy between endothelial dysfunction and insulin resistance. CCBs activate nitric oxide (NO) synthase in vitro and enhance NO production in vivo (4). This may impact on the roles of adiponectin, leptin, and resistin to influence metabolic signals, 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 improves endothelial function in patients with hypertension when compared with doses of nifedipine that result in comparable decreases in mean blood pressure (9). Therefore, we hypothesized that efonidipine therapy may simultaneously improve endothelial dysfunction, adipocytokine profiles, and other metabolic parameters in nondiabetic patients with hypertension.


   RESEARCH DESIGN AND METHODS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
RESULTS--
 CONCLUSIONS--
 References
 
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 eligible for this study. We excluded patients with severe hypertension, unstable angina, acute myocardial infarction, or renal insufficiency. None of our subjects were diabetic (based on history or criteria according to the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus [10]) or smokers. To minimize acute side effects, during an initial run-in period, study medication was titrated from 40 to 80 mg efonidipine upwards over a 2-week period if no hypotension (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, participants 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 before and after each treatment period. Assays for plasma insulin, malondialdehyde, adiponectin, leptin, and resistin were performed in duplicate by immunoradiometric assay or by enzyme-linked immunosorbent assay as previously described (11–13). Quantitative insulin sensitivity check index (QUICKI) was calculated as described (14). Imaging studies of the right brachial artery were performed by ultrasound 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. Pearson's or Spearman's correlation coefficient analysis was used to assess associations between parameters. We calculated that 30 subjects would provide 80% power for detecting an absolute increase of ≥1.5% in flow-mediated dilation of the brachial artery between placebo and efonidipine, with {alpha} = 0.05 (15). A value of P < 0.05 was considered to represent statistical significance.


   RESULTS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
CONCLUSIONS--
 References
 
The mean age of our subjects 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).


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  		Table 1— Effects of efonidipine in 38 patients with hypertension

 
When compared with placebo, efonidipine therapy reduced SBP and DBP by 9 ± 1% (P < 0.001) and 9 ± 1% (P < 0.001), respectively. When compared with placebo, efonidipine improved flow-mediated dilator response to hyperemia by 21 ± 7% (P < 0.001) and reduced plasma malondialdehyde levels by 8 ± 3% (P = 0.011).

There were positive correlations between baseline adiponectin and HDL cholesterol levels (r = 0.533, P < 0.001), as well as between baseline BMI and baseline adiponectin (r = –0.507, P = 0.001) or leptin (r = 0.508, P = 0.001) levels. When compared with placebo, efonidipine therapy increased plasma adiponectin levels by 15 ± 4% (P = 0.013) and decreased plasma leptin and resistin levels by 12 ± 4% (P = 0.030) and 1 ± 6% (P = 0.001), respectively. Insulin sensitivity assessed by QUICKI did not significantly change (increase of 3 ± 2%, P = 0.239). Plasma resistin levels were not correlated with either insulin sensitivity or BMI. There were no significant correlations between percentage changes in adiponectin and percentage changes in leptin or resistin levels following efonidipine therapy (–0.054 ≤ r ≤ –0.030). However, we did observe correlations between percentage changes in adiponectin and HDL cholesterol levels (r = 0.434, P = 0.006) and QUICKI (r = 0.379, P = 0.019) following efonidipine therapy. In a multiple regression model, percentage changes in adiponectin levels following efonidipine therapy persisted as an independent predictor of percentage changes in HDL cholesterol levels (ß = 0.459, P = 0.006) and QUICKI (ß = 0.467, P = 0.067).

Following efonidipine therapy, improvement in flow-mediated dilation was correlated with percentage changes in plasma levels of malondialdehyde (r = –0.479, P = 0.002), leptin (r = –0.424, P = 0.008), insulin (r = –0.354, P = 0.029), and QUICKI (r = 0.471, P = 0.003). Improvement in flow-mediated dilation persisted as an independent predictor of percentage changes in malondialdehyde (ß = –0.822, P = 0.017) and QUICKI (ß = 1.032, P = 0.034). Following efonidipine therapy, there were significant correlations between percentage changes in plasma levels of malondialdehyde and leptin (r = 0.364, P = 0.025).


   CONCLUSIONS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
References
 
Efonidipine has distinct properties when compared with other CCBs. Efonidipine has higher affinity for T-type Ca2+ channels (16) and a larger effect in improving endothelial function in patients with hypertension (9) when compared with nifedipine. Finally, urinary excretion of 8-hydroxy-2'-deoxyguanosine and serum malondialdehyde–modified LDL are both decreased by efonidipine, but not nifedipine, therapy. Although we did not directly compare efonidipine with other CCBs in the current study, it will be of interest to do so in future studies.

Potential mechanisms for CCBs to influence insulin sensitivity may relate to their ability to target the vicious synergy between endothelial dysfunction and insulin resistance. Therefore, we assessed metabolic parameters including plasma levels of lipids, adiponectin, leptin, resistin, and QUICKI. Efonidipine had a neutral metabolic effect with respect to the lipid profile and QUICKI. However, improvement in flow-mediated dilation persisted as an independent predictor of changes in QUICKI.

Amlodipine has no significant effect on adiponectin levels in patients with hypertension (17). In our study, efonidipine increased adiponectin levels without a corresponding change in BMI. Increasing adiponectin levels is predicted to improve both insulin sensitivity and endothelial function by multiple mechanisms (18). Regulation of metabolic homeostasis and hemodynamic homeostasis may be coupled by vascular actions of insulin to stimulate production of NO (19). In the current study, changes in adiponectin levels persisted as an independent predictor of changes in HDL cholesterol levels and QUICKI. Effects of efonidipine to reduce plasma leptin and malondialdehyde levels and improve endothelium-dependent dilation are significantly correlated. In summary, efonidipine therapy simultaneously improves blood pressure, endothelial function, and metabolic parameters without substantially altering insulin sensitivity in nondiabetic patients with hypertension.


   Acknowledgments
 
This study was supported by grants from an established investigator award (2005-1) from the Gil Medical Center, Gachon Medical School, Incheon, Korea.


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 10 March 2007. DOI: 10.2337/dc06-2267.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

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.

Received for publication November 5, 2006. Accepted for publication February 18, 2007.


   References
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 

  1. Kim J, Montagnani M, Koh KK, Quon MJ: Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 113:1888–1904, 2006[Abstract/Free Full Text]
  2. Garcia-Puig J, Ruilope LM, Luque M, Fernandez J, Ortega R, Dal-Re R, AVANT Study Group Investigators: Glucose metabolism in patients with essential hypertension. Am J Med 119:318–326, 2006[Medline]
  3. Taylor EN, Hu FB, Curhan GC: Antihypertensive medications and the risk of incident type 2 diabetes. Diabetes Care 29:1065–1070, 2006[Abstract/Free Full Text]
  4. Asano Y, Kim J, Ogai A, Takashima S, Shintani Y, Minamino T, Kitamura S, Tomoike H, Hori M, Kitakaze M: A calcium channel blocker activates both ecto-5(')-nucleotidase and NO synthase in HUVEC. Biochem Biophys Res Commun 311:625–628, 2003[Medline]
  5. Han SH, Quon MJ, Kim JA, Koh KK: Adiponectin and cardiovascular disease: response to therapeutic interventions. J Am Coll Cardiol 49:531–538, 2007[Abstract/Free Full Text]
  6. Correia ML, Haynes WG: Leptin, obesity and cardiovascular disease. Curr Opin Nephrol Hypertens 13:215–223, 2004[Medline]
  7. Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, Mickle DA: Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction. Circulation 108:736–740, 2003[Abstract/Free Full Text]
  8. Honda M, Hayashi K, Matsuda H, Kubota E, Tokuyama H, Okubo K, Takamatsu I, Ozawa Y, Saruta T: Divergent renal vasodilator action of L- and T-type calcium antagonists in vivo. J Hypertens 19:2031–2037, 2001[Medline]
  9. Oshima T, Ozono R, Yano Y, Higashi Y, Teragawa H, Miho N, Ishida T, Ishida M, Yoshizumi M, Kambe M: Beneficial effect of T-type calcium channel blockers on endothelial function in patients with essential hypertension. Hypertens Res 28:889–894, 2005[Medline]
  10. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 21(Suppl. 1):S5–S22, 1998
  11. Koh KK, Quon MJ, Han SH, Ahn JY, Jin DK, Kim HS, Kim DS, Shin EK: Vascular and metabolic effects of combined therapy with ramipril and simvastatin in patients with type 2 diabetes. Hypertension 45:1088–1093, 2005[Abstract/Free Full Text]
  12. Koh KK, Quon MJ, Han SH, Chung W-J, Lee Y, Shin EK: Anti-inflammatory and metabolic effects of candesartan in hypertensive patients. Int J Cardiol 108:96–100, 2006[Medline]
  13. Koh KK, Quon MJ, Han SH, Chung W-J, Ahn JY, Kim J, Kang WC, Lee Y, Shin EK: Additive beneficial effects of fenofibrate combined with candesartan in the treatment of hypertriglyceridemic, hypertensive patients. Diabetes Care 29:195–201, 2006[Abstract/Free Full Text]
  14. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ: Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85:2402–2410, 2000[Abstract/Free Full Text]
  15. Koh KK, Ahn JY, Han SH, Kim DS, Jin DK, Kim HS, Shin MS, Ahn TH, Choi IS, Shin EK: Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients. J Am Coll Cardiol 42:905–910, 2003[Abstract/Free Full Text]
  16. Lee TS, Kaku T, Takebayashi S, Uchino T, Miyamoto S, Hadama T, Perez-Reyes E, Ono K: Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology 78:11–20, 2006[Medline]
  17. Watanabe S, Okura T, Kurata M, Irita J, Manabe S, Miyoshi K, Fukuoka T, Murakami K, Higaki J: The effect of losartan and amlodipine on serum adiponectin in Japanese adults with essential hypertension. Clin Ther 28:1677–1685, 2006[Medline]
  18. Koh KK, Han SH, Quon MJ: Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions. J Am Coll Cardiol 46:1978–1985, 2005[Abstract/Free Full Text]
  19. Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ: Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 278:45021–45026, 2003[Abstract/Free Full Text]

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