European Heart Journal Advance Access originally published online on May 5, 2007
European Heart Journal 2007 28(12):1440-1447; doi:10.1093/eurheartj/ehm101
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Additive beneficial cardiovascular and metabolic effects of combination therapy with ramipril and candesartan in hypertensive patients
1 Cardiology, Gachon Medical School, Incheon, Korea
2 Diabetes Unit, NCCAM +, NIH, Bethesda, Maryland, USA
3 Department of Statistics, Ewha Womans University, Seoul, Korea
4 Laboratory Medicine, Gachon Medical School, Incheon, Korea
Received 31 October 2006; revised 13 March 2007; accepted 15 March 2007; online publish-ahead-of-print 5 May 2007.
* Corresponding author: Professor of Medicine Director, Vascular Medicine and Atherosclerosis Unit Cardiology, Gil Heart Center, Gachon Medical School 1198 Kuwol-dong, Namdong-gu, Incheon 405-760, Korea. Tel: +82 32 460 3683; fax: +82 32 460 3117/467 9302. E-mail address: kwangk{at}gilhospital.com
Aims: Ramipril and candesartan have distinct mechanisms of action to improve endothelial function. Therefore, we hypothesized that combination therapy has additive beneficial effects to simultaneously improve endothelial dysfunction and adipocytokine profiles in patients with hypertension.
Methods and results: Thirty-four patients were given ramipril 10 mg and placebo, ramipril 10 mg and candesartan 16 mg, or candesartan 16 mg and placebo daily in a randomized, double-blind, placebo-controlled cross-over trial with three treatment arms and two washout periods (each 2 months). Ramipril, candesartan, or combination therapy reduced blood pressure, improved flow-mediated dilation, and increased plasma adiponectin levels when compared with baseline values. However, combination therapy improved these outcome measures to a greater extent than either ramipril or candesartan alone (P < 0.001 and P = 0.016 for systolic and diastolic blood pressure, P < 0.001 and P = 0.048 for flow-mediated dilation and adiponectin levels by ANOVA). In addition, combination therapy reduced plasma leptin levels to a greater extent than either ramipril or candesartan alone (P = 0.042 by ANOVA). There were correlations between percent changes in adiponectin levels and percent changes in insulin sensitivity (determined by QUICKI) (r = 0.319, P = 0.066) following ramipril therapy, percent changes in QUICKI (r = 0.374, P = 0.029) following combination therapy, and percent changes in QUICKI (r = 0.607, P < 0.001) following candesartan therapy.
Conclusion: Ramipril in combination with candesartan improves blood pressure, endothelial function, and adipocytokine profiles to a greater extent than monotherapy with either drug in hypertensive patients.
Key Words: ACE-inhibitor • Angiotensin II receptor blocker • Endothelial function • Insulin resistance • Adipocytokines
We presented in part at the American College of Cardiology 55th Annual Scientific Session in Atlanta, GA, 7–10 March 2006, and published in abstracts form (J Am Coll Cardiol. 2006;110:Supplement III-811) and in the World Congress (European Society) of Cardiology 2006, Barcelona, Spain, September 2–6, 2006 and in the American Heart Association 2006, Chicago, IL, November 12–15, 2006.
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