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Abstract
Background and Objectives
Ramipril and candesartan have decreased the incidence of new onset diabetes in large scale randomized clinical studies. Because ramipril and candesartan have distinct mechanisms of action in the renin angiotensin aldosterone system, we hypothesized that combination therapy would have additive beneficial metabolic effects in patients with hypertension.
Subjects and Methods
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 being 2 months).
Results
Ramipril, combination therapy or candesartan significantly increased the plasma adiponectin levels relative to the baseline measurements by 17±6% (p=0.038), 25±5% (p<0.001), and 14±6% (p=0.016), respectively. Combination therapy significantly increased the plasma adiponectin levels more than either ramipril or candesartan alone (p=0.020 by ANOVA). Only combination therapy significantly increased the QUICKI level relative to the baseline measurements (p=0.002). There were no significant correlations between these changes of the metabolic parameters and reduction of the systolic blood pressure (-0.288≤r≤0.284) and reduction of the diastolic blood pressure (-0.282≤r≤0.190). On multivariate analysis, only the change of adiponectin levels was an independent predictor of the changes in the QUICKI levels (β=1.549, p=0.040) following combination therapy.
Conclusion
Ramipril in combination with candesartan increases the plasma adiponectin levels to a greater extent than monotherapy with either drug alone. Only combination therapy significantly improves insulin sensitivity relative to the baseline measurements. The only predictor for the improvement of insulin sensitivity is the increase of plasma adiponectin levels by combination therapy.
Figures and Tables
Fig. 1
The study design. This study was randomized, double-blind, placebo-controlled, with three treatment arms (each 2 months), and crossover with two washout periods (each 2 months). B1: baseline 1, B2: baseline2, B3: baseline 3.
Fig. 2
The effects of ramipril alone, combined therapy and candesartan alone on plasma adiponectin. A: ramipril, combination therapy, or candesartan significantly increased plasma adiponectin levels relative to baseline measurements (p=0.038, p<0.001, p=0.016, respectively). B: combination therapy significantly increased plasma adiponectin levels more than either ramipril or candesartan alone (p=0.020 by ANOVA). ANOVA: analysis of variance. Vertical line indicates standard error of mean from the respective baseline.
Fig. 3
The effects of ramipril alone, combined therapy and candesartan alone on QUICKI. A: only combination therapy significantly increased QUICKI relative to baseline measurements (p=0.002). B: there were no significant differences of percent changes in QUICK among 3 groups. QUICKI: quantitative Insulin-Sensitivity Check Index. Vertical line indicates standard error of mean from the respective baseline.
Table 1
Effects of ramipril, combined therapy, and candesartan in hypertensive patients
Data are expressed as means±SEM. There were no significant differences among each baseline values. *: p<0.05, †: p<0.01, ‡: p<0.001 for comparison with each baseline value. BP: blood pressure, FMD: flow mediated dilation, NTG: nitroglycerin, quantitative insulin-sensitivity check index (QUICKI)=1/[log (insulin)+log (glucose)], ANOVA: analysis of variance, R/C: ramipril vs combined therapy, R/A: ramipril vs candesartan, C/A: combined therapy vs candesartan, NS: not significant
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