Characteristics of the Studies
We identified 11 studies[12–22] that fully met the inclusion criteria for this meta-analysis. A flow chart of literature search and study selection is presented in Figure 1. The characteristics of the selected trials are presented in Table I. The included trials were published between 1996 and 2010. The sample size varied from 12 to 79, reaching a total of 387. All trials were randomized, double-blind, and placebo-controlled, of which 9 trials were parallel-designed and 2 had a crossover design. Five trials[16,18,20–22] had BP as a primary outcome. The duration of intervention lasted from 2 to 24 weeks, with a median of 4 weeks. Dose of L-arginine varied from 4 to 24 g/day, with a median of 9 g/day. Information on adverse effects of L-arginine intervention was available in 6 trials. Characteristics of participants enrolled in these trials varied across studies. Of note, two trials[18,22] were conducted in pregnant women with hypertension, and another trial presented results separately by hypertension status. Few of the remaining trials specified hypertension status, and most included participants were normotensive as indicated by mean BP levels at baseline.
Effect of L-arginine on BP
The net changes and corresponding 95% CIs for systolic and diastolic BP in each trial, and overall, are presented in Figure 2 and Figure 3. Compared with placebo, oral L-arginine intervention was associated with an average net change ranging from −23.0 to 2.8 mm Hg for systolic BP and from −11.0 to 1.0 mm Hg for diastolic BP. Most trials showed an intervention-related trend toward BP reductions, but only a few reached statistical significance. The combined effect size of L-arginine on systolic BP was −5.39 mm Hg (95% CI −8.54 to -2.25, P = .001), and substantial heterogeneity was observed (P < .001, I2 = 73.3%). For diastolic BP, the combined effect size was -2.66 mm Hg (95% CI −3.77 to −1.54, P < .001), with little evidence of heterogeneity (P = .12, I2 = 34.4%). Neither Begg's test nor Egger's test provided evidence of publication bias regarding effect of L-arginine on systolic or diastolic BP (all P > .30).
Meta-analysis of the effect of oral L-arginine supplementation on systolic blood pressure as compared with placebo. WMD, weighted mean difference.
Meta-analysis of the effect of oral L-arginine supplementation on diastolic blood pressure as compared with placebo. WMD, weighted mean difference.
To explore potential sources of heterogeneity across studies of oral L-arginine supplementation on systolic BP and to test robustness of the results, we performed sensitivity analyses. After excluding two trials[14,17] that showed large systolic BP reductions in response to L-arginine intervention, there was no heterogeneity (P = .59, I2 = 0%), and the combined effect size was −3.34 mm Hg (95% CI −4.93 to −1.86, P < .001). Restricting analysis to 8 trials with a duration of 4 weeks or longer did not change the overall BP estimates (systolic BP −3.96 mm Hg, 95% CI −5.68 to −2.24; diastolic BP -2.62 mm Hg, 95% CI −4.11 to −1.14). Restricting analysis to 7 trials in which participants did not use antihypertensive medications yielded similar results (systolic BP −3.92 mm Hg, 95% CI −6.47 to −1.37; diastolic BP −2.50 mm Hg, 95% CI −3.75 to −1.25). Additional analyses examining the influence of an individual trial on the combined effect size by omitting one trial in each turn yielded a range from −3.66 (95% CI −5.54 to −1.78) to −5.92 mm Hg (95% CI −9.33 to −2.51) for systolic BP and a range from −2.40 (95% CI −3.55 to −1.26) to −3.20 mm Hg (95% CI −4.68 to −1.73) for diastolic BP. None of the individual studies appeared to have appreciable impacts on the overall combined effect sizes.
We next performed meta-regression analyses to assess whether BP reductions were related to L-arginine dose, intervention duration, or baseline BP levels. None of these covariates had significant impacts on the combined effect sizes (Table II). However, there was a trend toward greater reductions in systolic BP among subjects with higher systolic BP at baseline (r = −0.22, P = .13, Figure 4).
Am Heart J. 2011;162(6):959-965. © 2011 Mosby, Inc.
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