Impact of inorganic nitrate on endothelial function in adults a systematic review of randomised controlled trials and meta analysis

Aim: Inorganic nitrate which is found in green leafy vegetables and beetroot reduces blood pressure via the nitrate-nitrite-NO pathway and may have other benefits such as improved endothelial function. It is assumed that endothelial dysfunction is key risk factor for CVDs. Therefore, in this systematic review and meta-analysis, we evaluated the impact of inorganic nitrate supplementation on endothelial function. Design and method: MEDLINE, Web of Science, and Scopus databases were searched by two independent authors up to November 2021. We included randomised controlled trials that test oral administration of dietary/non-dietary inorganic nitrate versus a control, adult male and female subjects with/without health conditions, measuring endothelial function by flow mediated dilatation (FMD) as an outcome. Risk and quality assessments were performed using a Cochrane risk of bias score and standardised mean differences of the outcomes were pooled using a random-effects model. Results: 3,521 studies were identified after a database search, of which 12 studies met the inclusion criteria. The pooled sample size was 362 and the number of participants per trial ranged from 10 to 65. Eight studies were acute, four studies were chronic and most of them included healthy participant arms (n = 12) with (n = 4) focusing on unhealthy populations. The mean difference in %FMD for nitrate versus the control was 1.57% (95% CI: 0.76–2.37), p = 0.01; high heterogeneity (I2 = 98.3%) was observed (Figure 1). Subgroup analyses were performed in terms of, nitrate amount (< more or less than 600 mg), type of intervention (dietary or non-dietary), participants health status (healthy and unhealthy), and study duration (acute or chronic). All sub-analysis still showed significant increases in %FMD. In acute studies, FMD response was higher (2.13% (95% CI: 0.87–3.40), p < 0.01, I2 = 98.5%) than chronic studies (0.90% (95% CI: 0.48–1.31), p < 0.01, I2 = 68.6%). Only one study showed low risk of bias; the other studies were classified as “some concern” due to a lack of information about randomisation and lack of pre-specified analysis plans. Conclusions: The meta-analysis provides evidence that inorganic nitrate improves FMD response and may be a useful strategy for preventing further CVD. Change in 1.5% of FMD as seen in this review could results in a reduction in CVD risk of ∼15%. However, due to the high heterogeneity of the results, further studies are needed to build a robust evidence base to inform dietary recommendations.