Limited Effects of Inorganic Nitrate Supplementation on Exercise Training Responses: A Systematic Review and Meta-analysis.

Background: Inorganic nitrate (NO₃⁻) supplementation is purported to benefit short-term exercise performance, but it is unclear whether NO₃⁻ improves longer-term exercise training responses (such as improvements in VO_2peak or time to exhaustion (TTE)) versus exercise training alone. The purpose of this systematic review and meta-analysis was to determine the effects of NO₃⁻ supplementation combined with exercise training on VO_2peak and TTE, and to identify potential factors that may impact outcomes. Methods: Electronic databases (PubMed, Medscape, and Web of Science) were searched for articles published through June 2022 with article inclusion determined a priori as: (1) randomized placebo-controlled trials, (2) exercise training lasted at least three weeks, (3) treatment groups received identical exercise training, (4) treatment groups had matched VO_2peak at baseline. Study quality was assessed using the Cochrane Risk-of-Bias 2 tool. Standardized mean difference (SMD) with 95% confidence intervals (CI) were calculated using restricted maximum likelihood estimation between pre- and post-training differences in outcomes. Moderator subgroup and meta-regression analyses were completed to determine whether the overall effect was influenced by age, sex, NO₃⁻ dosage, baseline VO_2peak, health status, NO₃⁻ administration route, and training conditions. Results: Nine studies consisting of eleven trials were included: n = 228 (72 females); age = 37.7 ± 21 years; VO_2peak: 40 ± 18 ml/kg/min. NO₃⁻ supplementation did not enhance exercise training with respect to VO_2peak (SMD: 0.18; 95% CI: -0.09, 0.44; p = 0.19) or TTE (SMD: 0.08; 95% CI: − 0.21, 0.37; p = 0.58). No significant moderators were revealed on either outcome. Subset analysis on healthy participants who consumed beetroot juice (BRJ) revealed stronger trends for NO₃⁻ improving VO_2peak (p = 0.08) compared with TTE (p = 0.19), with no significant moderators. Sunset funnel plot revealed low statistical power in all trials. Conclusions: NO₃⁻ supplementation combined with exercise training may not enhance exercise outcomes such as VO_2peak or TTE. A trend for greater improvement in VO_2peak in healthy participants supplemented with BRJ may exist (p = 0.08). Overall, future studies in this area need increased sample sizes, more unified methodologies, longer training interventions, and examination of sex as a biological variable to strengthen conclusions. Key Points: Despite the increased use and study of NO₃⁻ supplementation, most of these data have shown benefits during acute supplementation on exercise rather than a benefit to chronic training outcomes. This systematic review and meta-analysis revealed non-significant improvements in VO_2peak or time to exhaustion after exercise training with NO₃^- supplementation compared to exercise alone. A trend for improvement was found for improvements in healthy participants taking beetroot juice supplementation. These results suggest that NO₃^- may not have an impact on improving longer term training outcomes, but studies in this area suffer from low sample sizes and inconsistent study designs. [ABSTRACT FROM AUTHOR]