Ergogenic Effect of Nitrate Supplementation in Clinical Populations: A Systematic Review and Meta-Analysis

Abstract

Background/Objectives: Inorganic nitrate (NO₃^-) supplementation, via its conversion to nitric oxide (NO), has been purported to be ergogenic in healthy individuals. Many disease states are characterized by reduced NO bioavailability and are expected to derive a benefit from NO₃^-. This systematic review and meta-analysis evaluate the current literature on the ergogenic effect of NO₃^- supplementation in individuals with cardiopulmonary and metabolic diseases (CPMD). Methods: Relevant databases were searched up to December 2023 for randomized, placebo-controlled crossover trials for aerobic exercise outcome variables with CPMD. Results: Twenty-two studies were included, and 46% reported ergogenic benefits of inorganic nitrate supplementation. NO₃^- supplementation had no effect on aerobic performance with respect to maximal (SMD = 0.11, 95% CI: -0.12 to 0.34, p = 0.34) and submaximal (SMD = 0.16, 95% CI: -0.13 to 0.46, p = 0.27) TTE, VO_2peak (SMD = 0.002, 95% CI: -0.37 to 0.38, p = 0.99), or 6MW (SMD = 0.01, 95% CI: -0.29 to 0.28, p = 0.96). When the studies were limited to only cardiovascular disease conditions, NO₃^- supplementation had trivial effects on aerobic performance with respect to Timed Trials (SMD = 0.14, 95% CI: -0.04 to 0.33, p = 0.13), VO₂ (SMD = -0.02, 95% CI: -0.32 to 0.27, p = 0.87), and small effects on Distance Trials (SMD = 0.25, 95% CI: -0.18 to 0.69, p = 0.25). Sunset funnel plots revealed low statistical power in all trials. Conclusions: The results of this systematic review revealed that 46% of the individual studies showed a positive benefit from inorganic nitrate supplementation. However, the meta-analysis revealed a trivial effect on physical function in CPMD populations. This is likely due to the large heterogeneity and small sample sizes in the current literature.

Keywords: VO2Peak; clinical population; inorganic nitrate; time to exhaustion.

Figure 1

PRISMA Diagram.

Figure 2

Forest plot of overall model for TTE (during an incremental workload exercise test) trial [24,30,38,39,42,43,44]. Abbreviations: HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; PAD, peripheral arterial disease; CKD, chronic kidney disease.

Figure 3

Forest plot of overall model for submaximal TTE (fixed workload exercise test) trials [23,26,27,29]. Abbreviations: HFpEF, heart failure with preserved ejection fraction; COPD, chronic obstructive pulmonary disease; HFrEF, heart failure with reduced ejection fraction; 1x = acute treatment; 7d = 7-day treatment.

Figure 4

Forest plot of overall model for VO₂Peak trials [24,30,38,43,44]. Abbreviations: HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; PAD, peripheral arterial disease; CKD, chronic kidney disease.

Figure 5

Forest plot of overall model for 6MW trials. Abbreviations: T2D, type 2 diabetes; COPD, chronic obstructive pulmonary disease; HFrEF, heart failure with reduced ejection fraction.

Figure 6

Forest plot of overall model for Timed Exercise Trials in CVD populations only [24,27,29,30,37,39,42,43,44]. Abbreviations: HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; PAD, peripheral arterial disease; TTE, time to exhaustion during an incremental workload exercise/max test; TTE Sub, time to exhaustion during a fixed workload exercise test; COT, claudication onset time; 1x = acute treatment; 7d = 7-day treatment.

Figure 7

Forest plot of overall model for VO₂ in CVD populations only [24,27,30,43,44]. Abbreviations: HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; PAD, peripheral arterial disease; VO₂Peak, maximal/peak oxygen consumed during an incremental workload exercise test; VO₂Sub, maximal oxygen consumed during a submaximal/fixed workload exercise test; 1x = acute treatment; 7d = 7-day treatment.

Figure 8

Forest plot of overall model for Distance Exercise Trials in CVD populations only [25,33,36,37]. Abbreviations: PAD, peripheral arterial disease; HFrEF, heart failure with reduced ejection fraction; NIDC, non-ischemic dilated cardiomyopathy; 6MW, 6 min walk test/distance; COD, claudication onset distance (distance walked to the onset of claudication pain); ISWT, incremental shuttle walk test.