Effect of Dietary Supplements Which Upregulate Nitric Oxide on Walking and Quality of Life in Patients with Peripheral Artery Disease: A Meta-Analysis

Abstract

This systematic review pooled evidence from randomised controlled trials (RCTs) on the effectiveness of dietary upregulators of nitric oxide (NO) in improving the walking and quality of life of patients with peripheral artery disease (PAD). RCTs examining the effect of dietary upregulators of NO in patients with PAD were included. The primary outcome was the maximum walking distance. Secondary outcomes were the initial claudication distance, the six-minute walking distance, quality of life, the ankle-brachial pressure index (ABI), adverse events and risk of mortality, revascularisation or amputation. Meta-analyses were performed using random effects models. The risk of bias was assessed using Cochrane’s ROB-2 tool. Leave-one-out and subgroup analyses were conducted to assess the effect of individual studies, the risk of bias and intervention type on pooled estimates. Thirty-four RCTs involving 3472 participants were included. Seven trials tested NO donors, nineteen tested antioxidants, three tested NO synthase inducers and five tested enhancers of NO availability. Overall, the dietary supplements significantly improved the initial claudication (SMD 0.34; 95%CI 0.04, 0.64; p = 0.03) but not maximum walking (SMD 0.13; 95%CI −0.17, 0.43; p = 0.39) distances. Antioxidant supplements significantly increased both the maximum walking (SMD 0.36; 95%CI 0.14, 0.59; p = 0.001) and initial claudication (SMD 0.58; 95%CI 0.26, 0.90; p < 0.001) distances. The dietary interventions did not improve the physical function domain of the Short Form-36 (SMD −0.16; 95%CI −0.32, 0.00; p = 0.38), ABI or risk of adverse events, mortality, revascularisation or amputation. Dietary NO upregulators, especially antioxidants, appear to improve the initial claudication distance in patients with PAD. Larger high-quality RCTs are needed to fully examine the benefits and risks of these treatments. PROSPERO Registration: CRD42022256653.

Effects of short-term dietary nitrate supplementation on exercise and coronary blood flow responses in patients with peripheral artery disease

“…While there was an overall moderate improvement noted by these authors in claudication onset distance, when assessed across all 4 categories of NO-boosting supplements (i.e., NO donors including nitrate/nitrite, the NO modulators citrulline and/or arginine, NOS inducers, and antioxidants), the only supplement category that significantly improved claudication onset vs. placebo was antioxidants. The large variability in treadmill walk performance in PAD patients in general ( 20 , 44 ) and in our small cohort in particular ( Figure 3 ) coupled with the high antioxidant content of beetroot juice ( 45 ), are factors that likely diminished our ability to detect any potential improvements in walking performance in the present investigation. The large between-patient variability and the high content of antioxidants within both BR nitrate and BR placebo could also explain the lack of nitrate supplementation influence on exercise tolerance during our isolated plantar flexion testing.…”

“…However, two additional supplementation studies, one using BR nitrate acutely ( 28 ) (70 mL Beet-IT) and one that administered sodium nitrite tablets for 3 months ( 43 ) reported no significant improvements in walk distances relative to placebo. When examined collectively in a recent meta-analysis of studies investigating dietary nitrate and other upregulators of NO in PAD ( 44 ), it was reported that the improvements in maximum walk distance/duration did not achieve statistical significance. While there was an overall moderate improvement noted by these authors in claudication onset distance, when assessed across all 4 categories of NO-boosting supplements (i.e., NO donors including nitrate/nitrite, the NO modulators citrulline and/or arginine, NOS inducers, and antioxidants), the only supplement category that significantly improved claudication onset vs. placebo was antioxidants.…”

“…The double-blinded use of nitrate-depleted (true placebo) beetroot juice has been the gold standard for determining the physiological and exercise performance effects of dietary nitrate supplementation in healthy and patient groups ( 44 , 46 , 75 , 77 , 78 ). However, the high antioxidant content of beetroot juice, which has itself been found to improve walking tolerance in PAD ( 44 , 79 ), could obscure the ability to detect the ergogenic potential of beetroot juice when only nitrate-depleted beetroot juice is used as the placebo control.…”

“…The double-blinded use of nitrate-depleted (true placebo) beetroot juice has been the gold standard for determining the physiological and exercise performance effects of dietary nitrate supplementation in healthy and patient groups ( 44 , 46 , 75 , 77 , 78 ). However, the high antioxidant content of beetroot juice, which has itself been found to improve walking tolerance in PAD ( 44 , 79 ), could obscure the ability to detect the ergogenic potential of beetroot juice when only nitrate-depleted beetroot juice is used as the placebo control. It may be important, therefore, for future studies examining the effects of beetroot juice on exercise tolerance in PAD and other patient groups with high systemic oxidative stress, to include a third study visit/condition (e.g., a nitrate-rich, low antioxidant beverage) as a non-beetroot juice control.…”