The effect of dietary nitrate on endothelial function and cardiovascular risk parameters in adults: a protocol for systematic review and meta-analysis
DOI:
https://doi.org/10.66154/nmj.v2i2.13Keywords:
sodium nitrate, endothelial function, cardiovascular health, blood pressure, fasting glycemia, HbA1CAbstract
Objective: Cardiometabolic diseases comprise a group of conditions that include obesity, endothelial dysfunction (ED), dyslipidemia, diabetes mellitus type 2, systemic arterial hypertension and cardiovascular disorders and are the leading cause of death in the world. Given its high prevalence, it becomes important to investigate the potential of bioactive compounds such as the sodium nitrate (NO3) present in vegetables and supplements in treating and preventing those conditions, once this substance has vasodilation properties, which may offer positive outcomes in cardiometabolic health.
Methods: Our review will include all randomized clinical trials (RCTs) published in English, Spanish and Portuguese without publication date restrictions. The databases searched will be MEDLINE (PubMed), Web of Science, Cochrane, Scopus, EMBASE, LILACS, SciELO and the grey literature. To be eligible the studies must be performed in adults over 18y, with ingestion of NO3 in any form of administration or dosage, have a placebo group and assess endothelial function, arterial stiffness, blood pressure, lipid or glycemic profiles. The RoB2 tool will be used to evaluate the risk of bias and the GRADE system to evaluate the strength of evidence. Statistical analyses will be performed using RStudio for Windows and R package meta.
Perspectives: An updated meta-analysis evaluating the outcome of dietary nitrate in the endothelial function and control of cardiovascular parameters would fulfill a gap in the literature, facilitating access to the available information, helping healthcare professionals to make more assertive decisions when treating or preventing those conditions and evaluate the necessity for further RCTs.
Systematic review registration: PROSPERO registration no. CRD42024591474.
References
Yilmaz MI, Romano M, Basarali MK, Elzagallaai A, Karaman M, Demir Z, et al. The Effect of Corrected Inflammation, Oxidative Stress and Endothelial Dysfunction on Fmd Levels in Patients with Selected Chronic Diseases: A Quasi-Experimental Study. Sci Rep. 2020;10(1). doi: https://doi.org/10.1038/s41598-020-65528-6
Neves JA, Neves JA, Oliveira R de CM. Biomarcadores de função endotelial em doenças cardiovasculares: Hipertensão. J Vasc Bras. 2016; 15(3):224-233. doi: https://doi.org/10.1590/1677-5449.000316
Bockus L, Kim F. Coronary endothelial dysfunction: from pathogenesis to clinical implications. Open Heart. 2022;9(2):e002200. doi: https://doi.org/10.1136/openhrt-2022-002200
Steyers CM, Miller FJ. Endothelial dysfunction in chronic inflammatory diseases. Int J Mol Sci. 2014;15(7):11324–11349. doi: https://doi.org/10.3390/ijms150711324
Sharaf BL, Pepine CJ, Kerensky RA, Reis SE, Reichek N, Rogers WJ, et al. Detailed angiographic analysis of women with suspected ischemic chest pain (pilot phase data from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation [WISE] study angiographic core laboratory). Am J Cardiol. 2001;87(8):937-41. doi: https://doi.org/10.1016/S0002-9149(01)01424-2
Sara JD, Widmer RJ, Matsuzawa Y, Lennon RJ, Lerman LO, Lerman A. Prevalence of Coronary Microvascular Dysfunction Among Patients With Chest Pain and Nonobstructive Coronary Artery Disease. JACC Cardiovasc Interv. 2015;(11):1445-1453. doi: https://doi.org/10.1016/j.jcin.2015.06.017
Kumar S, Mehta PK, Eshtehardi P, Hung OY, Koh JS, Kumar A, et al. Functional coronary angiography in symptomatic patients with no obstructive coronary artery disease. Catheter Cardiovasc Interv. 2021;98(5):827-835. doi: https://doi.org/10.1002/ccd.29237
Zhou B, Carrillo-Larco RM, Danaei G, Riley LM, Paciorek CJ, Stevens GA, et al. Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. The Lancet. 2021;398:957-980. doi: https://doi.org/10.1016/S0140-6736(21)01330-1
Tinajero MG, Malik VS. An Update on the Epidemiology of Type 2 Diabetes: A Global Perspective. Endocrinol Metab Clin North Am. 2021;50(3):337-355. doi: https://doi.org/10.1016/j.ecl.2021.05.013
OMS. Obesity and overweight. 2024. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight#:~:text=Worldwide%20adult%20obesity%20has%20more,16%25%20were%20living%20with%20obesity
Jones AM, Vanhatalo A, Seals DR, Rossman MJ, Piknova B, Jonvik KL. Dietary Nitrate and Nitric Oxide Metabolism: Mouth, Circulation, Skeletal Muscle, and Exercise Performance. Med Sci Sports Exerc. 2021;53(2):280-294. doi: https://doi.org/10.1249/MSS.0000000000002470
Smith O. Nobel Prize for NO research. Nat Med. 1998;4(11):1215. doi: https://doi.org/10.1038/3182
Macuh M, Knap B. Effects of nitrate supplementation on exercise performance in humans: A narrative review. Nutrients. 2021;13(9):3183. doi: https://doi.org/10.3390/nu13093183
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. The BMJ. 2021;372:n71. doi: https://doi.org/10.1136/bmj.n71
Higgins JPT, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.5 (updated August 2024). 2024. www.training.cochrane.org/handbook.
Robinson KA, Dickersin K. Development of a highly sensitive search strategy for the retrieval of reports of controlled trials using PubMed. Int J Epidemiol. 2002;31(1):150-3. doi: https://doi.org/10.1093/ije/31.1.150
Glanville J, Foxlee R, Wisniewski S, Noel-Storr A, Edwards M, Dooley G. Translating the Cochrane EMBASE RCT filter from the Ovid interface to Embase.com: a case study. Health Info Libr J. 2019;36(3):264-277. doi: https://doi.org/10.1111/hir.12269
Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev. 2016;5(1):210. doi: https://doi.org/10.1186/s13643-016-0384-4
Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, et al. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017;87:4-13. doi: https://doi.org/10.1016/j.jclinepi.2017.05.006
Schünemann HJ, Brennan S, Akl EA, Hultcrantz M, Alonso-Coello P, Xia J, et al. The development methods of official GRADE articles and requirements for claiming the use of GRADE – A statement by the GRADE guidance group. J Clin Epidemiol. 2023;159:79-84. doi: https://doi.org/10.1016/j.jclinepi.2023.05.010
IntHout J, Ioannidis JPA, Rovers MM, Goeman JJ. Plea for routinely presenting prediction intervals in meta-analysis. BMJ Open. 2016;6(7):e010247. doi: https://doi.org/10.1136/BMJOPEN-2015-010247
Dias S, Sutton AJ, Welton NJ, Ades AE. Evidence synthesis for decision making 3: Heterogeneity - Subgroups, meta-regression, bias, and bias-adjustment. Med Decis Making. 2013;33(5):618-40. doi: https://doi.org/10.1177/0272989X13485157
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. doi: https://doi.org/10.1136/bmj.b2700
Deeks JJ, Macaskill P, Irwig L. The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol. 2005;58(9):882–93. doi: https://doi.org/10.1016/J.JCLINEPI.2005.01.016
Simmonds M. Quantifying the risk of error when interpreting funnel plots. Syst Rev. 2015;4(1):24. doi: https://doi.org/10.1186/s13643-015-0004-8
Page MJ, Higgins JPT, Sterne JAC. Assessing risk of bias due to missing results in a synthesis. In: Cochrane Handbook for Systematic Reviews of Interventions. 2019. doi: https://doi.org/10.1002/9781119536604.ch13
Mavridis D, Salanti G. How to assess publication bias: Funnel plot, trim-and-fill method and selection models. Evid Based Ment Health. 2014;17(1):30. doi: https://doi.org/10.1136/eb-2013-101699
Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455-63. doi: https://doi.org/10.1111/j.0006-341X.2000.00455.x
Boutron I. 2024. Chapter 7: Considering bias and conflicts of interest among the included studies [last updated August 2022]. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.5. Cochrane. www.training.cochrane.org/handbook
Balk EM, Earley A, Patel K, Trikalinos TA, Dahabreh IJ. Empirical Assessment of Within-Arm Correlation Imputation in Trials of Continuous Outcomes. Methods Research Reports. 2012;12. EHC141-EF.
Stanford Medicine Health Care. Endothelial Dysfunction. 2024. https://stanfordhealthcare.org/medical-conditions/blood-heart-circulation/endothelial-dysfunction.html
Mosher SL, Andy Sparks S, Williams EL, Bentley DJ, Naughton LRM. Ingestion of a nitric oxide enhancing supplement improves resistance exercise performance. J Strength Cond Res. 2016;30(12):3520-3524. doi: https://doi.org/10.1519/JSC.0000000000001437
Forster D, Waclawovsky G, Stefani GP. Effects of chronic nitrate supplementation on blood pressure in adults: a systematic review and meta-analysis of randomized clinical trials. Nutr Res. 2026;146:111–20. doi: https://doi.org/10.1016/j.nutres.2025.08.002
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Nutrition and Metabolism Journal: Clinical and Experimental

This work is licensed under a Creative Commons Attribution 4.0 International License.








