Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2019-032755 on 20 August 2020. Downloaded from Comparative effect of nutraceuticals on lipid profile: a protocol for systematic review and network meta- analysis Jakub Morze ,1 Tadeusz Osadnik,2,3 Kamila Osadnik,2 Mateusz Lejawa,2 Grzegorz Jakubiak,2 Natalia Pawlas ,2 Mariusz Gasior,4 Lukas Schwingshackl,5 Maciej Banach6,7,8 To cite: Morze J, Osadnik T, ABSTRACT Strengths and limitations of this study Osadnik K, et al. Comparative Introduction According to the common definition, effect of nutraceuticals on nutraceuticals are components found in food that can act ► This network meta- analysis will be the first to ex- lipid profile: a protocol for as therapeutic substances. Recently, the International Lipid systematic review and network plore the comparative effectiveness of different nu- Expert Panel published two position papers covering the meta- analysis. BMJ Open traceuticals on lipid profile. topic of lipid- lowering nutraceuticals and their potential 2020;10:e032755. doi:10.1136/ ► Results of our review will address the question use as a complementary treatment in addition to statins bmjopen-2019-032755 which nutraceutical is the most promising in terms or as an alternative treatment in statin- intolerant patients. of lowering plasma lipids. ► Prepublication history and The aim of this study was to compare the effect of ► Variations in trial design, base patient character- additional material for this different nutraceuticals on lipid profiles in a systematic paper are available online. To istics, doses and administration mode of nutra- review with pairwise and network meta- analyses. view these files, please visit ceuticals, which may increase heterogeneity and Methods and analysis Three databases, including the journal online (http:// dx. doi. inconsistency of networks, will be addressed by PubMed, Embase and the Cochrane Central Register org/ 10. 1136/ bmjopen- 2019- appropriate subgroup analyses. 032755). of Controlled Trials, will be searched without time or ► Different mechanisms of action of various publication language restrictions. The estimated end date nutraceuticals. Received 03 July 2019 for the searches will be 29 March 2020. Each stage of ► Low number of eligible head- to- head trials may pro- Revised 21 May 2020 the review, including the study section, data extraction, duce sparsely connected network of treatments. Accepted 03 July 2020 and risk of bias and quality of evidence assessments, will be performed in duplicate. Randomised controlled trials meeting the following criteria will be eligible for inclusion: http://bmjopen.bmj.com/ (1) participants aged ≥18 years, (2) intervention with a INTRODUCTION selected nutraceutical (artichoke, berberine, bergamot, Cardiovascular diseases (CVDs) account for soluble fibres, green tea, garlic, lupin, plant sterols and one-third of deaths and remain as the most stanols, red yeast rice, soybean, spirulina or a combination 1 of the aforementioned nutraceuticals), (3) administration common cause of mortality worldwide. of the treatment in the form of capsules, pills, powders, According to the Global Burden of Diseases, solutions, tablets or enriched food items, (4) comparison in 2015, the estimated global prevalence 2 with another nutraceutical or placebo, (5) intervention of CVD was more than 420 million cases. period ≥3 weeks and (6) lipid profile (low- density Among many modifiable risk factors, such as on September 26, 2021 by guest. Protected copyright. lipoprotein cholesterol, high- density lipoprotein cholesterol, smoking cessation, changes in dietary habits, total cholesterol, triglycerides) as an outcome. Random- weight loss, and blood pressure and glucose effect pairwise and network meta-analyses will be used control, lowering plasma cholesterol remains to summarise the relative effect of each nutraceutical a key factor in the primary prevention of in comparison to the effect of every other nutraceutical. CVD.3 Subgroup analyses will be stratified by age, sex, ethnicity, Statins remain the most widely used lipid- sample size, length of trial follow- up, baseline cholesterol 4 level and presence of other comorbidities. lowering drugs for CVD prevention. A © Author(s) (or their Ethics and dissemination This review will summarise large body of evidence from high-quality employer(s)) 2020. Re- use randomised clinical trials suggests that statin permitted under CC BY-NC. No findings from primary studies, and therefore no ethics commercial re- use. See rights approval is required. The results will be presented at therapy is effective at reducing levels of and permissions. Published by conferences as well as published in a peer- reviewed serum low- density lipoprotein cholesterol BMJ. journal. (LDL-C) and total cholesterol (TC) as well as For numbered affiliations see PROSPERO registration number CRD42019132877. the risk of cardiovascular events and deaths.5 end of article. The current American College of Cardi- Correspondence to ology/American Heart Association guide- Jakub Morze; lines recommend the inclusion of statins for jakub. morze@ uwm. edu. pl primary prevention in patients with diabetes, Morze J, et al. BMJ Open 2020;10:e032755. doi:10.1136/bmjopen-2019-032755 1 Open access BMJ Open: first published as 10.1136/bmjopen-2019-032755 on 20 August 2020. Downloaded from severe hypercholesterolemia and mild-to- moderate hyper- methods for conducting and describing the results of cholesterolemia depending on individual CVD risk.6 this review have been planned according to Preferred Despite the good general safety profile of statins, recent Reporting Items for Systematic Reviews and Meta- concerns have been raised about the prevalence of statin- Analyses (PRISMA) and its extensions dedicated to associated muscle syndrome or transient elevation of network meta- analyses.25 26 The text of the protocol was liver syndromes and other less frequent adverse effects written according to the Preferred Reporting Items for like occurrence of diabetes mellitus.7 Second- line drugs Systematic Review and Meta- Analysis Protocols guidelines like ezetimibe, although less frequently, can also cause for reporting protocols.27 muscle pain and liver enzyme elevation.8 Drugs like bile acid sequestrants or niacin are rarely used mainly due to Patient and public involvement 9 10 adverse effects leading to non- compliance. Discontin- Patients and the public were not involved in the design or uation of lipid- lowering treatment is associated with an planning of the study. increased risk of atherosclerotic CVD and mortality.11 Moreover, prescription of lipid- lowering drugs for the Eligibility criteria elderly patients in primary prevention is a subject of Studies fulfilling the eligibility criteria listed below will be debate.12 These issues have shifted efforts to identifying included in the systematic review. evidence for alternative therapies, whose use was not extensively addressed in previous guidelines. Due to lipid- lowering potential, some nutraceuticals Participants can be considered as an option in the therapy of lipid We will only include studies conducted with adults disorders. According to common definitions, nutraceuti- (subjects aged ≥18 years). Since previous meta-analyses cals are components found in food that can act as thera- indicated the vast use of nutraceuticals in patients with peutic substances.13 The potential lipid- lowering activity other metabolic disorders associated with increased of selected nutraceuticals can be explained by inhibiting CVD risk, participants will be included regardless of disease, normocholesterolemic or hypercholesterolemic liver cholesterol synthesis, decreasing cholesterol absorp- 17–23 tion and increasing cholesterol excretion, as well as influ- status. However, these conditions will provide a basis encing fatty acid metabolism.14 Additional benefits from for appropriate subgroup analyses. the use of nutraceuticals have been demonstrated on glycaemic control, blood pressure, endothelial function Interventions and comparators and subclinical inflammation.15 16 A large body of system- The literature includes data on more than 40 single and 28 atic reviews and meta- analyses reported a beneficial effect combined lipid- lowering nutraceuticals. Since LDL- C 3 of different nutraceuticals on plasma LDL-C, high-density is a primary lipid target in CVD prevention, the scope lipoprotein cholesterol (HDL-C), triglycerides (TG) and of this review will be limited to nutraceuticals with the http://bmjopen.bmj.com/ TC.17–23 However, the vast majority of these reviews did potential to lower LDL-C. To identify eligible agents, not report the quality of the summarised evidence, which we carefully evaluated recent position papers on nutra- is a key issue to address the confidence in the obtained ceuticals from the International Lipid Expert Panel and 14 24 results and inform clinical guidelines. related meta- analyses. The following interventions The International Lipid Expert Panel has published will be considered for inclusion: two position papers covering the topic of lipid- lowering ► Artichoke—extracts from Cynara scolymus and C. nutraceuticals and their potential use as a complementary cardunculus. treatment to statins or an alternative therapy for patients ► Berberine—isoquinoline alkaloids isolated from on September 26, 2021 by guest. Protected copyright. with statin intolerance.24 Since both reports described the barberry (Berberis vulgaris), tree turmeric (B. aristata),