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Ginseng supplementation and cardiovascular disease risk factors: a protocol for GRADE-assessed systematic review and dose-response meta-analysis

July 5, 2024
Articles From The BMJ

Introduction

Heart diseases represent a major global public health concern, with more than half a billion people worldwide continuing to be affected by cardiovascular diseases (CVDs). In 2021, CVD accounted for 20.5 million deaths, close to one-third of all global deaths. This represents an increase from the estimated 121 million CVD deaths in previous years.1 Despite ongoing efforts to mitigate the risk of CVD, heart disease continues to be the leading cause of death in the USA and worldwide.2 CVDs pose a significant global health challenge, primarily characterised by disruptions in blood circulation.3 This category encompasses a range of conditions, including coronary artery disease, heart failure, vascular disorders, dyslipidaemia and hypertension, collectively posing substantial health threats worldwide.3 4 CVDs stand as the leading causes of illness and mortality on a global scale. Notably, these cardiovascular ailments are particularly prevalent among adults exposed to Westernised diets, which have a detrimental impact on individuals of all ethnic backgrounds.5 In this context, cardiac risk factors such as oxidative stress, diabetes, hypertension, elevated low-density lipoprotein cholesterol (LDL-C) and decreased high-density lipoprotein cholesterol (HDL-C) levels are widely recognised as major contributors to the development of CVD.6 Studies have shed light on the potential involvement of vascular inflammation in the pathogenesis of atherosclerosis and coronary artery disease.7

In recent years, there has been growing recognition of the pivotal role that nutrition, phytomedicine, ethnomedicine and dietary patterns such as the Mediterranean diet play in cardiovascular health.8 The pathogenesis of CVDs involves a complex interplay between genetic, environmental and lifestyle factors, with inflammation, oxidative stress, dyslipidaemia and endothelial dysfunction emerging as key contributors.9 Dietary interventions rich in bioactive compounds, antioxidants and anti-inflammatory agents have garnered significant attention for their potential preventive effects against CVDs.10 Notably, dietary patterns, such as the Mediterranean diet, characterised by high consumption of fruits, vegetables, whole grains, fish and olive oil, have demonstrated remarkable cardioprotective effects.11 Furthermore, phytochemical-rich foods and traditional medicinal plants, such as ginseng, have been extensively studied for their cardiovascular benefits.12 13 These nutritional strategies offer promising avenues for mitigating CVD risk factors and improving cardiovascular outcomes.

Ginseng, a perennial herbaceous plant classified under the Araliaceae family, belongs taxonomically to the genus Panax. The term ‘Ginseng’ originates from the Chinese phrase ‘Jen Sheng’, which translates to ‘man-herb’ in English due to its humanoid shape.14 ‘Panax’, meaning ‘all healing’, reflects the traditional belief that ginseng possesses healing properties for all aspects of the body. The two primary species of ginseng commonly observed are Asian ginseng (Panax ginseng CA Meyer) and American ginseng (Panax quinquefolium L.).15 Ginseng, a medicinal herb with a long history of use, has been cultivated in various regions, including China, Japan, Korea and Russia.16 17 It is widely accepted that ginseng and its ginsenoside components have vasorelaxation, antioxidative, anti-inflammatory and anticancer effects. Ginsenosides have also demonstrated effects on both the central and peripheral nervous systems.18 19

Several systematic evaluations have been conducted to examine the impact of ginseng on various health outcomes. In a systematic review and meta-analysis conducted by Naseri et al, which included 20 separate trials up to 2022, it was concluded that ginseng supplementation may represent an efficacious approach for enhancing cardiometabolic characteristics in people diagnosed with pre-diabetes and type 2 diabetes mellitus. This study exclusively involved diabetic subjects.20 In another study, Park et al investigated the comprehensive effects of Panax ginseng on metabolic parameters, including 23 studies conducted up to September 2020. The findings of the study demonstrated that supplementation with P. ginseng may potentially function as an adjunctive measure in the prevention of metabolic disorders through its ability to enhance indicators associated with blood glucose, blood pressure and blood lipids.21 An umbrella review conducted in 202322 focused on the relationship between ginseng consumption and various health outcomes. However, this study had certain limitations, primarily originating from its reliance on a descriptive and narrative approach. Nevertheless, the findings of this umbrella review suggest that ginseng consumption demonstrates beneficial therapeutic effects across a spectrum of disorders. The umbrella review may suffer from heterogeneity and potential bias due to variations in the quality and scope of the included systematic reviews, which can limit the precision of its conclusions. In contrast, our forthcoming meta-analysis, rooted in clinical trial data, will offer a tailored and robust evaluation of the specific interventions in question, providing nuanced insights into treatment efficacy.

In the landscape of the existing literature, an update on recent evidence has become imperative. To date, there is no comprehensive systematic review and meta-analysis study that encompasses a broad spectrum of the population, including individuals of all health statuses, genders and ages over 18. Furthermore, we will perform dose-response and meta-regression analyses to evaluate the relationship between the combined effect size, dosage and duration of ginseng supplementation. Ultimately, we will assess the overall level of certainty of evidence in accordance with the principles provided by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Our study is designed to bridge this gap by conducting a meticulous examination of available clinical trial data, enabling us to provide a holistic and evidence-based assessment of the effects of ginseng supplementation on cardiovascular health in a wide-ranging population. In doing so, we aim to offer valuable insights that can inform clinical practice, guide future research endeavours, and ultimately contribute to better-informed decisions regarding ginseng supplementation as a potential intervention in CVD prevention and management.

Objectives

The primary objective of this literature review is to assess the efficacy of ginseng supplementation in modifying risk factors associated with CVD in both healthy and unhealthy participants. Our study objectives are as follows:

  1. To evaluate the impact of ginseng supplementation on lipid profiles compared with the control group in individuals aged 18 and above, encompassing both genders.

  2. To examine the effect of ginseng supplementation on glycaemic control compared with the control group in individuals aged 18 and above, encompassing both genders.

  3. To assess the influence of ginseng supplementation on anthropometric indices compared with the control group in individuals aged 18 and above, encompassing both genders.

  4. To investigate the impact of ginseng supplementation on inflammation indicators compared with the control group in individuals aged 18 and above, encompassing both genders.

  5. To analyse the effects of ginseng supplementation on blood pressure compared with the control group in individuals aged 18 and above, encompassing both genders.

  6. To evaluate the influence of ginseng supplementation on oxidative stress compared with the control group in individuals aged 18 and above, encompassing both genders.

  7. To assess the impact of ginseng supplementation on liver function tests compared with the control group in individuals aged 18 and above, encompassing both genders.

  8. To examine the effects of ginseng supplementation on adipokines compared with the control group in individuals aged 18 and above, encompassing both genders.

  9. To evaluate the influence of ginseng supplementation on heart rate compared with the control group in individuals aged 18 and above, encompassing both genders.

  10. To investigate the assessment of heterogeneity in primary studies and other sources.

Methods and analysis

The design of this systematic review adheres to the recommended guidelines outlined in the 2015 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.23 Furthermore, we will use the PRISMA flow chart to visually depict the number of primary studies that are included or excluded at different stages of this systematic review (figure 1). The systematic review protocol follows the guidelines of PRISMA-Protocols 2015 (PRISMA-P).23 The protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023465688).

Figure 1
Figure 1

PRISMA (preferred reporting items for systematic reviews and meta-analyses) flow diagram of study selection.

Eligibility criteria

Study design/characteristics

The systematic review will include primary studies that comprise randomised clinical trials (RCTs), ensuring that they are at least single-blind and possess either parallel or crossover designs. These studies must have concurrent control groups and be published in English, encompassing the period from the inception of the field up to September 2023. Excluded are methods other than RCTs conducted on humans, such as review articles, case studies, case series, observational studies (including cross-sectional, case–control and cohort studies) and experimental studies with animals or in vitro. The exclusion criteria also cover proceedings, editorials/commentaries, letters and reports that lack sufficient data on baseline or follow-up cardiometabolic factors, including lipid profiles, glycaemic control, anthropometric indices, inflammatory biomarkers and adipokines, blood pressure, oxidative stress, liver function, and heart rate in each group. Studies that report the combination of ginseng with other substances will also be excluded.

Subject types

Primary studies will be eligible for inclusion if the intervention being tested is directed towards individuals aged 18 years and above, regardless of gender.

Intervention(s)

Our focus is on RCTs employing daily ginseng supplementation, whether in the form of capsules, tablets, powder or any other form. The dosage may be divided throughout the day or administered as a single dose, with varying daily consumption. The intervention duration may vary in length.

Comparator(s)/control

Studies that meet the criteria for comparing ginseng supplementation to a control group with a placebo will be considered eligible for inclusion.

Outcome(s)

Studies providing data on the mean changes and their SDs of inflammatory biomarkers and adipokines, parameters related to glycaemic control, anthropometric, blood pressure, liver function tests, components of the lipid profile and heart rate throughout the trial’s duration for both the intervention and control groups, or those studies providing the necessary information to calculate these effect sizes are of interest.

Data sources

The systematic review will involve the examination of electronic bibliographic databases by two reviewers (AJ and AA) from the inception of the databases to September 2023. Relevant literature will be searched using specific keywords within the topics and abstracts of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Medline (http://www.ncbi.nlm.nih.gov/pubmed), SCOPUS and EMBASE (http://Embase.com) (online supplemental table 1). Additionally, to ensure thoroughness, we will manually review additional resources to identify any eligible studies. These resources will comprise prominent scholarly journals and the bibliographies of all relevant research articles, meta-analyses and review publications related to ginseng. In accordance with the guidelines established by the Institute of Medicine Standards and the Cochrane Handbook for Systematic Reviews of Interventions, we will also assess unpublished material from scholarly sources, commonly referred to as ‘grey literature’. This will involve reviewing dissertation data and summaries of papers presented at various conferences. To enhance comprehensiveness, we will communicate with the authors of these papers via email, using the provided information.

Supplemental material

Search strategy

The objective of our literature exploration methodology is to identify all relevant RCTs conducted on human subjects. We will use a carefully selected set of key search terms to define the concepts of ‘ginseng’ and ‘RCTs’. We have exclusively incorporated keywords related to interventions and the type of RCT study to ensure a comprehensive search without overlooking any studies (following the principle of search comprehensiveness). During the screening phase, each study will be meticulously reviewed individually, and only those meeting the desired criteria will proceed to the analysis phase. A distinct exploration approach will be implemented for each database, and the exploration approach, as well as the syntax used for the database search, will be thoroughly detailed in online supplemental table 1.

Study records

Data management

Two researchers (AJ and AA) will conduct the initial exploration of electronic databases using the search strategy outlined in accordance with the PRISMA-P statement. PBJ and FM will also carefully scrutinise the bibliographies of all the studies included in the analysis. For data management, we will use EndNote V.X7 software. The primary reviewer (AA) will import the findings of the literature searches into an EndNote library and subsequently remove any duplicate records.

Selection process

The selection phase of this systematic review will adhere to the PRISMA guidelines. Relevant studies for inclusion in the review will be determined through a three-step procedure. Initially, two independent reviewers (PBJ and FM) will assess the titles and abstracts of all records identified through database searches based on the specified inclusion/exclusion criteria to identify a subset of potentially appropriate articles. Any discrepancies regarding inclusion at each stage of the screening process (title/abstract and subsequently full-text review) will be resolved through discussion with a third researcher (AJ), who possesses specialised knowledge in the field of nutrition science and chronic diseases. Subsequently, full texts of the potentially eligible articles, which seem to meet our inclusion criteria based on their title/abstract, will be obtained. Two independent reviewers (PBJ and FM) will conduct the process of examining the full texts of the included abstracts. Throughout each stage of the selection process, comprehensive records of the reasons for excluding specific studies will be maintained and compiled into a table, which will be presented in the primary article.

Data extraction

A data extraction form, developed by the primary reviewer (AJ) and statistician (MV), will be used to extract data from all selected studies. Our team will pilot test the data extraction form on five selected studies and make necessary refinements to ensure the reliability of the data extraction process. Information from the included studies will be independently extracted by two reviewers (KK and HM). Data extraction will be conducted by using the entirety of the published reports or by means of correspondence with the study authors in instances where the data provided in the published articles is deemed inadequate for the extraction endeavour. Should any discrepancies arise during the data extraction process that cannot be resolved through consultation, the issue will be escalated to the project supervisor (AJ) to attain a unanimous consensus.

Data items

The utilisation of the Participants, Interventions, Comparisons, Outcomes, Study characteristics criteria will be employed to systematise the extraction of our information:

  1. Study characteristics encompass the identification of the primary author, study design, location and duration of the study, country of origin, year of publication and sample size divided into distinct groups.

  2. Sociodemographic characteristics of the participants include age, gender, number of participants, type of disease and initial state of health.

  3. Interventions and their specific attributes include dosage, duration of follow-up, method of administration and the sample size of the treatment group.

  4. Outcomes encompass the definition and measurements of various mean outcomes related to cardiovascular health. These include triglycerides, total cholesterol, LDL-C, HDL-C, very-LDL-C, apolipoprotein A-I, apolipoprotein B, lipoprotein(a), fasting blood glucose, haemoglobin A1c, insulin levels, homeostatic model assessment for insulin resistance, quick insulin sensitivity check index, body mass index, body fat percentage, hip circumference, waist circumference, weight, waist-to-hip ratio, C reactive protein, erythrocyte sedimentation rate, interferon-gamma, interleukin-1 beta, interleukin-4, interleukin-6, interleukin-8, interleukin-10, tumour necrosis factor-alpha, systolic blood pressure, diastolic blood pressure, mean arterial pressure, pulse pressure, reactive oxygen species, malondialdehyde, superoxide dismutase, total antioxidant capacity, glutathione, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, serum albumin, blood urea nitrogen, creatinine, leptin, adiponectin, resting heart rate, maximum heart rate and heart rate variability. Additionally, the study will assess heterogeneity in primary studies and provide mean and SD values for cardiovascular risk factors at different time points, specifically preintervention, postintervention and the change within each group. Furthermore, the analysis will consider other miscellaneous points of importance.

This extensive dataset will facilitate a thorough examination of the impact of ginseng on cardiovascular health. It will adhere to stringent data extraction protocols and follow PRISMA guidelines to ensure methodological rigour and enhance the reliability of the findings.

Missing data

In adherence to the criteria stipulated by the Cochrane Institute, our researchers will initiate communication with the respective authors of the investigations via electronic mail with the aim of acquiring further elucidation should the data provided in the study reports be deemed incomplete. In the event that the authors fail to respond to the initial electronic communication, it will be necessary for us to dispatch subsequent electronic reminders, up to a maximum of three attempts. Subsequent to three unsuccessful attempts at eliciting a response, the evaluators will classify the insufficiency of information as missing data.

Risk of bias assessment

The assessment of the risk of bias in the individual studies will be conducted by two independent authors (MA and SB), adhering to the guidelines of a Cochrane Collaboration tool.24 This tool aims to evaluate and report the risk of bias across seven specific criteria, which include:

  • Sequence generation.

  • Allocation concealment.

  • Blinding of participants and personnel.

  • Blinding of outcome assessment.

  • Incomplete outcome data.

  • Selective outcome reporting.

  • Other potential sources of biases.

To begin with, the two principal investigators (MA and SB) will pilot the Cochrane tool items on five primary articles. In the event of any disagreement regarding the risk of bias assessment, a third party (MV) will be consulted to facilitate reaching a resolution. For each component within our chosen domains, the options of yes, no or unclear will be used. Subsequently, the risk of bias will be categorised as low, moderate or high, based on our findings and using the Risk-of-bias VISualisation (robvis) tool.25

Data synthesis

The Stata software (V.17.0) (StataCorp) will be used for the purpose of conducting a meta-analysis. We will extract the means of pretreatment and post-treatment, SD, and the number of participants in both the intervention and placebo groups for each predetermined clinical outcome, namely lipid profile, glycaemic control, anthropometric indices, inflammation, blood pressure, oxidative stress, liver function, adipokines and heart rate. The impact of ginseng supplementation will be determined by assessing the standardised mean differences (SMDs) of changes between the intervention and placebo groups. Given that the included RCTs were conducted on diverse populations and settings, a random effects model will be employed to calculate the overall effect from the SMDs using the DerSimonian-Laird weighting method. The SDs of the change difference will be computed using the following formula: (SD=square root [(SD pretreatment) 2+(SD post-treatment) 2−(2R×SD pretreatment×SD post-treatment)], assuming a correlation coefficient (R)=0.5). The between-study heterogeneity will be evaluated by using the I2 statistic. Substantial statistical heterogeneity will be considered if the p value is <0.05 or if the I2 value exceeds 50%. Subgroup analyses will be performed to identify the effects of ginseng on clinical outcomes, taking into account relevant study characteristics such as study population, duration of follow-up and dose of ginseng, as potential sources of heterogeneity. Meta-regression will be employed to evaluate the potential impact of ginseng dosage (g/day) and duration on risk factors associated with CVDs. Furthermore, a non-linear model will be used to integrate dose-response data from various studies to assess the effect of ginseng supplementation on CVD risk factors.26 To investigate whether the results of the meta-analysis are dependent on a particular trial, we will recompute the meta-analysis statistic after omitting one study at a time (leave one out).

Assessment of possible reporting bias

We shall examine the probability of outcome reporting bias (including publication and other reporting biases) by employing the counter funnel plot technique, provided that the number of studies incorporated in a meta-analysis is adequate (approximately 10 studies). To gauge for asymmetry, Begg’s test and Egger’s test will also be employed. A p≤0.05 will be used to denote statistically significant correlation.

Ethics and dissemination

This research involves a protocol for a systematic review, which does not require ethics approval. The results from the comprehensive systematic review will be published in a peer-reviewed journal and presented at national and international academic and clinical conferences. Additionally, the study adhered to the guidelines outlined in the Declaration of Helsinki. Ethical approval for the study was obtained from the Ethics Committee of Golestan University of Medical Sciences (IR.GOUMS.REC.1402.298).

Assessing the quality of the evidence

The GRADE27 guidelines shall be used for the purpose of evaluating the quality of the evidence pertaining to the impact of ginseng on the primary outcomes (risk factors for CVD). The assessment of evidence quality shall be conducted by considering the subsequent domains: design and susceptibility to bias, coherence, relevance, accuracy and potential bias in publication.

Patient and public involvement

None.

This post was originally published on https://bmjopen.bmj.com