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Garlic (Allium sativum L.) in the Management of Hypertension and Dyslipidemia – A Systematic Review
Accepted Manuscript Title: Garlic (Allium sativum L.) in the Management of Hypertension and Dyslipidemia – A Systematic Review Authors: Wai-Jo J. Chan, Andrew J. McLachlan, Edward J. Luca, Joanna E. Harnett PII: DOI: Article Number:
S2210-8033(19)30039-9 https://doi.org/10.1016/j.hermed.2019.100292 100292
Reference:
HERMED 100292
To appear in: Received date: Revised date: Accepted date:
2 March 2018 26 November 2018 15 July 2019
Please cite this article as: Chan W-JoJ, McLachlan AJ, Luca EJ, Harnett JE, Garlic (Allium sativum L.) in the Management of Hypertension and Dyslipidemia – A Systematic Review, Journal of Herbal Medicine (2019), https://doi.org/10.1016/j.hermed.2019.100292 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Garlic (Allium sativum L.) in the Management of Hypertension and Dyslipidemia – A Systematic Review
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Running title: Garlic and Hypertension and Dyslipidaemia
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Wai-Jo J CHAN1, Andrew J McLACHLAN1, 2, Edward J LUCA1, Joanna E
for Education and Research in Ageing, Concord Hospital, NSW, Australia.
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2Centre
of Pharmacy, University of Sydney, NSW, Australia;
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1Faculty
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HARNETT1
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Correspondence: Joanna E Harnett, The University of Sydney, Camperdown, NSW
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Abstract
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2006, Australia. Tel: +612 935 170 09, Email: [email protected]
The herb garlic (Allium sativum L.) has traditionally been used to promote ‘cardiovascular
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health’. The aim of this systematic review was to evaluate the available evidence for the efficacy and safety of garlic in the management of hypertension and dyslipidemia and the quality of that evidence by utilising the elaborated CONSORT checklist. Double-blind randomized controlled trials written in English from inception to April 2017 were identified and evaluated.
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A total of 18 studies were included (n=1069): 4 studies reported a statistically significant reduction in systolic blood pressure (mean SBP reduction of 11.2 mmHg) and 2 studies reported a statistically significant reduction in various lipid components (LDL-C p <0.05; TC p = 0.003). Aged garlic extract (1.2 mg – 2.4 mg s-allyl cysteine/ day) and to a lesser extent coated garlic powder tablets (600 mg - 2400 mg/ day) demonstrated a hypotensive effect.
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Evidence for the role of garlic in the management of dyslipidemia is, however, less clear. Minor side effects were reported.
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Further high quality research is required to confirm these findings. The authors recommend researchers refer to the item 4 of the elaborated CONSORT checklist in the design and
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reporting phase of their studies.
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Keywords: Garlic, Dyslipidaemia, Hypertension, Allium sativum
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Introduction
Garlic is one of the most commonly used herbal medicines in Australia, the United
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Kingdom, Germany and the United States (Barnes et al., 2008; Goh et al., 2009; Posadzki et al., 2013; Reinert et al., 2007). Garlic (Allium Sativum) has traditionally
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been used in the management of a broad range of health conditions (Braun and Cohen, 2015). Early Egyptian, Greek and Chinese civilizations treasured garlic as a
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food and as a medicine (Bordia et al., 1975). In modern times, garlic has been the subject of pharmacological studies evaluating its potential anticancer, antimicrobial and immunomodulatory activities (Abdullah et al., 1988). Organosulfur compounds in garlic such as allicin and s-allyl cysteine are thought to be the main bioactive compounds responsible for the management of blood pressure and dyslipidemia
pg. 2
(Gebhardt and Beck 1996; Shouk et al., 2014). These compounds have been shown to inhibit transcription factor NF-κB and angiotensin converting enzyme, whilst enhancing the production of the vasodilatory compounds hydrogen sulphide and nitric oxide, mechanisms by which the herb is thought to reduce blood pressure and oxidative stress (Shouk et al., 2014). Other organosulfur compounds such as ajoene
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and allicin have been shown to inhibit cholesterol synthesis by inhibiting 3-hydroxy-3methyl-glutaryl-coenzyme A reductase (Gebhardt and Beck, 1996; Ferri et al.; 2003).
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A number of reviews have been conducted evaluating the role of garlic in
hypertension and dyslipidemia (Stabler et al., 2012; Kwak et al., 2014; Xiong et al.,
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2015; Ried, 2016). However, these reviews were not restricted to double blind
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randomized controlled trials, nor did they utilize the elaborated Consolidated
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Standards of Reporting Trials (CONSORT) extension for the reporting of herbal
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medicine interventions to evaluate the studies included (Gagnier et al.; 2006).
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The aim of this review was to evaluate the available evidence, and the quality of reporting of double-blind randomized controlled trials that evaluate the
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2. Methods
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efficacy and safety of garlic in the management of hypertension and dyslipidemia.
Studies evaluating the efficacy of garlic in the management of hypertension and dyslipidemia were searched for via the following databases: PubMed, MEDLINE,
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Embase, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Web of Science. An academic librarian provided assistance in developing a search strategy to conduct the search across each database. The search terms included: hypertension OR high blood pressure OR systolic blood pressure OR diastolic blood pressure OR dyslipidemia OR hyperlipidemia OR high cholesterol OR
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total cholesterol OR triglycerides OR high density lipoprotein OR low density lipoprotein AND garlic OR Allium sativum. Only double-blind randomized controlled trials from inception to April 2017 were included. Two authors decided on the search terms and inclusion and exclusion criteria. One of these two authors conducted the systematic search and
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the other author checked the search method. The two authors independently
screened the titles and abstracts of trials identified by the search strategy. Three
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authors reviewed the included trials for quality and meeting the inclusion and exclusion criteria (Figure 1).
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Item 4 of the elaborated CONSORT checklist for reporting randomized
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controlled trials of herbal medicine interventions (Gagnier et al., 2006) was employed
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to assess the quality of reporting of the studies included in this review. The Cochrane
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Risk of Bias Tool was employed to assess potential bias in each included study
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(Higgins and Green, 2011).The safety of each garlic preparation was assessed by reviewing trials that reported adverse reactions and possible drug interactions.
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Systematic reviews, meta-analyses, literature reviews, non-English publications and trials evaluating nutraceuticals or combination of complementary medicines were
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excluded in the search. Trials including healthy normolipidemic and/or normotensive individuals who were not at risk of cardiovascular events were excluded.
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The measurement outcomes recorded included changes from baseline in
average systolic blood pressure (SBP), diastolic blood pressure (DBP), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C), total cholesterol (TC) and triglycerides. Data including geographical location, study design, sample size, formulation, daily dosage, brand, duration, study population, concurrent medications,
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average baseline measurements, adverse reactions reported, control of confounders in particular diet, smoking status and family history were extracted and recorded. The statistical significance of the results between treatment and placebo groups were recorded for each outcome measured. Where the p-value was ≤ 0.05, it was considered to be statistically significant. Trials reporting positive outcomes were
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assessed by a statistically significant reduction in lipid profiles and/or blood pressure between the treatment and the placebo groups.
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If the included articles reported the lipid profiles without LDL-C measures, the LDL-C was estimated using the Friedewald’s formula which was validated in
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patients with metabolic syndrome (Knopfholz et al., 2014).
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Results for serum TC, HDL-C, LDL-C and triglyceride concentrations in this
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review were reported as mmol/L. Where a study reported TC, HDL-C and LDL-C in
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mg/dL, the results were converted by dividing the value by a factor of 38.67 to obtain
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value in mmol/L. Studies reporting serum triglyceride concentration measured in mg/dL, were converted by dividing the value by a factor of 88.57 to obtain the value
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3. Results
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in mmol/L.
A total of 1,126 articles were identified from 6 databases in the initial search (Figure 1). After removing duplicates, articles were screened by title and abstract for
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inclusion. 39 full-text articles were assessed for eligibility, resulting in a final total of 18 studies included in this systematic review. 21 articles were excluded for the reasons presented in Figure 1. [INSERT FIGURE 1 HERE]
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Tables 1 and 2 summarize the characteristics of the 18 trials evaluating the effect of garlic treatment, either as a sole therapy or as an adjunct to standard care in the management of dyslipidemia or hypertension. Ten studies evaluated the effect of garlic on individuals with hypertension, with 1 trial demonstrating a statistically significant reduction in both SBP and DBP (Sobenin et al., 2009) and 2 trials
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showing a statistically significant reduction in SBP only (Ried et al., 2013; Ried et al., 2016). One trial stratified participants into subgroups with baseline of SBP ≥ 140
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mmHg and was able to demonstrate a statistically significant reduction in SBP (Ried et al., 2010). Statistically significant reductions in various fractions of lipid profiles
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were reported in 2 of the 15 trials which studied garlic in the management of
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dyslipidemia (Sobenin et al., 2008; Sobenin et al., 2010).
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A total of 3 studies investigated the effect of garlic on hypertension alone
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(Sobenin et al., 2009; Ried et al., 2010; Ried et al., 2013) and 8 studies evaluated the effect of garlic treatment on dyslipidemia alone (Superko and Krauss 2000;
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Gardner et al., 2001; Budoff et al., 2004; van Doorn et al., 2006; Gardner et al., 2007; Sobenin et al., 2008; Sobenin et al., 2010; Jung et al., 2014). The remaining 7
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studies investigated garlic preparations in the management of both conditions
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(Isaacsohn et al., 1998; McCrindle et al., 1998; Williams et al., 2005; Sobenin et al., 2008; Gomez-Arbelaez et al., 2013; Atkin et al., 2016; Ried et al., 2016). Of the 18 trials, 3 trials were double-blind randomized cross-over trials
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(Williams et al., 2005; Gomez-Arbelaez et al., 2013; Atkin et al., 2016). The remaining 15 trials (Isaacsohn et al., 1998; McCrindle et al., 1998; Superko and Krauss, 2000; Gardner et al., 2001; Budoff et al., 2004; van Doorn et al., 2006; Gardner et al., 2007; Sobenin et al., 2008; Sobenin et al., 2008; Sobenin et al., 2009; Ried et al., 2010; Sobenin et al., 2010; Ried et al., 2013; Jung et al., 2014; Ried et
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al., 2016) were double-blind randomized controlled trials with a parallel group design. Seven of the studies included participants treated with garlic or placebo who were concurrently taking orthodox medications including antihypertensive, lipid lowering, anticoagulants, antidiabetic and antiplatelet agents (Budoff et al., 2004; Williams et al., 2005; Sobenin et al., 2008; Ried et al., 2010; Ried et al., 2013; Atkin et al., 2016;
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Ried et al., 2016).
Of the 10 trials evaluating the effect of garlic in the management of
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hypertension (Table 1), 6 used aged garlic extracts (Williams et al., 2005; Ried et al., 2010; Gomez-Arbelaez et al., 2013; Ried et al., 2013; Atkin et al., 2016; Ried et al.,
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2016) and an additional 4 trials used garlic powder (Isaacsohn et al., 1998;
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McCrindle et al., 1998; Sobenin et al., 2008; Sobenin et al., 2009). Amongst the trials
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identified were those that included branded preparations. These included KyolicTM
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(Wakunaga/Wagner, Madero, USA), KwaiTM (Lichtwer Pharma, Berlin, Germany) and AllicorTM (INAT-Farma, Marseille, France). Daily doses for aged garlic extract
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ranged from 240 – 2400 mg and for garlic powder from 600 – 2400 mg. The duration of therapy ranged from 2 – 12 weeks, with 6 trials conducted over a 12-week period
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(Isaacsohn et al., 1998; Sobenin et al., 2008; Ried et al., 2010; Gomez-Arbelaez et
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al., 2013; Ried et al., 2013; Ried et al., 2016). Similarly, in the 15 trials investigating garlic in the management of
dyslipidemia (Table 2), aged garlic extracts were used in 7 trials (Budoff et al., 2004;
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Williams et al., 2005; Gardner et al., 2007; Gomez-Arbelaez et al., 2013; Jung et al., 2014; Atkin et al., 2016; Ried et al., 2016), while 9 trials used garlic powder (Isaacsohn et al., 1998; McCrindle et al., 1998; Superko and Krauss, 2000; Gardner et al., 2001; van Doorn et al., 2006; Gardner et al., 2007; Sobenin et al., 2008; Sobenin et al., 2008; Sobenin et al., 2010) and 1 used raw garlic (Gardner et al.,
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2007). Kyolic™ (Wakunaga/Wagner, Madero, USA), Garlicin™ (Nature’s Way Products Inc, Sydney Australia), Kwai™ (Lichtwer Pharma, Berlin, Germany) and Allicor™ (INAT-Farma, Madero, France) were the brands used in the studies. The daily dose for garlic powder ranged from 500 - 2100 mg and for aged garlic extract daily doses ranged from 1200 - 6000 mg and raw garlic was 4000 mg. The duration
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of treatment ranged from 2 weeks to 1 year with 8 trials running for 12 weeks
(Isaacsohn et al., 1998; Superko and Krauss, 2000; Gardner et al., 2001; van Doorn
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et al., 2006; Sobenin et al., 2008; Gomez-Arbelaez et al., 2013; Jung et al., 2014; Ried et al., 2016).
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[INSERT TABLE 1 & 2 HERE]
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Table 3 presents the quality of the studies’ reporting of the intervention, as assessed
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using item 4 of the elaborated CONSORT checklist for reporting randomized
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controlled trials of herbal medicine interventions (Gagnier et al., 2006). Of the 18
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studies evaluated, none of the published articles met all the recommended reporting criteria outlined in the checklist. As can be seen from Table 3, all 18 articles provided
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information on the dosage and duration of the intervention and details of the practitioners and the majority of the articles reported the brand name and type of
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product used. The main CONSORT criteria that were missing from the articles included license registration details, which none of the article reported (many of the articles did provide details of the manufacturer and country of manufacture), type
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and concentration of extraction solvent and the content of quantified chemical constituents. From 10 criteria assessed, 10 trials (Isaacsohn et al., 1998; Superko and Krauss, 2000; Williams et al., 2005; van Doorn et al., 2006; Sobenin et al., 2008; Sobenin et al., 2009; Sobenin et al., 2010; Gomez-Arbelaez et al., 2013; Ried et al., 2013; Atkin et al., 2016) met 5 of these criteria and 5 trials (McCrindle et al., 1998;
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Gardner et al., 2001; Sobenin et al., 2008; Ried et al., 2010; Ried et al., 2016) met 6 of these criteria. Overall, the trial reporting was found to be of medium quality. Adverse effects were reported in 10 studies and are detailed in Table 1 (Isaacsohn et al., 1998; McCrindle et al., 1998; Gardner et al., 2001; van Doorn et al., 2006; Gardner et al., 2007; Sobenin et al., 2009; Ried et al., 2010; Ried et al.,
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2013; Atkin et al., 2016; Ried et al., 2016). Commonly reported adverse effects
included mild gastrointestinal discomfort (abdominal discomfort, belching, flatulence,
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reflux and upset stomach), changes in body odor and garlic breath or taste. Adverse effects which were reported less often included hypersensitivity, headache, dry
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mouth, cough, hot flushes, mouth ulcers and somnolence. No trials reported the use
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of garlic supplements during pregnancy and lactation. The trial that studied the use
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of garlic in individuals younger than 18 years old reported no significant adverse
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trials included in this review.
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effects (McCrindle, et al. 1998). No drug interactions were reported in any of the
[INSERT TABLE 3 HERE]
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Table 4 presents the results of the risk of bias analysis based on the Cochrane Risk of Bias Tool (Higgins and Green, 2011). The majority of the trials had either an
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unclear or low risk of bias for each bias type. The overall risk of bias was low. [INSERT TABLE 4 HERE]
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4. Discussion
The principal finding from this systematic review was the identification of moderate quality evidence to suggest that standardized aged garlic extracts containing 1.2 – 2.4 mg s-allyl cysteine or 600 - 2400 mg garlic powder per day are likely to be effective as an adjunct therapy to the standard treatment of hypertension in patient pg. 9
populations with SBP > 140 mmHg. There was also low quality evidence found to suggest that 300 - 600 mg per day of coated garlic powder is possibly effective in populations with a TC > 6.0 mmol/L and LDL-C > 3.0 mmol/L. There is unclear and conflicting evidence supporting other garlic formulations and doses due, in part, to the lack of details reported and poor study designs.
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This review is distinct from other recent reviews on garlic and hypertension
(Stabler et al., 2012; Kwak et al., 2014; Ried, 2016) in its utilization of item 4 of the
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elaborated CONSORT checklist for randomized controlled trials in herbal medicines (Gagnier et al., 2006) and its restriction of inclusion criteria to double-blind
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randomized controlled trials. In addition, this current review took into consideration
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confounding factors such as tobacco use, poor diet and genetic predisposition
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(Mendis et al., 2011) when evaluating the trial designs.
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The challenges with evaluating interventions for hypertension were also
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considered in the present review, such as the significant variability of blood pressure over a 24-hour period (Parati et al., 1987). Studies that reported a clinically and
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statistically significant reduction in blood pressure, monitored blood pressure with multiple measurements over 24-hour periods (Sobenin et al., 2009; Ried et al., 2010;
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Ried et al., 2013; Ried et al., 2016). In 3 of these studies (Ried et al., 2010; Ried et al., 2013; Ried et al., 2016), measurement reliability was further improved by monitoring blood pressure using a calibrated and validated digital
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sphygmomanometer. In addition, they considered the consumption of food and caffeinated beverages before blood pressure measurement (Ried et al., 2010; Ried et al., 2013; Ried et al., 2016).
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As presented in table 3, consistent limitations were found across all studies included in the present review that relate to the incomplete or lack of reporting of the parts of the plant used, authentication of raw materials and qualitative testing. This may be in part due to preclinical studies of the same herbal preparation cited within studies having previously reported these details.
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The exclusion of multiple ingredient nutraceuticals was considered necessary to improve the homogeneity of the garlic preparations evaluated in this review.
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However, this could be considered a limitation by advocates of synergistic
formulations that include a number of herbs and nutrients with potential hypotensive
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or hypolipdemic effects.
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Prior studies reviewing trials that have evaluated the effects of garlic in the
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management of hypertension and dyslipidemia have drawn similar conclusions to
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those of the present study (Stabler et al., 2012; Kwak et al., 2014; Ried, 2016).
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However, this review has identified a more specific finding related to the formulation and dose used for aged garlic extract preparations. In regard to the lipid-lowering
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effect of garlic, the conclusion differs from previous reviews which report stronger positive findings (Kwak et al., 2014; Ried, 2016). This difference likely relates to
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differences in inclusion criteria (Linde and Willich, 2003) and variations in the methodological quality and reporting of double-blind randomized clinical trials
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(Gagnier et al., 2006). Future studies are encouraged to consider the specific formulations used in
order to gain a better understanding of the bioavailability of known active constituents and how these relate to clinical outcomes. Garlic powder, produced by slicing and crushing garlic cloves, followed by drying and pulverizing into powder
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(Amagase et al., 2001), was the most common preparation used in the studies included in this review. This preparation is able to maintain many of the same constituents as raw garlic (Amagase et al., 2001). Garlic powder does not contain allicin; allicin is formed by enzymatic conversion of alliin by alliinase (Lawson et al., 2001). Since alliinase is inhibited by gastric pH, enteric coated formulations are
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preferred (Lawson and Hughes, 1992). The nature of coating of the tablets is,
therefore, a factor that may have impacted on the findings reported (Lawson et al.,
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2001). Two trials which studied the anti-lipidemic effect of garlic used the propriety garlic powder AllicorTM (INAT-Farma), reported that this garlic formulation had
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modified release characteristics that were associated with the positive outcomes of
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the trials (Sobenin et al., 2008; Sobenin et al., 2010).
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Aged garlic extracts were employed in a number of studies included in this
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review. Aged garlic extracts were prepared by soaking garlic gloves into extracting solution for up to 20 months (Amagase et al., 2001). This preparation enables the
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enzymatic formation of s-allyl cysteine from γ-glutamyl-s-allyl-L-cysteines (Amagase et al., 2001). Unlike alliin or allicin, s-allyl cysteine is more stable and can be finely
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standardized (Amagase, 2006). Future studies are also encouraged to investigate
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and report on any drug interactions between garlic preparations and conventional medications.
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Conclusion
This review identified moderate quality evidence to suggest that standardised aged garlic extracts are likely to be effective as an adjunct therapy to the standard treatment of hypertension in patient populations with SBP > 140 mmHg. The quality of evidence for the role of garlic in the management of dyslipidaemia is currently low.
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To improve the quality of research on this topic, we recommend that item 4 of the CONSORT checklist is referred to during study design and used to guide the reporting of the herbal intervention. Should these findings be supported by high quality, larger studies of longer duration, specific standardised formulations of garlic could play a promising new role in the management of hypertension and
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hyperlipidaemia.
Conflict of Interest
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There is no conflict of interest or disclosure.
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Shouk, R., Abdou, A., Shetty, K., Sarkar, D., Eid, A.H., 2014. Mechanisms underlying the antihypertensive effects of garlic bioactives. Nutr Res. 34, 106115.
pg. 17
Sobenin, I.A., Andrianova, I.V., Demidova, O.N., Gorchakova, T.V., Orekhov, A.N., 2008. Lipid-lowering effects of time-released garlic powder tablets in doubleblinded placebo-controlled randomized study. J Atheroscler Thrombo. 15, 334-338. Sobenin, I.A., Andrianova, I.V., Fomchenkov, I.V., Gorchakova, T.V., Orekhov, A.N.,
IP T
2009. Time-released garlic powder tablets lower systolic and diastolic blood
pressure in men with mild and moderate arterial hypertension. Hypertens Res.
SC R
32, 433-437.
Sobenin, I.A., Nedosugova, L.V., Filatova, L.V., Balabolkin, M.I., Gorchakova, T.V.,
U
Orekhov, A.N., 2008. Metabolic effects of time-released garlic powder tablets
A
study. Acta Diabetologica. 45, 1-6.
N
in type 2 diabetes mellitus: the results of double-blinded placebo-controlled
M
Sobenin, I.A., Pryanishnikov, V.V., Kunnova, L.M., Rabinovich, Y.A., Martirosyan, D.M., Orekhov, A.N., 2010. The effects of time-released garlic powder tablets
ED
on multifunctional cardiovascular risk in patients with coronary artery disease. Lipids Health Dis. 9, 119.
PT
Stabler, S.N., Tejani, A.M., Huynh, F., Fowkes, C., 2012. Garlic for the prevention of cardiovascular morbidity and mortality in hypertensive patients. Cochrane
CC E
Database Syst Rev. 8, Cd007653.
Superko, H.R., Krauss, R.M., 2000. Garlic powder, effect on plasma lipids,
A
postprandial lipemia, low-density lipoprotein particle size, high-density lipoprotein subclass distribution and lipoprotein(a). J Am Coll Cardiol 35, 321326.
Van Doorn, M.B., Espirito Santo, S.M., Meijer, P., Kamerling, I.M., Schoemaker, R.C., Dirsch, V., Vollmar, A., Haffner, T., Gebhardt, R., Cohen, A.F., Princen,
pg. 18
H.M., Burggraaf. J., 2006. Effect of garlic powder on C-reactive protein and plasma lipids in overweight and smoking subjects. Am J Clin Nutr. 84, 13241329. Williams, M.J., Sutherland, W.H., McCormick, M.P., Yeoman, D.J., de Jong, S.A., 2005. Aged garlic extract improves endothelial function in men with coronary
IP T
artery disease. Phytother Res 19, 314-319.
Xiong, X.J., Wang, P.Q., Li, S.J., Li, X.K., Zhang, Y.Q., Wang, J., 2015. Garlic for
A
CC E
PT
ED
M
A
N
U
controlled trials. Phytomedicine. 22, 352-361.
SC R
hypertension: A systematic review and meta-analysis of randomized
pg. 19
IP T SC R U N A M ED
A
CC E
PT
Figure 1. Literature Search Method
pg. 20
I N U SC R
DB-RCTcrossover; (n = 26)
GomezArbelaez D et al (2013); Colombia
DB-RCTcrossover (n = 43)
CC E A
Isaacsohn JL et al (1998); USA
McCrindle BW et al (1998); Canada
pg. 21
AGE; 1200 mg/day; Kyolic; 12 wks
DB-RCT; Garlic (n = 28); Placebo (n = 22)
GP; 900mg/d; Kwai; 12 wks
mean age = 57.5; M = 27; F = 23; mean BMI = 26.5
GP; 900 mg/d; Kwai; 8 wks
mean age = 14.0; age range = 818; M = 16; F = 14; mean BMI = 21.85
DB-RCT; Garlic (n = 15); Placebo (n = 15)
(-)
Average Baseline BP of BP Treatmen Change t Group s in Tx (SD) Group (mmHg) (mmHg) SBP = 130.3 SBP = (14.0); +0.5; DBP = DBP = 74.7 (7.5) 0.8 SBP = SBP = 123.73 2.59 (15.63); (1.91)*; DBP = DBP = 81.59 1.07 (10.86) (1.32)*
(-)
SBP = 119.3 (15.2); DBP = 73.2 (9.6)
Concurrent Anti-HT and/or lipidlowering Medication
M
Atkin M et al (2016); UK (
Study Population T2 DM; Mean age = 49.8; M = 19; F = 7; Mean BMI = 32; metabolic syndrome; mean age = 40.79; mean BMI = 33.07
ED
Study Design
Form; Dose; Brand; Duration AGE; 1200 mg/d; Kyolic; 4 wks
PT
Author (Year); Geographi cal Location
A
Table 1 Characteristics of studies – Garlic and Hypertension
(+)
(-)
SBP = 102 (9); DBP = 63 (10)
SBP = +2.2 (12.4); DBP = +1.1 (7.9) SBP = +2.1% (-7.1 to 11.3)#; DBP = 0% (-6.5 to + 6.5) #
Statistical Significanc e Between Tx vs Placebo
Adverse Reaction Reported
SBP (ns); DBP (ns)
indigestio n
SBP (ns); DBP (ns)
no serious side effects garlic breathe; change in body odour; abdomina l discomfor t
SBP (ns); DBP (ns)
unpleasa nt body odour; headache ; upset stomach
SBP (ns); DBP (ns)
Diet §
Smoke r§
Famil y Hx§
(-)
(+)
(-)
(+)
(-)
(-)
(+)
(+)
(-)
(+)
(+)
(+)
I N U SC R M
uncontrolled HT; mean age = 66; mean BMI = 30.1; M = 17; F= 8
ED
AGE; 960 mg/d; Kyolic; 12 wks
(+)
A
CC E
PT
Ried K et al (2010); Australia
DB-RCT; Garlic (n = 25); Placebo (n = 25)
A
overall SBP = 1.9; DBP = +1.5
Ried K et al (2013); Australia
pg. 22
DB-RCT; 240 mg/d (n = 21); 480 mg/d (n = 20); 960 mg/d (n = 19); Placebo (n = 19)
AGE; 240 mg/d; 480 mg/d; 960 mg/d; Kyolic; 12 wks
uncontrolled HT; mean age = 69.8; M = 42; F = 37; mean BMI = 29.3;
(+)
overall SBP (ns); DBP (ns);
sub-group baseline SBP = SBP ≥ sub-group 135.4 140 baseline SBP (14.1); mmHg ≥ 140 DBP = SBP = mmHg SBP 74.0 15.2; (ss); (10.3) DBP = (-) DBP (ns) 240 mg/d 240 mg/d SBP = SBP = 9.8 (4.0) @; 148.7 (2.8)@; DBP = DBP = 6.9 (1.9) @; 76.9 (2.9) 240mg/d @; SBP (ns); 480 mg/d DBP (ns) 480 mg/d SBP = SBP = 149.3 22.5 (3.7) @; (2.6) @; DBP DBP =480 mg/d =75.6 9.0 (1.8) SBP (ss); @; (2.8) @; DBP (ns); 960mg/d SBP = 149.4 (2.7) @; DBP = 75.9 (2.8)
960 mg/d SBP = 17.1 (3.9) @; DBP = 6.4 (1.9)
@
@
960mg/d SBP (ns); DBP (ns)
Gl discomfor t; belching; reflux; taste sensation
(-)
(+)
(+)
GI side effects; constipati on; bloating; flatulence ; reflux; garlic taste; dry mouth; cough
(-)
(+)
(+)
I N U SC R
AGE; 1200 mg/d; Kyolic; 12 wks
uncontrolled HT; mean age = 62.3; mean BMI = 27.7; M = 47; F = 41;
Sobenin IA et al (2008); Russia
DB-RCT; Garlic (n = 23); Placebo (n = 19)
GP; 600mg/d; Allicor; 12 wks
male; mean age = 51.7; mean BMI = 26.8
(+)
(-)
PT
ED
M
A
Ried K et al (2016); Australia
DB-RCT; Garlic (n = 50); Placebo (n = 38)
pg. 23
GP; Allicor 600 mg/d or Allicor 2400 mg/d or Kwai 900 mg/d; 8 wks
SBP = 143.4 (1.5)*; DBP = 88.8 (0.9)* 600 mg/d Allicor SBP = 158.0 (2.8)*; DBP= 97.0 (1.0)*; 2400 mg/d Allicor SBP =154.0 (3.4)*; DBP= 95.0 (0.6)*;
CC E A Sobenin IA et al (2009); Russia
DB-RCT; 600mg/d Allicor (n = 30); 2400mg/d Allicor (n = 18); Kwai (n = 16); Placebo (n = 20)
SBP= 148.7 (15.3); DBP = 89.9 (11.7)
mild and moderate arterial hypertension; male; age range = 3570
(-)
900 mg/d Kwai SBP=156. 9 (2.8)*; DBP = 97.5 (1.0)*
SBP = -8 (10.6); DBP = 3.7 (5.9)
SBP = 6.6; DBP = -5 600mg/d Allicor SBP = 7.0 (0.8)*; DBP= 3.8 (0.5)*; 2400mg/ d Allicor SBP = 9.3 (0.7)*; DBP= 3.2 (0.5)*; 900 mg/d Kwai SBP = 5.4 (1.6)*; DBP = 1.0 (1.2)*
SBP (ss); DBP (ns)
Reflux; garlic taste; hot flushes;
(-)
(+)
(+)
(-)
No side effects during study period
(+)
(+)
(+)
Allicor 2400mg/d and 900mg/d Kwai both reported GI complaint s
(+)
(+)
(+)
600 mg/d Allicor SBP (ss); DBP (ss);
2400 mg/d Allicor SBP (ss); DBP (ss);
900mg/d Kwai SBP (ss); DBP (ns)
I DB-RCTcrossover; (n = 15)
AGE; 2400 mg/d; Kyolic; 2 wks
N U SC R
Williams et al (2005); New Zealand
CAD male; mean age = 59; mean BMI = 28
(+)
SBP = 132 (22); DBP = 82 (11)
SBP = 6; DBP = -3
SBP (ns); DBP (ns)
(-)
(+)
(+)
(-)
A
CC E
PT
ED
M
A
ACEI = angiotensin converting enzyme inhibitor; AGE = aged garlic extract; Anti-DM = antidiabetic; Anti-HT = antihypertensive; CAD = coronary artery disease; CCB = calcium channel blocker; CHD = coronary heart disease; DBP = diastolic blood pressure; DB-RCT = doubleblind randomised controlled trials; Dx = diagnosis; GI = gastrointestinal; GP = garlic powder; HT = hypertension; Hx = history; mon = months; SBP = systolic blood pressure; SD = standard deviation; Tx = treatment; T2 DM = type II Diabetes mellitus; wks = weeks; (+) = present; (-) = no information available or not done; (ns) = not statistically significant; (ss) = statistically significant; * Data presented as mean (standard error of mean) # Data presented as mean % change (95% confidence interval) @ Data presented as mean (standard error) § Factors considered/controlled for
pg. 24
I N U SC R
Table 2 Characteristics of studies – Garlic and Dyslipidaemia
DB-RCTcross-over; (n = 26)
Budoff MJ et al (2004); USA
DB-RCT; Garlic (n = 9); Placebo (n = 10)
M
Atkin M et al (2016); UK
AGE; 1200 mg/d; Kyolic; 4 wks
Study Population T2 DM; Mean age = 49.8; M = 19; F = 7; Mean BMI = 32;
PT
ED
Study Design
Form; Dose; Brand; Duration
AGE; 1200 mg/d; Kyolic; 1 yr
CHD or high risk for CAD; mean age = 59.9; M = 13; F = 9
HT and/or lipidlowering Medicati on
(+)
(+)
A
CC E
Author (Year); Geographica l Location
A
Concurre nt Anti-
Gardner CD et al (2001); USA
pg. 25
DB-RCT; Half-dose (n = 17); Full-dose (n = 16); Placebo (n = 18)
GP; 500 or 1000 mg/d; unspecifi ed brand; 12 wks
non-DM; no heart disease; mean age = 51.7; mean BMI = 26.1
(-)
Average Baseline Lipid Profile for Tx Group (SD) (mmol/L)
TC = 4.2 (0.9); LDL = 2.5; HDL = 1.0 (0.3); TG = 1.4 (IQR 0.7) TC = 4.55 (0.96); LDL = 2.61 (0.83); HDL = 1.33 (0.41); TG = 1.59 (1.27) Half-dose TC = 5.97 (0.54); LDL = 3.90 (0.47); HDL = 1.40 (0.47); TG = 1.41 (0.71); Full-dose TC = 6.08 (0.7); LDL = 4.22 (0.47);
Lipid Profile Changes in Tx Group vs Baseline Mean (SD) (mmol/L)
TC = 0.0; LDL = +0.1; HDL = 0.0; TG = 0.0 TC= +0.18 (0.56); LDL= -0.08 (0.42); HDL = +0.08 (0.27); TG= +0.09 (0.448)
Statistical Significan ce Between Tx vs Placebo
Adverse Reaction Reported
TC (ns); HDL (ns); TG (ns)
§
Smoke r§
Famil y Hx§
indigestio n
(-)
(+)
(-)
TC (ns); LDL (ns); HDL (ns); TG (ns)
(-)
(+)
(+)
(+)
TC (ns); LDL (ns); HDL (ns); TG (ns)
belching; body odour; stomach gas; flatulence ; constipati on
(+)
(+)
(-)
Half-dose TC = +0.08; LDL = +0.05; HDL = +0.05; TG = -0.03; Full-dose TC = -0.26; LDL = -0.26; HDL = +0.08; TG = -0.08
Diet
I N U SC R ED
M
A
HDL = 1.19 (0.31); TG = 1.42 (0.63) Raw Garlic LDL = 3.67 (0.57); HDL = 1.42 (0.34); TG = 1.12 (0.54);
non-DM; no heart disease; mean age = 49.8; M = 96; F = 96; mean BMI = 25.3
A GomezArbelaez D et al (2013); Colombia
DB-RCTcross-over (n = 43)
AGE; 1200 mg/day; Kyolic;
metabolic syndrome; mean age = 40.79;
pg. 26
Garlicin LDL = 3.47 (0.49); HDL = 1.37 (0.28); TG = 1.38 (0.62);
PT DB-RCT; Raw Garlic (n = 49); Garlicin (n = 47); Kyolic (n = 48); Placebo (n = 48)
CC E
Gardner CD et al (2007); USA
raw garlic or GP or AGE; raw garlic 4000 mg/d; GP 1400 mg/d; AGE 1800 mg/d; raw garlic or Garlicin or Kyolic; all consume d6 days/wk; 6 mon
Kyolic LDL = 3.52 (0.52); HDL = 1.32 (0.23); TG = 1.42 (0.61) (-)
(-)
TC = 5.14 (0.80); LDL = 3.02 (0.73);
Raw Garlic LDL = +0.01 (-0.14 to 0.17)*; HDL = +0.06 (0.01 to 0.1)*; TG = -0.06 (-0.16 to 0.05)*; Garlicin LDL = +0.08 (-0.05 to 0.22)*; HDL = +0.03 (-0.01 to 0.06)*; TG = -0.07 (-0.22 to 0.08)*; Kyolic LDL = +0.005 (-0.14 to 0.15)*; HDL = -0.008 (-0.04 to 0.026)*; TG = -0.02 (-0.21 to 0.16)* TC = -0.11 (0.12) #; LDL = +0.10 (0.14) #;
LDL (ns); HDL (ns); TG (ns)
rash, heartburn , mouth ulcers, body and breath odour, flatulence
(+)
(+)
(-)
TC (ns); LDL (ns); HDL (ns); TG (ns)
no serious side effects
(+)
(-)
(-)
McCrindle BW et al (1998); Canada
GP; 900 mg/d; Kwai; 8 wks
Ried K et al (2016); Australia
DB-RCT; Garlic (n = 50); Placebo (n = 38)
AGE; 1200 mg/d; Kyolic; 12 wks
A
N U SC R
I AGE; 6000 mg/d; original formula; 12 wks
DB-RCT; Garlic (n = 15); Placebo (n = 15)
pg. 27
A
GP; 900mg/d; Kwai; 12 wks
HDL = 0.97 (0.15); TG = 2.49 (0.81)
mean age = 57.5; M = 27; F = 23; mean BMI = 26.5
(-)
ED
DB-RCT; Garlic (n = 28); Placebo (n = 27)
CC E
Jung ES et al (2014); Korea
DB-RCT; Garlic (n = 28); Placebo (n = 22)
PT
Isaacsohn JL et al (1998); USA
mean BMI = 33.07
M
12 wks
no history of CVD; mean age = 50.48; M = 20; F = 40; Mean BMI = 24.5
mean age = 14.0; M = 16; F = 14; mean BMI = 21.85 uncontrolled HT; mean age = 62.3; mean BMI = 27.7; M = 47; F = 41;
(-)
(-)
(+)
HDL = -0.04 (0.02) #; TG = -0.21 (0.14) #
TC = +1.64% (6.8) ¶; LDL = +1.82% (7.5) ¶; TC = 7.1 (0.9); HDL = +2.90% LDL = 4.9 (0.8); (10.8) ¶; HDL = 1.3 (0.3); TG = +0.38% TG = 1.9 (0.8) (26.3) ¶ TC = 6.23 (0.62); LDL = 3.90 (0.37); HDL = 1.21 TC= -0.2; (0.24); LDL= +0.13; TG = 1.58 HDL = +0.09; (0.62) TG= -0.221 TC = +0.1% (-0.29 to + 0.49) &; TC = 7.06 (1.61); LDL = +0.04% LDL = 5.59 (-0.35 to +0.43) &; (1.52); HDL = +0.03% HDL = 0.95 (-0.11 to + 0.17) &; (0.25); TG = 1.14 TG = -0.18% (0.38) (-0.66 to +0.30) &
TC = 5.5 (1.3); LDL = 0.8 (1.1); HDL = 1.7 (0.6); TG = 1.2 (0.6)
TC = -0.01 (0.75); LDL = -0.12 (0.7); HDL = -0.02 (0.27);
(-)
garlic breath; change in body odour; abdomina l discomfor t
(+)
(+)
(-)
TC (ns); LDL (ns); HDL (ns); TG (ns)
no moderate or serious adverse events
(+)
(-)
(-)
TC (ns); LDL (ns); HDL (ns); TG (ns)
unpleasa nt body odour; headache , upset stomach
(+)
(+)
(+)
TC (ns); LDL (ns); HDL (ns); TG (ns)
Reflux; garlic taste; hot flushes;
(-)
(+)
(+)
I N U SC R A
Sobenin IA et al (2008); Russia
Sobenin IA et al (2010); Russia
pg. 28
ED
PT
GP; 600 mg/d; Allicor; 4 wks
T2 DM; mean age = 48.2; M = 26; F = 34
DB-RCT; Garlic (n = 23); Placebo (n = 19)
GP; 600mg/d; Allicor; 12 wks
male; mean age = 51.7; mean BMI = 26.8
DB-RCT; Garlic (n = 26); Placebo (n = 25)
GP; 300 mg/d; Allicor; 12 mon
CHD; TC > 5.2mmol/L; mean age = 56.5; M = 28; F = 23;
CC E
Sobenin IA et al (2008); Russia
DB-RCT; Monotherapy: Garlic (n = 10); Placebo (n = 10); Combined Tx with sulfonylure a: Garlic (n = 20); Placebo (n = 20)
M
A
Monotherapy TC = 6.42 (0.18); LDL = 3.86 (0.21); HDL = 1.27 (0.11); TG = 2.96 (0.51);
(+)
(-)
(-)
Combined Tx TC = 6.81 (0.26); LDL = 4.19 (0.27); HDL = 1.3 (0.11); TG = 3.03 (0.31) TC = 6.97 (0.20) #; LDL = 5.00 (0.17) #; HDL = 1.06 (0.07) #; TG = 2.00 (0.26) #
TC = 6.96 (0.30); LDL = 4.81 (0.24);
TG = +0.15 (0.45)
Monotherapy TC = -0.19; LDL = +0.26; HDL = +0.01; TG = -1.06; Combined Tx TC = -0.29; LDL = +0.07; HDL = -0.02; TG = -0.78 TC = -7.6% (2.4)$; LDL = -11.8% (4.5) $; HDL = +11.5% (3.8) $; TG = -7.7% (9.0) $
TC = -0.87; LDL = -0.78; HDL = +0.02; TG= = -0.22
(-)
(-)
(+)
(-)
(-)
TC (ss); LDL (ss); HDL (ns); TG (ns)
no side effects during study period
(+)
(+)
(+)
TC (ns); LDL (ss); HDL (ns); TG (ns)
(-)
(-)
(+)
(+)
I N U SC R HDL = 1.32 (0.09); TG = 1.83 (0.22)
A
Williams et al (2005); New Zealand
GP; 2100 mg/d; Original formula; 12 wks
DB-RCTcross-over; (n = 15)
AGE; 2400 mg/d; Kyolic; 2 wks
(-)
TC = 5.47 (4.08 to 7.72) @; LDL = 3.37 (2.06 to 5.64) @; HDL = 1.27 (0.64 to 1.87) @; TG = 1.56 (0.83 to 6.11) @
TC = +0.12; LDL = 0.00; HDL = -0.08; TG = +0.08
TC (ns); LDL (ns); TG (ns)
abdomina l discomfor t; severe garlic odour
(+)
TC = 4.3 (0.9); LDL = 2.50 (0.76); HDL = 1.20 (0.35); TG = 1.2 (0.4)
TC = 0; LDL = +0.05; HDL = +0.01; TG= +0.1
TC (ns); LDL (ns); HDL (ns); TG (ns)
(-)
A (-)
M
GP; 900 mg/d; Kwai; 12 wks
mean age = 53; mean weight = 73.9
ED
DB-RCT; Garlic (n = 28); Atorvastati n (n = 30); Placebo (n = 26)
CC E
Van Doorn MBA et al (2006); Netherland
DB-RCT; Garlic (n = 25); Placebo (n = 25)
PT
Superko HR et al (2000); USA
TC = 6.46 (0.75); LDL = 4.37 (0.65); HDL = 1.33 (0.30); TG = 1.64 (0.61)
mean age = 48.1; M = 38; F = 46; BMI > 24.5; mean BMI = 29.5
CAD male; mean age = 59; mean BMI = 28
TC = -0.06 (0.68); LDL = -0.04 (0.66); HDL = -0.003 (0.17); TG = -0.05 (0.49)
TC (ns); LDL (ns); HDL (ns); TG (ns)
(-)
(+)
(-)
(+)
(-)
(+)
(-)
(+)
(+)
(-)
ACEI = angiotensin converting enzyme inhibitor; AGE = aged garlic extract; Anti-DM = antidiabetic; Anti-HT = antihypertensive; CAD = coronary artery disease; CCB = calcium channel blocker; CHD = coronary heart disease; DB-RCT = double-blind randomised controlled trials; Dx = diagnosis; GP = garlic powder; HDL = high density lipoprotein; HRT = hormone replacement therapy; HT = hypertension; Hx = history; LDL = low density lipoprotein; mon = months; NSAIDs = nonsteroidal anti-inflammatory drugs; SD = standard deviation; TC = total cholesterol; TG = triglycerides; T2 DM = type II Diabetes mellitus; Tx = treatment; wks = weeks; (+) = present; (-) = no information available or not done; (ns) = not statistically significant; (ss) = statistically significant; * Data were presented as mean (95% confidence interval) & Data were presented as mean % change (95% confidence interval) ¶ Data were presented as mean % change (SD)
pg. 29
I N U SC R
#
Data were presented as mean (Standard error of mean) were presented as mean % change (Standard error of mean) @ Data presented as median (Range) § Factors considered/controlled for
A
CC E
PT
ED
M
A
$ Data
pg. 30
I N U SC R
Table 3 Fulfilment of Item 4 of the Elaborated Consolidated Standards of Reporting Trials Checklist Herbal medicinal product name
Characteristics of the herbal product
Dosage regimen and quantitative description
a
b
c
d
g
h
i
j
Atkin M et al 2016
(0)
(+)
(0)
(+)
(0)
(+)
(+)
(0)
(0)
(0)
(0)
(+)
Budoff MJ et al 2004
(0)
(+)
(0)#
(+)
(0)
(0)
(0)
(+)
(0)
(0)
(0)
(0)
(+)
Gardner CD et al 2001
(0)
(0)
(+)
(0)
(0)
(0)
(+)
(+)
(+)
(0)
(+)
(+)
(+)
A
Jung MS et al 2014 McCrindle BW et al 1998
Ried K et al 2010
pg. 31
A
M
ED
f (0)
Placebo/ control
Practitioner
k
(+)
(0)#
(+)
(0)
(0)
(0)
(+)
(0)
(+)@
(0)
(+)
(+)
(+)
(+)
(0)
(+)
(0)
(0)
(0)
(+)
(0)
(0)
(0)
(0)
(+)
(0)
(+)
(0)#
(+)
(0)
(0)
(+)
(+)
(0)
(0)$
(0)
(+)¶
(+)
(+)
(0)*
(0)#
(+)
(0)
(0)
(+)
(+)
(+)
(+)
(0)
(+)
(+)
(+)
(+)
(0)
(0)
(0)
(0)
(0)
(+)
(0)
(+)
(0)
(+)
(+)
(0)
(0)
(0)
(+)
(0)#
(+)
(0)
(+)
(0)
(+)
(0)
(+)
(+)
CC E
Gardner CD et al 2007 GomezArbelaez et al 2013 Isaacsohn JL et al 1998
(0)
e
Qualitative testing
PT
Study
(+)
(0)#
(+)
Ried K et al 2016
(0)
(+)
(0)#
(+)
Sobenin IA et al 2008
(+)
(+)
(0)#
(+)
Sobenin IA et al 2008
(+)
(+)
(0)#
Sobenin IA et al 2009
(+)
(+)
Sobenin IA et al 2010
(+)
PT
I (0)
CC E
Superko HR et al 2000 (+)
N U SC R
Ried K et al 2013
(0)
(0)
(+)
(0)
(+)
(0)
(+)¶
(+)
(0)
(0)
(0)
(+)
(0)
(+)
(0)
(+)
(+)
(0)
(0)
(0)
(+)
(0)
(0)
(0)
(+)¶
(+)
(+)
(0)
(0)
(0)
(+)
(0)
(+)
(0)
(+)¶
(+)
(0)#
(+)
(0)
(0)
(0)
(+)
(0)
(0)
(0)
(+)¶
(+)
(+)
(0)#
(+)
(0)
(0)
(0)
(+)
(0)
(0)
(0)
(+)¶
(+)
(+)
(0)#
(+)
(0)
(0)
(0)
(+)
(0)
(0)&
(0)
(0)
(+)
ED
M
A
(0)
(0)
(0)*
(0)#
(+)
(0)
(0)
(+)
(+)
(0)
(+)
(0)
(+)¶
(+)
Williams et al 2005
(0)
(+)
(0)#
(+)
(0)
(0)
(0)
(+)
(0)
(0)
(0)
(+)
(+)
A
Van Doorn et al 2006
(+) = present; (0) = absent; * Original formula utilised #
Manufacturer and country of manufacture stated
$
Standardised to the weight of garlic or clove
&
Author claimed to use standardised product without stating the amount of bioactive constituent
pg. 32
I ¶
N U SC R
@
Garlic powder utilised was standardised, Aged garlic extract utilised was standardised to the weight of garlic
Matching or identical placebo stated, not giving exact ingredients in placebo.
A
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M
A
a Latin Binomial name, b Brand name, c Licensed registration, d Type of product, e Parts of plant used, f Authentication of raw materials, g Type and concentration of extraction solvent, h Dosage/ duration, i Content of quantified chemical constituents, j Standardisation, k Type of placebo used
pg. 33
I N U SC R
Table 4 - Risk of Bias*
Selection bias
Performance bias
Detection bias
Attrition bias
Reporting bias
Other Bias
Random Blinding of Allocation sequence participants and concealment generation personnel
Blinding of outcome assessment
Incomplete outcome data
Selective reporting
Funding
Conflict of Interest
unclear
Budoff MJ et al 2004
unclear
unclear
low
low
low
low
unclear
unclear
unclear
unclear
low
low
unclear
unclear
low
low
low
low
low
low
unclear
unclear
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Gardner CD et al 2001
unclear
ED
Atkin. M et al 2016
M
A
Study
low
low
low
low
low
low
low
unclear
Gomez-Arbelaez et al 2013
low
unclear
unclear
unclear
low
low
low
low
Isaacsohn JL et al 1998
unclear
unclear
low
unclear
low
low
high
unclear
Jung MS et al 2014
unclear
unclear
unclear
unclear
low
low
unclear
unclear
McCrindle BW et al 1998
low
low
low
unclear
low
low
high
unclear
Ried K et al 2010
low
unclear
high
low
low
low
low
low
Ried K et al 2013
low
low
low
low
low
low
low
low
Ried K et al 2016
low
low
low
low
low
low
low
low
A
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Gardner CD et al 2007
pg. 34
I unclear
Sobenin IA et al 2008
low
unclear
Sobenin IA et al 2009
low
unclear
Sobenin IA et al 2010
low
unclear
Superko HR et al 2000
unclear
Van Doorn et al 2006
unclear
A
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*(Higgins and Green, 2011)
pg. 35
unclear
unclear
low
High
unclear
unclear
unclear
unclear
unclear
low
unclear
unclear
low
unclear
low
low
unclear
unclear
unclear
unclear
low
low
unclear
unclear
unclear
unclear
unclear
unclear
low
unclear
unclear
unclear
low
unclear
low
low
high
low
unclear
high
unclear
unclear
low
unclear
unclear
M
ED unclear
PT
Williams et al 2005
N U SC R
unclear
A
Sobenin IA et al 2008
S2210-8033(19)30039-9 https://doi.org/10.1016/j.hermed.2019.100292 100292
Reference:
HERMED 100292
To appear in: Received date: Revised date: Accepted date:
2 March 2018 26 November 2018 15 July 2019
Please cite this article as: Chan W-JoJ, McLachlan AJ, Luca EJ, Harnett JE, Garlic (Allium sativum L.) in the Management of Hypertension and Dyslipidemia – A Systematic Review, Journal of Herbal Medicine (2019), https://doi.org/10.1016/j.hermed.2019.100292 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Garlic (Allium sativum L.) in the Management of Hypertension and Dyslipidemia – A Systematic Review
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Running title: Garlic and Hypertension and Dyslipidaemia
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Wai-Jo J CHAN1, Andrew J McLACHLAN1, 2, Edward J LUCA1, Joanna E
for Education and Research in Ageing, Concord Hospital, NSW, Australia.
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2Centre
of Pharmacy, University of Sydney, NSW, Australia;
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1Faculty
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HARNETT1
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Correspondence: Joanna E Harnett, The University of Sydney, Camperdown, NSW
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Abstract
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2006, Australia. Tel: +612 935 170 09, Email: [email protected]
The herb garlic (Allium sativum L.) has traditionally been used to promote ‘cardiovascular
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health’. The aim of this systematic review was to evaluate the available evidence for the efficacy and safety of garlic in the management of hypertension and dyslipidemia and the quality of that evidence by utilising the elaborated CONSORT checklist. Double-blind randomized controlled trials written in English from inception to April 2017 were identified and evaluated.
pg. 1
A total of 18 studies were included (n=1069): 4 studies reported a statistically significant reduction in systolic blood pressure (mean SBP reduction of 11.2 mmHg) and 2 studies reported a statistically significant reduction in various lipid components (LDL-C p <0.05; TC p = 0.003). Aged garlic extract (1.2 mg – 2.4 mg s-allyl cysteine/ day) and to a lesser extent coated garlic powder tablets (600 mg - 2400 mg/ day) demonstrated a hypotensive effect.
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Evidence for the role of garlic in the management of dyslipidemia is, however, less clear. Minor side effects were reported.
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Further high quality research is required to confirm these findings. The authors recommend researchers refer to the item 4 of the elaborated CONSORT checklist in the design and
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reporting phase of their studies.
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Keywords: Garlic, Dyslipidaemia, Hypertension, Allium sativum
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Introduction
Garlic is one of the most commonly used herbal medicines in Australia, the United
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Kingdom, Germany and the United States (Barnes et al., 2008; Goh et al., 2009; Posadzki et al., 2013; Reinert et al., 2007). Garlic (Allium Sativum) has traditionally
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been used in the management of a broad range of health conditions (Braun and Cohen, 2015). Early Egyptian, Greek and Chinese civilizations treasured garlic as a
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food and as a medicine (Bordia et al., 1975). In modern times, garlic has been the subject of pharmacological studies evaluating its potential anticancer, antimicrobial and immunomodulatory activities (Abdullah et al., 1988). Organosulfur compounds in garlic such as allicin and s-allyl cysteine are thought to be the main bioactive compounds responsible for the management of blood pressure and dyslipidemia
pg. 2
(Gebhardt and Beck 1996; Shouk et al., 2014). These compounds have been shown to inhibit transcription factor NF-κB and angiotensin converting enzyme, whilst enhancing the production of the vasodilatory compounds hydrogen sulphide and nitric oxide, mechanisms by which the herb is thought to reduce blood pressure and oxidative stress (Shouk et al., 2014). Other organosulfur compounds such as ajoene
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and allicin have been shown to inhibit cholesterol synthesis by inhibiting 3-hydroxy-3methyl-glutaryl-coenzyme A reductase (Gebhardt and Beck, 1996; Ferri et al.; 2003).
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A number of reviews have been conducted evaluating the role of garlic in
hypertension and dyslipidemia (Stabler et al., 2012; Kwak et al., 2014; Xiong et al.,
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2015; Ried, 2016). However, these reviews were not restricted to double blind
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randomized controlled trials, nor did they utilize the elaborated Consolidated
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Standards of Reporting Trials (CONSORT) extension for the reporting of herbal
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medicine interventions to evaluate the studies included (Gagnier et al.; 2006).
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The aim of this review was to evaluate the available evidence, and the quality of reporting of double-blind randomized controlled trials that evaluate the
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2. Methods
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efficacy and safety of garlic in the management of hypertension and dyslipidemia.
Studies evaluating the efficacy of garlic in the management of hypertension and dyslipidemia were searched for via the following databases: PubMed, MEDLINE,
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Embase, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Web of Science. An academic librarian provided assistance in developing a search strategy to conduct the search across each database. The search terms included: hypertension OR high blood pressure OR systolic blood pressure OR diastolic blood pressure OR dyslipidemia OR hyperlipidemia OR high cholesterol OR
pg. 3
total cholesterol OR triglycerides OR high density lipoprotein OR low density lipoprotein AND garlic OR Allium sativum. Only double-blind randomized controlled trials from inception to April 2017 were included. Two authors decided on the search terms and inclusion and exclusion criteria. One of these two authors conducted the systematic search and
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the other author checked the search method. The two authors independently
screened the titles and abstracts of trials identified by the search strategy. Three
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authors reviewed the included trials for quality and meeting the inclusion and exclusion criteria (Figure 1).
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Item 4 of the elaborated CONSORT checklist for reporting randomized
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controlled trials of herbal medicine interventions (Gagnier et al., 2006) was employed
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to assess the quality of reporting of the studies included in this review. The Cochrane
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Risk of Bias Tool was employed to assess potential bias in each included study
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(Higgins and Green, 2011).The safety of each garlic preparation was assessed by reviewing trials that reported adverse reactions and possible drug interactions.
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Systematic reviews, meta-analyses, literature reviews, non-English publications and trials evaluating nutraceuticals or combination of complementary medicines were
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excluded in the search. Trials including healthy normolipidemic and/or normotensive individuals who were not at risk of cardiovascular events were excluded.
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The measurement outcomes recorded included changes from baseline in
average systolic blood pressure (SBP), diastolic blood pressure (DBP), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C), total cholesterol (TC) and triglycerides. Data including geographical location, study design, sample size, formulation, daily dosage, brand, duration, study population, concurrent medications,
pg. 4
average baseline measurements, adverse reactions reported, control of confounders in particular diet, smoking status and family history were extracted and recorded. The statistical significance of the results between treatment and placebo groups were recorded for each outcome measured. Where the p-value was ≤ 0.05, it was considered to be statistically significant. Trials reporting positive outcomes were
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assessed by a statistically significant reduction in lipid profiles and/or blood pressure between the treatment and the placebo groups.
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If the included articles reported the lipid profiles without LDL-C measures, the LDL-C was estimated using the Friedewald’s formula which was validated in
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patients with metabolic syndrome (Knopfholz et al., 2014).
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Results for serum TC, HDL-C, LDL-C and triglyceride concentrations in this
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review were reported as mmol/L. Where a study reported TC, HDL-C and LDL-C in
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mg/dL, the results were converted by dividing the value by a factor of 38.67 to obtain
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value in mmol/L. Studies reporting serum triglyceride concentration measured in mg/dL, were converted by dividing the value by a factor of 88.57 to obtain the value
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3. Results
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in mmol/L.
A total of 1,126 articles were identified from 6 databases in the initial search (Figure 1). After removing duplicates, articles were screened by title and abstract for
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inclusion. 39 full-text articles were assessed for eligibility, resulting in a final total of 18 studies included in this systematic review. 21 articles were excluded for the reasons presented in Figure 1. [INSERT FIGURE 1 HERE]
pg. 5
Tables 1 and 2 summarize the characteristics of the 18 trials evaluating the effect of garlic treatment, either as a sole therapy or as an adjunct to standard care in the management of dyslipidemia or hypertension. Ten studies evaluated the effect of garlic on individuals with hypertension, with 1 trial demonstrating a statistically significant reduction in both SBP and DBP (Sobenin et al., 2009) and 2 trials
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showing a statistically significant reduction in SBP only (Ried et al., 2013; Ried et al., 2016). One trial stratified participants into subgroups with baseline of SBP ≥ 140
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mmHg and was able to demonstrate a statistically significant reduction in SBP (Ried et al., 2010). Statistically significant reductions in various fractions of lipid profiles
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were reported in 2 of the 15 trials which studied garlic in the management of
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dyslipidemia (Sobenin et al., 2008; Sobenin et al., 2010).
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A total of 3 studies investigated the effect of garlic on hypertension alone
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(Sobenin et al., 2009; Ried et al., 2010; Ried et al., 2013) and 8 studies evaluated the effect of garlic treatment on dyslipidemia alone (Superko and Krauss 2000;
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Gardner et al., 2001; Budoff et al., 2004; van Doorn et al., 2006; Gardner et al., 2007; Sobenin et al., 2008; Sobenin et al., 2010; Jung et al., 2014). The remaining 7
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studies investigated garlic preparations in the management of both conditions
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(Isaacsohn et al., 1998; McCrindle et al., 1998; Williams et al., 2005; Sobenin et al., 2008; Gomez-Arbelaez et al., 2013; Atkin et al., 2016; Ried et al., 2016). Of the 18 trials, 3 trials were double-blind randomized cross-over trials
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(Williams et al., 2005; Gomez-Arbelaez et al., 2013; Atkin et al., 2016). The remaining 15 trials (Isaacsohn et al., 1998; McCrindle et al., 1998; Superko and Krauss, 2000; Gardner et al., 2001; Budoff et al., 2004; van Doorn et al., 2006; Gardner et al., 2007; Sobenin et al., 2008; Sobenin et al., 2008; Sobenin et al., 2009; Ried et al., 2010; Sobenin et al., 2010; Ried et al., 2013; Jung et al., 2014; Ried et
pg. 6
al., 2016) were double-blind randomized controlled trials with a parallel group design. Seven of the studies included participants treated with garlic or placebo who were concurrently taking orthodox medications including antihypertensive, lipid lowering, anticoagulants, antidiabetic and antiplatelet agents (Budoff et al., 2004; Williams et al., 2005; Sobenin et al., 2008; Ried et al., 2010; Ried et al., 2013; Atkin et al., 2016;
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Ried et al., 2016).
Of the 10 trials evaluating the effect of garlic in the management of
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hypertension (Table 1), 6 used aged garlic extracts (Williams et al., 2005; Ried et al., 2010; Gomez-Arbelaez et al., 2013; Ried et al., 2013; Atkin et al., 2016; Ried et al.,
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2016) and an additional 4 trials used garlic powder (Isaacsohn et al., 1998;
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McCrindle et al., 1998; Sobenin et al., 2008; Sobenin et al., 2009). Amongst the trials
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identified were those that included branded preparations. These included KyolicTM
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(Wakunaga/Wagner, Madero, USA), KwaiTM (Lichtwer Pharma, Berlin, Germany) and AllicorTM (INAT-Farma, Marseille, France). Daily doses for aged garlic extract
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ranged from 240 – 2400 mg and for garlic powder from 600 – 2400 mg. The duration of therapy ranged from 2 – 12 weeks, with 6 trials conducted over a 12-week period
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(Isaacsohn et al., 1998; Sobenin et al., 2008; Ried et al., 2010; Gomez-Arbelaez et
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al., 2013; Ried et al., 2013; Ried et al., 2016). Similarly, in the 15 trials investigating garlic in the management of
dyslipidemia (Table 2), aged garlic extracts were used in 7 trials (Budoff et al., 2004;
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Williams et al., 2005; Gardner et al., 2007; Gomez-Arbelaez et al., 2013; Jung et al., 2014; Atkin et al., 2016; Ried et al., 2016), while 9 trials used garlic powder (Isaacsohn et al., 1998; McCrindle et al., 1998; Superko and Krauss, 2000; Gardner et al., 2001; van Doorn et al., 2006; Gardner et al., 2007; Sobenin et al., 2008; Sobenin et al., 2008; Sobenin et al., 2010) and 1 used raw garlic (Gardner et al.,
pg. 7
2007). Kyolic™ (Wakunaga/Wagner, Madero, USA), Garlicin™ (Nature’s Way Products Inc, Sydney Australia), Kwai™ (Lichtwer Pharma, Berlin, Germany) and Allicor™ (INAT-Farma, Madero, France) were the brands used in the studies. The daily dose for garlic powder ranged from 500 - 2100 mg and for aged garlic extract daily doses ranged from 1200 - 6000 mg and raw garlic was 4000 mg. The duration
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of treatment ranged from 2 weeks to 1 year with 8 trials running for 12 weeks
(Isaacsohn et al., 1998; Superko and Krauss, 2000; Gardner et al., 2001; van Doorn
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et al., 2006; Sobenin et al., 2008; Gomez-Arbelaez et al., 2013; Jung et al., 2014; Ried et al., 2016).
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[INSERT TABLE 1 & 2 HERE]
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Table 3 presents the quality of the studies’ reporting of the intervention, as assessed
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using item 4 of the elaborated CONSORT checklist for reporting randomized
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controlled trials of herbal medicine interventions (Gagnier et al., 2006). Of the 18
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studies evaluated, none of the published articles met all the recommended reporting criteria outlined in the checklist. As can be seen from Table 3, all 18 articles provided
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information on the dosage and duration of the intervention and details of the practitioners and the majority of the articles reported the brand name and type of
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product used. The main CONSORT criteria that were missing from the articles included license registration details, which none of the article reported (many of the articles did provide details of the manufacturer and country of manufacture), type
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and concentration of extraction solvent and the content of quantified chemical constituents. From 10 criteria assessed, 10 trials (Isaacsohn et al., 1998; Superko and Krauss, 2000; Williams et al., 2005; van Doorn et al., 2006; Sobenin et al., 2008; Sobenin et al., 2009; Sobenin et al., 2010; Gomez-Arbelaez et al., 2013; Ried et al., 2013; Atkin et al., 2016) met 5 of these criteria and 5 trials (McCrindle et al., 1998;
pg. 8
Gardner et al., 2001; Sobenin et al., 2008; Ried et al., 2010; Ried et al., 2016) met 6 of these criteria. Overall, the trial reporting was found to be of medium quality. Adverse effects were reported in 10 studies and are detailed in Table 1 (Isaacsohn et al., 1998; McCrindle et al., 1998; Gardner et al., 2001; van Doorn et al., 2006; Gardner et al., 2007; Sobenin et al., 2009; Ried et al., 2010; Ried et al.,
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2013; Atkin et al., 2016; Ried et al., 2016). Commonly reported adverse effects
included mild gastrointestinal discomfort (abdominal discomfort, belching, flatulence,
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reflux and upset stomach), changes in body odor and garlic breath or taste. Adverse effects which were reported less often included hypersensitivity, headache, dry
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mouth, cough, hot flushes, mouth ulcers and somnolence. No trials reported the use
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of garlic supplements during pregnancy and lactation. The trial that studied the use
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of garlic in individuals younger than 18 years old reported no significant adverse
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trials included in this review.
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effects (McCrindle, et al. 1998). No drug interactions were reported in any of the
[INSERT TABLE 3 HERE]
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Table 4 presents the results of the risk of bias analysis based on the Cochrane Risk of Bias Tool (Higgins and Green, 2011). The majority of the trials had either an
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unclear or low risk of bias for each bias type. The overall risk of bias was low. [INSERT TABLE 4 HERE]
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4. Discussion
The principal finding from this systematic review was the identification of moderate quality evidence to suggest that standardized aged garlic extracts containing 1.2 – 2.4 mg s-allyl cysteine or 600 - 2400 mg garlic powder per day are likely to be effective as an adjunct therapy to the standard treatment of hypertension in patient pg. 9
populations with SBP > 140 mmHg. There was also low quality evidence found to suggest that 300 - 600 mg per day of coated garlic powder is possibly effective in populations with a TC > 6.0 mmol/L and LDL-C > 3.0 mmol/L. There is unclear and conflicting evidence supporting other garlic formulations and doses due, in part, to the lack of details reported and poor study designs.
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This review is distinct from other recent reviews on garlic and hypertension
(Stabler et al., 2012; Kwak et al., 2014; Ried, 2016) in its utilization of item 4 of the
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elaborated CONSORT checklist for randomized controlled trials in herbal medicines (Gagnier et al., 2006) and its restriction of inclusion criteria to double-blind
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randomized controlled trials. In addition, this current review took into consideration
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confounding factors such as tobacco use, poor diet and genetic predisposition
A
(Mendis et al., 2011) when evaluating the trial designs.
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The challenges with evaluating interventions for hypertension were also
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considered in the present review, such as the significant variability of blood pressure over a 24-hour period (Parati et al., 1987). Studies that reported a clinically and
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statistically significant reduction in blood pressure, monitored blood pressure with multiple measurements over 24-hour periods (Sobenin et al., 2009; Ried et al., 2010;
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Ried et al., 2013; Ried et al., 2016). In 3 of these studies (Ried et al., 2010; Ried et al., 2013; Ried et al., 2016), measurement reliability was further improved by monitoring blood pressure using a calibrated and validated digital
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sphygmomanometer. In addition, they considered the consumption of food and caffeinated beverages before blood pressure measurement (Ried et al., 2010; Ried et al., 2013; Ried et al., 2016).
pg. 10
As presented in table 3, consistent limitations were found across all studies included in the present review that relate to the incomplete or lack of reporting of the parts of the plant used, authentication of raw materials and qualitative testing. This may be in part due to preclinical studies of the same herbal preparation cited within studies having previously reported these details.
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The exclusion of multiple ingredient nutraceuticals was considered necessary to improve the homogeneity of the garlic preparations evaluated in this review.
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However, this could be considered a limitation by advocates of synergistic
formulations that include a number of herbs and nutrients with potential hypotensive
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or hypolipdemic effects.
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Prior studies reviewing trials that have evaluated the effects of garlic in the
A
management of hypertension and dyslipidemia have drawn similar conclusions to
M
those of the present study (Stabler et al., 2012; Kwak et al., 2014; Ried, 2016).
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However, this review has identified a more specific finding related to the formulation and dose used for aged garlic extract preparations. In regard to the lipid-lowering
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effect of garlic, the conclusion differs from previous reviews which report stronger positive findings (Kwak et al., 2014; Ried, 2016). This difference likely relates to
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differences in inclusion criteria (Linde and Willich, 2003) and variations in the methodological quality and reporting of double-blind randomized clinical trials
A
(Gagnier et al., 2006). Future studies are encouraged to consider the specific formulations used in
order to gain a better understanding of the bioavailability of known active constituents and how these relate to clinical outcomes. Garlic powder, produced by slicing and crushing garlic cloves, followed by drying and pulverizing into powder
pg. 11
(Amagase et al., 2001), was the most common preparation used in the studies included in this review. This preparation is able to maintain many of the same constituents as raw garlic (Amagase et al., 2001). Garlic powder does not contain allicin; allicin is formed by enzymatic conversion of alliin by alliinase (Lawson et al., 2001). Since alliinase is inhibited by gastric pH, enteric coated formulations are
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preferred (Lawson and Hughes, 1992). The nature of coating of the tablets is,
therefore, a factor that may have impacted on the findings reported (Lawson et al.,
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2001). Two trials which studied the anti-lipidemic effect of garlic used the propriety garlic powder AllicorTM (INAT-Farma), reported that this garlic formulation had
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modified release characteristics that were associated with the positive outcomes of
N
the trials (Sobenin et al., 2008; Sobenin et al., 2010).
A
Aged garlic extracts were employed in a number of studies included in this
M
review. Aged garlic extracts were prepared by soaking garlic gloves into extracting solution for up to 20 months (Amagase et al., 2001). This preparation enables the
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enzymatic formation of s-allyl cysteine from γ-glutamyl-s-allyl-L-cysteines (Amagase et al., 2001). Unlike alliin or allicin, s-allyl cysteine is more stable and can be finely
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standardized (Amagase, 2006). Future studies are also encouraged to investigate
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and report on any drug interactions between garlic preparations and conventional medications.
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Conclusion
This review identified moderate quality evidence to suggest that standardised aged garlic extracts are likely to be effective as an adjunct therapy to the standard treatment of hypertension in patient populations with SBP > 140 mmHg. The quality of evidence for the role of garlic in the management of dyslipidaemia is currently low.
pg. 12
To improve the quality of research on this topic, we recommend that item 4 of the CONSORT checklist is referred to during study design and used to guide the reporting of the herbal intervention. Should these findings be supported by high quality, larger studies of longer duration, specific standardised formulations of garlic could play a promising new role in the management of hypertension and
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hyperlipidaemia.
Conflict of Interest
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There is no conflict of interest or disclosure.
pg. 13
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Amagase, H., Petesch, B.L., Matsuura, H., Kasuga S., Itakura, Y., 2001. Intake of
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Braun, L., Cohen M., 2015. Herbs and Natural Supplements, Volume 2: An Evidence-Based Guide, fourth ed. Elsevier, Sydney.
Budoff, M.J., Takasu, J., Flores, F.R., Niihara, Y., Lu, B., Lau, BH., Rosen R.T.,
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Amagase, H., 2004. Inhibiting progression of coronary calcification using Aged Garlic Extract in patients receiving statin therapy: A preliminary study. Prev Med. 39, 985-991.
pg. 14
Ferri, N., Yokoyama, K., Sadilek, M., Paoletti, R., Apitz-Castro, R., Gelb, M.H., Corsini A., 2003. Ajoene, a garlic compound, inhibits protein prenylation and arterial smooth muscle cell proliferation. Br J Pharmacol. 138, 811-818. Gagnier, J.J., Boon, H., Rochon, P., Moher, D., Barnes, J., Bombardier C., 2006.
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Gardner, C.D., Lawson, L.D., Block, E., Chatterjee, L.M., Kiazand, A., Balise, R.R.,
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Kraemer, H.C., 2007. Effect of raw garlic vs commercial garlic supplements
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Rodriguez, Y., Garcia, R.G., Camacho, P.A., Lopez-Jaramillo, P., 2013. Aged garlic extract improves adiponectin levels in subjects with metabolic syndrome: a double-blind, placebo-controlled, randomized, crossover study. Mediators Inflamm. 2013, 285795.
pg. 15
Higgins, J.P.T., Green, S., 2011. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 The Cochrane Collaboration. Isaacsohn, J.L., Moser, M., Stein, E.A., Dudley, K., Davey, J.A., Liskov, E., Black H.R., 1998. Garlic powder and plasma lipids and lipoproteins: a multicenter, randomized, placebo-controlled trial. Arch Intern Med. 158, 1189-1194.
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Jung, E.S., Park, S.H., Choi, E.K., Ryu, B.H., Park, B.H., Kim, D.S., Kim, Y.G., Chae, S.W., 2014. Reduction of blood lipid parameters by a 12-wk supplementation
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of aged black garlic: A randomized controlled trial. Nutrition. 30, 1034-1039. Knopfholz, J., Disserol, C.C., Pierin, A.J., Schirr, F.L., Streisky, L., Takito, L.L.,
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Massucheto Ledesma P., Faria-Neto, J.R., Olandoski, M., da Cunha, C.L.,
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Bandeira, A.M., 2014. Validation of the friedewald formula in patients with
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metabolic syndrome. Cholesterol. 2014, 261878.
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Kwak, J.S., Kim, J.Y., Paek, J.E., Lee, Y.J., Kim, H.R., Park, D,S., Kwon, O., 2014. Garlic powder intake and cardiovascular risk factors: A meta-analysis of
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randomized controlled clinical trials. Nutr Res Pract. 8, 644-654. Lawson, L.D., Hughes, B.G., 1992. Characterization of the formation of allicin and
PT
other thiosulfinates from garlic. Planta Med. 58, 345-350. Lawson, L.D., Wang, Z.J., Papadimitriou, D., 2001. Allicin release under simulated
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gastrointestinal conditions from garlic powder tablets employed in clinical trials on serum cholesterol. Planta Med. 67, 13-18.
A
Linde, K., Willich, S.N., 2003. How objective are systematic reviews? Differences between reviews on complementary medicine. J R Soc Med. 96, 17-22.
McCrindle, B.W., Helden, E., Conner, W.T., 1998. Garlic extract therapy in children with hypercholesterolemia. Arch Pediatr Adolesc Med. 152, 1089-1094.
pg. 16
Mendis, S., Puska, P., Norrving, B., 2011. Global atlas on cardiovascular disease prevention and control, World Health Organization, Geneva. Parati, G., Pomidossi, G., Albini, F., Malaspina, D., Mancia, G., 1987. Relationship of 24-hour blood pressure mean and variability to severity of target-organ damage in hypertension. J Hypertens. 5, 93-98.
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Posadzki, P., Watson, L.K., Alotaibi, A., Ernst, E., 2013. Prevalence of herbal
medicine use by UK patients/ consumers: a systematic review of surveys. Clin
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Med (London). 13, 126-31
Reinert, A., Rohrmann, S., Becker, N., Linseisen, J., 2007. Lifestyle and diet in peopl
U
using dietary supplements: a German cohort study. Eur J Nutr. 46, 165-73.
N
Ried, K. 2016. Garlic lowers blood pressure in hypertensive individuals, regulates
M
review. J Nutr. 146, 389S-396S.
A
serum cholesterol, and stimulates immunity: An updated meta-analysis and
Ried, K., Frank, O.R., Stocks, N.P., 2010. Aged garlic extract lowers blood pressure
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in patients with treated but uncontrolled hypertension: a randomised controlled trial. Maturitas. 67, 144-150.
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Ried, K., Frank, O.R., Stocks, N.P., 2013. Aged garlic extract reduces blood pressure in hypertensives: a dose-response trial. Eur J Clin Nutr. 67, 64-70.
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Ried, K.,Travica, N., Sali, A., 2016. The effect of aged garlic extract on blood pressure and other cardiovascular risk factors in uncontrolled hypertensives:
A
The AGE at Heart trial. Integr Blood Pressure Control. 9, 9-21.
Shouk, R., Abdou, A., Shetty, K., Sarkar, D., Eid, A.H., 2014. Mechanisms underlying the antihypertensive effects of garlic bioactives. Nutr Res. 34, 106115.
pg. 17
Sobenin, I.A., Andrianova, I.V., Demidova, O.N., Gorchakova, T.V., Orekhov, A.N., 2008. Lipid-lowering effects of time-released garlic powder tablets in doubleblinded placebo-controlled randomized study. J Atheroscler Thrombo. 15, 334-338. Sobenin, I.A., Andrianova, I.V., Fomchenkov, I.V., Gorchakova, T.V., Orekhov, A.N.,
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2009. Time-released garlic powder tablets lower systolic and diastolic blood
pressure in men with mild and moderate arterial hypertension. Hypertens Res.
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32, 433-437.
Sobenin, I.A., Nedosugova, L.V., Filatova, L.V., Balabolkin, M.I., Gorchakova, T.V.,
U
Orekhov, A.N., 2008. Metabolic effects of time-released garlic powder tablets
A
study. Acta Diabetologica. 45, 1-6.
N
in type 2 diabetes mellitus: the results of double-blinded placebo-controlled
M
Sobenin, I.A., Pryanishnikov, V.V., Kunnova, L.M., Rabinovich, Y.A., Martirosyan, D.M., Orekhov, A.N., 2010. The effects of time-released garlic powder tablets
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on multifunctional cardiovascular risk in patients with coronary artery disease. Lipids Health Dis. 9, 119.
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Stabler, S.N., Tejani, A.M., Huynh, F., Fowkes, C., 2012. Garlic for the prevention of cardiovascular morbidity and mortality in hypertensive patients. Cochrane
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Database Syst Rev. 8, Cd007653.
Superko, H.R., Krauss, R.M., 2000. Garlic powder, effect on plasma lipids,
A
postprandial lipemia, low-density lipoprotein particle size, high-density lipoprotein subclass distribution and lipoprotein(a). J Am Coll Cardiol 35, 321326.
Van Doorn, M.B., Espirito Santo, S.M., Meijer, P., Kamerling, I.M., Schoemaker, R.C., Dirsch, V., Vollmar, A., Haffner, T., Gebhardt, R., Cohen, A.F., Princen,
pg. 18
H.M., Burggraaf. J., 2006. Effect of garlic powder on C-reactive protein and plasma lipids in overweight and smoking subjects. Am J Clin Nutr. 84, 13241329. Williams, M.J., Sutherland, W.H., McCormick, M.P., Yeoman, D.J., de Jong, S.A., 2005. Aged garlic extract improves endothelial function in men with coronary
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artery disease. Phytother Res 19, 314-319.
Xiong, X.J., Wang, P.Q., Li, S.J., Li, X.K., Zhang, Y.Q., Wang, J., 2015. Garlic for
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M
A
N
U
controlled trials. Phytomedicine. 22, 352-361.
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hypertension: A systematic review and meta-analysis of randomized
pg. 19
IP T SC R U N A M ED
A
CC E
PT
Figure 1. Literature Search Method
pg. 20
I N U SC R
DB-RCTcrossover; (n = 26)
GomezArbelaez D et al (2013); Colombia
DB-RCTcrossover (n = 43)
CC E A
Isaacsohn JL et al (1998); USA
McCrindle BW et al (1998); Canada
pg. 21
AGE; 1200 mg/day; Kyolic; 12 wks
DB-RCT; Garlic (n = 28); Placebo (n = 22)
GP; 900mg/d; Kwai; 12 wks
mean age = 57.5; M = 27; F = 23; mean BMI = 26.5
GP; 900 mg/d; Kwai; 8 wks
mean age = 14.0; age range = 818; M = 16; F = 14; mean BMI = 21.85
DB-RCT; Garlic (n = 15); Placebo (n = 15)
(-)
Average Baseline BP of BP Treatmen Change t Group s in Tx (SD) Group (mmHg) (mmHg) SBP = 130.3 SBP = (14.0); +0.5; DBP = DBP = 74.7 (7.5) 0.8 SBP = SBP = 123.73 2.59 (15.63); (1.91)*; DBP = DBP = 81.59 1.07 (10.86) (1.32)*
(-)
SBP = 119.3 (15.2); DBP = 73.2 (9.6)
Concurrent Anti-HT and/or lipidlowering Medication
M
Atkin M et al (2016); UK (
Study Population T2 DM; Mean age = 49.8; M = 19; F = 7; Mean BMI = 32; metabolic syndrome; mean age = 40.79; mean BMI = 33.07
ED
Study Design
Form; Dose; Brand; Duration AGE; 1200 mg/d; Kyolic; 4 wks
PT
Author (Year); Geographi cal Location
A
Table 1 Characteristics of studies – Garlic and Hypertension
(+)
(-)
SBP = 102 (9); DBP = 63 (10)
SBP = +2.2 (12.4); DBP = +1.1 (7.9) SBP = +2.1% (-7.1 to 11.3)#; DBP = 0% (-6.5 to + 6.5) #
Statistical Significanc e Between Tx vs Placebo
Adverse Reaction Reported
SBP (ns); DBP (ns)
indigestio n
SBP (ns); DBP (ns)
no serious side effects garlic breathe; change in body odour; abdomina l discomfor t
SBP (ns); DBP (ns)
unpleasa nt body odour; headache ; upset stomach
SBP (ns); DBP (ns)
Diet §
Smoke r§
Famil y Hx§
(-)
(+)
(-)
(+)
(-)
(-)
(+)
(+)
(-)
(+)
(+)
(+)
I N U SC R M
uncontrolled HT; mean age = 66; mean BMI = 30.1; M = 17; F= 8
ED
AGE; 960 mg/d; Kyolic; 12 wks
(+)
A
CC E
PT
Ried K et al (2010); Australia
DB-RCT; Garlic (n = 25); Placebo (n = 25)
A
overall SBP = 1.9; DBP = +1.5
Ried K et al (2013); Australia
pg. 22
DB-RCT; 240 mg/d (n = 21); 480 mg/d (n = 20); 960 mg/d (n = 19); Placebo (n = 19)
AGE; 240 mg/d; 480 mg/d; 960 mg/d; Kyolic; 12 wks
uncontrolled HT; mean age = 69.8; M = 42; F = 37; mean BMI = 29.3;
(+)
overall SBP (ns); DBP (ns);
sub-group baseline SBP = SBP ≥ sub-group 135.4 140 baseline SBP (14.1); mmHg ≥ 140 DBP = SBP = mmHg SBP 74.0 15.2; (ss); (10.3) DBP = (-) DBP (ns) 240 mg/d 240 mg/d SBP = SBP = 9.8 (4.0) @; 148.7 (2.8)@; DBP = DBP = 6.9 (1.9) @; 76.9 (2.9) 240mg/d @; SBP (ns); 480 mg/d DBP (ns) 480 mg/d SBP = SBP = 149.3 22.5 (3.7) @; (2.6) @; DBP DBP =480 mg/d =75.6 9.0 (1.8) SBP (ss); @; (2.8) @; DBP (ns); 960mg/d SBP = 149.4 (2.7) @; DBP = 75.9 (2.8)
960 mg/d SBP = 17.1 (3.9) @; DBP = 6.4 (1.9)
@
@
960mg/d SBP (ns); DBP (ns)
Gl discomfor t; belching; reflux; taste sensation
(-)
(+)
(+)
GI side effects; constipati on; bloating; flatulence ; reflux; garlic taste; dry mouth; cough
(-)
(+)
(+)
I N U SC R
AGE; 1200 mg/d; Kyolic; 12 wks
uncontrolled HT; mean age = 62.3; mean BMI = 27.7; M = 47; F = 41;
Sobenin IA et al (2008); Russia
DB-RCT; Garlic (n = 23); Placebo (n = 19)
GP; 600mg/d; Allicor; 12 wks
male; mean age = 51.7; mean BMI = 26.8
(+)
(-)
PT
ED
M
A
Ried K et al (2016); Australia
DB-RCT; Garlic (n = 50); Placebo (n = 38)
pg. 23
GP; Allicor 600 mg/d or Allicor 2400 mg/d or Kwai 900 mg/d; 8 wks
SBP = 143.4 (1.5)*; DBP = 88.8 (0.9)* 600 mg/d Allicor SBP = 158.0 (2.8)*; DBP= 97.0 (1.0)*; 2400 mg/d Allicor SBP =154.0 (3.4)*; DBP= 95.0 (0.6)*;
CC E A Sobenin IA et al (2009); Russia
DB-RCT; 600mg/d Allicor (n = 30); 2400mg/d Allicor (n = 18); Kwai (n = 16); Placebo (n = 20)
SBP= 148.7 (15.3); DBP = 89.9 (11.7)
mild and moderate arterial hypertension; male; age range = 3570
(-)
900 mg/d Kwai SBP=156. 9 (2.8)*; DBP = 97.5 (1.0)*
SBP = -8 (10.6); DBP = 3.7 (5.9)
SBP = 6.6; DBP = -5 600mg/d Allicor SBP = 7.0 (0.8)*; DBP= 3.8 (0.5)*; 2400mg/ d Allicor SBP = 9.3 (0.7)*; DBP= 3.2 (0.5)*; 900 mg/d Kwai SBP = 5.4 (1.6)*; DBP = 1.0 (1.2)*
SBP (ss); DBP (ns)
Reflux; garlic taste; hot flushes;
(-)
(+)
(+)
(-)
No side effects during study period
(+)
(+)
(+)
Allicor 2400mg/d and 900mg/d Kwai both reported GI complaint s
(+)
(+)
(+)
600 mg/d Allicor SBP (ss); DBP (ss);
2400 mg/d Allicor SBP (ss); DBP (ss);
900mg/d Kwai SBP (ss); DBP (ns)
I DB-RCTcrossover; (n = 15)
AGE; 2400 mg/d; Kyolic; 2 wks
N U SC R
Williams et al (2005); New Zealand
CAD male; mean age = 59; mean BMI = 28
(+)
SBP = 132 (22); DBP = 82 (11)
SBP = 6; DBP = -3
SBP (ns); DBP (ns)
(-)
(+)
(+)
(-)
A
CC E
PT
ED
M
A
ACEI = angiotensin converting enzyme inhibitor; AGE = aged garlic extract; Anti-DM = antidiabetic; Anti-HT = antihypertensive; CAD = coronary artery disease; CCB = calcium channel blocker; CHD = coronary heart disease; DBP = diastolic blood pressure; DB-RCT = doubleblind randomised controlled trials; Dx = diagnosis; GI = gastrointestinal; GP = garlic powder; HT = hypertension; Hx = history; mon = months; SBP = systolic blood pressure; SD = standard deviation; Tx = treatment; T2 DM = type II Diabetes mellitus; wks = weeks; (+) = present; (-) = no information available or not done; (ns) = not statistically significant; (ss) = statistically significant; * Data presented as mean (standard error of mean) # Data presented as mean % change (95% confidence interval) @ Data presented as mean (standard error) § Factors considered/controlled for
pg. 24
I N U SC R
Table 2 Characteristics of studies – Garlic and Dyslipidaemia
DB-RCTcross-over; (n = 26)
Budoff MJ et al (2004); USA
DB-RCT; Garlic (n = 9); Placebo (n = 10)
M
Atkin M et al (2016); UK
AGE; 1200 mg/d; Kyolic; 4 wks
Study Population T2 DM; Mean age = 49.8; M = 19; F = 7; Mean BMI = 32;
PT
ED
Study Design
Form; Dose; Brand; Duration
AGE; 1200 mg/d; Kyolic; 1 yr
CHD or high risk for CAD; mean age = 59.9; M = 13; F = 9
HT and/or lipidlowering Medicati on
(+)
(+)
A
CC E
Author (Year); Geographica l Location
A
Concurre nt Anti-
Gardner CD et al (2001); USA
pg. 25
DB-RCT; Half-dose (n = 17); Full-dose (n = 16); Placebo (n = 18)
GP; 500 or 1000 mg/d; unspecifi ed brand; 12 wks
non-DM; no heart disease; mean age = 51.7; mean BMI = 26.1
(-)
Average Baseline Lipid Profile for Tx Group (SD) (mmol/L)
TC = 4.2 (0.9); LDL = 2.5; HDL = 1.0 (0.3); TG = 1.4 (IQR 0.7) TC = 4.55 (0.96); LDL = 2.61 (0.83); HDL = 1.33 (0.41); TG = 1.59 (1.27) Half-dose TC = 5.97 (0.54); LDL = 3.90 (0.47); HDL = 1.40 (0.47); TG = 1.41 (0.71); Full-dose TC = 6.08 (0.7); LDL = 4.22 (0.47);
Lipid Profile Changes in Tx Group vs Baseline Mean (SD) (mmol/L)
TC = 0.0; LDL = +0.1; HDL = 0.0; TG = 0.0 TC= +0.18 (0.56); LDL= -0.08 (0.42); HDL = +0.08 (0.27); TG= +0.09 (0.448)
Statistical Significan ce Between Tx vs Placebo
Adverse Reaction Reported
TC (ns); HDL (ns); TG (ns)
§
Smoke r§
Famil y Hx§
indigestio n
(-)
(+)
(-)
TC (ns); LDL (ns); HDL (ns); TG (ns)
(-)
(+)
(+)
(+)
TC (ns); LDL (ns); HDL (ns); TG (ns)
belching; body odour; stomach gas; flatulence ; constipati on
(+)
(+)
(-)
Half-dose TC = +0.08; LDL = +0.05; HDL = +0.05; TG = -0.03; Full-dose TC = -0.26; LDL = -0.26; HDL = +0.08; TG = -0.08
Diet
I N U SC R ED
M
A
HDL = 1.19 (0.31); TG = 1.42 (0.63) Raw Garlic LDL = 3.67 (0.57); HDL = 1.42 (0.34); TG = 1.12 (0.54);
non-DM; no heart disease; mean age = 49.8; M = 96; F = 96; mean BMI = 25.3
A GomezArbelaez D et al (2013); Colombia
DB-RCTcross-over (n = 43)
AGE; 1200 mg/day; Kyolic;
metabolic syndrome; mean age = 40.79;
pg. 26
Garlicin LDL = 3.47 (0.49); HDL = 1.37 (0.28); TG = 1.38 (0.62);
PT DB-RCT; Raw Garlic (n = 49); Garlicin (n = 47); Kyolic (n = 48); Placebo (n = 48)
CC E
Gardner CD et al (2007); USA
raw garlic or GP or AGE; raw garlic 4000 mg/d; GP 1400 mg/d; AGE 1800 mg/d; raw garlic or Garlicin or Kyolic; all consume d6 days/wk; 6 mon
Kyolic LDL = 3.52 (0.52); HDL = 1.32 (0.23); TG = 1.42 (0.61) (-)
(-)
TC = 5.14 (0.80); LDL = 3.02 (0.73);
Raw Garlic LDL = +0.01 (-0.14 to 0.17)*; HDL = +0.06 (0.01 to 0.1)*; TG = -0.06 (-0.16 to 0.05)*; Garlicin LDL = +0.08 (-0.05 to 0.22)*; HDL = +0.03 (-0.01 to 0.06)*; TG = -0.07 (-0.22 to 0.08)*; Kyolic LDL = +0.005 (-0.14 to 0.15)*; HDL = -0.008 (-0.04 to 0.026)*; TG = -0.02 (-0.21 to 0.16)* TC = -0.11 (0.12) #; LDL = +0.10 (0.14) #;
LDL (ns); HDL (ns); TG (ns)
rash, heartburn , mouth ulcers, body and breath odour, flatulence
(+)
(+)
(-)
TC (ns); LDL (ns); HDL (ns); TG (ns)
no serious side effects
(+)
(-)
(-)
McCrindle BW et al (1998); Canada
GP; 900 mg/d; Kwai; 8 wks
Ried K et al (2016); Australia
DB-RCT; Garlic (n = 50); Placebo (n = 38)
AGE; 1200 mg/d; Kyolic; 12 wks
A
N U SC R
I AGE; 6000 mg/d; original formula; 12 wks
DB-RCT; Garlic (n = 15); Placebo (n = 15)
pg. 27
A
GP; 900mg/d; Kwai; 12 wks
HDL = 0.97 (0.15); TG = 2.49 (0.81)
mean age = 57.5; M = 27; F = 23; mean BMI = 26.5
(-)
ED
DB-RCT; Garlic (n = 28); Placebo (n = 27)
CC E
Jung ES et al (2014); Korea
DB-RCT; Garlic (n = 28); Placebo (n = 22)
PT
Isaacsohn JL et al (1998); USA
mean BMI = 33.07
M
12 wks
no history of CVD; mean age = 50.48; M = 20; F = 40; Mean BMI = 24.5
mean age = 14.0; M = 16; F = 14; mean BMI = 21.85 uncontrolled HT; mean age = 62.3; mean BMI = 27.7; M = 47; F = 41;
(-)
(-)
(+)
HDL = -0.04 (0.02) #; TG = -0.21 (0.14) #
TC = +1.64% (6.8) ¶; LDL = +1.82% (7.5) ¶; TC = 7.1 (0.9); HDL = +2.90% LDL = 4.9 (0.8); (10.8) ¶; HDL = 1.3 (0.3); TG = +0.38% TG = 1.9 (0.8) (26.3) ¶ TC = 6.23 (0.62); LDL = 3.90 (0.37); HDL = 1.21 TC= -0.2; (0.24); LDL= +0.13; TG = 1.58 HDL = +0.09; (0.62) TG= -0.221 TC = +0.1% (-0.29 to + 0.49) &; TC = 7.06 (1.61); LDL = +0.04% LDL = 5.59 (-0.35 to +0.43) &; (1.52); HDL = +0.03% HDL = 0.95 (-0.11 to + 0.17) &; (0.25); TG = 1.14 TG = -0.18% (0.38) (-0.66 to +0.30) &
TC = 5.5 (1.3); LDL = 0.8 (1.1); HDL = 1.7 (0.6); TG = 1.2 (0.6)
TC = -0.01 (0.75); LDL = -0.12 (0.7); HDL = -0.02 (0.27);
(-)
garlic breath; change in body odour; abdomina l discomfor t
(+)
(+)
(-)
TC (ns); LDL (ns); HDL (ns); TG (ns)
no moderate or serious adverse events
(+)
(-)
(-)
TC (ns); LDL (ns); HDL (ns); TG (ns)
unpleasa nt body odour; headache , upset stomach
(+)
(+)
(+)
TC (ns); LDL (ns); HDL (ns); TG (ns)
Reflux; garlic taste; hot flushes;
(-)
(+)
(+)
I N U SC R A
Sobenin IA et al (2008); Russia
Sobenin IA et al (2010); Russia
pg. 28
ED
PT
GP; 600 mg/d; Allicor; 4 wks
T2 DM; mean age = 48.2; M = 26; F = 34
DB-RCT; Garlic (n = 23); Placebo (n = 19)
GP; 600mg/d; Allicor; 12 wks
male; mean age = 51.7; mean BMI = 26.8
DB-RCT; Garlic (n = 26); Placebo (n = 25)
GP; 300 mg/d; Allicor; 12 mon
CHD; TC > 5.2mmol/L; mean age = 56.5; M = 28; F = 23;
CC E
Sobenin IA et al (2008); Russia
DB-RCT; Monotherapy: Garlic (n = 10); Placebo (n = 10); Combined Tx with sulfonylure a: Garlic (n = 20); Placebo (n = 20)
M
A
Monotherapy TC = 6.42 (0.18); LDL = 3.86 (0.21); HDL = 1.27 (0.11); TG = 2.96 (0.51);
(+)
(-)
(-)
Combined Tx TC = 6.81 (0.26); LDL = 4.19 (0.27); HDL = 1.3 (0.11); TG = 3.03 (0.31) TC = 6.97 (0.20) #; LDL = 5.00 (0.17) #; HDL = 1.06 (0.07) #; TG = 2.00 (0.26) #
TC = 6.96 (0.30); LDL = 4.81 (0.24);
TG = +0.15 (0.45)
Monotherapy TC = -0.19; LDL = +0.26; HDL = +0.01; TG = -1.06; Combined Tx TC = -0.29; LDL = +0.07; HDL = -0.02; TG = -0.78 TC = -7.6% (2.4)$; LDL = -11.8% (4.5) $; HDL = +11.5% (3.8) $; TG = -7.7% (9.0) $
TC = -0.87; LDL = -0.78; HDL = +0.02; TG= = -0.22
(-)
(-)
(+)
(-)
(-)
TC (ss); LDL (ss); HDL (ns); TG (ns)
no side effects during study period
(+)
(+)
(+)
TC (ns); LDL (ss); HDL (ns); TG (ns)
(-)
(-)
(+)
(+)
I N U SC R HDL = 1.32 (0.09); TG = 1.83 (0.22)
A
Williams et al (2005); New Zealand
GP; 2100 mg/d; Original formula; 12 wks
DB-RCTcross-over; (n = 15)
AGE; 2400 mg/d; Kyolic; 2 wks
(-)
TC = 5.47 (4.08 to 7.72) @; LDL = 3.37 (2.06 to 5.64) @; HDL = 1.27 (0.64 to 1.87) @; TG = 1.56 (0.83 to 6.11) @
TC = +0.12; LDL = 0.00; HDL = -0.08; TG = +0.08
TC (ns); LDL (ns); TG (ns)
abdomina l discomfor t; severe garlic odour
(+)
TC = 4.3 (0.9); LDL = 2.50 (0.76); HDL = 1.20 (0.35); TG = 1.2 (0.4)
TC = 0; LDL = +0.05; HDL = +0.01; TG= +0.1
TC (ns); LDL (ns); HDL (ns); TG (ns)
(-)
A (-)
M
GP; 900 mg/d; Kwai; 12 wks
mean age = 53; mean weight = 73.9
ED
DB-RCT; Garlic (n = 28); Atorvastati n (n = 30); Placebo (n = 26)
CC E
Van Doorn MBA et al (2006); Netherland
DB-RCT; Garlic (n = 25); Placebo (n = 25)
PT
Superko HR et al (2000); USA
TC = 6.46 (0.75); LDL = 4.37 (0.65); HDL = 1.33 (0.30); TG = 1.64 (0.61)
mean age = 48.1; M = 38; F = 46; BMI > 24.5; mean BMI = 29.5
CAD male; mean age = 59; mean BMI = 28
TC = -0.06 (0.68); LDL = -0.04 (0.66); HDL = -0.003 (0.17); TG = -0.05 (0.49)
TC (ns); LDL (ns); HDL (ns); TG (ns)
(-)
(+)
(-)
(+)
(-)
(+)
(-)
(+)
(+)
(-)
ACEI = angiotensin converting enzyme inhibitor; AGE = aged garlic extract; Anti-DM = antidiabetic; Anti-HT = antihypertensive; CAD = coronary artery disease; CCB = calcium channel blocker; CHD = coronary heart disease; DB-RCT = double-blind randomised controlled trials; Dx = diagnosis; GP = garlic powder; HDL = high density lipoprotein; HRT = hormone replacement therapy; HT = hypertension; Hx = history; LDL = low density lipoprotein; mon = months; NSAIDs = nonsteroidal anti-inflammatory drugs; SD = standard deviation; TC = total cholesterol; TG = triglycerides; T2 DM = type II Diabetes mellitus; Tx = treatment; wks = weeks; (+) = present; (-) = no information available or not done; (ns) = not statistically significant; (ss) = statistically significant; * Data were presented as mean (95% confidence interval) & Data were presented as mean % change (95% confidence interval) ¶ Data were presented as mean % change (SD)
pg. 29
I N U SC R
#
Data were presented as mean (Standard error of mean) were presented as mean % change (Standard error of mean) @ Data presented as median (Range) § Factors considered/controlled for
A
CC E
PT
ED
M
A
$ Data
pg. 30
I N U SC R
Table 3 Fulfilment of Item 4 of the Elaborated Consolidated Standards of Reporting Trials Checklist Herbal medicinal product name
Characteristics of the herbal product
Dosage regimen and quantitative description
a
b
c
d
g
h
i
j
Atkin M et al 2016
(0)
(+)
(0)
(+)
(0)
(+)
(+)
(0)
(0)
(0)
(0)
(+)
Budoff MJ et al 2004
(0)
(+)
(0)#
(+)
(0)
(0)
(0)
(+)
(0)
(0)
(0)
(0)
(+)
Gardner CD et al 2001
(0)
(0)
(+)
(0)
(0)
(0)
(+)
(+)
(+)
(0)
(+)
(+)
(+)
A
Jung MS et al 2014 McCrindle BW et al 1998
Ried K et al 2010
pg. 31
A
M
ED
f (0)
Placebo/ control
Practitioner
k
(+)
(0)#
(+)
(0)
(0)
(0)
(+)
(0)
(+)@
(0)
(+)
(+)
(+)
(+)
(0)
(+)
(0)
(0)
(0)
(+)
(0)
(0)
(0)
(0)
(+)
(0)
(+)
(0)#
(+)
(0)
(0)
(+)
(+)
(0)
(0)$
(0)
(+)¶
(+)
(+)
(0)*
(0)#
(+)
(0)
(0)
(+)
(+)
(+)
(+)
(0)
(+)
(+)
(+)
(+)
(0)
(0)
(0)
(0)
(0)
(+)
(0)
(+)
(0)
(+)
(+)
(0)
(0)
(0)
(+)
(0)#
(+)
(0)
(+)
(0)
(+)
(0)
(+)
(+)
CC E
Gardner CD et al 2007 GomezArbelaez et al 2013 Isaacsohn JL et al 1998
(0)
e
Qualitative testing
PT
Study
(+)
(0)#
(+)
Ried K et al 2016
(0)
(+)
(0)#
(+)
Sobenin IA et al 2008
(+)
(+)
(0)#
(+)
Sobenin IA et al 2008
(+)
(+)
(0)#
Sobenin IA et al 2009
(+)
(+)
Sobenin IA et al 2010
(+)
PT
I (0)
CC E
Superko HR et al 2000 (+)
N U SC R
Ried K et al 2013
(0)
(0)
(+)
(0)
(+)
(0)
(+)¶
(+)
(0)
(0)
(0)
(+)
(0)
(+)
(0)
(+)
(+)
(0)
(0)
(0)
(+)
(0)
(0)
(0)
(+)¶
(+)
(+)
(0)
(0)
(0)
(+)
(0)
(+)
(0)
(+)¶
(+)
(0)#
(+)
(0)
(0)
(0)
(+)
(0)
(0)
(0)
(+)¶
(+)
(+)
(0)#
(+)
(0)
(0)
(0)
(+)
(0)
(0)
(0)
(+)¶
(+)
(+)
(0)#
(+)
(0)
(0)
(0)
(+)
(0)
(0)&
(0)
(0)
(+)
ED
M
A
(0)
(0)
(0)*
(0)#
(+)
(0)
(0)
(+)
(+)
(0)
(+)
(0)
(+)¶
(+)
Williams et al 2005
(0)
(+)
(0)#
(+)
(0)
(0)
(0)
(+)
(0)
(0)
(0)
(+)
(+)
A
Van Doorn et al 2006
(+) = present; (0) = absent; * Original formula utilised #
Manufacturer and country of manufacture stated
$
Standardised to the weight of garlic or clove
&
Author claimed to use standardised product without stating the amount of bioactive constituent
pg. 32
I ¶
N U SC R
@
Garlic powder utilised was standardised, Aged garlic extract utilised was standardised to the weight of garlic
Matching or identical placebo stated, not giving exact ingredients in placebo.
A
CC E
PT
ED
M
A
a Latin Binomial name, b Brand name, c Licensed registration, d Type of product, e Parts of plant used, f Authentication of raw materials, g Type and concentration of extraction solvent, h Dosage/ duration, i Content of quantified chemical constituents, j Standardisation, k Type of placebo used
pg. 33
I N U SC R
Table 4 - Risk of Bias*
Selection bias
Performance bias
Detection bias
Attrition bias
Reporting bias
Other Bias
Random Blinding of Allocation sequence participants and concealment generation personnel
Blinding of outcome assessment
Incomplete outcome data
Selective reporting
Funding
Conflict of Interest
unclear
Budoff MJ et al 2004
unclear
unclear
low
low
low
low
unclear
unclear
unclear
unclear
low
low
unclear
unclear
low
low
low
low
low
low
unclear
unclear
PT
Gardner CD et al 2001
unclear
ED
Atkin. M et al 2016
M
A
Study
low
low
low
low
low
low
low
unclear
Gomez-Arbelaez et al 2013
low
unclear
unclear
unclear
low
low
low
low
Isaacsohn JL et al 1998
unclear
unclear
low
unclear
low
low
high
unclear
Jung MS et al 2014
unclear
unclear
unclear
unclear
low
low
unclear
unclear
McCrindle BW et al 1998
low
low
low
unclear
low
low
high
unclear
Ried K et al 2010
low
unclear
high
low
low
low
low
low
Ried K et al 2013
low
low
low
low
low
low
low
low
Ried K et al 2016
low
low
low
low
low
low
low
low
A
CC E
Gardner CD et al 2007
pg. 34
I unclear
Sobenin IA et al 2008
low
unclear
Sobenin IA et al 2009
low
unclear
Sobenin IA et al 2010
low
unclear
Superko HR et al 2000
unclear
Van Doorn et al 2006
unclear
A
CC E
*(Higgins and Green, 2011)
pg. 35
unclear
unclear
low
High
unclear
unclear
unclear
unclear
unclear
low
unclear
unclear
low
unclear
low
low
unclear
unclear
unclear
unclear
low
low
unclear
unclear
unclear
unclear
unclear
unclear
low
unclear
unclear
unclear
low
unclear
low
low
high
low
unclear
high
unclear
unclear
low
unclear
unclear
M
ED unclear
PT
Williams et al 2005
N U SC R
unclear
A
Sobenin IA et al 2008