garlic shows promise for improving some cardiovascular risk

8/20/2019 Garlic Shows Promise for Improving Some Cardiovascular Risk

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Garlic Shows Promise for ImprovingSome Cardiovascular Risk Factors

Ronald T. Ackermann, MD; Cynthia D. Mulrow, MD, MSc; Gilbert Ramirez, DrPH;Christopher D. Gardner, PhD; Laura Morbidoni, MD; Valerie A. Lawrence, MD, MSc

Objectives: To summarize the effects of garlic on sev-eral cardiovascular-related factors and to note its ad-verse effects.

Methods: English and non-English citations were iden-tified from 11 electronic databases, references, manufac-turers, and experts from January 1966 through February2000 (depending on thedatabase searched). Reports of car-diovascular-relatedeffects werelimited to randomized con-trolled trials lasting at least 4 weeks. Reports of adverse ef-fects were notlimited by study design. From 1798 pertinentrecords, 45 randomized trialsand 73 additional studies re-porting adverseevents wereidentified. Two physicians ab-stracted outcomes and assessed adequacy of randomiza-tion, blinding,andhandlingof dropouts. Standardizedmeandifferences of lipid outcomes from placebo-controlled tri-als were adjusted for baseline differences and pooled us-ing random effects methods.

Results: Compared with placebo, garlic preparations maylead to small reductions in the total cholesterol level at 1month (range of average pooled reductions, 0.03-0.45

mmol/L [1.2-17.3 mg/dL]) and at 3 months (range of av-erage pooled reductions 0.32-0.66 mmol/L [12.4-25.4mg/ dL]), but not at 6 months. Changes in low-density lipo-protein levels and triglyceride levels paralleled totalcholesterol level results;no statistically significantchangesin high-density lipoprotein levels wereobserved.Trials alsoreported significant reductions in platelet aggregation andmixed effects on blood pressure outcomes. No effects onglycemic-related outcomes werefound. Proven adverseef-fects included malodorous breath and body odor. Otherunproven effects included flatulence, esophageal and ab-dominal pain, allergic reactions, and bleeding.

Conclusions: Trials suggest possiblesmall short-termben-efits of garlic on some lipid and antiplatelet factors, insig-nificant effects on blood pressure, and no effect on glu-coselevels. Conclusions regarding clinical significancearelimitedby themarginal qualityand short duration of manytrials andby the unpredictable release andinadequate defi-nition of active constituents in study preparations.

Arch Intern Med. 2001;161:813-824

AMERICAN CONSUMER use of complementary and alter-native medicine is escalat-ing rapidly. Out-of-pocketexpenditures for herbal

therapiesare estimated at more than $5 bil-lion per year in the United States alone.1

Garlic ( Allium sativum) is clearly one of themost popular herbal remedies worldwidetoday.Animal studies suggest that garlichaspotential antilipidemic, antihypertensive,antiglycemic,antithrombotic, and antiath-erogenic properties.2-7 Although somesmallstudies in humans corroborate the find-ings of animal studies, the results are of-ten conflicting.5,8-14 Several previous re-views summarizetrials in humans, but theycite different original studies, emphasizesingle cardiovascular factors (eg, lipid lev-elsor hypertension only),and provide vari-able attention to specific garlic prepara-tions and constituents.15-21

Inabilities to blind subjects to thesmell and taste of garlic as well as unpre-dictability in the release of potentialactive ingredients have limited clinicalapplicability of prior trial results. Someinvestigators have simply conductednonblinded trials with various odor-con-taining garlic preparations. Others haveused “odor-free” commercial prepara-tions, such as dehydrated tablets (eg,Kwai, Lichtwer Pharmaceuticals, Berlin,Germany; Sapec, Lichtwer Pharmaceuti-cals; Pure-Gar Deodorized Garlic, Essen-tially Pure Ingredients, Chatsworth,Calif) and “aged garlic extract” (eg,Kyolic, Wakunage of America, MissionViejo, Calif), or have instead comparedgarlic with matching odor- or taste-containing placebos. Dehydrated prepa-rations are used most commonly andreportedly contain most constituentsfound naturally in whole garlic. Many

REVIEW ARTICLE

From the San AntonioEvidence-based Practice Center,University of Texas HealthScience Center (Drs Ackermann, Mulrow,Ramirez, and Lawrence),Veterans Evidence-basedResearch DisseminationImplementation Center, AudieL. Murphy Memorial VeteransHospital, San Antonio

(Drs Mulrow, Ramirez, andLawrence); Center for Researchin Disease Prevention, StanfordUniversity, Palo Alto, Calif (Dr Gardner); and the Istitutodi Clinica Medica Universitadegli Studi di Ancona, Ancona,Italy (Dr Morbidoni).Dr Gardner is now with theCenter for Advanced Studies inNutrition and Social Marketing,University of California, Davis.

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dehydrated preparations are fur-ther “standardized” according toparticular constituents, most com-monly to the compound S-allyl cys-teine–S-oxide (alliin). Standardiza-tion to alliin is believed to providea greater potential for liberation of the thiosulfinate compound alli-cin, which is produced enzymati-cally from alliin following hydra-

tion. Allicin has been shown inanimalmodelsto have significant an-tilipidemic potential.22,23 Alterna-tively, aged garlic extract (Kyolic) isbased on the content of S-allyl cys-teine, as it is reportedly prepared byallowing more volatile compoundsfound in chopped garlic (eg, alli-cin) to slowly evaporate in the pres-ence of aqueous alcohol. Through-out the remainder of this review,“standardized” will refer to com-mercial garlic preparations that aremarketed by their potential to lib-erate a weight-based percentage of allicin after human consumption.

This systematic review willcarefully scrutinize the internal va-lidityof trialsusing oral garlic prepa-rations, focus on the importance of differences among various prepara-tions, and comprehensively summa-rize multiple reported cardiovascu-lar-related effects and potentialadverse effects of various oral gar-lic preparations.

MATERIALS AND METHODS

DATA SOURCES

English and non-English citationswere identified from 11 electronicdatabases, references of pertinentarticles, symposia, manufacturers,and experts. Electronic databases,including AMED, CISCOM, theC o c h r a n e L i b r a r y , E M B A S E ,MEDLINE, and NAPRALERT, weresearchedfromJanuary 1996 through July 1999 (depending on the data-

base) using the following terms: “2-propenesulfenic acid,” “aglio,” “ajo,”“ajoene,” “alisat,” “allicin,” “al-liinase,” “ Alliumsativum,” “allyl mer-captan,” “diallyl disulphide,” “dial-lyl sulfide,” “diallyl sulphide,”“dipropyl disulphide,” “dipropyl sul-phide,” “garlic,” “garlic extract,”“garlic oil,” “knoblauch,” Kwai,Kyolic, “S-allyl cysteine,” “thioallylderivative,” “thiosulfinates,”and “vi-

nyl dithiin.” This search was up-dated on PubMed in February 2000.

STUDY SELECTION

Reports of effects on cardiovascu-lar outcomes were limited to ran-domized controlled human trials,lasting at least 4 weeks, and com-paring garlic with placebo, no gar-

lic, or another active agent. Re-ports of adverse effects included anyhuman study that identified ad-verse clinicalsymptoms or events as-sociated with garlic exposure. From1798 possible pertinent records, 2independent reviewers (C.D.M. andV.A.L.) identified 45 randomized tri-als and 73 additional studies report-ing adverse effects. One additionaltrial, available only in abstract form,was not reviewed.24

DATA EXTRACTION

Two independent physicians (R.T.A.andC.D.M.) abstracteddatafrom tri-als, and one physician (L.M.) ab-stracted studies of adverse effects.Original authors were contactedandrequested to provide informationwhen data were unreported. No for-mal reliability tests of abstractionswereconducted;disagreements wereresolved by consensus (R.T.A.,C.D.M., and L.A.).

DATA SYNTHESIS

Placebo-controlled randomized tri-als with lipid level outcomes werequantitatively pooled because (1)multiple small to moderate-sizedstudies with lipid level outcomeswere available, (2) similar controlgroups were used, and (3)lipid leveloutcomes were measured using simi-lar parameters at similar follow-uptimes. Standardized mean differ-ences, adjusted for baseline differ-ences, were used as the effect size

measure rather than mean differ-ences.25,26 Effect sizes calculated asmean differences can be variably in-fluenced by underlying populationvalues whenstudies exhibit substan-tial heterogeneity at baseline; greaterabsolute effects are more likely, forexample, to occur among patientswith high baseline cholesterol lev-els than among those with lowerbaseline cholesterol levels.26 We tried

to identify outlier studies with Gal-braith plots, a standard 2 test, andfunnel plots. Studies were consid-ered outliersif the2 test was P.10and/or if they fell outside of the Gal-braith or funnel plot.

Data were pooled using a ran-dom effects estimate both with andwithout studies that were identi-fied as outliers.27 (Results pre-

sented in the text are without out-liers, while figures give results of both analyses.) Subgroup analyseswere conducted for trials that (1)used similar dried standardizedpreparations of garlic, (2) enrolledsubjects with hypercholesterol-emia, and (3) used double-blind de-signs. A study that evaluated a gar-lic and fish oil combination was notpooled because of possible indepen-dent effects of fish oil on lipid lev-els. Effect sizes were converted toclinical laboratory units using thefollowing weighted average pooledSDs: total cholesterol level, 1.05mmol/L (40.8 mg/dL); low-densitylipoprotein cholesterol level (LDL-C),0.75 mmol/L(29.1 mg/dL); high-density lipoprotein cholesterol level(HDL-C), 0.29 mmol/L (11.4 mg/ dL); and triglyceride levels, 0.97mmol/L (85.9 mg/dL).

RESULTS

OVERVIEW OF TRIAL

QUALITYRandomized trials werepublished inscientific journals (n=37), sympo-sia proceedings (n=5), a book chap-ter (n=1), a thesis(n= 1), and anab-stract (n= 1; full report wasobtainedfromthe corresponding author).De-tails of randomization procedureswere scant. Whether 2 trials wereactually randomized was unclear; at-tempts to contact the original au-thors for clarification were unsuc-cessful.28,29 Equivalencies between

randomized groups for baselinelipidlevels, blood pressure, body mass,diet, or activity levels were re-ported in 16 trials.21,30-44

Of 34 trials with double-blinddesigns, only one, which used anodor-free dehydrated tablet, as-sessed adequacy of blinding throughdirect questioning. Blinding was re-portedly not successful.33 Eight tri-als reported adverse effects clearly





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Table 1. All Randomized Trials With Serum Lipid Endpoints of 4 Weeks or Longer Comparing Garlic to Placebo or Other Therapy

Source, ySampleSize (N)

% of MaleSubjects

Mean Age(Range), y Recruitment Setting Characteristics of Subjects*

RandomizationProcess†

Adler and Holub,33 1997 25 100 46 Unclear Hyperlipidemia Unclear

Auer et al,55 1990 47 45 58 11 General practices Hypertension; 45% of thesubjects had a total

cholesterol level 6.46mmol/L

Unclear

Barrie et al,48 1987 20 Unclear 26 Student volunteers All previously healthy;total cholesterol levelsranged from 3.36-6.98mmol/L

Unclear

Berthold et al,49 1998 26 54 58 Community volunteers Hyperlipidemia Probably adequate

Bordia et al,64 1981 25 100 55 Unclear Known coronaryartery disease;hyperlipidemia

Unclear

Bordia,29 1989 432 Unclear Not given Unclear History of myocardialinfarction

Unclear (potentiallyinadequate)

Bordia et al,28 1998 60 Unclear Not given Unclear History of myocardialinfarction

Unclear (potentiallyinadequate)

Buhshan et al,65 1979 25 100 (18-35) Unclear Hyperlipidemia Unclear

Chutani and Bordia,66 1981 30 Unclear 50 Unclear Ischemic heart disease Unclear

Czerny andSamochowiec,67 1996

100 65 55 Unclear Hyperlipidemia;atherosclerotic disease;and hypertensive

Unclear

Gardner et al,30 1999 53 51 52 Unclear Hyperlipidemia Unclear

Holzgartner et al,34 1992 98 39 57 5 General practices Hyperlipoproteinemia typesIia, IIb, or IV; 35% ofthe subjects hadhypertension

Probably adequate

Isaacsohn et al,58 1998 50 54 58 Specialty clinic Hyperlipidemia Probably adequate

Jain et al,9 1993 42 45 52 Community volunteers Hyperlipidemia Unclear

Kandziora,60 1988 40 Unclear (43-65) Unclear Hypertension; hyperlipidemia Unclear

Kandziora,59 1988 40 83 56 Unclear Hypertension; hyperlipidemia Unclear

Kannar,45 1998 46 54 (30-74) Community volunteers Hyperlipidemia; no diabetesmellitus

Adequate

Kenzelmann andKade,35 1993

46 33 43 Volunteers and4 general practices

Hyperlipidemia Probably adequate

Kiesewetter et al,32 1991 60 30 24 Volunteers Elevated spontaneousplatelet aggregation

Unclear

Kiesewetter et al,40 1993 80 67 60 Unclear Peripheral vascular disease;hyperlipidemia

Unclear

Koscielny et al,43 1999 280 71 60 Unclear Asymptomatic advancedatherosclerosis;hyperlipidemia; and 38%

of the subjects hadhypertension

Unclear

Lash et al,62 1998 35 49 45 Unclear Hyperlipidemia; all after renaltransplantation

Unclear

Lau et al,36 1987

1 32 56 52 Community orclinic volunteers

Hyperlipidemia; 44% of thesubjects were vegetarians

Unclear

2 14 56 26 Community orclinic volunteers

Normolipidemia; 57% of thesubjects were vegetarian

Unclear





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Intervention(Daily Garlic Dosage)‡ Control Group

Double-blindStudy

Endpoints§

TrialLength, wk

% of Dropoutsper Group

ClinicalSymptoms

LipidLevels

BloodPressure

GlucoseLevel

ThromboticState

Dehydrated tablet:Kwai (900 mg)

Placebo Yes X X 12 Garlic treated, 8;placebo, 8


Placebo Yes X X X 12 Unclear

Oil macerate (18 mg) Placebo Yes X X X 4 Unclear

Garlic distillate: Tegra(5 mg)

Placebo Yes X 12 Pooled, 4

Garlic ether extract (0.25mg/kg of body weight)


Garlic ether extract(6-10 g)

Habitual coronarytherapy

Unclear X X X 156 Unclear

Garlic ether extract (1 g) Placebo Unclear X X X 13 Unclear

Raw garlic (10 g) No garlic treatment No X 8 Unclear

Raw or fried garlic No garlic treatment No X 4 Unclear

A combination of oilmacerate, soya lectin,hawthorn oil, andwheat germ(400 mg)

Placebo Yes X X X X X 16 Unclear

Dehydrated tablet:(500 mg and 1000 mg)



Antilipidemic Yes X X 12 0 (4% Excluded forprotocol violations)


Placebo Yes X X 12 Garlic treated, 14;Placebo, 18






Antihypertensive Single X X X 12 Unclear

Dehydrated tablet:Garlic 100 (880 mg)


Dehydrated tablet with ginkobaextract: Allium Plus (200 mg)

Placebo Yes X 8 Garlic treated, 4;placebo, 9


Placebo Yes X X X X 4 Unclear


Placebo Yes X X X X 12 Garlic treated, 20;placebo, 20


Placebo Yes X X X X 208 Garlic treated, 40;placebo (at 6 mo),21

Dehydrated tablet:Pure-Gar (1360 mg)

Placebo Unclear X 12 Unclear

Aged garlic extract:Kyolic (4 mL ofextract = 1000 mg)

Placebo Unclear X 26 Garlic treated, 6;placebo, 25

Aged garlic extract:Kyolic (4 mL ofextract = 1000 mg)

Placebo Unclear X 26 Unclear

(Continued)





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Table 1. All Randomized Trials With Serum Lipid Endpoints of 4 Weeks or Longer Comparing Garlic to Placebo or Other Ther apy (cont)

Source, ySampleSize (N)

% of MaleSubjects

Mean Age(Range), y Recruitment Setting Characteristics of Subjects*

RandomizationProcess†

Luley et al,53 19861 34 Unclear Not given Unclear Hyperlipoproteinemia types IIa,

IIb, or IVUnclear

2 51 Unclear Not given Unclear Hyperlipoproteinemia types IIa,

IIb, or IV

Unclear

Lutomski,41 1984 102 49 52 Unclear Nonspecific functionalcomplaints; 44% of thesubjects had hypertension andnormolipidemia

Unclear

Mader,39 1990 261 44 59 Community clinic Hyperlipidemia; 47% of thesubjects had hypertension

Probably adequate

Mansell et al,46 1996 60 77 63 Unclear All subjects had type 2 diabetesmellitus

Unclear

McCrindle et al,52 1998 31 52 14 Specialty clinic Hyperlipidemia; family history ofhigh lipid levels; and earlycoronary artery disease

Probably adequate

Melvin,51 1996 34 47 54 Volunteers Hyperlipidemia Unclear

Morcos,68 1997 40 58 53 Community clinicvolunteers

Hyperlipidemia Unclear

Neil et al,21 1996 115 61 53 Community clinic Hyperlipidemia; obesity Adequate

Plengvidhya et al,63 1988 30 47 49 Unclear Hyperlipidemia Unclear

Rotzsch et al,61 1992 24 42 37 Unclear HDL-C2 level: 0.26 mmol/L,men; 0.39 mmol/L, women

Unclear

Santos and Grunwald,56 1993 60 39 52 Community clinic Hyperlipidemia Unclear

Santos and Jones,57 1995 80 35 57 Single specialistpractice

Hyperlipidemia Unclear

Saradeth et al,38 1994 72 31 39 Community volunteers Hyperlipidemia Unclear

Simons et al,47 1995 31 53 54 Community volunteers Hyperlipidemia Unclear

Sitprija et al,31 1987 40 33 50 Outpatient clinic All subjects had diabetes mellituswithout complications

Unclear

Steiner,50,69 1996 52 100 (32-68) Unclear Hyperlipidemia Unclear

Superko and Krauss,44 2000 50 Unclear 53 Unclear Hyperlipidemia Unclear

Ventura et al,37 1990 40 38 59 Community volunteers Hyperlipidemia; peripheralvascular disease

Unclear

Vorberg and Schneider,54 1990 40 43 50 Community clinic Hyperlipidemia Unclear

Yeh et al,42 1997 34 100 48 Collegiate community Hyperlipidemia Unclear

*To convert the total cholesterol high-density lipoprotein cholesterol-subfraction 2 (HDL-C2) levels to milligrams per deciliters, multiply by 0.02586.†The randomization process was classified as follows: unclear, probably adequate, and adequate. Unclear indicates that the process was not described in significant

enough detail to ensure adequacy. Probably adequate indicates the use of sealed envelopes but not sequentially numbered or opaque; list of random numbers read by someone enrolling the subject into the trial (open list); description suggests adequate concealment but other features such as markedly different characteristics among intervention and control groups are suspicious. Adequate indicates centralized randomization by telephone; randomization scheme controlled by pharmacy; numbered or coded identical containers administered sequentially; on-site computer system that can only be accessed after entering the characteristics of an enrollee; and sequentially numbered, sealed, and opaque envelopes.

‡The manufacturers of the garlic products mentioned in this column are as follows: Kwai, Lichtwer Pharmaceuticals, Berlin, Germany; Tegra, Hermes Pharmaceuticals,Munich, Germany; Garlic 100, Cotter Foods, Melbourne, Australia; Allium-Plus, Zeller AG, Romanshorn, Switzerland; Pure-Gar Deodorized Garlic, Essentially PureIngredients, Chatsworth, Clif; Kyolic, Wakunaga of America, Mission Viejo, Calif; Ilja Rogoff Garlic Tablets with Rutin, Woelm Pharmaceuticals GmbH & Company,Eschwege, Germany; LipoGuard, Viva America Incorporated, Costa Mesa, Calif; and Fitoaglio, Farmaceutici Procemsa, Torino, Italy.

§An X indicates that that particular outcome was reported by the original authors.Publication contained 2 distinctly different studies presented in a single publication; therefore, the same reference has been assigned.¶This was a crossover study.#These were clearly stated to not be commercial tablets.





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Intervention(Daily Garlic Dosage)‡ Control Group

Double-BlindStudy

Endpoints§

TrialLength, wk

% of Dropoutsper Group

ClinicalSymptoms

LipidLevels

BloodPressure

GlucoseLevel

ThromboticState

Dehydrated tablet(594 mg)

Placebo Yes X X X 6 0

Dehydrated tablet

(1350 mg)

Placebo Yes X X X X 6 0

Dehydrated tablet/other:Ilja Rogoff Garlic Tabletswith Rutin (300 mg)

Placebo Yes X X 12 Pooled, 5 (15%excluded for protocolviolations)


Placebo Yes X X 16 Garlic treated, 4; placebo,7 (10% excludedfor protocolviolations)


Placebo Unclear X X X 12 Unclear


Placebo Yes X X X 8 Pooled, 3


Placebo Yes X 4¶ Pooled, 44 (excluded forprotocol violations)

Dehydrated tablet with fishoil: LipoGuard (1200 mg)

Placebo Single X 4¶ Unclear



Dehydrated tablet(700 mg)#

Placebo Yes X 6¶ Unclear


Placebo Yes X 6 Unclear




Garlic oil: HoefelsOriginal Garlic Oil(1.98 mg/d)

No X X 16 Tablet treated, 10;oil treated, 15


Placebo Yes X X 15 Garlic treated, 1;placebo, 4 (22%excluded forincomplete data)


Placebo Yes X X 12¶ Pooled, 6

Dehydrated tablet(700 mg)#


Aged garlic extract:Kyolic (7200 mg)

Placebo Yes X X 26¶ 21 (cumulative)


Placebo Yes X X 12 Unclear

Dehydrated tablet,hawthorn, and other:Fitoaglio (450 mg)

Placebo Yes X X 8 0


Placebo Yes X X 16 0

Aged garlic extract:Kyolic (7200 mg)

Placebo Yes X X 22 Pooled, 6





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half of the studies did not presentnumerical data that could be used ina quantitative analysis, multiple dif-ferent methods of blood pressuremeasurement were used, and fewstudies had a priori hypotheses re-lated to blood pressure.

Antiglycemic Effects

Twelve trials assessed the effect of garlic on the serum glucose level.*Two studied adults with diabetesmellitus and considered serumglucose level as a primary out-come.31,46 Only one4-weektrial, con-ducted in nondiabetic persons, re-ported a statistically significantlygreater reduction in the serum glu-cose level with standardized dehy-drated garlic tablets (Kwai) com-pared withplacebo.32 No statisticallysignificant effects were reported forglycosylated hemoglobin,46 seruminsulin and C-peptide levels,46 andresponsiveness of serum insulin lev-els to an oral glucose challenge.31

Antithrombotic Effects

Tentrialsassessedtheeffectivenessof garlic on potentialprothrombotic riskfactors.† Of 6 of these 10 trials mea-suring effects on spontaneous plate-let aggregation, 5 provided re-sults32,40,48,67,69; 4 ofthese10 trials, allprohibiting intake of additional anti-platelet medications, reported mod-est but significant decreases in plate-let aggregation with garlic treatmentcompared with placebo,32,40,48,67 andthe other reported significant de-creases in epinephrine-induced, butnotadenosinediphosphate–induced,plateletaggregation.69Mixedeffectsonfibrinolytic activity28,53,66 and plasmaviscosity were reported,whileno tri-als assessing serum fibrinogen lev-els28,32,52,53 or serum homocysteinelevels52 reported significant results.

Effects on CardiovascularMorbidity and Mortality

Clinical trial data for cardiovascu-lar morbidity outcomes are lim-ited. Two trials assessed improve-

–3.0 –2.5 0–2.0 0.5–1.5 1.0–1.0 1.5–0.5 2.0 2.5

Total Cholesterol Level, mmol/L

A

All Studies Without Outliers

Vorberg and Schneider54

S t a n d a r d i z e d

N o t S t a n d a r d i z e d

Lash et al62

Jain et al9

Auer et al55

Mader39

Adler and Holub33

Simons et al47

Kiesewetter et al32

Saradeth et al38 Without Outlier

With OutlierLau et al36

Kenzelmann and Kade35

Bordia et al28

Sitprija et al31

Gardner et al30Lau et al36

Without OutlierBordia et al64

With Outlier

All Studies With Outliers

–0.26 (–0.45 to –0.08)

–0.31 (–0.49 to –0.13)

0.01 (–0.28 to 0.31)

0.25 (–0.44 to 0.68)

–0.19 (–0.34 to –0.03)

–0.08 (–0.31 to 0.15)

–3.0 –2.5 0–2.0 0.5–1.5 1.0–1.0 1.5–0.5 2.0 2.5

B


N o t S t a n d a r d i z e d

Lash et al62

Jain et al9

Kannar45

Kandziora60

De Santos and Grunwald56

Auer et al55

Kiesewetter et al40

Mader39

McCrindle et al52

Adler and Holub33

Superko and Krauss44

Saradeth et al38 Without Outlier

Vorberg and Schneider54

Isaacsohn et al58 With Outlier

Lau et al36

Kenzelmann and Kade35

Plengvidhya et al63

Berthold et al49

Ventura et al37

Bordia et al28

Steiner et al50

Yeh et al42

Czerny and Samochowiec67

Gardner et al30

Buhshan et al65

Lau et al36 Without Outlier

Bordia et al64 With Outlier

All Studies Without Outliers All Studies With Outliers

–0.50 (–0.66 to –0.34)

–0.48 (–0.78 to –0.18)

–0.36 (–0.56 to –0.16)

–0.19 (–0.52 to 0.14)–0.44 (–0.56 to –0.32)–0.35 (–0.57 to –0.12)

0 0.2–0.6 0.4–0.4 –0.2 0.6

C

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D u r a t i o n o f S t u d i e s ,

w k

A l l S t u d i e s

N o t S

t a n d a r d i z e d

4-6

8-12

20-24

4-6

8-12

20-24

4-6

20-24

–0.44 (–0.57 to –0.32)

–0.03 (–0.28 to 0.21)

–0.26 (–0.45 to –0.08)

–0.50 (–0.66 to –0.34)

–0.07 (–0.37 to 0.22)

0.01 (–0.28 to 0.31)

–0.36 (–0.56 to –0.16)

0.02 (–0.53 to 0.57)

Forest plot of studies with total cholesterol level results at 4 to 6 weeks (A) and at 8 to 12 weeks (B).C, Forest plot of pooled results of total cholesterol level findings at different periods. All Forest plot levels are measured in millimoles per liter. To calculate the conventional units of milligram per deciliter for the total cholesterol levels multiply by the conversion factor of 38.67. The numbers in parentheses indicate 95% confidence intervals for the pooled standarzied mean differences (in millimoles per liter). The minus signs indicate that these levels were reduced relative to pacebo changes over the intervention period.Solid squares indicate those studies using standardized preparations; open squares, those studies using nonstandardized preparations; and solid circles, all preparations together.

*References 9, 28, 31, 32, 43, 46, 53, 55,59, 60, 67.†References 28, 32, 40, 43, 48, 52, 53, 66,67, 69.





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ment in pain-free walking distancein subjects with lower extremity pe-ripheralvascular diseasetreated withgarlic vs placebo.40,67 Although theauthors of one trial reported signifi-cant increases in the walking dis-tance with standardized dehy-drated tablets (Kwai), there was a20%dropout rate with no intention-to-treat analysis, significant dis-parities in the reporting of a garlictaste between garlic-treated and pla-cebo groups that suggested pos-sible inadequate blinding, and a re-analysis using baseline walkingdistances from the time of random-ization rather than during a run-inphase no longer yielded significantresults.40 The second trial reportedstatistically significant increasesin pain-free walking but used a gar-lic oil macerate–soya lecithin–hawthorn oil–wheat germ oil com-bination,making it difficult to assessthe independent effect of garlic onthis end point.67

One 3-year trial assessing rein-farction rates in 432 patients withevidence of a prior myocardial in-farction reported 11 deaths and 15

reinfarctions in 222 subjects ran-domized to a garlic extract (0.1 g/kgper day for body mass)and 20 deathsand 22 reinfarctions in the 210 pla-cebo recipients.29 Although the au-thor reported significant differ-ences, reanalysis of between-groupcomparisons using a 2 test re-vealed no statistically significant dif-ferences in total mortality (P =.07)or myocardial infarction (P =.13).

The trial was not published in peer-reviewed literature, and details of randomization processes, blinding,and handling of dropouts could notbe obtained despite attempts to con-tact the original author.

Original authors of a placebo-controlledtrial with standardized de-hydratedtablets(Kwai)involving 280subjects have reported statisticallysignificant (P.001) regression inatherosclerotic plaque volume over48 months.43 AsofFebruary2000, theauthenticity of this trial wasunder in-vestigation owing to concerns regard-ing the validity of theultrasound im-ages accompanying the publishedtext, unsuccessful randomizationprocedures, an unusually high (46%)unequal dropout rate, and inappro-priate analyses.70

Adverse Effects

Approximately half of the trials re-ported adverse effects. Of those re-porting adverse effects, 8 reportedsignificantly greater numbers of subjects assigned garlic treatment hadmalodorous breath or body odor (as

perceived by themselves or others)compared with subjects assigned pla-cebo.21,33,39,40,43,45-47 The other trialsthat reported adverse effects statedthat persons assigned to dehy-drated garlic tablets self-reportedmalodorousbreath or body odor, ab-dominal pain, fullness, anorexia, orflatulence, but had too few num-bers to statistically compare differ-ences between groups. In addition

to the trials, 73 further studies werefound that addressed adverse ef-fects (Table 2). Most (97%) werecase reports or small case series. Re-ported adverse effects of garlic inges-tion (dietary and supplements) weredermatitis, rhinitis, Meniere dis-ease, asthma, myocardial infarction,bleeding, epidural hematoma, in-creased International Normalized Ra-tio in persons taking warfarin so-dium, small-intestine obstruction,esophageal and abdominal pain, andflatulence. The frequency of ad-verse effects and whether they var-ied by particular preparations werenot studied.

COMMENT

Although inconclusive, random-ized controlled trial data are com-patible with the hypothesis that gar-lic supplementation may producemild short-term benefits on the lev-els of total cholesterol, triglycer-ides, and LDL-C, and on platelet ag-gregation. Several small short-termtrials show mixed, but never large,effects of garlic on blood pressure

outcomes, and no effects on glyce-mic-related outcomes. Given theoverall marginal quality of many tri-als with respect to adequacy of ran-domization and blinding, as well asan inadequate definition of the spe-cific biologically active garlic con-stituents in tested preparations, theseresults have limited clinical appli-cability. Although multiple adverseeffects of garlic ingestion have been

Table 2. Summary of Adverse Effects

Adverse Effect Type of Garlic Exposure Level of Evidence

Breath or body odor Oral use of standardized dehydrated tablet Randomized controlled trial s

Skin manifestations: contact dermatitis, ulcerus necroticlesions; and blisters, bullae, and vesicles

Oral use for 1 case of contact dermatitis;topical use for the remaining lesions

Case series and multiple case reports withresolution of lesions after discontinuation ofgarlic treatment; no rechallenge tests

Allergic manifestations: asthma, rhinitis, conjunctivitis,urticaria, and anaphylaxis; angioedema

Oral use for 1 case of asthma and rhinitis;garlic dust inhalation for the remainingcases

Case series and multiple case reports withresolution of symptoms after discontinuationof garlic treatment; positive rechallenge test

results for asthmaCardiovascular dysfunction: myocardial infarction Oral use 1 Case report

Coagulation dysfunction: postoperative bleeding,spontaneous spinal epidural hematoma, increasedInternational Normalized Ratio, clotting timeprolongation, and failure of platelet aggregation test

Oral use Case reports

Gastrointestinal tract dysfunction: small-intestineobstruction, epigastric and esophageal pain, andflatulence; hematemesis and hematochezia

Oral use Case reports and case series

Other: Meniere disease Oral use Case report





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reported, causality is establishedonlyfor malodorous breath and bodyodor. The most serious potential ad-verse effect that has been cited isspontaneous epidural bleeding. Theexpected frequency of adverseeffects, whether they are “dose-related,” and whether they are spe-cific to or occur more commonlywith particular garlic preparationsthan others are unclear.

Fewtrials clearly reported error-free randomization procedures.Blinding of subjects was impossiblein many trials that evaluated odor-producing preparations, and severaldouble-blind trials that used odor-free coated preparations still re-ported adverse effects discernable tosubjects that were clearly attribut-able to garlic. The inability to ad-equately blind subjects may have ledto systematic overestimation or un-derestimation of garlic’s effects. Forexample, it is possible that true pu-tative healthbenefits of ingestinggar-lic are attributable to the presence,concentration, and form of its manysulfur-containing compounds.Thesesulfur-containing compounds gen-erate the uniquetaste and odor ofgar-lic. Studies of garlic treatment thatsuccessfully blind subjects to groupassignments may be using garlicproducts that not only have unde-tectable taste and odor but that alsohave low levels of active sulfur-containing compounds.If benefitsaretied to sulfur-containing com-pounds, such studies might under-estimate them.

Concealment of random alloca-tion from investigators, blinding of subjects, and proper handling of missing data arethe only quality vari-ables that have been empiricallyshown to affect trial outcomes.71 Be-cause of unclear adequacy of double-blindingtechniquesand because veryfew trials performed intention-to-treat analyses or reported no drop-

outs, distinguishing higher-qualitytrials was infeasible for performingsensitivity analyses. These method-ological limitations affect the clini-cal relevanceof even statistically sig-nificant results and further limit theuse of attempting to rationalize thesignificance of trends in the pooleddata analyses.

Several issues related to the in-trinsicqualitiesof garlicfurther com-

plicate interpretation of currenthuman studies.First, there is no uni-versal consensus regarding exactlywhich constituents of garlichave major effects on particular cardiovascu-lar risk factors in vivo and by whatmechanism theseeffects areachieved.Second, the relative ingredient con-tent of whole garlic is affected bygrowth conditions such as soil com-position. Finally, variation in themethods of preparing particular gar-lic preparations results in significantdifferences in final composition. Forinstance, crushing or cutting wholegarlic commingles the ingredient al-liin with an enzyme, alliinase, result-ingin liberation ofallicin,which isbe-lievedby most garlicresearchersto bethe major ingredient responsible forpotential antilipidemic effects. Theherbal industry is unable to guaran-tee allicin content within tablets be-cause of limitations in the stability of this compound. Most allicin-basedpreparations are,therefore, designedto generate allicin enzymatically fromalliin after ingestion. Although com-mercial tablets are standardized tofixed amounts of alliin and allinasewith the intention of maximizing al-licin production after consumption,allinase quickly denatures at low gas-tric pHs. Maximal allicin release,therefore, depends not only on highalliin concentration and alliinase ac-tivity in the tablet, but also protec-tion of allinase from gastric acid pHfollowed by rapid tablet dissolutionin enteric pH. Despite theaddition of tablet coatings to prevent prematuredissolution, most preparations havenot beensystematically testedagainstUS Pharmacopeia methods for com-pliance with enteric-coating stan-dards. Notably, differential libera-tionofallicinfromotherwise identicalstandardized dehydrated garlic tab-lets, produced by the same manu-facturer but in differen batches, hasbeen demonstrated.72 This variabil-

ity in allicin liberation, despite stan-dardization, has recently been sug-gested to correlate with variability inantilipidemiceffectsamong many re-cent trials using particular standard-ized dehydrated garlic tablet prepa-rations.73

Additionally, although severaltrials reported equivalent baselinebody mass, diet, or activity level be-tween groups, few assessed whether

these factors remained matchedthroughout the trial intervention.The presence of confounding ef-fects is supported by several trialsthat reported significant,39,40 or atrend toward significant,* benefitfrom placebo administration alone.Even accounting for regressionto themean, some investigatorsarguesucheffects are more likely attributable

to unanticipated cointerventions orpoor control for bias than true pla-ceboeffects.74-76 Severaltrialsusedvol-unteer subjects who may potentiallybe seeking lifestyle modifications forpoor baseline dietary andactivityhab-its. Studying such populations couldincrease the perception of beneficialshort-term effects simply as a resultof drift toward a more average life-style during the intervention pe-riod—an effect that may begreater ina motivated groupthat is awareof re-ceiving a presumablybeneficialstudymedication.74,75

Pooledanalysesoftrials doshowreductions in the total cholesterollevel at 4 to 6 weeks with trends to-ward further reductions at 8 to 12weeks, although this trend did notpersist at 20 to 24 weeks.Despite sev-eral possible explanations for thesetrends, the marginal statistical sig-nificanceof observedshort-termben-efits and the generalized method-ological shortcomings of trials makefurther conjecture unwarranted.Pooledanalyses also suggestthatstan-dardized dehydrated preparationsmay result in greater mean short-term (4-12 weeks) cholesterol levelreductions than other preparations,but this difference is neither clini-cally (approximately 0.12-0.26mmol/L [5-10 mg/dL]) nor statisti-cally (P.10)significant. Absence of a significantdisparity between prepa-rations believed to contain distinctlydifferent ingredients might gener-ally suggest that there is a commonactive constituent among all prepa-rations or that reported resultsareac-tually due to something other thangarlic itself, such as an unmeasuredlifestyle modification. Alternatively,it isalsopossible that theexpected dif-ferences in ingredient availability af-ter ingestion were minimized by in-

*References 9, 28, 36, 37, 48, 51, 54-56,58, 59, 63, 68.





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advertent selection of particularpreparationsthathave been shown tohave substantially limited capabili-tiesof liberating allicin under gastro-intestinal conditions.

Studies with significant re-sults, written in English, or fundedby pharmaceutical companies his-torically have been more likely to bepublished.77 Of 45 randomized tri-

als in our analysis, 36 (80%) werepublished in peer-reviewed jour-nals, 38 (84%)were publishedin theEnglish languageonly, and 35 (78%)were sponsored, to some degree, byherbal manufacturers. Although webelieve our search was comprehen-sive, and significant efforts weremade to retrieve unreported datafrom investigators, the potential formissing data and publication bias inour review is still real.

CONCLUSIONS

One of the most readily apparentproblemswithhuman research abouttheeffects of garlic treatmentis inad-equate definition of biologically ac-tiveconstituentsandpredictableavail-ability of these constituents afteringestion. Delineatingmajor active in-gredients andtheir mechanismsof ac-tion are essential before conductingmore trials. Although studies in hu-mansreportpromising potential lipid-lowering and antithrombotic ben-efits, they are limited by unclearrandomization procedures, short du-rations, and unclear adequacy of blinding to treatment administra-tion and outcome assessments. Fur-ther studies with similar design fea-tures are useless. Rather, a few well-designedtrialsof longer duration arewarranted. Such trials should detaila clear andunbiased recruitment andselection process, a clearly adequaterandomization procedure, andassess-ment of the successfulness of blind-ing techniques. Additional empha-sison controlling cointerventionsthatcan affect outcomes, clearly definingtheconstituents anddissolution prop-erties of garlic preparations beingstudied, and using intention-to-treatanalyses are also necessary.

Accepted for publication November 1, 2000.

This study was prepared by theSan Antonio Evidence-based Practice

Center under contract 290-97-0012,task order 3, to the Agency for Health-care Research and Quality (formerlythe Agency for Health Care Policy andResearch), Rockville, Md.

Presented as an abstract at theComplementary and AlternativeMedi-cine in Cardiovascular, Lung, andBloodResearch, NationalHeart, Lung,and BloodInstitute Campus, Bethesda,

Md, June 12-13, 2000, and the Evi-dence-based Complementary Medi-cine Congress, Munich, Germany, April 8, 2000.

We are indebted to the follow-ing persons for their contributions tothis project: Eric Block, PhD, for in- put regarding the chemistry of gar-lic; Paul Heidenreich, MD, MS, for ex- pert cardiological advice; Christine Aguilar, MD, MPH, Mark Loveland,andDavid Mullins forhelp in abstract-ing data; Andrew Vickers, MD, andMolly Harris, MLS, MA, for conduct-ing the literature searches; and Jen-nifer Arterburn, MTSC, for assistingwith technical writing.

Reprints: Cynthia D. Mulrow,MD, MSc, Audie L. Murphy Memo-rial Veterans Hospital, 7400 MertonMinterBlvd (11C6), San Antonio, TX 78284 (e-mail: [email protected]).

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