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Garlic Shows Promise for Improving Some 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
Arch Intern Med. 2001;161:813-824.
ABSTRACT
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Objectives To summarize the effects of garlic on several cardiovascular-related
factors and to note its adverse effects.
Methods English and non-English citations were identified from 11 electronic
databases, references, manufacturers, and experts from January 1966 through
February 2000 (depending on the database searched). Reports of cardiovascular-related
effects were limited to randomized controlled trials lasting at least 4 weeks.
Reports of adverse effects were not limited by study design. From 1798 pertinent
records, 45 randomized trials and 73 additional studies reporting adverse
events were identified. Two physicians abstracted outcomes and assessed adequacy
of randomization, blinding, and handling of dropouts. Standardized mean differences
of lipid outcomes from placebo-controlled trials were adjusted for baseline
differences and pooled using random effects methods.
Results Compared with placebo, garlic preparations may lead to small reductions
in the total cholesterol level at 1 month (range of average pooled reductions,
0.03-0.45 mmol/L [1.2-17.3 mg/dL]) and at 3 months (range of average pooled
reductions 0.32-0.66 mmol/L [12.4-25.4 mg/dL]), but not at 6 months. Changes
in low-density lipoprotein levels and triglyceride levels paralleled total
cholesterol level results; no statistically significant changes in high-density
lipoprotein levels were observed. Trials also reported significant reductions
in platelet aggregation and mixed effects on blood pressure outcomes. No effects
on glycemic-related outcomes were found. Proven adverse effects included malodorous
breath and body odor. Other unproven effects included flatulence, esophageal
and abdominal pain, allergic reactions, and bleeding.
Conclusions Trials suggest possible small short-term benefits of garlic on some
lipid and antiplatelet factors, insignificant effects on blood pressure, and
no effect on glucose levels. Conclusions regarding clinical significance are
limited by the marginal quality and short duration of many trials and by the
unpredictable release and inadequate definition of active constituents in
study preparations.
INTRODUCTION
AMERICAN CONSUMER use of complementary and alternative medicine is escalating
rapidly. Out-of-pocket expenditures for herbal therapies are estimated at
more than $5 billion per year in the United States alone.1
Garlic (Allium sativum) is clearly one of the most
popular herbal remedies worldwide today. Animal studies suggest that garlic
has potential antilipidemic, antihypertensive, antiglycemic, antithrombotic,
and antiatherogenic properties.2-7
Although some small studies in humans corroborate the findings of animal studies,
the results are often conflicting.5, 8-14
Several previous reviews summarize trials in humans, but they cite different
original studies, emphasize single cardiovascular factors (eg, lipid levels
or hypertension only), and provide variable attention to specific garlic preparations
and constituents.15-21
Inabilities to blind subjects to the smell and taste of garlic as well
as unpredictability in the release of potential active ingredients have limited
clinical applicability of prior trial results. Some investigators have simply
conducted nonblinded trials with various odor-containing garlic preparations.
Others have used "odor-free" commercial preparations, such as dehydrated tablets
(eg, Kwai, Lichtwer Pharmaceuticals, Berlin, Germany; Sapec, Lichtwer Pharmaceuticals;
Pure-Gar Deodorized Garlic, Essentially Pure Ingredients, Chatsworth, Calif)
and "aged garlic extract" (eg, Kyolic, Wakunage of America, Mission Viejo,
Calif), or have instead compared garlic with matching odor- or taste-containing
placebos. Dehydrated preparations are used most commonly and reportedly contain
most constituents found naturally in whole garlic. Manydehydrated preparations
are further "standardized" according to particular constituents, most commonly
to the compound S-allyl cysteine–S-oxide (alliin). Standardization to
alliin is believed to provide a greater potential for liberation of the thiosulfinate
compound allicin, which is produced enzymatically from alliin following hydration.
Allicin has been shown in animal models to have significant antilipidemic
potential.22-23 Alternatively,
aged garlic extract (Kyolic) is based on the content of S-allyl cysteine,
as it is reportedly prepared by allowing more volatile compounds found in
chopped garlic (eg, allicin) to slowly evaporate in the presence of aqueous
alcohol. Throughout the remainder of this review, "standardized" will refer
to commercial garlic preparations that are marketed by their potential to
liberate a weight-based percentage of allicin after human consumption.
This systematic review will carefully scrutinize the internal validity
of trials using oral garlic preparations, focus on the importance of differences
among various preparations, and comprehensively summarize multiple reported
cardiovascular-related effects and potential adverse effects of various oral
garlic preparations.
MATERIALS AND METHODS
DATA SOURCES
English and non-English citations were identified from 11 electronic
databases, references of pertinent articles, symposia, manufacturers, and
experts. Electronic databases, including AMED, CISCOM, the Cochrane Library,
EMBASE, MEDLINE, and NAPRALERT, were searched from January 1996 through July
1999 (depending on the database) using the following terms: "2-propenesulfenic
acid," "aglio," "ajo," "ajoene," "alisat," "allicin," "alliinase," "Allium sativum," "allyl mercaptan," "diallyl disulphide,"
"diallyl sulfide," "diallyl sulphide," "dipropyl disulphide," "dipropyl sulphide,"
"garlic," "garlic extract," "garlic oil," "knoblauch," Kwai, Kyolic, "S-allyl
cysteine," "thioallyl derivative," "thiosulfinates," and "vinyl dithiin."
This search was updated on PubMed in February 2000.
STUDY SELECTION
Reports of effects on cardiovascular outcomes were limited to randomized
controlled human trials, lasting at least 4 weeks, and comparing garlic with
placebo, no garlic, or another active agent. Reports of adverse effects included
any human study that identified adverse clinical symptoms or events associated
with garlic exposure. From 1798 possible pertinent records, 2 independent
reviewers (C.D.M. and V.A.L.) identified 45 randomized trials and 73 additional
studies reporting adverse effects. One additional trial, available only in
abstract form, was not reviewed.24
DATA EXTRACTION
Two independent physicians (R.T.A. and C.D.M.) abstracted data from
trials, and one physician (L.M.) abstracted studies of adverse effects. Original
authors were contacted and requested to provide information when data were
unreported. No formal reliability tests of abstractions were conducted; disagreements
were resolved by consensus (R.T.A., C.D.M., and L.A.).
DATA SYNTHESIS
Placebo-controlled randomized trials with lipid level outcomes were
quantitatively pooled because (1) multiple small to moderate-sized studies
with lipid level outcomes were available, (2) similar control groups were
used, and (3) lipid level outcomes were measured using similar parameters
at similar follow-up times. Standardized mean differences, adjusted for baseline
differences, were used as the effect size measure rather than mean differences.25-26 Effect sizes calculated as mean differences
can be variably influenced by underlying population values when studies exhibit
substantial heterogeneity at baseline; greater absolute effects are more likely,
for example, to occur among patients with high baseline cholesterol levels
than among those with lower baseline cholesterol levels.26
We tried to identify outlier studies with Galbraith plots, a standard  2 test, and funnel plots. Studies were considered outliers if the 2 test was P<.10 and/or if they fell outside
of the Galbraith or funnel plot.
Data were pooled using a random effects estimate both with and without
studies that were identified as outliers.27
(Results presented in the text are without outliers, while figures give results
of both analyses.) Subgroup analyses were conducted for trials that (1) used
similar dried standardized preparations of garlic, (2) enrolled subjects with
hypercholesterolemia, and (3) used double-blind designs. A study that evaluated
a garlic and fish oil combination was not pooled because of possible independent
effects of fish oil on lipid levels. Effect sizes were converted to clinical
laboratory units using the following weighted average pooled SDs: total cholesterol
level, 1.05 mmol/L (40.8 mg/dL); low-density lipoprotein 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, 0.97 mmol/L (85.9
mg/dL).
RESULTS
OVERVIEW OF TRIAL QUALITY
Randomized trials were published in scientific journals (n = 37), symposia
proceedings (n = 5), a book chapter (n = 1), a thesis (n = 1), and an abstract
(n = 1; full report was obtained from the corresponding author). Details of
randomization procedures were scant. Whether 2 trials were actually randomized
was unclear; attempts to contact the original authors for clarification were
unsuccessful.28-29 Equivalencies
between randomized groups for baseline lipid levels, blood pressure, body
mass, diet, or activity levels were reported in 16 trials.21, 30-44
Of 34 trials with double-blind designs, only one, which used an odor-free
dehydrated tablet, assessed adequacy of blinding through direct questioning.
Blinding was reportedly not successful.33 Eight
trials reported adverse effects clearly attributable to garlic (ie, body odor,
breath, or taste) that occurred significantly more frequently in garlic-treated
subjects than in those receiving placebo; all of these trials used standardized
dehydrated tablets.21, 33, 39-40,43, 45-47
Four trials specifically used a placebo with garlic odor or taste.30, 35, 48-49 One
of these, which involved a nonstandardized dehydrated preparation, reported
that an insignificant number of subjects correctly guessed their assignment.30
Four trials had dropout rates that were 20% or greater.40, 43, 50-51
Five excluded subjects from the statistical analysis due to insufficient compliance,
protocol violations, or missed visits,34, 38-41
and 3 reported rates of compliance that were less than 80%.21, 50, 52
Only 6 specifically conducted intention-to-treat analyses or reported no dropouts.21, 34, 37, 53-54
INTERVENTION AND CONTROL GROUPS
Twenty-two studies evaluated dehydrated garlic preparations that were
standardized to an alliin content of 1.3% of the weight of active powder within
each tablet (Table 1, Part A,
and Table 1, Part B).9, 21, 32-34,38-40,43-44,46-47,51-52,54-61 Other preparations were
standardized to a minimum release of 0.3% allicin,62
and 4.6 mg of alliin per tablet.45 The remainder
used various nonstandardized preparations alone,28-33,36, 42, 48-50,53, 57, 63-66
or in combination with either fish oil, hawthorn, soya lecithin, gingko biloba,
or other lesser ingredients.35, 37, 41, 67-68
Compliance of preparations with gastrointestinal dissolution standards were
rarely reported.46
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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
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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 (cont)
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Placebos were used as control comparisons except for a no-garlic control,65 an antilipidemic agent,34
an antihypertensive agent,59 and a head-to-head
comparison of 2 different garlic preparations.57
Ten studies specified low-fat, low-cholesterol, high-fiber diets.21, 34, 44-45,47, 50, 52, 56, 58, 62
other studies defined no specific dietary measures and generally allowed usual
diets. Seven trials reported no changes in diet during follow-up,30, 33, 42, 44, 47, 49, 52
15 reported no changes in body mass,9, 30, 33-35,38, 42, 44, 47, 49-52,56, 58
and 2 reported no changes in physical activity.30, 52
Trials used various lipid measurement protocols; a few clearly followed current
suggested guidelines.21, 30, 42, 44-45,58
TRIAL OUTCOMES
Antilipidemic Effects
Meta-analyses of placebo-controlled trials that reported total cholesterol
level outcomes at 4 to 6 weeks, 8 to 12
weeks, and 20 to 24 weeks are shown
in Figure 1. Combining all studies
regardless of garlic preparation showed that compared with placebo the total
cholesterol level was reduced on average by 0.19 mmol/L (7.2 mg/dL) (95% confidence
interval [CI], 0.03-0.34 mmol/L [1.2-13.15 mg/dL]) after 4 to 6 weeks of therapy
(n = 14) and 0.44 mmol/L (17.1 mg/dL) (95% CI, 0.32-0.57 mmol/L [12.37-22.04
mg/dL]) after 8 to 12 weeks (n = 24). Studies evaluating standardized dehydrated
garlic preparations revealed average reductions of 0.26 mmol/L (10.2 mg/dL)
(95% CI, 0.08-0.45 mmol/L [3.09-17.40 mg/dL]) after 4 to 6 weeks (n = 8) and
0.50 mmol/L (19.2 mg/dL) (95% CI, 0.34-0.66 mmol/L [13.15-25.52 mg/dL]) after
8 to 12 weeks (n = 12). Average reductions after 20 to 24 weeks of treatment
were not statistically significant (all garlic preparations [n = 6]: 0.03
mmol/L (1.2 mg/dL) 95% CI, -0.21 to 0.28 mmol/L (-8.12 to 10.83
mg/dL); standardized dehydrated garlic preparations only [n = 3]: 0.07 mmol/L
(2.8 mg/dL) (95% CI, -0.22 to 0.37 mmol/L (-8.51 to 14.31 mg/dL).
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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.
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At 8 to 12 weeks, average triglyceride level reductions from placebo-controlled
trials, regardless of garlic preparation type (n = 17), were 0.21 mmol/L (19.1
mg/dL) (95% CI, 0.09-0.34 mmol/L [3.48-13.15 mg/dL]); average reductions among
trials evaluating standardized dehydrated garlic tablets (n = 13) were 0.24
mmol/L (21.1 mg/dL) (95% CI, 0.09-0.38 mmol/L [3.48-14.69 mg/dL]). At 8 to
12 weeks, average LDL-C level reductions across all garlic preparation types
(n = 13) were 0.16 mmol/L (6.2 mg/dL) (95% CI, 0.02-0.30 mmol/L [0.77-11.6
mg/dL]), and standardized dehydrated garlic tablets alone (n = 10) were 0.17
mmol/L (6.7 mg/dL) (95% CI, 0-0.34 mmol/L [0-13.15 mg/dL]). At 8 to 12 weeks
the average HDL-C level reduction from all garlic
preparations combined (n = 14) was 0.02 mmol/L (0.9 mg/dL) (95% CI, -0.03
to 0.07 mmol/L [-1.2 to 2.70 mg/dL]), whereas reduction from standardized
dehydrated garlic preparations (n = 10) was 0.01 mmol/L (0.2 mg/dL) (95% CI, -0.05
to 0.06 mmol/L [-1.93 to 2.32 mg/dL]). Analyses limited to trials with
only subjects with hyperlipidemia or that used double-blind methods did not
vary significantly from those presented earlier.
The only head-to-head trial compared a standardized dehydrated preparation
(Kwai) to garlic oil (Hoefels Original Garlic Oil with Rutin; Seven Seas Limited,
Marfleet Hull, England). This unblinded trial found a statistically significant
reduction in LDL-C level, but not total cholesterol or HDL-C level, favoring
the dehydrated preparation after 4 months of therapy.57
The one trial that compared a commercial antilipidemic agent (bezafibrate)
with a garlic preparation (Kwai) found no differences in lipid level outcomes
after 3 months of therapy.34
Antihypertensive Effects
Of 30 trials measuring blood pressure outcomes, 23 reported results
from placebo comparisons (3 did not report results29, 39, 43;
4 used nonplacebo controls34, 57, 59-60).
Three trials focused on subjects with hypertension and studied blood pressure
as the primary outcome.55, 59-60
Seven clearly excluded use of additional antihypertensive agents.32-33,47, 55-57,67
Although several trials reported significant reductions in blood pressure
among subjects given garlic (within group comparisons), only 3 demonstrated
statistically significant reductions in diastolic blood pressure (range, 2%-7%),33, 54-55 and 1 in systolic
blood pressure (approximately 3%)33 between
persons given garlic and those given placebo. These data were not pooled because
about half of the studies did not present numerical data that could be used
in a quantitative analysis, multiple different methods of blood pressure measurement
were used, and few studies had a priori hypotheses related to blood pressure.
Antiglycemic Effects
Twelve trials assessed the effect of garlic on the serum glucose level.9, 28, 31-32,43, 46, 53, 55, 59-60,67
Two studied adults with diabetes mellitus and considered serum glucose level
as a primary outcome.31, 46 Only
one 4-week trial, conducted in nondiabetic persons, reported a statistically
significantly greater reduction in the serum glucose level with standardized
dehydrated garlic tablets (Kwai) compared with placebo.32
No statistically significant effects were reported for glycosylated hemoglobin,46 serum insulin and C-peptide levels,46
and responsiveness of serum insulin levels to an oral glucose challenge.31
Antithrombotic Effects
Ten trials assessed the effectiveness of garlic on potential prothrombotic
risk factors.28, 32, 40, 43, 48, 52-53,66-67,69
Of 6 of these 10 trials measuring effects on spontaneous platelet aggregation,
5 provided results32, 40, 48, 67, 69;
4 of these 10 trials, all prohibiting intake of additional antiplatelet medications,
reported modest but significant decreases in platelet aggregation with garlic
treatment compared with placebo,32, 40, 48, 67
and the other reported significant decreases in epinephrine-induced, but not
adenosine diphosphate–induced, platelet aggregation.69
Mixed effects on fibrinolytic activity28, 53, 66
and plasma viscosity were reported, while no trials assessing serum fibrinogen
levels28, 32, 52-53
or serum homocysteine levels52 reported significant
results.
Effects on Cardiovascular Morbidity and Mortality
Clinical trial data for cardiovascular morbidity outcomes are limited.
Two trials assessed improvement in pain-free walking distance in subjects
with lower extremity peripheral vascular disease treated with garlic vs placebo.40, 67 Although the authors of one trial
reported significant increases in the walking distance with standardized dehydrated
tablets (Kwai), there was a 20% dropout rate with no intention-to-treat analysis,
significant disparities in the reporting of a garlic taste between garlic-treated
and placebo groups that suggested possible inadequate blinding, and a reanalysis
using baseline walking distances from the time of randomization rather than
during a run-in phase no longer yielded significant results.40
The second trial reported statistically significant increases in pain-free
walking but used a garlic oil macerate–soya lecithin–hawthorn
oil–wheat germ oil combination, making it difficult to assess the independent
effect of garlic on this end point.67
One 3-year trial assessing reinfarction rates in 432 patients with evidence
of a prior myocardial infarction reported 11 deaths and 15 reinfarctions in
222 subjects randomized to a garlic extract (0.1 g/kg per day for body mass)
and 20 deaths and 22 reinfarctions in the 210 placebo recipients.29 Although the author reported significant differences,
reanalysis of between-group comparisons using a 2 test revealed
no statistically significant differences 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 not be obtained despite
attempts to contact the original author.
Original authors of a placebo-controlled trial with standardized dehydrated
tablets (Kwai) involving 280 subjects have reported statistically significant
(P<.001) regression in atherosclerotic plaque
volume over 48 months.43 As of February 2000,
the authenticity of this trial was under investigation owing to concerns regarding
the validity of the ultrasound images accompanying the published text, unsuccessful
randomization procedures, an unusually high (46%) unequal dropout rate, and
inappropriate analyses.70
Adverse Effects
Approximately half of the trials reported adverse effects. Of those
reporting adverse effects, 8 reported significantly greater numbers of subjects
assigned garlic treatment had malodorous breath or body odor (as perceived
by themselves or others) compared with subjects assigned placebo.21, 33, 39-40,43, 45-47
The other trials that reported adverse effects stated that persons assigned
to dehydrated garlic tablets self-reported malodorous breath or body odor,
abdominal pain, fullness, anorexia, or flatulence, but had too few numbers
to statistically compare differences between groups. In addition to the trials,
73 further studies were found that addressed adverse effects (Table 2). Most (97%) were case reports or small case series. Reported
adverse effects of garlic ingestion (dietary and supplements) were dermatitis,
rhinitis, Meniere disease, asthma, myocardial infarction, bleeding, epidural
hematoma, increased International Normalized Ratio in persons taking warfarin
sodium, small-intestine obstruction, esophageal and abdominal pain, and flatulence.
The frequency of adverse effects and whether they varied by particular preparations
were not studied.
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Table 2. Summary of Adverse Effects
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COMMENT
Although inconclusive, randomized controlled trial data are compatible
with the hypothesis that garlic supplementation may produce mild short-term
benefits on the levels of total cholesterol, triglycerides, and LDL-C, and
on platelet aggregation. Several small short-term trials show mixed, but never
large, effects of garlic on blood pressure outcomes, and no effects on glycemic-related
outcomes. Given the overall marginal quality of many trials with respect to
adequacy of randomization and blinding, as well as an inadequate definition
of the specific biologically active garlic constituents in tested preparations,
these results have limited clinical applicability. Although multiple adverse
effects of garlic ingestion have been reported, causality is established only
for malodorous breath and body odor. The most serious potential adverse effect
that has been cited is spontaneous epidural bleeding. The expected frequency
of adverse effects, whether they are "dose-related," and whether they are
specific to or occur more commonly with particular garlic preparations than
others are unclear.
Few trials clearly reported error-free randomization procedures. Blinding
of subjects was impossible in many trials that evaluated odor-producing preparations,
and several double-blind trials that used odor-free coated preparations still
reported adverse effects discernable to subjects that were clearly attributable
to garlic. The inability to adequately blind subjects may have led to systematic
overestimation or underestimation of garlic's effects. For example, it is
possible that true putative health benefits of ingesting garlic are attributable
to the presence, concentration, and form of its many sulfur-containing compounds.
These sulfur-containing compounds generate the unique taste and odor of garlic.
Studies of garlic treatment that successfully blind subjects to group assignments
may be using garlic products that not only have undetectable taste and odor
but that also have low levels of active sulfur-containing compounds. If benefits
are tied to sulfur-containing compounds, such studies might underestimate
them.
Concealment of random allocation from investigators, blinding of subjects,
and proper handling of missing data are the only quality variables that have
been empirically shown to affect trial outcomes.71
Because of unclear adequacy of double-blindin techniques and because very
few trials performed intention-to-treat analyses or reported no dropouts,
distinguishing higher-quality trials was infeasible for performing sensitivity
analyses. These methodological limitations affect the clinical relevance of
even statistically significant results and further limit the use of attempting
to rationalize the significance of trends in the pooled data analyses.
Several issues related to the intrinsic qualities of garlic further
complicate interpretation of current human studies. First, there is no universal
consensus regarding exactly which constituents of garlic have major effects
on particular cardiovascular risk factors in vivo and by what mechanism these
effects are achieved. Second, the relative ingredient content of whole garlic
is affected by growth conditions such as soil composition. Finally, variation
in the methods of preparing particular garlic preparations results in significant
differences in final composition. For instance, crushing or cutting whole
garlic commingles the ingredient alliin with an enzyme, alliinase, resulting
in liberation of allicin, which is believed by most garlic researchers to
be the major ingredient responsible for potential antilipidemic effects. The
herbal industry is unable to guarantee allicin content within tablets because
of limitations in the stability of this compound. Most allicin-based preparations
are, therefore, designed to generate allicin enzymatically from alliin after
ingestion. Although commercial tablets are standardized to fixed amounts of
alliin and allinase with the intention of maximizing allicin production after
consumption, allinase quickly denatures at low gastric pHs. Maximal allicin
release, therefore, depends not only on high alliin concentration and alliinase
activity in the tablet, but also protection of allinase from gastric acid
pH followed by rapid tablet dissolution in enteric pH. Despite the addition
of tablet coatings to prevent premature dissolution, most preparations have
not been systematically tested against US Pharmacopeia
methods for compliance with enteric-coating standards. Notably, differential
liberation of allicin from otherwise identical standardized dehydrated garlic
tablets, produced by the same manufacturer but in differen batches, has been
demonstrated.72 This variability in allicin
liberation, despite standardization, has recently been suggested to correlate
with variability in antilipidemic effects among many recent trials using particular
standardized dehydrated garlic tablet preparations.73
Additionally, although several trials reported equivalent baseline body
mass, diet, or activity level between groups, few assessed whether these factors
remained matched throughout the trial intervention. The presence of confounding
effects is supported by several trials that reported significant,39-40 or a trend toward significant,9, 28, 36-37,48, 51, 54-56,58-59,63, 68
benefit from placebo administration alone. Even accounting for regression
to the mean, some investigators argue such effects are more likely attributable
to unanticipated cointerventions or poor control for bias than true placebo
effects.74-76
Several trials used volunteer subjects who may potentially be seeking lifestyle
modifications for poor baseline dietary and activity habits. Studying such
populations could increase the perception of beneficial short-term effects
simply as a result of drift toward a more average lifestyle during the intervention
period—an effect that may be greater in a motivated group that is aware
of receiving a presumably beneficial study medication.74-75
Pooled analyses of trials do show reductions in the total cholesterol
level at 4 to 6 weeks with trends toward further reductions at 8 to 12 weeks,
although this trend did not persist at 20 to 24 weeks. Despite several possible
explanations for these trends, the marginal statistical significance of observed
short-term benefits and the generalized methodological shortcomings of trials
make further conjecture unwarranted. Pooled analyses also suggest that standardized
dehydrated preparations may result in greater mean short-term (4-12 weeks)
cholesterol level reductions than other preparations, but this difference
is neither clinically (approximately 0.12-0.26 mmol/L [5-10 mg/dL]) nor statistically
(P>.10) significant. Absence of a significant disparity
between preparations believed to contain distinctly different ingredients
might generally suggest that there is a common active constituent among all
preparations or that reported results are actually due to something other
than garlic itself, such as an unmeasured lifestyle modification. Alternatively,
it is also possible that the expected differences in ingredient availability
after ingestion were minimized by inadvertent selection of particular preparations
that have been shown to have substantially limited capabilities of liberating
allicin under gastrointestinal conditions.
Studies with significant results, written in English, or funded by pharmaceutical
companies historically have been more likely to be published.77
Of 45 randomized trials in our analysis, 36 (80%) were published in peer-reviewed
journals, 38 (84%) were published in the English language only, and 35 (78%)
were sponsored, to some degree, by herbal manufacturers. Although we believe
our search was comprehensive, and significant efforts were made to retrieve
unreported data from investigators, the potential for missing data and publication
bias in our review is still real.
CONCLUSIONS
One of the most readily apparent problems with human research about
the effects of garlic treatment is inadequate definition of biologically active
constituents and predictable availability of these constituents after ingestion.
Delineating major active ingredients and their mechanisms of action are essential
before conducting more trials. Although studies in humans report promising
potential lipid-lowering and antithrombotic benefits, they are limited by
unclear randomization procedures, short durations, and unclear adequacy of
blinding to treatment administration and outcome assessments. Further studies
with similar design features are useless. Rather, a few well-designed trials
of longer duration are warranted. Such trials should detail a clear and unbiased
recruitment and selection process, a clearly adequate randomization procedure,
and assessment of the successfulness of blinding techniques. Additional emphasis
on controlling cointerventions that can affect outcomes, clearly defining
the constituents and dissolution properties of garlic preparations being studied,
and using intention-to-treat analyses are also necessary.
AUTHOR INFORMATION
Accepted for publication November 1, 2000.
This study was prepared by the San Antonio Evidence-based Practice Center
under contract 290-97-0012, task order 3, to the Agency for Healthcare Research
and Quality (formerly the Agency for Health Care Policy and Research), Rockville,
Md.
Presented as an abstract at the Complementary and Alternative Medicine
in Cardiovascular, Lung, and Blood Research, National Heart, Lung, and Blood
Institute Campus, Bethesda, Md, June 12-13, 2000, and the Evidence-based Complementary
Medicine Congress, Munich, Germany, April 8, 2000.
We are indebted to the following persons for their contributions to
this project: Eric Block, PhD, for input regarding the chemistry of garlic;
Paul Heidenreich, MD, MS, for expert cardiological advice; Christine Aguilar,
MD, MPH, Mark Loveland, and David Mullins for help in abstracting data; Andrew
Vickers, MD, and Molly Harris, MLS, MA, for conducting the literature searches;
and Jennifer Arterburn, MTSC, for assisting with technical writing.
Reprints: Cynthia D. Mulrow, MD, MSc, Audie L. Murphy Memorial Veterans
Hospital, 7400 Merton Minter Blvd (11C6), San Antonio, TX 78284 (e-mail: mulrowc{at}uthscsa.edu).
From the San Antonio Evidence-based Practice Center, University of
Texas Health Science Center (Drs Ackermann, Mulrow, Ramirez, and Lawrence),
Veterans Evidence-based Research Dissemination Implementation Center, Audie
L. Murphy Memorial Veterans Hospital, San Antonio (Drs Mulrow, Ramirez, and
Lawrence); Center for Research in Disease Prevention, Stanford University,
Palo Alto, Calif (Dr Gardner); and the Istituto di Clinica Medica Universita
degli Studi di Ancona, Ancona, Italy (Dr Morbidoni). Dr Gardner is now with
the Center for Advanced Studies in Nutrition and Social Marketing, University
of California, Davis.
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