Evidence Report/Technology Assessment

Number 20

Prepared for:
Agency for Healthcare Research and Quality

U.S. Department of Health and Human Services
2101 East Jefferson Street
Rockville, MD 20852
http://www.ahrq.gov/

Contract No. 290-97-0012

Prepared by:
San Antonio Evidence-based Practice Center based at
The University of Texas Health Science Center at San Antonio
and the Veterans Evidence-based Research, Dissemination, and Implementation Center, a
Veterans Affairs Health Services Research and Development Center of Excellence

Cynthia Mulrow, M.D., M.Sc.
Program Director

Valerie Lawrence, M.D., M.Sc.
Principal Investigator

Ronald Ackermann, M.D.
Gilbert Ramirez, Dr.P.H.
Laura Morbidoni, M.D.
Christine Aguilar, M.D., M.P.H.
Jennifer Arterburn, M.T.S.C.
Erick Block, Ph.D.
Elaine Chiquette, Pharm.D.
Christopher Gardener, Ph.D.
Martha Harris, M.L.S., M.A.
Paul Heidenreich, M.D., M.S.
David Mullins
MaryAnn Richardson, Dr.P.H.
Nancy Russell, M.P.H.
Andrew Vickers, M.D.
Veonica Young, Pharm.D.

AHRQ Publication No. 01-E023

October 2000

On December 6, 1999, under Public Law 106-129, the Agency for Health Care Policy and Research (AHCPR) was reauthorized and renamed the Agency for Healthcare Research and Quality (AHRQ). The law authorizes AHRQ to continue its research on the cost, quality, and outcomes of health care and expands its role to improve patient safety and address medical errors.

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

The Agency for Healthcare Research and Quality (AHRQ), formerly the Agency for Health Care Policy and Research, through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.

John M. Eisenberg, M.D.	Douglas B. Kamerow, M.D.
Director Agency for Healthcare Research and Quality	Director, Center for Practice and Technology Assessment Agency for Healthcare Research and Quality

The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, test, treatment, or other clinical service.

This evidence report summarizes the effects of garlic on cardiovascular-related factors and disease, associations between garlic and cancer, and possible adverse effects of garlic.

English and non-English citations were identified through February 2000 from 11 electronic databases, references of pertinent articles and reviews, manufacturers, and technical experts.

We limited review of cardiovascular-related effects to randomized controlled trials in humans that lasted at least 4 weeks and compared garlic with placebo, no garlic, or another active agent. Review of associations with cancer was limited to controlled studies that compared any precancerous or cancerous lesions in humans consuming varying amounts of garlic. All types of studies in humans were used to assess adverse clinical effects.

Two physicians abstracted data from cardiovascular and cancer studies; one physician abstracted data about adverse effects. Lipid outcomes from cardiovascular trials were examined quantitatively using standardized and unstandardized mean differences (adjusted for baseline differences).

• Thirty-seven randomized trials, all but one in adults, consistently showed that compared with placebo, various garlic preparations led to small, statistically significant reductions in total cholesterol at 1 month (range of average pooled reductions 1.2 to 17.3 milligrams per deciliter [mg/dL]) and 3 months (range of average pooled reductions 12.4 to 25.4 mg/dL). Eight trials with outcomes at 6 months showed no significant reductions of garlic compared with placebo. Changes in low-density lipoprotein (LDL) levels and triglycerides mirrored total cholesterol results; no significant changes in high-density lipoprotein (HDL) levels were found.
• Twenty-seven small, randomized, placebo-controlled trials, all but one in adults, reported mixed but never large effects of various garlic preparations on blood pressure outcomes.
• Twelve small, randomized trials suggested that various garlic preparations had no clinically significant effect on glucose in persons with or without diabetes. Two small short trials reported no statistically significant effects of garlic compared with placebo on serum insulin or C peptide levels.
• Ten small trials, all but one in adults and of short duration, showed the effects of various garlic preparations on platelet aggregation and mixed effects on plasma viscosity and fibrinolytic activity.
• There were insufficient data to confirm or refute garlic's effects on clinical outcomes such as myocardial infarction and claudication.
• Scant data, primarily from case-control studies, suggest, but do not prove, that dietary garlic consumption is associated with decreased odds of laryngeal, gastric, colorectal, and endometrial cancer and adenomatous colorectal polyps.
• Adverse effects of oral ingestion of garlic are "smelly" breath and body odor. Other possible, but not proven, adverse effects include flatulence, esophageal and abdominal pain, small intestinal obstruction, dermatitis, rhinitis, asthma, and bleeding.

Trials show several promising, modest, short-term effects of garlic supplementation on lipid and antithrombotic factors. Effects on clinical outcomes are not established, and effects on glucose and blood pressure are none to minimal. High dietary intake of garlic may be associated with decreased odds of multiple cancers. Ability to interpret existing data is substantively limited by marked variability in types of garlic preparations that have been studied and inadequate definition of active constituents in the various preparations.

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.

Suggested Citation:
Mulrow C, Lawrence V, Ackermann R, et al. Garlic: effects on cardiovascular risks and disease, protective effects against cancer, and clinical adverse effects. Evidence Report/Technology Assessment No. 20 (Contract 290-97-0012 to the San Antonio Evidence-based Practice Center based at The University of Texas Health Science Center at San Antonio and the Veterans Evidence-based Research, Dissemination, and Implementation Center, a Veterans Affairs Health Services Research and Development Center of Excellence). AHRQ Publication No. 01-E023. Rockville, MD: Agency for Healthcare Research and Quality. October 2000.

This evidence report is a systematic review that summarizes clinical studies of garlic in humans. It addresses three areas: (1) effects on cardiovascular-related disease and factors such as lipids, blood pressure, glucose, atherosclerosis, and thrombosis; (2) any protective associations with cancer; and (3) clinical adverse effects. The report was requested by the National Center for Complementary and Alternative Medicine, a component of the National Institutes of Health, and sponsored by the Agency for Healthcare Research and Quality. The following are the rationale for this report: (1) availability of multiple clinical studies with promising but conflicting results, and (2) high consumer usage of garlic as a health supplement. The report is intended primarily for agencies interested in funding clinical garlic studies, clinicians, and researchers, and secondarily for consumers.

The report addresses the following topics:

• Whether oral ingestion of garlic (fresh, cooked, or supplements) compared with no garlic, other oral supplements, or drugs lowers lipids, blood pressure, glucose, and cardiovascular morbidity and mortality.
• Whether garlic increases insulin sensitivity and antithrombotic activity.
• Associations between garlic and precancerous lesions, cancer, or cancer-related morbidity and mortality
• Types and frequency of adverse effects of oral, topical, and inhaled garlic dust.
• Interactions between garlic and commonly used medications.

Eleven electronic databases, including AMED, CISCOM, the Cochrane Library (including DARE and the Cochrane Controlled Trials Registry), EMBASE, MEDLINE, and NAPRALERT, were searched 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 extract, garlic oil, garlic, knoblauch, Kwai, Kyolic, S-allylcysteine (SAC), thioallyl derivative, thiosulfinates, and vinyl dithiin. English and non-English citations were identified through July 1999 from these electronic databases, references in pertinent articles and reviews, manufacturers, and technical experts. Finally, an electronic update search using PubMed was conducted in February 2000.

Reports of garlic's effects on cardiovascular factors and outcomes were limited to randomized controlled trials (RCTs) lasting at least 4 weeks that compared garlic with placebo, no garlic, or another active agent. Reports of preventive effects on occurrence of precancerous lesions and cancer were limited to case-control and cohort studies that compared varying levels of garlic consumption. All types of studies in humans were used to assess adverse clinical effects.

Two independent physicians abstracted data from trials, and one physician abstracted data about adverse effects. Data were synthesized descriptively, emphasizing methodological characteristics of the studies such as populations enrolled, definitions of selection and outcome criteria, sample sizes, adequacy of randomization process, interventions and comparisons, cointerventions, biases in outcome assessment or intervention administration, and study designs. Relationships among clinical outcomes, participant characteristics, and methodological characteristics were examined in evidence tables and graphical summaries. Lipid outcomes of trials were examined quantitatively using standardized and unstandardized mean differences (adjusted for baseline differences). Hedges' g was used to compute the standardized mean difference for each trial.

• Thirty-seven randomized trials, all but one in adults, consistently showed that compared with placebo, various garlic preparations led to small, statistically significant reductions in total cholesterol at 1 month (range of average pooled reductions 1.2 to 17.3 milligrams per deciliter [mg/dL]) and 3 months (range of average pooled reductions 12.4 to 25.4 mg/dL). Garlic preparations that were studied included standardized dehydrated tablets (Kwai , Pure-Gar , or noncommercial enteric-coated tablets), dehydrated tablets, "aged garlic extract ^TM ," oil macerates, distillates, raw garlic, and combination tablets. Eight placebo-controlled trials reported total cholesterol outcomes at 6 months; pooled analyses showed no significant reductions of total cholesterol with garlic compared with placebo. It is not clear if statistically significant positive short-term effects-but negative longer term effects-are due to: systematic differences in studies that have longer or shorter followup durations; fewer longer term studies; or time-dependent effects of garlic. Statistically significant reductions in low-density lipoprotein levels (LDL) (range 0 to 13.5 mg/dL) and in triglycerides (range 7.6 to 34.0 mg/dL) also were found in pooled analyses at 3 months. No significant changes in high-density lipoprotein levels (HDL) were seen in pooled analyses at 1 and 3 months. One multicenter trial involving 98 adults with hyperlipidemia found no differences in lipid outcomes at 3 months between persons who were given an antilipidemic agent and persons who were given a standardized dehydrated garlic preparation. Interpreting the lipid results is best tempered by recognizing that trials often had unclear randomization processes, short durations, and no intention-to-treat analyses.
• Twenty-seven small, randomized, placebo-controlled trials, all but one in adults and of short duration, reported mixed but never large effects of various garlic preparations on blood pressure outcomes. Most studies did not find significant differences between persons randomized to garlic compared with those randomized to placebo. The one small trial (n=40) that directly compared a standardized dehydrated garlic preparation with an active antihypertensive agent found no differences in blood pressure between groups. Because of unclear randomization processes, lack of intention-to-treat analyses, missing data, and variability in blood pressure measurement techniques, no firm conclusions can be drawn from these trials.
• Twelve small, randomized trials, all in adults, suggested that various garlic preparations had no clinically significant effect on glucose in persons with or without diabetes. Two small short trials, both in adults, reported no statistically significant effects of garlic compared with placebo on serum insulin or C peptide levels.
• Ten small, randomized trials, all but one in adults and of short duration, showed promising effects of various garlic preparations on platelet aggregation and mixed effects on plasma viscosity and fibrinolytic activity. Because the trials had only 409 participants, short followup periods, unclear randomization processes, no intention-to-treat analyses, missing data, and variability in techniques used to assess outcomes, no firm conclusions can be drawn.
• There were insufficient data to confirm or refute effects of garlic on clinical outcomes such as myocardial infarction and claudication. One 3-year randomized trial with 492 participants found no statistically significant decreases in numbers of myocardial infarctions and deaths when placebo was compared with 6 to 10 grams of garlic ether extract. This trial was not published in peer-reviewed literature; details confirming its randomization process and followup were not obtained, despite requests to the author.
• Two double-blind trials in participants with atherosclerotic lower extremity disease evaluated whether garlic increased pain-free walking distance at 12 to 16 weeks compared with placebo. In one trial, 64 of 80 (80 percent) participants completed followup. Pain-free walking increased by approximately 40 meters with standardized dehydrated garlic (Kwai ) compared with approximately 30 meters with placebo. In the other trial, with 100 participants, the maximum walking distance increased significantly (114 percent) among persons randomized to a combination treatment of garlic oil macerate/soya lecithin/hawthorn oil/wheat germ oil compared with those randomized to placebo (17 percent) (p<0.05).
• RCTs did not establish whether garlic effectiveness varies across preparations or dosages. Limited data not derived from head-to-head comparisons suggest, but do not prove, that standardized dehydrated preparations may result in greater short-term (1- to 3-month) drops in total cholesterol than other preparations.

• Scant data, primarily from case-control studies, suggest, but do not prove, dietary garlic consumption is associated with decreased odds of laryngeal, gastric, colorectal, and endometrial cancer and adenomatous colorectal polyps. Single case-control studies suggest, but do not prove, dietary garlic consumption is not associated with breast or prostate cancer. No epidemiological study has assessed whether using particular types of garlic supplements is associated with reductions in cancer incidence. Preliminary 3-year evidence from a large cohort study suggests consumption of "any" garlic supplement does not reduce risk of breast, lung, colon, or gastric cancer. This study has not reported associations relevant to consumption of fresh or raw garlic, and its data about supplements are limited because information is not available about different types and brands of garlic supplementations.

• Adverse effects of oral ingestion of garlic are "smelly" breath and body odor. Other possible, but not proven, adverse effects include flatulence, esophageal and abdominal pain, small intestinal obstruction, contact dermatitis, rhinitis, asthma, bleeding, and myocardial infarction. There are two reports of patients taking warfarin who experienced increases in International Normalized Ratio (INR) when taking garlic pearls or tablets. The content and method of preparation of the pearls and tablets were not given. The frequency of adverse effects with oral ingestion of garlic and whether they vary by particular preparations are not established. Adverse effects of inhaled garlic dust include allergic reactions such as asthma, rhinitis, urticaria, angioedema, and anaphylaxis. Adverse effects of topical exposure to raw garlic include contact dermatitis, skin blisters, and ulcero-necrotic lesions. Frequency of reactions to inhaled garlic dust or topical exposures of garlic is not established.

There are insufficient data to draw conclusions regarding garlic's effects on clinical cardiovascular outcomes such as claudication and myocardial infarction. Garlic preparations may have small, positive, short-term effects on lipids; whether effects are sustainable beyond 3 months is unclear. Consistent reductions in blood pressure with garlic were not found, and no effects on glucose or insulin sensitivity were found. Some promising effects on antithrombotic activity were reported, but few data are available for definitive conclusion.

Using "any" garlic supplement for less than 3 to 5 years was not associated with decreased risks of breast, lung, gastric, colon, or rectal cancer. Some case-control studies suggest that high dietary garlic consumption may be associated with decreased risks of laryngeal, gastric, colorectal, and endometrial cancers, and adenomatous colorectal polyps.

Multiple adverse effects, including smelly breath and body odor, dermatitis, bleeding, abdominal symptoms, and flatulence, have been reported. Whether adverse effects occur more commonly with certain preparations than others was not established. Furthermore, the causality of the adverse effects was not clear, except for breath and body odor, and the expected frequency of adverse effects was not determined.

Notable limitations in summarizing findings from garlic research include the substantial variability in types of garlic and garlic preparations that have been studied and an inadequate definition of the active, biologically available constituents in the various preparations. In addition, many trials that evaluated the effects of garlic on cardiovascular-related endpoints are limited by short durations; inadequate randomization and blinding procedures; lack of clear specification of contents of garlic preparations-including their constituents and dissolution properties; lack of intention-to-treat analyses; and incomplete reporting of data. The meta-analysis we performed is limited by some missing data at different time points and by the need to impute variability data from some trials.

We found few studies assessing associations between garlic consumption and cancer. Some pertinent studies may have been missed because they addressed associations with multiple foods and either did not report or analyze findings specific to garlic. Studies that were found sometimes failed to distinguish the type of garlic exposure (raw, cooked, or specific supplement), used subject recall to assess different frequencies of use over varying time periods, and adjusted for various potential confounders in different ways. Although we believe that we found most reported adverse-effect literature regarding garlic, adverse effects in general are frequently underreported or reported in ways that do not allow causality and frequency to be determined.

Before undertaking future trials that evaluate the efficacy of garlic, the equivalency and the amount of release of the main constituents of various garlic preparations must be established. Placebos designed to simulate garlic odor should be developed, and adequacy of blinding should be assessed in trials. Well-designed randomized trials that are longer than 6 months in duration and that are powered to assess morbidity and mortality outcomes, as well as lipid and thrombotic outcomes, are needed. Appropriate analyses that are intention-to-treat and two-tailed should be used.

Additional cohort and case-control studies that assess associations between garlic and precancerous and cancerous lesions are likely to be helpful only if the frequency, types, and formulations of garlic that are consumed are specified clearly. Such studies should use sampling techniques that allow multiple levels of garlic consumption to be represented. Consideration should be given to mounting more trials, such as the ongoing Chinese trial, that evaluate the protective effects of different garlic preparations in persons with very high risk of cancer or precancerous lesions. Future reviews in this area should search more broadly for diet-related population studies and aim to place findings specific to garlic in a broader context that takes into account findings regarding other Allium-containing vegetables as well as other foods.

The frequency and severity of adverse effects related to garlic should be quantified. Whether adverse effects are specific to particular preparations, constituents, or doses should be elucidated. In particular, adverse effects related to bleeding and interactions with other drugs such as aspirin and warfarin warrant study.