Garlic for treating hypercholesterolemia. A meta-analysis of randomized clinical trials. Stevinson C, Pittler MH, Ernst E.
Overall Study Question
Two previous meta-analyses have been published on the effect of garlic on serum total cholesterol levels. The last meta-analysis was published in 1994 and several independent studies have conducted since this time. The objective of the current article was to conduct a an updated meta-analysis of all studies meeting the inclusion criteria and to thus reassess the effect of garlic (as compared to placebo) on total serum cholesterol in patients with elevated (i.e. greater than 5.17 mmol/L) levels. No efforts were made by the investigators to distinguish between studies that focused on patients with coronary heart disease (CHD) versus those without.
Are the Results of the Study Valid?
Did the overview address a focused clinical question?
Were the criteria used to select articles for inclusion appropriate?
Yes. In order to be included in the meta-analysis, studies were required to be of randomized, double-blind, and placebo-controlled design. Furthermore, treatments were required to include single entity garlic preparations, patients enrolled in the clinical trials had to have had elevated total cholesterol levels of at least 5.17 mmol/L, and total cholesterol levels had to be an endpoint of the included study. It is unclear as to whether or not studies were required to have used total cholesterol as the primary endpoint (vs. secondary) in order to be included in the meta-analysis.
Is it unlikely that important, relevant studies were missed?
Yes. The authors utilized a variety of databases from European and United States sources to identify relevant articles. Searches were performed from the earliest date each database was created through to November 1998. Efforts were made to identify additional published or unpublished articles by contacting experts in the field, manufacturers of garlic preparations, and by searching the bibliographies of all papers. Articles of all languages were reviewed. Thirty nine studies were identified, however, 13 met the inclusion criteria and thus were included in the analysis.
Was the validity of the included studies appraised?
Yes. The quality of the methods utilized by each study identified was assessed using a scale which quantified the likelihood of bias of the trial based upon the description of the randomization, blinding, and patient withdrawals. The article did not indicate the score (if any) that was needed to be attained in order for a study to be included in the analysis.
Were assessments of studies reproducible?
Yes. The meta-analysis used the chi-square test although the specific type of test used was not identified. This test for heterogeneity was significant indicating statistical heterogeneity amongst the trials. The heterogeneity was due to one study in particular. When study was excluded, homogeneity between the remaining 12 studies was found. No further tests for heterogeneity were undertaken.
What were the Results?
What are the overall results of the review?
Thirty-nine studies were identified, however only 13 met the inclusion criteria for meta-analysis. There were 796 patients enrolled in the 13 studies, 10 trials reported benefits with garlic, while 3 found no difference as compared to placebo. Overall, the meta-analysis revealed that garlic significantly (p<0.01) reduced total cholesterol levels. Treatment with garlic resulted in a 5.8% reduction in total cholesterol levels from baseline. The authors did not report the reduction in cholesterol levels that occurred with placebo. The authors also evaluated the effect of garlic on total cholesterol levels using the 12 homogenous studies and found a smaller (4.3%) reduction in cholesterol levels with garlic. Gastrointestinal symptoms and garlic breath were the most frequently reported adverse effects. It is unclear if there were significant differences in the incidence of adverse effects between the garlic and placebo groups.
How precise were the results?
Among the 13 studies included, treatment with garlic resulted in a 5.8% reduction in total cholesterol levels from baseline. The weighted mean difference was – 0.41 mmol/L (95% CI, -0.66 to -0.15 mmol/L). Among the 12 homogenous studies, the reduction in total cholesterol levels with garlic was 4.3%, equivalent to a mean difference of -0.30 mmol/L (95% CI, – 0.48 to – 0.11 mmol/L).
How much does allowance for uncertainty change the results?
Two sensitivity analyses were performed. The first analysis utilized 5 methodologically similar studies (i.e. same garlic preparation, same dose and also controlled for dietary factors). No significant difference in the reduction of total cholesterol with garlic (as compared to placebo) was found. The second analysis included 6 of diet-controlled studies and, once again, the authors found no significant difference between garlic and placebo in the reduction of cholesterol.
Will the Results Help Me in Caring for My Patients?
Can the results be applied to my patient care?
No. While the current meta-analysis found garlic to reduce total cholesterol levels by at best 5.8%, there are numerous unanswered questions which make applying the results of this trial to direct patient care difficult. The reduction in cholesterol levels seen with garlic is considerably less than that seen with other effective lipid-lowering interventions, such as diet or the HMG-CoA reductase inhibitors. Furthermore, it is unclear from this analysis of the effect of garlic on other endpoints that are more relevant than total cholesterol levels such as the incidence of coronary heart disease, mortality, and morbidity. While this analysis included all patients with elevated total cholesterol levels, it is unclear whether specific groups of patients would derive greater benefit (i.e. those with or without CHD, elevated low-density lipoprotein, or low high-density lipoprotein. It is also unclear as to the length of therapy required with garlic to derive a 5.8% reduction. The duration of therapy of the studies included in the meta-analysis ranged from 8 weeks to 24 weeks. The benefits of longer therapy are unknown.
Were all clinically important outcomes considered?
No. While the use of total cholesterol as a study endpoint is easily measured, it is not the most relevant endpoint to evaluate. Future studies should focus on clinically relevant endpoints, such as the effects of garlic on the specific lipoproteins, such as the atherogenic low-density lipoprotein or high-density lipoprotein, or clinical outcomes, for example total mortality, the incidence of CHD, or death from myocardial infarction and/or CHD.
Are the benefits worth the harms and costs?
No. The benefit of garlic in reducing cholesterol levels, in the absence of other relevant clinical endpoints, is likely not worth the costs, despite the minimal adverse effects observed. Lipid-lowering diets are more cost effective than garlic. Furthermore, patients can derive greater cholesterol reductions with diet therapy alone.
Cardiovascular disease, of which CHD is the most common, is the leading cause of death in Canada. Elevated cholesterol is an independent risk factor for heart disease. Numerous studies have shown that the incidence of coronary heart disease and elevated cholesterol to be continuous and graded. Numerous large, randomized, controlled trials have shown that reducing cholesterol levels with HMG-CoA reductase inhibitors, in patients with and without CHD, and with elevated and “average” cholesterol levels reduces mortality and morbidity. In addition to knowing which patients derive the greatest benefit from therapy, the duration of therapy required to obtain benefits, the side effects from these medications are known, and for the most part, minimal. In order to be considered an “alternative” to standard therapies, studies evaluating other forms of lipid-lowering interventions, such as garlic, need to evaluate clinically relevant endpoints, as have the HMG-CoA reductase trials. In the absence of these studies, recommending these “alternative” interventions is difficult. Numerous unanswered questions exist from the current meta-analysis on the use of garlic in reducing total cholesterol levels. As previously mentioned, there are no data on the effect of garlic on the incidence of coronary heart disease, reductions in fatal or non-fatal myocardial infarctions, hospital admissions, or total mortality. Furthermore, it is unclear which types of patients derive the greatest benefit. The meta-analysis included patients with and without CHD and children. The form of garlic administered to patients enrolled in the studies varied from essential oil to standardized powder, or spray-dried powder. Whether there are differences in endpoints based upon the form of garlic used is unknown. Furthermore, the dose of garlic required is unknown. Patients inquiring about the use of garlic for reducing cholesterol should be informed of the minimal reduction in cholesterol levels observed in clinical trials and the aforementioned pitfalls of the current literature. Future randomized, controlled studies of garlic, should evaluate specific groups of patients, specific garlic preparations and doses, and evaluate clinically important endpoints.