OLD AND SLOW WORKS FOR GARLIC!

Ryan Bradley, ND, MPH     January, 2011

Garlic and other Allium vegetables like onions, shallots, leaks and chives have a long history of reported cardiovascular benefit. Much of this belief has been based on large population-based nutrition studies in which frequent intake of these foods has been associated with reduced risk for cardiovascular disease and cardiovascular events. However, the mechanism for this apparent protection is not well established. A few small clinical trials suggested garlic may be helpful in helping to reduce cholesterol levels in the blood, leading to the popularization of garlic supplements for treating cholesterol. Additional clinical trials suggested garlic may lower blood pressure. Other studies have focused exclusively on possible mechanisms of protection, specifically the antioxidant action of various garlic products. The antioxidant activity of garlic may improve arterial function via protection of the innermost layer of the vascular wall, called the endothelium, improving dilation or opening of the vessel, leading to improvements in circulation and reduced blood pressure.

However, the current state of the research on garlic is very mixed, with one of the main sources of confusion being the preparation method of the garlic product under investigation. As the chemistry of garlic changes considerably between fresh garlic and aged garlic, it is important to differentiate each type separately. Similarly, recent preparations have included enteric-coated and time-released formulas, further complicating discussion. In this article, I will briefly review the clinical trials performed on these various garlic preparations, focusing on the research on cholesterol and blood pressure.

Early Support for Antioxidant Activity of Garlic

For decades clinical and basic science research has established that garlic, and especially aged garlic, has potent antioxidant activity relevant to vascular function. Specifically, in 1993 Phelps et al. demonstrated a 34% reduction in the susceptibility of LDL cholesterol to oxidation after aged garlic supplementation (Kwai, 600 mg/day) was administered to 10 healthy adult participants for just 2 weeks. [1] As oxidized LDL cholesterol is known to bind to specific receptors and stimulate the activation of numerous pro-inflammatory changes in the vascular wall, this activity was submitted as a mechanism of garlic protection, and more detailed studies were conducted to further establish this action. In 1999, Ide and Lau reported that aged garlic extract specifically preserved antioxidant reserves in cultured endothelial cells, as well as reduced the accumulation of potent oxidants called peroxides in endothelial cell models.[2] The same research group also demonstrated that the observed activity appeared to be due to the action of S-allycysteine, a sulphur-based antioxidant formed exclusively during the aging of garlic.[3]

Whether this antioxidant action was unique to aged garlic or could also be extended to other forms of garlic was explored a few years later by Munday et al. in a translational clinical study in which human participants were supplemented with either aged garlic (2.4 grams/day), raw garlic (6 grams/day), or vitamin E (0.8 grams/day) for 7 days and LDL samples were collected and measured again for susceptibility to oxidation. Their results suggested that the aged garlic group, but not the raw garlic group, showed reduced susceptibility to oxidative stress when measured outside of the body, and that the degree of protection from peroxidation was similar in magnitude to vitamin E supplementation.[4] These four mechanistic studies were surprisingly consistent in their findings and clearly demonstrated a plausible mechanism of action for aged garlic as a protective agent for the cardiovascular system. However, despite the consistency of these findings, larger studies measuring clinically meaningful risk factors like cholesterol and blood pressure levels were also needed to fully understand how garlic may, or may not, fit into the clinical management of risk for heart disease.

Garlic for Cholesterol-Lowering?

Despite various discussions contradicting the significance of cholesterol, LDL cholesterol remains the most established, and the greatest - though certainly not the only- risk factor for developing atherosclerosis and cardiovascular disease, and there is general agreement in most areas of medicine that lowering LDL will help reduce the odds of having a heart attack or a stroke.

One of the earliest controlled clinical trials of garlic for cholesterol lowering was published in1996 by Steiner et al. in which the group administered 7.2 grams of aged garlic extract to 41 patients with elevated cholesterol and measured changes in their total cholesterol and LDL cholesterol after 6 months of treatment.[5] In this small clinical trial, total cholesterol was reduced by about 6% compared to the changes in the placebo group of the study. Additionally, they also observed a 5.5 mmHg reduction in blood pressure (specifically systolic pressure, or “the top number”). Although these reductions were modest at best, the findings were significant, and led to a series of follow-up trials to further test garlic preparations for cholesterol lowering properties.

Two subsequent clinical trials of garlic powder (standardized, non-aged garlic), and one trial of garlic oil went on to find no effect of these garlic preparations for reducing cholesterol or LDL. [6-8] These conflicting studies led to controversy about the effectiveness of garlic for cholesterol lowering, and fortunately, led to a definitive study.

In 2007 Gardner et al. published the results of a four-group, parallel-designed, placebo controlled trial of raw garlic vs. aged garlic vs. standardized garlic in a tablet vs. placebo in 192 adults with moderately elevated total cholesterol.[9] All doses were designed to be equivalent to an averaged sized garlic clove, essentially eaten daily for 6 days/week for 6 months. Despite being designed to detect a 10% reduction in cholesterol, specifically LDL cholesterol, this trial found no effect of any of the garlic preparations on lowering total or LDL cholesterol.

Although this trial was the most definitive, and unfortunately negative, trial of garlic for reducing cholesterol, there are two additional outlier studies that deserve discussion. In 2001, Kannar et al. published a very small clinical trial of an enteric-coated garlic preparation in which they treated 46 patients with elevated cholesterol for just 12 weeks[10]; at the end of the trial, LDL cholesterol was reduced approximately 6.6%, although, interestingly, HDL cholesterol (the healthy kind) actually lowered in the active garlic treatment group, compared to the placebo group, which is an unexpected result for a therapy proposed to improve lipid profiles (i.e., the typical goal for lipid treatment is to raise HDL cholesterol and lower LDL cholesterol, thus lowering the LDL to HDL ratio). The finding in this small clinical trial is notable for two reasons. The first reason is that enteric-coated garlic was not a comparison group used in the trial by Gardner et al., so even though the Gardner study was so neutral, a doubt still remained regarding possible effectiveness of the enteric-coated product. Secondly, this study was performed in participants who had either failed other therapy (interestingly the subject of drug therapy failing is often the patient, when in fact it is the drug that was ineffective) or in patients who were not adherent to other therapies, suggesting their may be potential to use this product in situations were drugs are not effective or preferred.

Adding further support for the potential of more slowly absorbed/time-released garlic for treating cholesterol was a second independent study published in 2008 by Sobenin et al. in which 46 men with elevated lipids were treated for with a non-aged, time-released garlic product (Allicor, 600mg/day).[11] At the end of the 12 weeks study, LDL cholesterol was significantly lower in the active treatment group compared to the placebo group by 11.5%, and the difference in LDL from the start of the trial to the end of the trial in the active group was 13.8%! One key difference in this trial was that HDL cholesterol also improved, increasing by 11.5%. Although this study still needs to be replicated, ideally in larger study groups, an 11.5% reduction in LDL cholesterol, especially alongside a 11.5% increase in HDL cholesterol, is a clinically significant treatment affect that deserves additional research.

Garlic for Blood Pressure Lowering?

During the same time research was evaluating garlic products for cholesterol lowering, additional research was being performed to study garlic for blood pressure lowering. Reduction of oxidized LDL has the potential to reduce blood pressure by preventing reductions in a compound called nitric oxide, resulting in improved vessel expansion or dilation. The potential role of garlic for blood pressure lowering was supported by a recent meta-analysis of ten clinical trials by Reinhart et al. in which results from studies of various garlic preparations on blood pressure were combined and analyzed together [12]. This formal meta-analysis found that garlic appears to significantly lower blood pressure in patients with hypertension by approximately 16 mmHg systolic (the top number) and 9 mmHg diastolic (the bottom number).

Since this meta-analysis, one additional clinical trial evaluating garlic for blood pressure lowering has been published. In 2009, Sobenin et al. compared time-released garlic (600 mg/day) to placebo, and simultaneously compared aged garlic (Kwai 900 mg/day) to time-released garlic (Allicor, 2400 mg/day) in 84 patients following 8 weeks of treatment. [13] The results of their clinical trial demonstrated Allicor resulted in a 7 mmHg reduction in both systolic and diastolic blood pressures, while Kwai resulted in the same reduction in systolic, but not diastolic, suggesting the slower release of the Allicor maybe critical for optimal effects. Also notable, the increased dose of Allicor used in the study (2400 mg/day) had no additional effect beyond the lower dose (600 mg/day).

Conclusions

Although no final determination can be made about the use of garlic or garlic supplements for the reduction of cardiovascular risk, mainly because definitive studies measuring differences in disease outcomes like heart attack rates and stroke rates have not been performed, there are several consistencies in the literature. Human translational evidence studying aged garlic has consistently demonstrated that aged garlic, and not other forms, improves the antioxidant capacity of LDL cholesterol in humans, increases vascular wall antioxidant reserves, and reduces measures of inflammation in immune cells relevant in heart disease.

Nearly as consistent is the evidence that most garlic products do not meaningfully reduce LDL cholesterol, whether aged or fresh, with two small exceptions; two small studies of enteric-coasted garlic and time-released garlic have demonstrated modest LDL lowering effects. However these studies need to be replicated in larger samples before definitive conclusions can be made. Also consistent is that both aged and time-released garlic products appear to reduce blood pressure in clinically meaningful ways, with the current state of the science suggesting that time-released garlic (Allicor) may be more effective in reducing both systolic and diastolic blood pressures. This blood pressure lowering effect may be due to the same mechanism of action, i.e. improvement in endothelial function secondary to reducing the oxidation of LDL cholesterol and subsequent improvements in vasodilation. All of the results apply to individual garlic products, and garlic supplements vary in their preparation, including the concentration of compounds like S-allycysteine.

One last discussion: how does this all relate to garlic in the diet? Although this question has not been definitively evaluated, I will offer a little conjecture based on common sense. Given that s-allycysteine begins to be formed after garlic is crushed, it is feasible that considerable amounts of this compound are ingested from the diet if garlic is consumed regularly. Similarly, although time-released garlic supplements have the most consistently positive results for LDL lowering and blood pressure lowering, the value of the time-released product is to increase absorption of the garlic, but also to extend the absorption of the active garlic compounds, so while a special product formulation can accomplish this result, so too would frequent consumption of garlic in the diet, i.e. although the maximum concentration may be lower, frequent dosing may at least result in similar average concentrations over a lifetime.

Also supporting dietary garlic intake is that garlic is a well-represented component of the Mediterranean dietary pattern, which has clearly demonstrated cardiovascular disease protection in patients with and without diabetes. So while old/aged and slow garlic supplements may be effective, old and slow dietary patterns like the Mediterranean diet may accomplish the same effects. Regardless of your choice- find a way to incorporate more garlic into your life- and please brush your teeth!

In health- Ryan Bradley, ND, MPH

REFERENCES:

1. Phelps, S. and W.S. Harris, Garlic supplementation and lipoprotein oxidation susceptibility. Lipids, 1993. 28(5): p. 475-7.

2. Ide, N. and B.H. Lau, Aged garlic extract attenuates intracellular oxidative stress. Phytomedicine, 1999. 6(2): p. 125-31.

3. Ide, N. and B.H. Lau, S-allylcysteine attenuates oxidative stress in endothelial cells. Drug Dev Ind Pharm, 1999. 25(5): p. 619-24.

4. Munday, J.S., et al., Daily supplementation with aged garlic extract, but not raw garlic, protects low density lipoprotein against in vitro oxidation. Atherosclerosis, 1999. 143(2): p. 399-404.

5. Steiner, M., et al., A double-blind crossover study in moderately hypercholesterolemic men that compared the effect of aged garlic extract and placebo administration on blood lipids. Am J Clin Nutr, 1996. 64(6): p. 866-70.

6. Berthold, H.K., T. Sudhop, and K. von Bergmann, Effect of a garlic oil preparation on serum lipoproteins and cholesterol metabolism: a randomized controlled trial. JAMA, 1998. 279(23): p. 1900-2.

7. Isaacsohn, J.L., et al., Garlic powder and plasma lipids and lipoproteins: a multicenter, randomized, placebo-controlled trial. Arch Intern Med, 1998. 158(11): p. 1189-94.

8. Superko, H.R. and R.M. Krauss, Garlic powder, effect on plasma lipids, postprandial lipemia, low-density lipoprotein particle size, high-density lipoprotein subclass distribution and

9. Gardner, C.D., et al., Effect of raw garlic vs commercial garlic supplements on plasma lipid concentrations in adults with moderate hypercholesterolemia: a randomized clinical trial. Arch Intern Med, 2007. 167(4): p. 346-53.

10. Kannar, D., et al., Hypocholesterolemic effect of an enteric-coated garlic supplement. J Am Coll Nutr, 2001. 20(3): p. 225-31.

11. Sobenin, I.A., et al., Lipid-lowering effects of time-released garlic powder tablets in double-blinded placebo-controlled randomized study. J Atheroscler Thromb, 2008. 15(6): p. 334-8.

12. Reinhart, K.M., et al., Effects of garlic on blood pressure in patients with and without systolic hypertension: a meta-analysis. Ann Pharmacother, 2008. 42(12): p. 1766-71.

13. Sobenin, I.A., et al., Time-released garlic powder tablets lower systolic and diastolic blood pressure in men with mild and moderate arterial hypertension. Hypertens Res, 2009. 32(6): p. 433-7.