Garlic and Cardiovascular Disease

By Dónal P. O'Mathùna, PhD, Senior Lecturer in Ethics, Decision-Making & Evidence, School of Nursing & Human Sciences, Dublin City University, Ireland. Dr. O'Mathùna reports no financial relationships relevant to this field of study.

Cardiovascular disease (CVD) is a complex group of heart-related conditions that are the leading cause of death among Americans and Europeans.1 The prevalence of CVD is growing rapidly in developing countries also.2 Finding safe and effective strategies to prevent and treat CVD is a major priority around the world.

Many factors contribute to the development of CVD, which encompasses high blood pressure, coronary artery disease, heart failure, stroke, and congenital cardiovascular defects. Epidemiological studies exploring cardiovascular risk factors have pointed to the role of elevated serum lipids (including cholesterol and triglycerides), elevated blood pressure, increased platelet aggregation, increased plasma fibrinogen and coagulation factors, alterations in glucose metabolism, and smoking.3 Reduced risk of CVD is associated with increased serum levels of high-density lipoprotein (HDL-C), normalization of abnormal lipid levels, inhibition of platelet aggregation, and, in some studies, increased antioxidant status.

Dietary factors are known to play a role in CVD, with Mediterranean diets, fish, fruit, and whole grains known to reduce CVD risk.1 One study in which patients admitted with acute vascular disease were interviewed found that 78% were taking natural health products; such usage had been documented by pharmacists in 41% of patients, by physicians in 22%, and by nurses in 19%.4 These numbers include some overlapping in documentation. Garlic (Allium sativa, Family Liliaceae) continues to be in the top five best-selling herbs, and is the most popular herb used by patients with CVD.5

History

Garlic has been an important component of peoples' diets in many cultures for centuries.2 Ancient Ayurvedic texts refer to health benefits of garlic in terms of improving blood flow and strengthening the heart.6 The Egyptian Codex Ebers (1500 BC) recommended garlic for heart disease, and also for tumors, worms, bites, and many other conditions. The Greek physician, Hippocrates (400 BC), and the Roman authority, Pliny the Elder (77 AD), recommended garlic for the cardiovascular system.7

Clinical work as early as 1926 found garlic to have beneficial effects on cardiovascular disease. These effects were again mentioned in the 1960s and 1970s when a number of studies noted reductions in serum cholesterol and triglyceride levels.6 However, these early studies were conducted with raw garlic administered at very high doses (between seven and 28 cloves per day).

Pharmacology

Garlic's odor problem has led to much work being done to find more palatable and less odorous formulations. The odor, as well as garlic's cardiovascular effects, is caused by sulfur-containing compounds.8 Garlic cloves contain almost all their sulfur in a storage compound called alliin (a name coming from garlic's botanical name, Allium sativum). Raw garlic also contains an enzyme called alliinase. When raw garlic is cut or crushed, the alliinase interacts with alliin to produce allicin.9 The distinctive aroma and taste of garlic is due to allicin, which is very volatile and unstable, breaking down either in a few hours at room temperature or after a few minutes of cooking. An in vitro study found that garlic's ability to inhibit platelet aggregation was not changed after 3 minutes or less of immersion in boiling water. After 6 minutes, garlic cloves had no activity, while crushed garlic retained some activity. After 10 minutes, all activity was gone. Microwaving for about 2 minutes removed all activity from all samples.10

As allicin breaks down or is metabolized, dozens of other more stable sulfur compounds are formed. Many of these are biologically active. If garlic is macerated with oil, allicin is converted into ajoene and polysulfides that can be stable for more than a year.11 However, the precise activity of each specific compound remains uncertain.10 Most regard the sulfur-containing compounds as crucial to the health benefits of garlic, although those compounds are also responsible for garlic's odor-problems. The various ways garlic is processed lead to preparations with different compounds, which may account for some of the inconsistency observed in clinical trials. Table 1 lists the characteristics of some of the most commonly available formulations.

Mechanism of Action

In spite of considerable numbers of in vitro studies, the ingredient(s) in garlic responsible for cardiovascular effects remain unclear.12 Garlic impacts the cardiovascular system via several mechanisms, but many of its constituents are biologically active and uncertainty remains about how they all interact. Ajoene and other compounds inhibit platelet aggregation, which can help prevent CVD.2 Allicin has antiplatelet aggregating activity, although its instability makes it difficult to study its clinical effects. Several garlic constituents inhibit liver enzymes involved in making cholesterol, including HMG-CoA reductase (the enzyme inhibited by statins), and others lower plasma cholesterol and triglyceride levels via unclear mechanisms of action.13 Garlic also contains antioxidants that can counteract the development of atherosclerosis. Other constituents cause smooth muscle relaxation, which could contribute to reduced hypertension.

Various sulfur compounds derived from garlic cause the release of hydrogen sulfide (H2S) from human red blood cells.14 H2S is a naturally occurring cell signaling molecule with several cardioprotective effects, including vascular smooth muscle relaxation, decreased blood pressure, and protection against oxidative damage. This new research sheds light on garlic's potential mechanisms of action, and may lead to a means of standardizing garlic preparations.15

Clinical Studies

Many laboratory and animal tests have demonstrated that garlic and its constituents have biological activities related to CVD; however, controversy continues over the clinical significance of these findings.16 Results of trials have been contradictory, with early studies often finding beneficial effects which were not replicated in more recent trials that were usually larger, longer, and of higher methodological quality.12

The impact of garlic ingestion or supplementation on serum cholesterol and lipid levels has received the most research attention.11 Two meta-analyses published in 1993 and 1996 generated much interest in garlic because they reported 9% and 12% reductions in total cholesterol levels, respectively.17 More recent meta-analyses have come to different conclusions; one published in 2009 concluded that there was no evidence from randomized controlled trial (RCTs) of garlic having any beneficial effects on serum cholesterol.18 However, the search strategy in that meta-analysis has been criticized for not being comprehensive.12 The most recent evaluation reviewed literature published up to October 201112 and included 26 RCTs reporting the effects of garlic on various serum lipids. Overall, garlic significantly reduced serum total cholesterol by 0.28 mmol/L (P = 0.001) and triglycerides by 0.13 mmol/L (P < 0.001). At the same time, no significant differences were found for low-density lipoprotein cholesterol (LDL-C), HDL-C, apolipoprotein B, and total cholesterol/HDL-C ratio. The reviewers considered these results "unimpressive" and "modest," especially in comparison with dietary interventions and statin therapy. They calculated that the significant differences were equivalent to a 5.4% reduction in total cholesterol levels for someone with a baseline level of 5 mmol/L and a 6.5% reduction in triglyceride levels for someone starting with a 2 mmol/L level. The daily doses most commonly used in the studies reviewed were 10-15 mg garlic oil, 900 mg garlic powder, and 1-7 g aged garlic extract.12 Study duration ranged from 2 weeks to 12 months, with most trials lasting 3 or 6 months.

Many studies have examined the role of garlic preparations in lowering blood pressure. A 1994 meta-analysis of 10 randomized, controlled trials reported an overall significant reduction in systolic and diastolic blood pressure of 8 and 5 mmHg, respectively.11 Another meta-analysis published in 2008 included 11 RCTs and reported an overall reduction of 4.56 mmHg in systolic blood pressure for those taking garlic (P < 0.001).19 Diastolic blood pressure did not change significantly compared to placebo. A planned sub-group analysis was conducted comparing those who were normotensive or hypertensive at baseline. The hypertensive subgroup had significant reductions of 8.4 and 7.3 mmHg for systolic and diastolic blood pressures, respectively. The normotensive subgroup did not show significant reductions. The reviewers noted that reductions of 4-5 mmHg systolic and 2-3 mmHg diastolic are held to be clinically significant. At the same time, some RCTs have found no significant differences between groups taking garlic and placebo.

Although many of garlic's components have demonstrated antioxidant properties, relatively few studies have been conducted on the clinical significance of these effects. Most of the research to date has involved in vitro or animal studies, especially with one particular standardized garlic powder extract called Kwai. Another product called aged garlic extract (AGE; brand name Kyolic) is made by soaking garlic slivers in alcohol for 20 months, removing most allicin, and leaving an extract high in antioxidant capacity.7 An RCT with 65 patients examined the impact of AGE (250 mg/d) and multivitamins on subclinical atherosclerosis.20 After 1 year, those in the AGE group had significantly better outcomes than the control group for oxidative markers, vascular function, and progression of atherosclerosis. Another RCT found that those taking 960 mg AGE had significantly more reduction in systolic blood pressure (by 10.2 mmHg; P = 0.03).21 However, the total number of clinical studies evaluating AGE remains small.

Garlic and its components have been found to impact platelet aggregation and other aspects of blood clotting.15 Fibrinolysis leads to the breakdown of blood clots, and this process is promoted by various types of garlic preparations.7 Platelet aggregation has been beneficially affected by garlic in a small number of clinical trials.3 However, an Agency for Healthcare Research and Quality review concluded that these results must be taken as preliminary.22 While all the studies identified for this review had beneficial results, the studies were all very small, of limited duration, and some had serious methodological flaws.

Adverse Effects

Garlic is well-known for its problematic breath and body odor after oral ingestion. These are the most commonly reported complaints from trial participants.23 Eating raw garlic and high doses of some supplements also can cause mouth and gastrointestinal irritation, heartburn, nausea, vomiting, and diarrhea.24 Some people also are susceptible to allergic reactions to garlic, with one observational study estimating that 1.1% of people are susceptible to allergic reactions at therapeutic doses.23

The effects of garlic on platelet aggregation and fibrinolysis may increase the risk of bleeding, but this is mostly theoretical.23 While few studies or case reports have found such adverse effects, people taking anticoagulants, those scheduled for an invasive procedure, or those with bleeding problems should be aware of this potential adverse effect.15 Some case reports of postoperative bleeding have been reported.23 However, a randomized, controlled trial found no change in bleeding events among people taking warfarin when given either garlic (AGE formulation) or placebo.25 In vitro analyses have identified enzymes whose activities are impacted by aged garlic extracts.26 These results raise concerns that garlic may interfere with the metabolism of various drugs. Few actual interactions have been reported, although patients taking HIV protease inhibitors did have reduced drug serum levels after taking garlic.

Formulation

The two most commonly used powdered formulations are dried garlic powder and aged garlic extract (AGE). During the aging process, the volatile components are lost, thus leading to AGE being called odorless garlic. Garlic oil also is available, made using three different methods, with each leading to different mixtures of lipid-soluble sulfur compounds. The most commonly used form in clinical trials is a standardized garlic powder extract called Kwai (200-300 mg tid).12 A small number of high-quality studies have been conducted with AGE (Kyolic).

Conclusion

Overall, garlic preparations have some value as a complementary agent in reducing some risk factors associated with cardiovascular disease. The evidence from studies conducted in the 1990s suggested a broad range of modest benefits. However, many of these studies had small numbers of participants, were of short duration, or had other methodological weaknesses.2 Most recent, higher-quality studies have found more limited benefits. Modest reductions in total cholesterol, triglycerides, and blood pressure have been identified in meta-analyses. Several other CVD-related beneficial effects have been found with in vitro research. Given its good safety profile, garlic may provide some protection against CVD.

Recommendation

In light of the many associations between garlic and cardiovascular health, and the results of some research studies, garlic can be recommended as part of an overall heart-healthy diet. One clove a day (maybe two) should provide sufficient sulfur compounds, though this is debated and very much open to personal taste. However, given the modest benefits, garlic should not be used instead of conventional medical treatments for CVD. While garlic supplements are generally safe, people taking garlic along with other medications should be closely monitored for drug interactions, especially those taking HIV protease therapy. The diversity of garlic formulations available makes it difficult to recommend specific brands with confidence. Unless carefully standardized, products claiming to eliminate the odor may remove all the therapeutic effectiveness as well. Eating a clove or two daily can certainly be recommended.

References

1. Slevin M, et al. Unique vascular protective properties of natural products: Supplements or future main-line drugs with significant anti-atherosclerotic potential? Vasc Cell 2012;4:9.

2. Yang Y, et al. Effects of some common food constituents on cardiovascular disease. ISRN Cardiol 2011;2011:397136.

3. Rahman K, Lowe GM. Garlic and cardiovascular disease: A critical review. J Nutr 2006;136:736S-740S.

4. Alherbish A, et al. The prevalence of natural health product use in patients with acute cardiovascular disease. PLoS One 2011, 6:19623.

5. Blumenthal M, et al. Herb sales continue growth – up 3.3% in 2010. HerbalGram 2011;90:64-67.

6. Rahman K. Historical perspective on garlic and cardiovascular disease. J Nutr 2001;131:977S-979S.

7. Banerjee SK, Maulik SK. Effect of garlic on cardiovascular disorders: A review. Nutr J 2002;1:4-18.

8. Rahman K. Effects of garlic on platelet biochemistry and physiology. Mol Nutr Food Res 2007;51:1335-1344.

9. Amagase H. Clarifying the real bioactive constituents of garlic. J Nutr 2006;136:716S-725S.

10. Cavagnaro PF, et al. Effect of cooking on garlic (Allium sativum L.) antiplatelet activity and thiosulfinates content. J Agric Food Chem 2007;55:1280-1288.

11. Pittler MH, Ernst E. Clinical effectiveness of garlic (Allium sativum). Mol Nutr Food Res 2007;51:1382-1385.

12. Zeng T, et al. A meta-analysis of randomized, double-blind, placebo-controlled trials for the effects of garlic on serum lipid profiles. J Sci Food Agric 2012 Jan 10 [Epub ahead of print].

13. Allison GL, et al. Aged garlic extract and its constituents inhibit platelet aggregation through multiple mechanisms. J Nutr 2006;136:782S-788S.

14. Benavides GA, et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci USA 2007;104:17977-179782.

15. Ginter E, Simko V. Garlic (Allium sativum L.) and cardiovascular diseases. Bratisl Lek Listy 2010;111: 452-456.

16. Aviello G, et al. Garlic: Empiricism or science? Nat Prod Commun 2009;4:1785-1796.

17. Brace LD. Cardiovascular benefits of garlic (Allium sativum L). J Cardiovasc Nurs 2002;16:33-1649.

18. Khoo YS, Aziz Z. Garlic supplementation and serum cholesterol: A meta-analysis. J Clin Pharm Ther 2009 Apr;34:133-145.

19. Ried K, et al. Effect of garlic on blood pressure: A systematic review and meta-analysis. BMC Cardiovasc Dis.2008;8:13.

20. Budoff MJ, et al. Aged garlic extract supplemented with B vitamins, folic acid and L-arginine retards the progression of subclinical atherosclerosis: A randomised clinical trial. Prev Med 2009;49:101–107.

21. Ried K, et al. Aged garlic extract lowers blood pressure in patients with treated but uncontrolled hypertension: A randomised controlled trial. Maturitas 2010;67:144-150.

22. Mulrow C, et al. Garlic: Effects on cardiovascular risks and disease, protective effects against cancer, and clinical adverse effects. Rockville, MD: Agency for Healthcare Research and Quality; 2000. AHRQ publication 01-E023. Available at: http://www.ncbi.nlm.nih.gov/books/NBK33263/. Accessed May 8, 2012.

23. Borrelli F, et al. Garlic (Allium sativum L.): Adverse effects and drug interactions in humans. Mol Nutr Food Res 2007;51:1386-1397.

24. Gardner CD, 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;167:346-353.

25. Macan H, et al. Aged garlic extract may be safe for patients on warfarin therapy. J Nutr 2006;136:793S-795S.

26. Berginc K, Kristl A. The mechanisms responsible for garlic-drug interactions and their in vivo relevance. Curr Drug Metab 2011 Aug 12. Epub ahead of print.