August 2010 Issue

Alternative Avenues — Supplements and Nutraceuticals for Treating Cardiovascular Disease
By Lisa S. Brown, PhD, RD, and Stefanie Giampa
Today’s Dietitian
Vol 12 No. 8 P. 40

Suggested CDR Learning Codes: 2010, 3070, 3100, 5160; Level 2

Cardiovascular disease (CVD) has been the leading cause of morbidity and mortality in the United States for more than 80 years. One in three adults currently lives with some form of CVD; more than one half of these individuals are younger than the age of 65.1

In the 1980s, companies introduced numerous medications for treating CVD. The most effective (ie, statins) were designed to lower blood lipids and prevent atherosclerotic plaques from forming. While these drugs work, they also have undesirable side effects that many patients may prefer to avoid.

During the 1990s, a new era of CVD treatment emerged centering on dietary supplements and nutraceutical foods. Because many consumers assume that dietary supplements have no side effects since they are created from “natural” ingredients, they gravitate toward these products in addition to or in place of other medications. But some claims for these products fall through regulatory cracks.

In 1994, Congress began regulating the marketing of dietary supplements and nutraceuticals. The Dietary Supplement Health and Education Act requires manufacturers to notify the FDA when a new product is introduced and to provide assurance that the product is safe. However, supplement-testing standards are much less stringent than those established for medications and food additives, and once a product is on the market, the FDA must prove that a supplement is unsafe before it can remove it from the shelves.

The FDA keeps a close watch on supplement labels’ health claims but plays only a passive role in monitoring whether the “active” ingredients are safe and does not evaluate whether the product is effective as long as the label does not falsely claim a specific effect. The resulting label-claim word games tend to mislead rather than enlighten. Therefore, dietitians must stay informed about these products and advise their patients accordingly.

While many supplements claim to combat high cholesterol or high triglycerides, only a few have any solid research behind them. This article will explore the current research on a few of the most common ones.

Plant Sterols and Stanols
Nutraceutical foods containing plant sterols and stanols, promising to lower cholesterol, are appearing on supermarket shelves in astounding numbers. In 2000, the FDA approved a health claim for foods containing plant sterols and stanols, and the food industry responded. Consumers can now find yogurts, salad dressings, mayonnaise, breads, and even cookies with plant sterols.

Dietitians must ask not only whether these products are effective but also whether they are safe. While plant sterols and stanols are naturally found in the walls of plant cell membranes, they are concentrated to unnatural levels in common nutraceutical foods. The National Cholesterol Education Program Expert Panel and the American Heart Association (AHA), as well as several other international heart associations, have endorsed their use, but Health Canada, the Drug Commission of the German Medical Association, and other organizations oppose their use.2,3

The Claim
Consuming plant sterols and stanols can reduce LDL cholesterol concentrations by 5% to 15%.

Amount Recommended
Two grams/day, not to exceed 3 g/day (more could interfere with fat-soluble vitamin absorption), is the amount recommended.

Mechanism of Action
Plant sterols and stanols reduce the absorption of cholesterol in the gut by competing for the same binding sites in the gastrointestinal tract.

The Evidence
Most studies agree that properly formulated plant sterols are effective at lowering LDL cholesterol, but several factors appear to influence their action, including the food carrier, dosing schedule, and individual variation in responses.4

Plant sterol effectiveness varies dramatically by the type of food carrier. While certain products perform very well, including dairy (with the exception of cheese), salad dressings, mayonnaise, and margarine, other products, including orange juice, chocolate, and breads, do not.4
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As for dosing, studies show that multiple doses per day (two to three evenly spaced throughout the day) appear most effective for lowering LDL, but consuming one dose at lunchtime lowered it almost as much as multiple doses.4 Breakfast doses have not been associated with LDL improvements.4

Individual response to plant sterols also varies. People with higher LDL levels appear to have a greater reduction compared with individuals with normal and borderline LDL levels.4 Genetic factors are also related to effectiveness. Individuals with the ApoE-4 homozygote have increased cholesterol absorption capacity and appear to respond better to plant sterol use.4 Neither age nor gender has been linked to differences in response.

Sterols and stanols do not appear to interact with other cholesterol-lowering agents, including commonly prescribed statins.4,5 In fact, using the two products together appears to have synergistic effects, with one study showing a 35% reduction in LDL and a 32% reduction in triglycerides when a plant stanol yogurt drink was used in combination with simvastatin.5

Concerns
The current major concern is that plant sterols may inhibit the absorption of beta-carotene, vitamin E, and other fat-soluble vitamins.

It is also important to note that all current research on plant sterols uses LDL levels as the final study end point. From this point of view, plant sterols appear to be safe and effective. But no studies have shown that supplementation with plant sterols reduces actual cardiovascular events, which is the ultimate purpose of these products.

A few studies have even raised concerns that using plant sterols may actually increase cardiovascular risk.6 Animal studies and mechanistic data suggest that vascular deposits of sterols, when compared with cholesterol, result in increased oxidation and the release of free radicals, which may increase the chance of a cardiac event. Concern has arisen about whether excess levels of plant sterols in the human body facilitate plaque formation and raise atherosclerotic risk compared with other treatments (eg, statins). Controlled studies of the safety of plant sterols are only available for a period of up to one year and, in most studies, the number of participants was low, so possible proatherosclerotic effects due to long-term consumption may not be detected.

A recent meta-analysis in the Journal of the American Dietetic Association suggested that plant stanols may not have the same absorption rate as plant sterols, suggesting that although stanols were found to be as effective at lowering cholesterol, they may ultimately be safer.7

More research is needed to determine whether plant sterols and stanols are effective for lowering cholesterol or whether they increase the risk of CVD-related events despite lowering LDL cholesterol.

The Bottom Line
Plant sterols and stanols in 2- to 3-g doses lower LDL in most subjects and appear to be particularly effective in those with high cholesterol. However, dietitians may want to hold off on recommending plant sterols until more conclusive data prove a benefit using a hard end point such as heart attacks and strokes. If you do recommend these products to your clients, do not recommend them for kids or pregnant or breast-feeding women unless approved by a physician.

Fish Oil
Found naturally in fatty fish, fish oil is high in omega-3 fatty acids and is a rich source of EPA and DHA. A great deal of research has led the AHA to recommend that people eat fish, particularly fatty fish, twice per week for cardiovascular benefits.2 Based on the association between eating fish and reducing the likelihood of cardiovascular events, many supplement manufacturers began producing fish oil supplements and promoting their benefits. The AHA endorses the use of fish oil itself for patients with documented coronary heart disease and/or hypertriglyceridemia under a physician’s guidance. Otherwise, the association recommends two servings of fatty fish per week for CVD prevention.

The Claim
Consuming fish oil can reduce blood triglycerides by 20% to 50%, may lower blood pressure, and may reduce overall inflammation.

Amount Recommended
Two to 4 g/day, not to exceed 4 g/day, is recommended. Doses greater than 3 g may interfere with blood coagulation and increase bleeding. Patients should check with their physician.

Mechanism of Action
The mechanism of action is not fully understood; it is likely multifactorial. Several are suggested, including anticlotting effects and membrane stabilization effects, which may help regulate heart rhythm. Finally, fish oil is believed to promote a general reduction in inflammation within the body.

The Evidence
Studies have shown a significant effect in lowering triglycerides (by as much as 25% to 30% at doses of 2 to 4 g/day) and a potential increase in HDL, with little or no impact on LDL.8

Fish oil does not appear to negatively interact with other cholesterol-lowering agents, including statins. Use of the products together appears to have synergistic effects. One study showed a 19% reduction in cardiovascular events in adults taking a statin and fish oil.9

Concerns
While fish oil and statins appear to be safe when taken together, fish oil should be used with extreme caution in combination with blood-thinning medications (including aspirin and nonsteroidal anti-inflammatory drugs) and blood pressure medications. Fish oil appears to inhibit clotting, which may lead to increased bleeding and blood pressure may drop too low. If planning to take the two agents together, patients should consult their physician.9

Another common concern about fish oil is possible mercury contamination. However, a recent analysis of 41 supplements by ConsumerLab.com found few or no contaminants, including mercury and PCBs, in fish oil supplements.

The Bottom Line
Doses of up to 3 g appear to be safe and can lower triglycerides, but whether using such supplements will reduce cardiac events or death is unclear. More research is needed to determine whether consuming fish oil in isolation has the same overall effect as regularly eating fish. Dietitians can recommend fish oil for most people, but those taking multiple medications, especially blood-thinning and high blood pressure medications, should use it with caution. Recommending that clients eat fish once or twice per week is a better bet.

Red Yeast Rice Extract
Red yeast rice extract is yeast grown on fermented rice. It is found naturally in certain Asian foods, including Peking Duck, and is commonly used in powdered form as a food coloring. In addition to duck, it is used for coloring fish, alcoholic beverages, and cheese.

The Claim
Red yeast rice extract is “nature’s statin.” Consuming red yeast rice extract can reduce LDL cholesterol concentrations by 20% to 50%.

Amount Recommended
Product dosage recommends 1,200 mg/day split in two. Research doses have used 1,800 mg.

Mechanism of Action
Red yeast rice extract contains monacolin K (the same ingredient in the statin Mevacor), which acts to block a key enzyme necessary to make endogenous cholesterol. It may also contain isoflavonoids, monounsaturated fats, and sterols, other components that may contribute to cholesterol-lowering effects.

The Evidence
Several studies on pure red yeast rice extract have shown positive support for the lowering of LDLs (both in subjects taking statins and those who were not). One multicenter trial showed a 16% drop in total cholesterol over an eight-week period.10
Pure red yeast rice extract also appears to be safe and can be used in combination with a statin; however, a physician should supervise its use, since it essentially equates to a dose of statin. Side effects are generally similar to statins, including the potential for muscle damage and hepatotoxicity. Similar to when taking statins, patients may want to take coenzyme Q10, since levels will be lowered.11

Concerns
The quality of over-the-counter products can be inconsistent, and several of the tested formulations are not available in the United States. Cholestin was a popular brand of red yeast rice extract in the United States, but the FDA considered it a drug (like lovastatin) and required more testing before allowing the product to remain on the market. The manufacturer finally removed it from the U.S. market and since that time, many red yeast rice extract supplements sold in the country have been found to lack significant amounts of the active ingredient.11

In trials involving pure red yeast rice extract, adverse effects were found in 77 studies, including dizziness, low appetite, nausea, stomachache, and diarrhea. Case reports have shown potential reactions of myopathy or rhabdomyolysis, which are concerns similar to those associated with the use of statin medications.11

The Bottom Line
The effects of red yeast rice extract are very similar to those of statins, including both the benefits and side effects. Patients will likely be better off taking a statin, which is standardized and supervised by a physician.

Pomegranate Juice

The Claim
Pomegranate juice (or seeds or supplements) acts like a “roto-rooter” for plaque deposits in the arteries. The juice can decrease hardening of the arteries and may even reverse it.

Amount Recommended
Studies have used 50 to 240 mL of juice.

Mechanism of Action
Pomegranate contains polyphenols, which act as antioxidants (similar to compounds found in wine). Polyphenols are believed to reduce the deposition of cholesterol in plaques and reduce cholesterol production in the liver. Pomegranate may also increase the production of nitric oxide in blood vessels, causing vasodilatation.

The Evidence
The most interesting support for pomegranate juice comes from a three-year Israeli study conducted on patients with coronary artery disease that suggested pomegranate juice decreased LDL oxidation, blood pressure, and carotid intima-media thickness (a surrogate end point for CVD).12 Most significantly, the treatment group experienced a decrease in carotid artery plaque by 35% compared with a 9% increase in control subjects. Although the study was promising, there were only 10 subjects in the treatment group and all had severe plaque.

A follow-up study involving members of the same research team found less-impressive results when they examined individuals with risk factors for CVD but not diagnosed with heart disease. In this study, individuals with increased oxidative stress showed some benefit from drinking pomegranate juice, while those who did not have increased oxidative stress showed no particular benefit.13 Other studies are inconsistent regarding whether LDL cholesterol and blood pressure are lowered in subjects who take it.14 Many of the promoted benefits are based on studies of cell reaction and mouse studies and may be overstated for effectiveness in humans.

Concerns
Due to potential action as a vasodilator, pomegranate may pose a problem for individuals with low blood pressure or who are on a blood pressure-lowering medication. There have also been some concerns about allergic reactions to the product.15 One major concern is the lack of product standardization. Even products labeled “100% pomegranate juice” appear to be of inconsistent quality, with some juices including the outer layers and peel of the pomegranate, which appear to lessen the therapeutic impact.

The Bottom Line
Regularly drinking 8 oz of pomegranate juice probably won’t harm most people, so long as doing so fits into their calorie budget. But there is no conclusive evidence that it will help, either. Dietitians should advise patients to look for 100% pomegranate juice and that bitterness may be a sign that the juice contains more of the outer fruit, which may not have the same therapeutic impact.

Summary
Although dietary supplements and nutraceutical foods are appealing to many of our clients, as dietitians we need to be aware that the safety and efficiency of these products are not well regulated. Patients should use these products with caution and with the knowledge or consultation of their physician.

Plant sterols and stanols are effective at lowering LDL cholesterol, although there are still very serious questions about whether these products will reduce cardiac events and even concerns that sterols in particular may increase risk. More research is needed before dietitians can confidently recommend them to clients. Fish oil appears to be of marginal benefit in lowering cholesterol but may be a good strategy as part of an overall dietary approach to CVD prevention and treatment and is effective for reducing blood triglycerides. Dietitians should be careful to recommend consumption of fatty fish twice per week over consumption of supplements. Pomegranate juice shows promise for individuals with diagnosed CVD but may be of only marginal benefit to those trying to prevent the disease. More research is needed before we can make any real conclusions. Pure red yeast rice extract and plant sterols are effective for lowering cholesterol but may not be preferable to prescription medications.

— Lisa S. Brown, PhD, RD, is an assistant professor of nutrition at Simmons College in Boston. Stefanie Giampa is a graduate student in the nutrition and health promotion program at Simmons College.

 

Learning Objectives
After completing this continuing education exercise, the student should be able to:

1. List several common supplements and nutraceutical foods for treating cardiovascular disease (CVD).

2. Discuss the importance of monitoring both supplement and medication use in individuals with CVD.

3. Understand the current process for regulating dietary supplements.

4. Describe the risks and benefits of recommending common dietary supplements to clients.

Examination
1. Plant sterols may reduce LDL cholesterol by:
a. reducing the absorption of cholesterol by competing for the same binding sites in the gastrointestinal (GI) tract.
b. binding to cholesterol and carrying it out of the GI tract.
c. filling people up so they eat less of everything, including foods high in cholesterol.
d. All of the above

2. People should practice caution when consuming plant sterols because:
a. they may inhibit the absorption of beta-carotene, vitamin E, and other fat-soluble vitamins.
b. they may increase cholesterol absorption if taken in doses higher than 3 g.
c. they may interact negatively with commonly prescribed statins, producing unhealthy side effects.
d. they may interact negatively with certain food ingredients such as wheat and soy.

3. Fish oil is suggested to reduce triglyceride concentrations by which of the following mechanisms?
a. Improving the impact of other cholesterol-reducing agents such as statins
b. The mechanism is probably multifactorial (like promoting full-body anti-inflammation and anticlotting effects)
c. Lowering LDL concentration
d. By blocking the absorption of saturated fats and trans fatty acids

4. Fish oil should be taken:
a. in as much concentration as a person can tolerate.
b. with every meal.
c. in daily doses of 2 to 4 g, not to exceed 4 g.
d. in combination with vitamins A and D.

5. Red yeast rice extract is:
a. used in Asian bread baking.
b. used as a common ingredient in statins.
c. always pure when found in supplement form.
d. grown on fermented rice and found naturally in certain Asian foods such as Peking Duck.

6. Red yeast rice extract may lower LDL concentration by 20% to 50%. The mechanism proposed to be in action here is:
a. unknown because red yeast rice extract is too rare to study.
b. the same mechanism in the statin Mevacor (monacolin K), which blocks a key enzyme necessary for creating endogenous cholesterol.
c. coenzyme Q10.
d. that it blocks cholesterol absorption in the gut, reducing the amount of exogenous cholesterol absorbed.

7. Some reported side effects of taking red yeast rice extract are:
a. GI upset, including nausea and diarrhea.
b. flulike symptoms, including fever and body aches.
c. seizures and muscle spasms.
d. generally similar to side effects for statins: the potential for muscle damage and hepatotoxicity.

8. While studies have been inconsistent regarding pomegranate juice and its ability to reduce the deposition of cholesterol, it has been established that taking pomegranate in any form should come with a warning for some people. This warning is:
a. pomegranate juice causes GI upset.
b. because of its vasodilating effects, pomegranate juice may cause problems for people with low blood pressure or those on blood pressure-lowering medications.
c. pomegranate juice causes urine discoloration.
d. consuming excess calories such as those found in juice may lead to weight gain in some individuals.

9. Pomegranate juice claims to decrease hardening of the arteries by:
a. the mechanism is still unclear; more conclusive, human studies need to be conducted.
b. the action of its polyphenol components.
c. working in collaboration with blood pressure medications.
d. reducing production of endogenous cholesterol within the body.

10. Overall, every dietitian should know the following about novel approaches to treating dyslipidemia:
a. Primary prevention appears to be most effective for reducing morbidity and mortality, and novel dietary interventions should be done with caution and with the knowledge/consultation of a patient’s physician.
b. Fish oil appears to be of marginal benefit in lowering cholesterol but may be a good strategy as part of an overall dietary approach.
c. Pomegranate juice shows a lot of promise but needs more research.
d. Red yeast rice extract and plant sterols are effective at lowering cholesterol but may not be preferable to prescription medications.
e. All of the above

 

References
1. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics—2008 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117(4):e25-146.

2. American Heart Association Nutrition Committee. Diet and lifestyle recommendations revision 2006: A scientific statement from the American Heart Association Nutrition Committee. Circulation. 2006;114(1):82-96.

3. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421.

4. Abumweis SS, Barake R, Jones PJ. Plant sterols/stanols as cholesterol lowering agents: A meta-analysis of randomized controlled trials. Food Nutr Res. 2008;52:10.3402/fnr.v52i0.1811.

5. Plat J, Brufau G, Dallinga-Thie GM, Dasselaar M, Mensink RP. A plant stanol yogurt drink alone or combined with a low-dose statin lowers serum triacylglycerol and non-HDL cholesterol in metabolic syndrome patients. J Nutr. 2009;139(6):1143-1149.

6. Weingärtner O, Böhm M, Laufs U. Controversial role of plant sterol esters in the management of hypercholesterolaemia. Eur Heart J. 2009;30(4):404-409.

7. Talati R, Sobieraj DM, Makanji SS, Phung OJ, Coleman CI. The comparative efficacy of plant sterols and stanols on serum lipids: A systematic review and meta-analysis. J Am Diet Assoc. 2010;110(5):719-726.

8. O’Keefe JH, Carter MD, Lavie CJ. Primary and secondary prevention of cardiovascular diseases: A practical evidence-based approach. Mayo Clin Proc. 2009;84(8):741-757.

9. Bays HE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol. 2007;99(6A):35C-43C.

10. Wang J, Lu Z, Chi J, et al. Multicenter clinical trial of serum lipid-lowering effects of a Monascus purpureus (red yeast) rice preparation from traditional Chinese medicine. Curr Ther Res. 1997;58(12):964-978.

11. Vercelli L, Mongini T, Olivero N, et al. Chinese red rice depletes muscle coenzyme Q10 and maintains muscle damage after discontinuation of statin treatment. J Am Geriatr Soc. 2006;54(4):718-720.

12. Aviram M, Rosenblat M, Gaitini D, et al. Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr. 2004;23(3):423-433.

13. Davidson MH, Maki KC, Dicklin MR, et al. Effects of consumption of pomegranate juice on carotid intima-media thickness in men and women at moderate risk for coronary heart disease. Am J Cardiol. 2009;104(7):936-942.

14. Basu A, Penugonda K. Pomegranate juice: A heart-healthy fruit juice. Nutr Rev. 2009;67(1):49-56.

15. Gaig P, Bartolomé B, Lleonart R, et al. Allergy to pomegranate (Punica granatum). Allergy. 1999;54(3):287-288.