Hypercholesterolemia

Natural supplements are widely used by the American public but, while claims of their therapeutic effects abound, medical research does not always support their effectiveness. Clinical trials using Q10 for the management of congestive heart failure have had conflicting results; hawthorn is prescribed in Germany for the treatment of this condition, but no trials have been conducted in the United States. Although initial research about the use of garlic in the management of hypercholesterolemia was encouraging, follow-up studies have failed to verify these results. Substituting soy protein for high-fat animal protein diets, however, does have a beneficial effect on serum lipid levels. So far, cholestin (a natural product containing several statins) has proved to be a cost-saving lipid-lowering medication, and fenugreek may offer modest improvement as well. Gugulipid is also promising but requires further research. (Am Fam Physician 2000;62:1325-30.)

In 1997, Americans spent more than $12 billion on natural supplements; a 1993 study showed that one third of Americans polled used some form of alternative medicine.(1) Family physicians must be aware of the widespread use of these products. We must be able to separate anecdotal from evidence-based benefits, and we must be aware of side effects and potential interactions between medications and herbs or supplements if we are to offer informed consultation to our patients.

American Family Physician has previously published articles that focus on herbal products and their side effects, as well as herb/drug interactions.(2,3) The first part of this article, published in the previous issue, reviewed the use of herbs and supplements in the management of diabetes, depression and obesity. This part of the article highlights the role that supplements can play in the management of two other conditions commonly encountered in the family physician's office: congestive heart failure and hypercholesterolemia. Table 1 summarizes information about the natural products discussed.

Congestive Heart Failure

Of the many adjunctive treatments for congestive heart failure (CHF), two of the most widely publicized in recent years are Q10 and hawthorn.

Ubiquinone: Q10

Q10 is a coenzyme found in all tissues of the body (hence its common name, ubiquinone). It is necessary for certain metabolic reactions, including oxidative respiration, and its concentration is increased in the heart, liver and pancreas. Its use in heart disease stems from its antioxidant effects, its stabilization of sodium- and potassium-activated adenosine triphosphate (NaK ATPase) and its effect on calcium channels.(4)

To date, the clinical benefits of Q10 supplementation have not been clearly proved. Two well-researched meta-analyses(5) have shown improved ejection fractions, stroke volume, cardiac output, cardiac index and end diastolic volume in patients taking Q10 supplement; each also suggested that Q10 may have a role in the treatment of CHF. However, the clinical significance of these findings has not yet been proved.

In clinical trials, a 1999 study(6) showed that 22 patients enrolled in a randomized, double-blind, placebo-controlled, crossover trial of Q10 experienced an increased stroke index at rest and at work and a decreased pulmonary capillary wedge at rest. The study concluded that patients with congestive heart failure may benefit from supplementation with Q10. Two other recent clinical trials(7,8) refuted this finding. A randomized, double-blind, placebo- controlled, crossover trial(7) evaluated 30 patients for three months and found no increase in resting systolic function despite plasma levels of Q10 that were twice the normal baseline values. Another randomized, double-blind, placebo-controlled, crossover study8 of 79 patients with CHF measured ejection fraction, exercise tolerance and quality of life. This study found a nonsignificant increase in ejection fraction and, possibly, a slightly increased exercise tolerance and slightly increased subjective quality of life in the subjects taking Q10

In light of the above evidence, it can be concluded that if Q10 has a beneficial role in the management of CHF, it is modest at best. These studies found no adverse side effects of Q10 at dosages of 100 mg daily for six years or 200 mg daily for one year.

HAWTHORN

The hawthorn plant contains pharmacologically active flavonoids that inhibit vasoconstriction and actively dilate blood vessels. One of these flavonoids has also been reported to block vasoconstriction by inhibiting angiotensin-converting enzyme. These actions, as well as in vitro increases in coronary circulation (from 20 to 140 percent) and inhibition of the adenosine 3',5'-cyclic monophosphate phosphodiesterase, give hawthorn its theoretic basis for use in congestive heart failure.(9)

As for its actual observed effect in human studies, a 1996 review(10) of German literature concludes that rigorous clinical trials have shown benefit in objective signs and subjective symptoms of stage II CHF. A multicenter, placebo-controlled, double-blind trial(11) studied 136 patients with stage II CHF. A clear improvement in the subjects receiving hawthorn was observed and documented as an improvement in the pressure-heart rate product, while the conditions of the subjects receiving placebo deteriorated. The hawthorn group also had a subjective improvement in quality of life and mental well-being. The study concluded that hawthorn was an effective, low-risk phytotherapeutic form of treatment in patients with stage II cardiac insufficiency.(11) Hawthorn is sold as a prescription medication in Europe and Asia. In Germany, it has been approved and is prescribed for mild cardiac insufficiency.

Despite studies mentioned in the German literature, we did not find that any double-blind, randomized, placebo-controlled, crossover trials had been performed in the United States, nor could we find any studies documenting echocardiographic improvements or improvements in exercise tolerance.

Because hawthorn may potentiate the action of cardiac glycosides and may interfere with digoxin or digoxin monitoring, it has been recommended that patients using digitalis or other cardiovascular drugs refrain from using hawthorn unless monitored by a physician. Neither we nor the authors of a 1998 review12 could find any clinical studies documenting this potential interaction.

Hypercholesterolemia

GARLIC

Despite the many early promising studies and meta-analyses evaluating garlic's effect as a lipid-lowering agent, more recent, rigorous studies have failed to substantiate these benefits.(13-16) There is no current role for garlic as an antihyperlipidemic agent.

SOY

The precise mechanism by which soy proteins are thought to decrease serum lipid levels is unclear. Possible mechanisms include decreased cholesterol absorption, decreased bile reabsorption in the gut or possibly a change in endocrine status associated with biologically active substances such as isoflavones (phytoestrogens) or saponins present in soy.(17) Several well-conceived animal studies(18-20) have clearly shown a decrease in total cholesterol and low-density lipoprotein (LDL) levels when dietary soy protein was substituted for animal protein. Human observational studies, as well as human intervention trials, have also shown soy's beneficial effect on levels of total cholesterol and LDL.(21) A recent meta-analysis(22) also showed a trend toward decreased cholesterol levels and decreased LDL levels among subjects taking soy, with an average decrease of 9 percent in total cholesterol levels, 13 percent in LDL levels and 10 percent in triglyceride levels.

In 1998, Potter and associates(23) corroborated this meta-analysis and found that consumption of soy protein, substituted for animal fat, lowered total cholesterol levels an average of 6 percent and non-high-density lipoprotein cholesterol levels by 7 percent in postmenopausal women with hypercholesterolemia. In 1998, Wong and colleagues(24) demonstrated similar lipid-lowering effects in men with normal cholesterol levels and men with hypercholesterolemia.

In October 1999, the U.S. Food and Drug Administration approved a "health claim" labeling for soy products. It was concluded that, "Diets low in saturated fat and cholesterol that include 25 g of soy protein may reduce the risk of heart disease." To carry the health claim labeling, foods must contain at least 6.25 g of soy per serving and be low in fat, saturated fat and cholesterol. In reviewing all of the literature, consumption of at least 25 g of soy per day is needed to see a decrease in levels of cholesterol and LDL. Table 2 includes some of the more common sources of soy and their soy protein content.

CHOLESTIN

Cholestin is a fermented product of rice on which red yeast is grown. This "red rice yeast product" has been used for centuries in China and contains starch, protein, fiber and at least eight statin compounds, which function as human menopausal gonadotropin coenzyme A (HMG CoA) reductase inhibitors.

Chinese studies claiming that this product decreased total cholesterol levels by 11 to 32 percent have recently been verified by U.S. studies. In a recent double-blind, placebo-controlled study(25-27) involving 83 patients with hypercholesterolemia, total cholesterol levels decreased by about 15 percent and LDL levels decreased by about 22 percent in the patients receiving cholestin. As expected, these results are similar to those obtained with commercially available "drug statins" because the active compounds are essentially the same.

Cholestin may be a cost-saving option for patients who require lipid-lowering medication but who are unable to afford the more expensive, commercially available medications. Although no adverse effects have been reported with the use of cholestin, it would be prudent to monitor liver function as well as creatine kinase just as would be done when administering commercially available statins.

FENUGREEK

Fenugreek, a legume sold as a dried seed, is native to Asia and southeastern Europe. It contains fiber and active steroid saponins that have been documented as having a hypoglycemic effect in mild cases of type 2 diabetes (formerly known as non-insulin-dependent diabetes).(28) The lipid-lowering potential of this product has also been proved in rats, dogs and humans.(29,30)

A recent study(28) of patients with coronary artery disease and type 2 diabetes showed a decrease in levels of total cholesterol and triglycerides with use of fenugreek. A 1990 double-blind, placebo-controlled study(31) of 10 patients with type 1 diabetes (formerly known as insulin-dependent diabetes) also showed a significant decrease in levels of total cholesterol, LDL and very-low-density lipoprotein (VLDL) in the patients receiving fenugreek. It is still too early to fully evaluate the lipid-lowering effects of this product, but some modest improvement is apparent. Well-designed clinical trials should be undertaken in the future.

GUGULIPID (GUGGUL GUM)

Gugulipid (guggul gum) is widely used in India for the treatment of hypercholesterolemia. Two placebo-controlled studies(32,33) have been published in India. In one multicenter trial(34) with 205 subjects, gugulipid was found to reduce total cholesterol levels by 22 percent and triglyceride levels by 25 percent, compared with placebo, in 70 percent of patients. In the other study of 61 patients, gugulipid was found to decrease cholesterol levels by 11 percent, LDL levels by 12 percent and triglyceride levels by 12 percent.

In each of these studies, side effects in the subjects receiving gugulipid were no different from those of the subjects receiving placebo, and the cost of gugulipid was markedly lower than that of the available statin drugs. The suggested dosage is the equivalent of 75 mg of guggulsterone per day.

In conclusion, although there were problems with the studies (e.g., short-term nature, no correlation with cardiovascular morbidity and mortality, data gathered from less than 200 patients), preliminary results indicate the need for further studies.

REFERENCES

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(34.) Singh RB, Niaz MA, Ghosh S. Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia. Cardiovasc Drugs Ther 1994;8: 659-64.

This is Part II of a two-part article on alternative therapies. Part I, on alternative therapies for depression, diabetes and obesity appeared in the last issue (Am Fam Physician 2000; 62:1051-60.)

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