Given that cardiovascular disease is the number one killer of women in the US, we as physicians need to pay far more attention to the unique aspects of heart disease in women. Conventional medical researchers have only recently begun to recognize that women are not simply smaller men. While many risk factors are the same across the genders, women’s unique endocrine and metabolic milieu strongly influence the disease process and response to treatment.

Lipid-lowering statin drugs have largely defined conventional medicine’s approach to managing heart disease risk for the last decade. In many ways, the natural medicine world has followed this lead, evidenced by the large number of plant-based products touted as cholesterol lowering alternatives.

It is wonderful to have natural options, but two things need to be kept in mind: first, the science on natural lipid-lowering agents is quite variable, and second, lipids are only one part of the cardiovascular disease equation. A holistic approach needs to cover many other aspects including vascular compliance, inflammation, sympathetic-parasympathetic balance, overall dietary health, psychosocial and emotional issues.

That said, patients are likely to hear a lot about natural lipid lowering agents, so it pays to keep abreast of the latest science in this field.

Soy and Cholesterol

Soy protein and soy isoflavones have been widely touted for lowering lipids, and the scientific argument has gone back and forth as to their clinical utility.

Researchers at the Department of Nutrition and Food Science, San Jose State, Calif., recently published a review of the impact of soy protein and soy isoflavones on plasma lipid profiles in postmenopausal women. The review included 17 studies in which women were given soy protein and 9 studies in which they were given soy isoflavones.

The authors concluded that the effect of both soy protein and soy isoflavones had only a very small effect on total cholesterol, mostly LDL. “The data are not quantitatively impressive and raises substantial questions about the clinical importance of the hypocholesterolemic effects observed,” they wrote (Dewell A, Hollenbeck P, Hollenbeck C. J Clin Endocrinol Metab. 2006; 91: 772–780).

Why is it that this issue remains so contentious? A previous landmark metanalysis of 38 studies concluded that if we consume 31–47 grams of soy protein daily, this could reduce both total cholesterol and LDL by 10–12%. Animal and human epidemiological evidence up to and including that paper, was enough to convince the American Heart Association to revise its 2000 guidelines to recommend soy for reducing the risk of coronary heart disease.

In the last few years, newer studies have shown no effects or minimal impact from increased soy intake, prompting AHA to change its advice, which currently states that, “The direct cardiovascular health benefit of soy protein or isoflavone supplements is minimal at best.” AHA’s scientific advisory panel on soy and cardiovascular health reviewed 22 randomized trials in humans, comparing isolated soy protein with isoflavones to milk or other proteins. They found soy reduced LDL an average of 3%, but had no significant effects on HDL, triglycerides, lipoprotein (a), or blood pressure (Sacks F, et al. Circulation. 2006; 113: 1034–1044). Another 19 studies of purified soy isoflavones found no consistent effects on LDL or other lipid risk factors.

There now seems to be some clarity as to why soy isoflavones produce beneficial lipid changes in monkeys and in some humans, but not others. It comes down to soy isoflavone metabolism. Monkeys excrete isoflavones in the form of aglycones. Women excrete isoflavones mainly in the form of glucuronides. Monkeys also convert nearly all of the daidzein, a key soy isoflavone, into equol, a potent phytoestrogen. However, only about one third of humans can convert daidzein to equol, In those who do, conversion is a lot lower than it is in other primates.

Ken Setchell, PhD, one of the most prominent soy researchers, has proposed that women who produce equol, are those that receive lipid benefits from soy, while those who do not produce equol, don’t receive that benefit. The ability to convert daidzein appears to be related to specific gut flora. Researchers have been able to show that if gut flora are wiped out in monkeys by giving enteric antibiotics, this reduces the lipid-lowering benefits of a soy diet.

So, what should we advise our patients about the cardiovascular benefits of soy? A few things to remember: Cardiovascular health is not all about lipids. Soy foods contain only 18% fat, primarily polyunsaturated fats and only a small amount of saturated fats, so they’re still very healthy foods, whether or not they lower LDL.

Further, increased soy isoflavone intake is associated with improvement in arterial compliance (Nestel P, et al. Arterioscler Thromb Vasc Biol. 1997; 17: 3392–3398), and decreased aortic stiffness (Van der Schouw Y, et al. Arterioscler Thromb Vasc Biol. 2002; 22: 1316–1322).

We may have to wait for the completion of the first randomized, controlled, double-blind, placebo-controlled trial now underway through the NIH. The Women’s Isoflavone Soy Health (WISH) trial is looking at the role of soy isoflavones and atherosclerosis in postmenopausal women. For now, I will continue to advise my patients to include soy foods in their diet, not only for their potential cardiovascular benefits, but for their high protein content, dietary fiber, essential fatty acids, and association with slowing bone loss, and their potential to reduce our risk of hormonally-sensitive cancers.

New Data Challenge Efficacy of Policosanol

Policosanol, a sugar cane derived substance originally pioneered by researchers in Cuba, has also been promoted for its lipid-lowering effect. A large body of data from the Cuban investigators suggested that policosanol, at doses in the range of 5–40 mg per day, was comparable to statin drugs in reducing LDL.

Investigators at the Institute for Clinical Research, Center for Cardiovascular Diseases, Rotenburg an der Fulda, Germany, have punched a hole in this notion.

Their well designed, multi-center randomized, placebo-controlled trial involved 143 people aged 18 to 80 years, with hypercholesterolemia or combined hyperlipidemia. Participants were randomized to receive 10, 20, 40, or 80 mg/day of policosanol or placebo. The product used was sugar cane-derived policosanol, not the bees’ wax derived variant sold widely in the US. The patients were treated for 12 weeks, with blood draws at baseline, 6 weeks and 12 weeks.

The disappointing news was that LDL-C levels did not decrease by more than 10% from baseline in any of the five treatment groups, and there was no significant difference between policosanol and placebo. Policosanol had no significant effects on the ratio of total cholesterol or LDL to HDL, and there were no meaningful effects on other lipid measures (Berthold HA, et al. JAMA. 2006; 295: 22629).

These findings were a surprise to me. Not only had previous research been well documented, my observations of policosanol in clinical practice were quite favorable, with some patients showing LDL reductions in the 20% range. That said, all previous studies had been conducted by a single research group, and some of the statistical analysis has been questioned.

Should we or should we not continue using policosanol? The German study certainly weighs against it, and another small clinical trial published this year also found no significant effect of policosanol, 20 mg day, on serum lipid levels after 12 weeks of 20 mg/day (British J Nutr. 2006; 95: 96875). The real lesson here is that we should not rely on any single agent as a be-all, end-all treatment for cardiovascular risk.

Other Natural Lipid-Lowering Agents

Garlic has long been popular as a lipid-lowering herb, but its effect is slight, at best. Numerous collected analyses have shown reductions in total cholesterol of 5% to 12%, but recent reports have suggested that these trials may have been too brief to draw firm conclusions.

Most garlic supplements have a standardized allicin content as a measure of its potency, and are generally enterically coated, to prevent gastric acid inactivation of the allicin-producing enzyme allicinase. The great variation in the amount of allicin in garlic products may account for some of the variability in research results. Even the studies showing a positive effect are plagued by lack of long-term follow-up, standardized laboratory measurements, and adequate dietary controls.

Some controlled trials have yielded a different picture, one in which the short-term beneficial effect of garlic on cardiovascular risk are associated not so much with a lipid lowering effect but with blood pressure reductions, inhibition of clot formation, and healthier regulation of heart rhythms. Garlic may indeed be good for the heart, overall, but it has only limited effects on lipids.

Guggul is a resin from a tree indigenous to India, Pakistan, and Afghanistan. Guggul appears to prevent the oxidation of LDL and may regulate the level of bile acids, helping the body to excrete cholesterol. Guggulsterones are thought to be one of the main active constituents responsible for these effects. Studies have shown that guggul can decrease total cholesterol levels by 11.7%, LDL by 12.5%, and TG by 12.0%, with no change in HDL values.

Extracts of the leaves of the Globe artichoke have also been found to have some lipid-lowering activity. One clinical trial used 1,800 mg of artichoke extract versus placebo for 6 weeks for the treatment of elevated cholesterol. The decrease in total cholesterol values was 18.5% in the artichoke group versus 8.6% in the placebo group. Also, LDL values fell by a significant 22.9%. Be aware, though, that patients with gallstones or other bile-duct obstructions should avoid artichoke supplements, as they tend to have choleretic activity.

Dozens of observational and clinical studies have shown that vitamin C levels are inversely associated with cholesterol levels. In one of the best studies, the higher the serum vitamin C, the lower the total cholesterol and triglyceride levels, and the higher HDL (good cholesterol). For each 0.5 mg/dl increase in vitamin C in the blood, there was an increase in HDL cholesterol of 14.9 mg/dl in the women studied(not a bad effect from a simple vitamin.

Pantethine, the most active form of pantothenic acid (vitamin B5), is involved in the transport of fats to and from cells. There is evidence that pantethine supplementation reduces serum triglycerides by 32%, total cholesterol by 19%, and LDL cholesterol by 21%, while increasing HDL cholesterol by 23%. Its mechanism of action is to inhibit cholesterol synthesis and to increase the utilization of fat as a source of energy.