DIETARY SUPPLEMENTS TO PREVENT DISEASE
Objectives:
Upon completion of this module, the student will be able to:
1. Discuss the biological basis for the lipid lowering effects of policosanol and the chemopreventive effects of soy.
2. Critically appraise the research literature pertinent to the safety and efficacy of policosanol to treat hyperlipidemia and soy to prevent cancer.
3. Identify the clinical and patient education implications pertinent to the use of policosanol to treat hyperlipidemia and soy to prevent cancer.
HYPERLIPIDEMIA
Statement of the Problem
A preponderance of epidemiological, clinical, and animal model data indicate that elevations in serum lipids are associated with increased risk for cardiac-related morbidity and mortality (reviewed in Harper & Jacobson, 1999). As a result, many persons are modifying their lifestyles and/or using pharmacologically active agents to normalize unhealthy lipid profiles or to maintain already healthy lipid profiles. Lifestyle modifications may include adhering to low fat diets and engaging in regular aerobic exercise. Pharmacologically active agents that are used include FDA-approved prescription drugs and over-the-counter (OTC) dietary supplements.
In this module, we’re going to look closely at some of the OTC dietary supplements that people are using to lower their serum lipid levels. But before we examine the safety and efficacy of these agents, let’s review the mechanisms that underlie lipid-mediated atherogenesis. The first step is to find the Harper & Jacobson article that’s on the reference list. You can download the full text of this article by going to OVIDWeb from the Rush University Home Page www.rushu.rush.edu. Once there, click on “Library Services” then OVIDWeb, which is located under the “Databases” heading. From OVIDWeb, you can enter the citation information (below in reference list) to retrieve and download the article. If you are not a registered student at Rush University, you may obtain the article through your local medical library, or you may order through "loansome doc" available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=&DB=PubMed.
Now that you've downloaded the full text, click on Figure 1. Figure 1 is based on data collected in the Framingham Heart Study. As you remember, serum cholesterol consists of two subpopulations: low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). Figure 1 shows that there is a greater risk of coronary heart disease (CHD) when LDL-C is high and HDL-C is low. However, higher HDL-C levels can offset some of the risk associated with lower LDL-C levels. This can be seen by looking at the relative risk of CHD when the LDL-C level is 220 mg/dL. At this LDL-C level, the relative risk of CHD declines by more than 50% when the HDL-C is increased from 65 mg/dL to 85 mg/dL. In contrast, look at the relative risk for CHD at this LDL-C level (220 mg/dL) when the HDL-C is 25 mg/dL! In short, there is strong evidence that HDL-C is highly predictive of CHD.
Let's look at why HDL-C is such a strong predictor of CHD. Start by clicking on Figure 2. This figure shows the structure of HDL-C. As you can see, it’s a sphere whose core contains cholesterol and triglycerides. Additionally, embedded in the surface are apolipoproteins, the protein components of lipoproteins. Now, read the sections entitled “HDL-C Biochemistry and Atherosclerosis” and “HDL-C and its Antiatherogenic Effect.”
Based on this reading, consider the following questions (answers at end):
A 56 year old male presents to the clinic for a physical examination prior to purchasing a life insurance policy. A fasting lipid profile is performed and the following results are obtained:
Parameter Result Reference range
Total cholesterol 288 mg/dL desirable = < 200 desirable
borderline elevated = 200-239
elevated = > 240
HDL cholesterol 27 mg/dL male = 29-72
LDL cholesterol 210 mg/dL older than 50 years = < 209
Is this patient at risk for CHD? Why or why not?
What is the goal of therapy for someone with an atherogenic-promoting lipid profile?
How might we achieve the goals in #2?
Answers
Yes this patient is at risk for CHD. Look at Figure 1 in the Harper & Jacobson article. This lipid profile falls into the area represented by the upper right corner of the figure. Hence, this patient is at high risk for CHD based on lipids alone. Factor in other possible risk factors, such as family history of heart disease, smoking, hypertension, and obesity and the risk becomes even greater.
The patient is at high risk for CHD based on lipids alone because there is a high concentration of LDL-C. We know that LDL-C can become oxidized when they penetrate endothelial cells in the coronary arteries. Oxidation of LDL-C initiates CHD. When oxidized, LDL-C are highly susceptible to ingestion by resident macrophages in the intima. These resident macrophages accumulate cholesterol intracellularly and become foam cells, a constituent of atherosclerotic plaques. Oxidized LDL-C also stimulate endothelial cells to secrete substances that recruit monocytes to the intima, where they differentiate into macrophages. Thus oxidized LDL-C can promote local accumulation of macrophages and subsequent formation of foam cells. Macrophages themselves can recruit monocytes by upregulating endothelial expression of adhesion molecules that “trap” monocytes.
This process is nicely illustrated in Figure 242-cd3 in Harrison’s OnLine. To view, go to
http://www.harrisonsonline.com/server-java/Arknoid/harrisons/1096-7133/Chapters/ch-242?Page=1
If you don't have access to Harrison's Online, please obtain Harrison's Internal Medicine 15th ed. (2001) and refer to figure 241-1, p. 1378.
The patient is also at high risk for CHD because his HDL-C levels are suboptimal. HDL-C confers protection against CHD because it is involved in reverse cholesterol transport, that is, transport of cholesterol from the tissues to the liver. HDL-C particles accept cholesterol and transport it to the liver. It is believed that HDL-C particles remove cholesterol from macrophages, thus preventing formation of foam cells.
The goals of therapy are to reduce LDL-C and increase HDL-C concentrations.
There are nonpharmacological approaches such as lowering intake of saturated fat and engaging in aerobic activity. However, for many persons (i.e., persons with diabetes, Syndrome X, familial hyperlipidemia), only modest improvements can be achieved with dietary and activity modifications alone. These persons may require pharmacological intervention.
A standard pharmacological therapy to normalize serum lipids is the class of drugs known as statins. Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. In both the liver and extrahepatic sites, HMG CoA reductase catalyzes the conversion of HMG CoA to mevalonate, which is an early and rate-limiting step in cholesterol synthesis (Mosby’s GenRX, 1999). The decrease in intracellular cholesterol concentration results in a compensatory upregulation of surface LDL receptors, which in turn, mediates clearance of LDL from the plasma (Farnier & Davignon, 1998). In hepatocytes, the endocytosed LDL particles are converted to bile salts and excreted in the stool (Lennernas & Fager, 1997).
You can view the cholesterol synthesis pathway and identify the step that is inhibited by statins by clicking on the following link: http://www.people.virginia.edu/~rjh9u/hmgcoa.html
Why Use Complementary or Alternative Therapies to Lower Lipid Levels? Statin drugs are highly effective in lowering lipid levels. So why do people use alternative therapies when the “conventional” therapy is effective? One reason may be cost. In 1996, the annual cost of lovastatin, a type of statin drug, ranged from $759 to $2738 depending upon the dose (Perreault, Hamilton, Lavoie, & Grover, 1998). Cost may be particularly important for elderly persons, because they often live on fixed incomes and because Medicare does not reimburse prescription drug costs.
Another reason is that many persons prefer a “natural” approach to lower lipids, in the belief that natural substances are less toxic. Although relatively safe, statins have been associated with elevations in liver function tests and rhabdomyolysis (Hardman & Limbird, 1996).
Culture may also influence the decision to use complementary or alternative therapies to lower lipids. Some individuals may place greater trust in their culture’s traditional healers than in allopathic practitioners. This belief may be reinforced by research findings that indicate that certain alternative therapies are efficacious. For example, garlic is used by many Bulgarians to treat a variety of diseases (Petkov, 1986), and two meta-analyses have concluded that garlic can lower lipid levels (Silagy & Neil, 1994; Warshafsky, Kramer, & Sivak, 1993).
Critical Appraisal of CAM Therapies to Lower Lipid Levels
Let's look next at the available scientific literature on three widely-used CAM therapies to lower lipid levels: policosanol, garlic, and fish oil.
Policosanol. Policosanol is an over-the-counter dietary supplement that is marketed in the US as a cholesterol-lowering agent. It is a mixture of high molecular weight alcohols that are derived from either sugar cane wax or beeswax (Menendez et al., 1994). Policosanol inhibits cholesterol synthesis at an unknown point in the pathway (Mas et al., 1999), although it has been determined that it is not an HMG CoA reductase inhibitor (Menendez, Amor, Gonzalez, Fraga, & Mas, 1996). Your assignment is to (a) read the article cited below, and (b) meet with your small group, either in person or electronically, and discuss the questions below, and (c) submit a 2-3 page, double-spaced, group paper that answers the questions that follow the citation.
Mas, R., Castano, G., Illnair, J., Fernandez, L., Fernandez, J., Aleman, C., Pontigas, V., & Lescay, M. (1999). Effects of policosanol in patients with type II hypercholesterolemia and additional coronary risk factors. Clinical Pharmacology & Therapeutics, 65, 439-447.
What are the methodological strengths and weaknesses of the study by Mas et al.? In your judgment, are the conclusions of the study valid?
Your 62 year old female patient who has hypertriglyceridemia and a low HDL:LDL has elected to treat her dyslipidemia with policosanol rather than an FDA-approved drug. What are the patient teaching implications?
References
1. Farnier M., & Davignon, J. (1998). Current and future treatment of hyperlipidemia: The role of statins. American Journal of Cardiology, 82, 3J-10J.
2. Harper, C.R., & Jacobson, T.A. (1999). New perspectives on the management of low levels of high-density lipoprotein cholesterol. Archives of Internal Medicine, 159, 1049-1057.
3. Hardman, J.G., & Limbird, L.E. (Eds.). (1996). Goodman & Gilman's The pharmacological basis of therapeutics (9th ed.). New York: McGraw-Hill.
4. Lennernas, H., & Fager, G. (1997). Pharmacodynamics and pharmacokinetics of HMG-CoA reductase inhibitors. Clinical Pharmacokinetics, 32, 403-425.
5. Mas, R., Castano, G., Illnair, J., Fernandez, L., Fernandez, J., Aleman, C., Pontigas, V., & Lescay, M. (1999). Effects of policosanol in patients with type II hypercholesterolemia and additional coronary risk factors. Clinical Pharmacology & Therapeutics, 65, 439-447.
6. Menendez, R., Fernandez, S.I., Del Rio, A., Gonzalez, R.M., Fraga, V., Amor, A.M., & Mas, R.M. (1994). Policosanol inhibits cholesterol biosynthesis and enhances low density lipoprotein processing in cultured human fibroblasts. Biological Research, 27, 199-203.
7. Menendez, R., Amor, A.M., Gonzalez, R.M., Fraga, V., & Mas, R.M. (1996). Effect of policosanol on the hepatic cholesterol biosynthesis of normocholesterolemic rats. Biological Research, 29, 253-257.
8. Perreault, S., Hamilton, V.H., Lavoie, F., & Grover, S. (1998). Treating hyperlipidemia for the primary prevention of coronary disease: Are higher doses of lovastatin cost-effective? Archives of Internal Medicine, 158, 375-381.
9. Silagy, D., & Neil, A. (1994). Garlic as a lipid lowering agent: A meta-analysis. Journal of the Royal College of Physicians of London, 28, 39-45.
10. Warshafsky, S., Kramer, R.S., & Sivak, S.L.(1993). Effect of garlic on total serum cholesterol: A meta-analysis. Annals of Internal Medicine, 119, 599-605.
