CHOLESTEROL (and other cardiovascular risk markers)

 

What is cholesterol?

  • Cholesterol is a waxy, fat-like substance that is present in all animals, but not in plants (phytosterols are present in plants instead).
  • Every cell in our body contains cholesterol; we cannot live without it. 
    • Cholesterol is a vital component of cell membranes. 
      • Plays a key role in membrane fluidity, thus influencing transmembrane signaling.
      • According to the Weston Price Foundation, it is a potent antioxidant that protects against free radical damage to the cell membrane.
    • Cholesterol is also in many of the cellular organelles.
    • Cholesterol in the brain promotes myelin formation and neuronal plasticity (Prog Neurobiol. 2006. 80. 165-176).
    • Cholesterol is the biochemical precursor to all steroid hormones, vitamin D, and bile acids.
  • 93% of cholesterol in the body is found in the cells of the body, 7% in the blood.
  • Cholesterol alone is not very soluble in blood, so it is carried in the bloodstream by molecules called lipoproteins.
  • Lipoproteins are named based on their density.
  • We know from the careful study of cholesterol metabolism that high density lipoprotein (HDL) is "good" - it transports cholesterol to the liver.
  • Low density lipoprotein (LDL) is "bad" - oxidized LDL gets deposited in the walls of arteries, contributing to arteriosclerosis.

 

What is the source of cholesterol in the blood?

  • The liver makes cholesterol.
    • In general, the higher the saturated fat content of the diet, the more cholesterol made by the liver.
    • Approximately 80% of total body cholesterol is synthesized in the liver.
  • Most cells can make cholesterol – high insulin levels signal cells to make cholesterol instead of taking up cholesterol from the bloodstream.
  • The cholesterol in the food we eat contributes little to the blood cholesterol level. Current average cholesterol intake estimated at 430 mg/day, prehistoric intake estimated at 520 mg/day.

 

Why is the blood cholesterol level important?

  • Consistent evidence links increased cholesterol levels to an increased risk of coronary heart disease (CHD)
    • Data gathered in The Seven Countries Study linked blood cholesterol levels to coronary mortality (Keys A, et al. Acta Med Scand. 1966. 460 [suppl]. 1-392).
    • Japanese who moved to Hawaii and San Francisco had higher blood cholesterol levels and coronary event rates than Japanese who did not migrate (Am J Cardiol. 1977. 39. 239-243).
    • Epidemiologic data from the Framingham study confirms the link between cholesterol levels and CHD risk (Ann Epidemiol. 1992. 2. 23-28).
    • Data from the ARIC study, a prospective study with 15 year follow up, shows that a that each 1% increment in LDL is associated with a 2-3% increment in cardiovascular risk (N Engl J Med. 2006.354. 1264-1272 and 1310-1312)
    • A long-term outcome study in 3277 healthy Finnish businessmen aged 30-45 at baseline who were followed for 39 years found that above a total cholesterol of 5 mmol/L (194 mg/dl), higher total cholesterol was associated with a higher total mortality and a worse physical quality of life, as assessed by the RAND-36 questionnaire (J Am Coll Cardiol. 2004. 44. 1002-1008, as abstracted in Cardiology Review. 2006. 23 (1). 13-16).
    • Note: For reasons that are not yet understood, population studies show that the blood cholesterol level in people over age 70 is not correlated very strongly with the risk of heart attack (JAMA. 1994. 272. 1335-1340).
    • Note: The total cholesterol level in the blood is not as important as the ratio of total cholesterol (TC) to HDL cholesterol.
      • Recent data indicate that this ratio predicts the risk of heart attack independent of the level of LDL cholesterol in the blood (Ann Intern Med. 1994. 121. 641-647).
      • The higher the ratio of TC: HDL, the higher the statistical risk of plaque building up on the walls of the coronary arteries which supply the heart with blood.
  • Note that despite convincing evidence from clinical trials that statins reduce the risk of stroke, the data from epidemiologic trials with regard to the relationship between serum cholesterol and stroke risk is mixed (Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet. 1995. 346. 1647-1653).

 

What are the other risk factors for heart attacks?

  • The level of triglycerides in the blood stream - the statistical correlation between blood triglyceride level and heart attack risk is not as strong as the statistical correlation between the blood cholesterol level and heart attack risk.
  • Smoking.
  • High blood pressure.
  • Diabetes.
  • Obesity.
  • Sedentary lifestyle.
  • Family history (defined as a male relative with a heart attack under age 55 or a female relative with a heart attack under age 65).

 

What is a good blood cholesterol level?

  • In general, the lower the better, at least down to a cholesterol level of 140.
  • The normal LDL cholesterol amongst hunter-gatherers, healthy human neonates, and free living primates is 50-70 (J Am Coll Cardiol. 2004. 43. 2142-2146).
  • For total cholesterol, the upper limit of normal used to be defined arbitrarily as the level two standard deviations above the average cholesterol level for Americans - approximately 360 on most lab reports.
    • Based on this definition, only 5% of the population had an abnormal cholesterol level.
    • In the 1980's, as researchers learned more about the dangers of high cholesterol levels, the upper limit of normal was arbitrarily redefined as 200 on most lab reports.
  • HDL should be greater than 35 - this can be measured along with total cholesterol in a nonfasting state.
  • LDL should be less than 130 - a valid measurement requires a 12 hour fast.
  • In diabetics, or in people with a previous history of heart attack, stroke, or peripheral vascular disease, LDL should be less than 100.
  • Triglycerides should be less than 150 - a valid measurement requires a 12 hour fast.
  • Note on terminology and pathophysiology - there is only one type of cholesterol in the diet, but in the blood cholesterol is carried by proteins and these are called lipoproteins and HDL refers to high density lipoprotein and LDL refers to low density lipoprotein.  We know that HDL carries cholesterol back to the liver whereas LDL deposits cholesterol in the walls of arteries.

 

What are the benefits of lowering the blood cholesterol level?

  • Current data in aggregate indicates that at least in middle aged men, lowering LDL cholesterol by 1% (either by lifestyle changes or medications) decreases coronary events by approximately 1%.
  • Note that early intervention trials to reduce coronary events by lowering blood cholesterol levels yielded mixed results (Steinberg D. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans (J Lipid Res. 2005. 46. 179-190), such that at least one review concluded in 1992 that “lowering serum cholesterol concentrations does not reduce mortality and is unlikely to prevent coronary heart disease” (BMJ. 1992. 305. 15-19).
  • One early positive trial was the Lipid Research Clinics Primary Prevention Trial in which 3806 asymptomatic middle aged men with hypercholesterolemia were randomized to placebo or cholestyramine and followed for a mean of 7.4 years, a 13% greater reduction in LDL was associated with a 19% reduction in the primary end point, a composite of cardiac death or MI (JAMA. 1984. 251. 351-364).
  • The statin trials, the first of which was published in 1994 (4S Trial), in aggregate have shown conclusively that lowering serum cholesterol reduces not just cardiovascular mortality, but also total mortality, at least in secondary prevention trials.

 

What are the risks associated with lowering the cholesterol level?

  • A scientific statistical meta-analysis of six major primary prevention trials (BMJ. 1993. 306. 1367-1373) shows that the 15% decrease in deaths from heart disease in the cholesterol lowering treatment groups is offset by increases in deaths from gallbladder disease, cancer, and injuries.
    • The cause of this recurrent finding of increased noncardiac death rates in patients on cholesterol lowering medication is unclear, but it suggests that in young, otherwise healthy adults, the risks of medication treatment for high cholesterol may outweigh the benefits.
    • Noncardiovascular mortality was NOT statistically significantly increased in any of the large statin trials.
  • There is some animal data indicating that some cholesterol lowering drugs (fibric acid derivatives such as Lopid and Atromid, and possibly the HMG CoA reductase inhibitors) may cause cancer.
  • Anecdotally, lowering cholesterol can cause memory impairment.
  • There does not seem to be a risk of lowering cholesterol by lifestyle changes; the risk seems to be seen only when medications are used.

 

Should a high cholesterol level be lowered in seniors (>age 65) without known atherosclerosis?

  • This is controversial – from a statistical standpoint elevated cholesterol in seniors is not as strong a predictor of heart disease as elevated cholesterol in middle aged individuals.
  • Anecdotally, lowering cholesterol in seniors may cause memory impairment.
  • There is statistical data that low cholesterol levels in seniors is associated with increased all-cause mortality, with a prospective study of 2277 individuals showing that this association is independent of comorbid illnesses (J Am Geriatr Soc. 2005. 53. 219-226).

 

How often should the blood cholesterol level be measured?

  • The National Cholesterol Education Project (NCEP) and some other authorities call for measuring a blood cholesterol level for screening purposes in all adults over age 20, every 5 years.
  • The United States Preventative Services Task Force (USPSTF) and the American College of Physicians (ACP) currently recommend every 5 year screening only in males over age 35 and females over age 45, in the absence of other risk factors for heart disease (see the list above).
    • The basis of this recommendation is data which suggests that most of the cardiovascular risk associated with a high cholesterol can be reversed within two years of starting treatment in a middle aged, high risk population.
    • Note: Policy documents formulated by groups consisting mostly of clinical epidemiologists (USPSTF) recommend initiation of screening at a later age than documents formulated by groups consisting mostly of lipid specialists NCEP).
  • Anytime cholesterol is measured for screening purposes, HDL should also be measured.
  • It is debatable as to whether screening cholesterol levels should be measured in adults over age 70, since the statistical correlation between cholesterol levels and heart disease risk is either very weak or non existent after age 70.
  • If the total cholesterol is over 240 in an adult without other risk factors for heart disease, or is over 200 in an adult with at least two other risk factors for heart disease, NCEP recommends repeating screening cholesterol levels every year.
  • Cholesterol should be rechecked after 6-8 weeks in somebody on treatment (either lifestyle changes or medications).
  • NOTE, based on data in 4162 subjects in the PROVE-IT-TIMI 22 Study, there is evidence of seasonal variation in LDL and HDL levels in individuals on statin medications, with LDL statistically significantly lower in the summer than the winter (magnitude 4-6 mg/dl) and HDL statistically significantly higher in the summer than the winter (magnitude 1-2 mg/dl) [Am J Cardiol. 2009. 103. 1056-1060].

 

How can one improve ones cholesterol: HDL cholesterol ratio?

  • Smoking cessation lowers cholesterol and LDL cholesterol, and raises HDL cholesterol.
  • Relaxation techniques (meditation, yoga) lower cholesterol and LDL cholesterol.
  • Weight loss raises HDL cholesterol.
  • Aerobic exercise
    • Consistent aerobic exercise lowers the cholesterol: HDL cholesterol ratio by 15% (Circulation. 1995. 92. 773-777).
    • A meta-analysis of 25 RCTs shows that (1) a minimum exercise volume of 120 minutes of exercise per week or 900 kcal of energy expenditure per week is necessary to raise HDL, (2) mean net change in HDL is statistically significant but moderate at 2.53 mg/dl, (3) exercise duration per session seems to be the most important factor in determining the effect of aerobic exercise on HDL levels, with every 10 minute prolongation of exercise per session associated with a 1.4 mg/dl increase in HDL, and (4) exercise is most effective in individuals who at baseline have total cholesterol of >220 mg/dl or a BMI < 28 (Arch Intern Med. 2007. 167. 999-1008).
  • Alcohol (1-2 drinks per day) raises HDL cholesterol.
  • Ultraviolet light (i.e. sunlight) -in one experiment, 97% of subjects experienced a 13% decrease in serum cholesterol two hours after exposure to ultraviolet light, and 86% maintained the drop in cholesterol 24 hours later (Circulation. 1953. 8. 438).
  • Dietary modification:
    • A diet low in saturated fat lowers cholesterol and LDL cholesterol.
      • Studies show that a population based educational approach is associated with a 1-11% reduction in cholesterol levels.
      • Other studies show that an individual counseling approach is associated with a 5-14% reduction in cholesterol levels (75-80% of the reduction seen in "metabolic ward studies" in which the individual is in a controlled environment in which dietary intake of saturated fat is accurately determined by a professional).
      • In 4 RCTs in which individuals started with diets high in saturated fat and reduced saturated fat intake by 10% of energy intake, a 12-15% decrease in total cholesterol was seen, and this was associated with a significant reduction in cardiovascular disease (Circulation. 1969. 60. 111S-163S; Circulation. 1970. 42. 935-942; Int J Epidemiol. 1979. 8. 99-118 as cited in the Comment section of JAMA. 2006. 295. 655-666).
    • A diet low in trans fats lowers cholesterol and raises HDL - Return to Home Page, click on "Nutrition" and scroll to trans fats for more detail.
    • A diet low in simple sugars and low in high glycemic index carbohydrates may raise HDL. In one study in 14 young men, increased intake of sucrose from 115 to 260 grams/day was associated with 16% decrease in HDL (Br Med J. 1980. 281. 1396).
    • A diet with 2-10 grams/day of soluble fiber lowers cholesterol levels 15-18% (Am J Clin Nutr. 1999. 69. 30-42).
      • More information below under the heading of herbs – see konjac root and psyllium.
      • There is some data that rye fiber lowers cholesterol and blood sugar more than wheat fiber (Am J Clin Nutr. 2003. 77. 385-391).
    • A plant-based diet
      • in a 4 week outpatient feeding study in 120 adults, the group that incorporated more vegetables, legumes, and  whole grains into a low fat diet (AHA Step I guidelines) achieved an average 17.6 mg/dl drop in total cholesterol compared to an average 9.2 mg/dl drop in the low fat control group (P=0.01)and an average 13.8 mg/dl drop in LDL compared to an average7.0 mg/dl drop in the low fat control group (P=0.02).  The HDL dropped an average of 3.8 mg/dl in the plant group compared to an average of 2.5 mg/dl in the control group (P=0.13) and the triglycerides increased an average of 0.1 mg/dl in the plant group compared to 1.2 mg/dl in the control group (P>0.2).  The two diets in this study were designed to have identical levels of total fat (30%), saturated fat (10%), and cholesterol (<300 mg/day) [Ann Intern Med. 2005. 142. 725-733].
      • A review of 27 clinical trials, a mix of RCTs and observational trials found that a plant based diet lowered LDL cholesterol as much as 35% (Am J Cardiol. 2009. 104. 947-956 and editorial  957-958)
  • Polymeal (also referred to as a Dietary Portfolio)

o        A diet rich in foods sometimes referred to as functional foods which are known individually to lower cholesterol lowered LDL 28.6% and CRP by 28.2% (JAMA. 2003. 290. 502-510).

o        A crossover trial in 34 hyperlipidemic patients found that a diet high in plant sterols, soy-protein foods, almonds, and viscous fibers from oats, barley, psyllium, and the vegetables eggplant and okra reported a 29% decrease in LDL at 4 weeks, compared with a 33.3% decrease in LDL in those patients on lovastatin 20 mg/day (Am J Clin Nutr. 2005. 81. 380-387).

o        A 6 month RCT at 4 participating academic centers across Canada in which 351 participants were randomized to receive information on either (1) low saturated fat diet, (2) dietary portfolio with instruction at 2 clinic visits over 6 months, and (3) dietary portfolio with instruction at 7 clinic visits over 6 months. The counseling in the dietary portfolio group emphasized incorporation into the diet of plant sterols, soy protein, viscous fiber, and nuts. In a modified intention-to-treat analysis for 345 participants, LDL cholesterol dropped by 13.8% in the intensive dietary portfolio group, 13.1% in the routine dietary portfolio group, and 3.0% in the low saturated fat diet group. The percentage reductions in each of the dietary portfolio groups were greater than the percentage reduction in the low saturated fat diet group (p<0.001). Among participants randomized to the dietary portfolio groups, percentage reduction LDL cholesterol was associated with dietary adherence (p<0.001) [JAMA. 2011. 306. 831-839].

  • Certain foods (references are Food: Your Miracle Medicine  by Jean Carper and Nutritional Therapy in Medical Practice Reference Manual by Alan Gaby and Jonathan Wright):
    • Almonds – see ‘Prevention of MI’ outline (Primary Prevention – Nuts) for scientific citations and the information on the FDA health claim.
    • Apples (soluble fiber)
    • Avocados
    • Barley (Am J Clin Nutr. 2004. 80. 1185-1193)
    • Beans (pintos, kidney, black, navy, lentils, chickpeas), one cup/day, may lower LDL as much as 20% and, after 1-2 years,  raise HDL as much as 9%.
    • Carrots (soluble fiber) [Am J Clin Nutr. 1979. 32. 1889].
    • Chili peppers
    • Chocolate (dark) improves the HDL: LDL cholesterol ratio (Brit J Nutr. 2002. 88. 479-488).
    • Cordyceps sinensis mushrooms lower cholesterol – also available as a dietary supplement (see dosing information below).
    • Fatty fish (salmon, sardines, herring, mackerel, whitefish, and bluefin tuna) raise HDL and lower triglycerides.  Fish oil capsules do the same.
    • Flax meal or flax oil
    • Grape seed oil raises HDL.
    • Hazel nuts – see ‘Prevention of MI’ outline (Primary Prevention – Nuts) for scientific citations.
    • Macadamia nuts – see ‘Prevention of MI’ outline (Primary Prevention – Nuts) for scientific citations and the information on the FDA health claim.
    • Margarine lowers cholesterol, but the trans fatty acids created by the chemical process of hydrogenation by which margarine is converted from a liquid into a solid are now clearly associated with significant health risks which offset the benefits of stick margarine with regard to cholesterol lowering. Newer margarines made from plant sterols or plant stanols seem to be a safe and effective way of lowering cholesterol.
    • Oat bran lowers cholesterol and LDL and raises HDL. In one study, two ounces of oat bran per day was associated with a 16% lowering of LDL and, after 3 months, an increase in HDL of as much as 15% (JAMA. 1991. 285. 1833-1839). Another study also showed benefit (Am J Clin Nutr. 1980. 33. 915).
    • Olive oil raises HDL, lowers LDL, and interferes with the oxidation of LDL cholesterol.
    • Onions (half a raw onion/day) may raise HDL as much as 30%.
    • Pecans – see ‘Prevention of MI’ outline (Primary Prevention – Nuts) for scientific citations and the information on the FDA health claim.
    • Pistachios – see ‘Prevention of MI’ outline (Primary Prevention – Nuts) for scientific citations and the information on the FDA health claim.
    • Plant sterols and stanols            (Am J Cardiol. 2005. 96 [supplement])
      • Effectiveness at lowering LDL cholesterol as much as 10-20 % in doses of approximately 2-3 grams/day documented in more than 20 published studies.  Based on a meta-analysis of 113 studies, plant stanols are twice as potent as plant sterols. One of the proposed reasons is that stanols are relatively less absorbed in the intestinal tract as compared to sterols, so they more effectively block cholesterol absorption (Prostaglandins Leukot Essent Fatty Acids. Feb 2011).  Data indicates lack of further benefit with doses higher than 3 grams/day.  Maximum effect  seen after 16-24 weeks on treatment. Effect at cholesterol lowering is additive to that of prescription statins.
      • Presumed mechanism of action – block absorption of cholesterol in the intestinal tract (similar mechanism of action as the prescription drug Zetia).  This is accomplished by competing with cholesterol for incorporation into mixed micelles required for cholesterol absorption and by increasing the flux of cholesterol from the enterocyte back into the lumen of the intestine.  Note that dietary intake of cholesterol is only 50-750 mg/day, biliary cholesterol input to the intestine is 500-2400 mg/day.
      • The FDA in 2000 authorized the use of a therapeutic label claim for foods containing at least 0.65 grams of plant sterols per serving or at least 1.7 grams of plant stanols per serving.  The claim states that "Diets low in saturated fat and cholesterol that include at least 1.3 grams of plant sterol esters or 3.4 grams of plant stanol esters, consumed in two meals with other foods, may reduce the risk of heart disease."  Note that average dietary intake of plant sterols is only 150-350 mg/day and average dietary intake of plant stanols is only 50 mg/day, so achieving therapeutic intake for purposes of LDL lowering requires supplementation.
      • Take Control is a margarine spread which contains plant sterols derived from soybeans.  A portion containing 1.7 grams of plant sterols when consumed twice a day lowered LDL by up to 17%.
      • Benecol is a margarine spread which contains plant stanols derived from soy, beans, and corn.  A portion containing 1.7 grams of plant sterols when consumed three times a day lowered LDL by up to 14%.
      • Benecol SoftGels contain 1.1 grams of plant stanols per serving of 2 capsules.
      • Cholesterol Success Plus by Twinlab and Cholest-Off by Nature Made are brand names of other supplements.
      • CholestePure (Emerson Ecologicals) and UltraMeal Plus (Metagenics) are other products with phytosterols.
      • To date (7/04) no significant side effects have been reported in numerous studies, but long term effects are unknown.
      • 5-12% of plant sterols are absorbed into the bloodstream; 1-5% of plant stanols are absorbed into the bloodstream.
      • There is a theoretical concern that regular long-term consumption may interfere with absorption of fat soluble vitamins and nutrients.  Current data indicates no effect on absorption of vitamins A, D, and K, but some decrease in absorption of tocopherols and carotenoids.
      • Plant sterols increase plasma plant sterol levels whereas plant stanols decrease plasma plant sterol levels – clinical significance uncertain.
      • Absorption of plant sterols downregulates bile acid synthesis, which attenuates their cholesterol-lowering efficacy, so plant stanols may be preferable for long-term management of hypercholesterolemia (Am J Cardiol. 2005. 96. 29D-36D).
    • Raisins - in one study, one cup per day lowered LDL 14% and TC 9% (Lipids Health Dis. 2008. 7. 14).
    • Reishi mushrooms lower cholesterol – also available as a dietary supplement (see dosing information below).
    • Sesame seeds (40 grams/day ground seeds) based on a trial in 21 patients (Nutr Res. 2005. 25. 559-567).
    • Shiitake mushrooms lower cholesterol – also available as a dietary supplement (see dosing information below).
    • Soybeans (raw soybeans, soy milk, soy nuts, tempeh, and tofu but not soy sauce, soy oil, or many brands of soy burgers, soy cheeses, or soy hotdogs) are as potent as the other beans above at lowering LDL and raising HDL. 
      • A meta-analysis of 38 clinical studies on the effects of ingesting 31-47 grams of soy protein on serum cholesterol levels found that soy on average was associated with a 9.3% decrease in total cholesterol, a 12.9% decrease in LDL cholesterol, a 2.4% increase in HDL cholesterol, and a 10.5% decrease in triglycerides (New Engl J Med. 1995. 333. 276-282). 
      • Based on a number of published studies (New Engl J Med. 1995. 333. 276-282; Am J Clin Nutr. 1998. 68. 1375S-1379S; Am J Clin Nutr. 1998. 68. 1385S-1389S), the FDA in 10/99 approved a "health claim" label for soy products, stating that "Diets low in saturated fat and cholesterol that include at least 25 grams of soy protein may reduce the risk of heart disease" (Fed Regist. 1999. 64. 57700-57733). The cholesterol lowering benefits of soy protein require consumption of at least 25 grams per day, based on a literature review. 
      • A meta-analysis of studies published between 1995 and 2002 found that intake of soy protein containing isoflavones was associated with a 3.77% reduction in total cholesterol, 5.25% reduction in LDL, 7.27% reduction in triacylglycerols, and a 3.02% increase in HDL (Am J Clin Nutr. 2005. 81. 397-408).
      • A meta-analysis of 41 RCTs published between 1996 and 2005 and using soy protein supplementation found a mean reduction of 5.26 mg/dl in serum total cholesterol and 4.25 mg/dl in LDL and 6.26 mg/dl in triglycerides, and a mean increase of 0.77 mg/dl in HDL (Am J Cardiol. 2006. 98. 633-640).
      • Another meta-analysis reported that the average LDL-lowering effect of soy protein with isoflavones was 3%, and that isolated isoflavones did NOT have an LDL-lowering effect (Circulation. 2006. 113. 1034-1044).
      • Presumed mechanism of action – reduced hepatic cholesterol synthesis.
        1. NOTE it is unclear to what extent soy isoflavones are responsible for the lipid-lowering effect of soy, as there is not a significant linear correlation between reduction in LDL cholesterol and soy-protein ingestion or isoflavone intake (Am J Clin Nutr. 2007. 85. 1148-1156). The lipid lowering effect of soy may arise from a synergistic action of constituents in soy protein, isoflavones, cotyledon fibers in the cell wall of the plant, phospholipids, saponins, and phytosterols (IMCJ. 2009. 8[4]. 30-40).
        2. It has been proposed that only the 1/3 of individuals who convert daidzein to equol benefit from soy with regard to the lipid profile. The ability to convert daidzein to equol appears to be related in part to the composition of the diet (amount of prebiotic in the diet) and in part to specific gut flora. Lactobacillus sporogenes facilitates this conversion.
    • Walnuts – see ‘Prevention of MI’ outline (Primary Prevention – Nuts) for scientific citations and the information on the FDA health claim. See also Alt Med Alert. 2007. 10. 17-21.
  • Certain herbs (Herbs for serum cholesterol reduction: a systematic review. J Fam Pract. 2003. 52. 468-478).
    • Arjuna (Terminalia arjuna, an Ayurvedic herb) – a systematic review identified 6 RCTs, 4 of intermediate quality and 2 of high quality, and all showed efficacy greater than placebo (Alt Ther Health Med. 2007. 13[4]. 22-28).
    • Artichoke leaf – in one 6 week trial 1800 mg of artichoke leaf extract, total cholesterol was lowered 18.5% in the treatment group vs. 8.6% in the placebo group (Arzneimittelforschung. 2000. 50. 260-265). In another trial, artichoke extract reduced LDL, reduced LDL oxidation and improved endothelial function (Life Sci. 2004. 76. 775-782). Slight benefit of an extract at 1280 mg/day (4.2% reduction in total cholesterol) seen in a 12 week RCT of 75 patients (Phytomedicine. 2008. 15. 668-675).
    • Fenugreek - lowers cholesterol and triglycerides along with lowering blood sugar (Prostaglandins Leukot Essent Fatty Acids. 1997. 56. 379-384).
    • Garlic 300 mg 3 times a day
      • A meta-analysis of the effect of garlic on serum total cholesterol found a significant decrease of 22.8 mg/dL or 9% compared to placebo.  This figure was based on four statistically homogenous trials including a total of 324 participants (Ann Intern Med. 1993. 119. 599-605).
      • A subsequent meta-analysis of 16 trials including 952 persons reported a reduction in total cholesterol of 29.7 mg/dL or 12% (J R Coll Physicians Lond. 1994. 28. 39-45).
      • A more recent meta-analysis of 13 RCT's with 796 persons, all with baseline total cholesterol greater than 200 mg/dL, showed a reduction in total cholesterol of 15.7 mg/dL [confidence interval -25.6 mg/dL to -5.7 mg/dL].  However, 6 diet-controlled trials with the highest scores for methodologic quality revealed a non-significant difference between garlic and the placebo groups.  An additional 21 trials of garlic were identified by a literature search but excluded because either they were not placebo-controlled, not randomized, not double-blind, or did not use a garlic monopreparation.  Ten of the 13 trials used Kwai garlic powder, one used spray-dried powder, and two used oil.  (Ann Intern Med. 2000. 133. 420-429).
      • Since the 1993 meta-analysis, 11 of 27 RCTs showed some reduction in serum cholesterol, but 16 of 27 showed no effect on cholesterol (Mol Nutr Food Res. 2007. 51. 1382-1385).
      • An AHRQ evidence report concluded based on review of 37 studies that there was some modest short-term improvement in lipid measures, but effects on cardiovascular outcomes were either not measured or not found (Mulrow C et al. 2000. 1-4).
      • Negative, rigorous study – a  6 month parallel design trial in 192 adults randomly assigned to one of four treatment arms (1) raw garlic, 4 grams blended, (2) powdered garlic supplement, Garlicin 4 tablets/day, (3) aged garlic extract, Kyolic 6 tablets/day, and (4) placebo showed that none of the forms of garlic, when administered 6 days/week for 6 months had statistically or clinically significant effects on LDL, HDL, or triglyceride levels in adults with moderate hypercholesterolemia at baseline (Arch Intern Med. 2007. 167. 346-353). An accompanying editorial points out (1) the only significant design flaw in this trial was the failure to mention whether dietary fat intake changed with time in any of the groups, and (2) lack of benefit in lowering LDL does NOT imply lack of benefit in cardiovascular disease prevention, as there is some data that garlic increases the resistance of LDL to oxidation (see Prevention of MI outline – Primary Prevention for citation) [Arch Intern Med. 2007. 167. 325-326].
      •  Note that garlic oil in one published study did not lower cholesterol (JAMA. 1998. 279. 1900-1902).
    • Guggulipid
      • This is a standardized extract of the herb Commiphora mukul, used in India for 2000 years.
      • In one study, 200 mg four times a day lowers cholesterol 14% - 27% and lowers triglycerides 22% - 30% with no side effects noted (Cardiovasc Drugs Ther. 1994. 8. 659-664).
      • Numerous other studies (approximately 20) suggested beneficial effects.
      • An 8 week RCT in 85 hypercholesterolemic subjects who received either placebo, guggulipid 1000 mg three times a day, or guggulipid 2000 mg three times a day failed to show benefit (JAMA. 2003. 290. 765-772). HOWEVER re-analysis of the data for other endpoints showed an association of guggulipid with reductions in glucose, serum insulin, systolic blood pressure, and hs-CRP (Internal Medicine News. 1/15/04. 49).
      • A systematic review identified 7 RCTs, 2 of intermediate quality and 5 of high quality, and 6 of the 7 trials showed efficacy greater than placebo (Alt Ther Health Med. 2007. 13[4]. 22-28).
      • Usual dose is 500 mg three times a day of a product standardized to 5% guggulsterone.
      • Herb-drug interactions - stimulates a PXR cell receptor, which triggers a liver enzyme which accelerates metabolism of many prescription drugs, including AZT, some anticancer drugs, and statins (J Pharmacol and Exp Ther).
    • Gummar (Gymnema sylvestre) – trials in diabetics show a cholesterol lowering effect.
    • Konjac root – contains a very viscous water-soluble fiber called glucomannan, which is 5 times more potent than psyllium, oat fiber, or guar gum in lowering cholesterol, secondary to its high viscosity.
    • Psyllium (Metamucil)
      • 15 cc (one tablespoon) twice a day lowers cholesterol 15% and LDL cholesterol 20% in adults on a Step I American Heart Association Diet (Arch Intern Med. 1988. 148. 292-296).
      • A meta-analysis of 5 studies using a total of 10.2 grams per day of psyllium seed husk as an adjunct to Step I AHA diet found that psyllium was associated with significant reductions in total cholesterol and LDL cholesterol (Am J Clin Nutr. 2000. 71. 472-479).
      • In an 8 week trial in 68 hyperlipidemic adults, psyllium fiber 15 grams + simvastatin 10 mg is as effective at lowering LDL cholesterol as 20 mg of simvastatin (Arch Intern Med. 2005. 165. 1161-1166).
      • Presumed mechanism of action – increases excretion of cholesterol by increasing excretion as opposed to enterohepatic recirculation of bile acids.
      • FDA allows health claim for heart disease risk reduction.
    • Red yeast rice
      • 600 mg two tablets twice a day lowers cholesterol by 17%, LDL cholesterol 22%, and triglycerides by 12% after 12 weeks in a randomized, controlled trial.  No significant effect on HDL cholesterol (Am J Clin Nutr. 1999. 69. 231-236).
      • Red yeast rice is still available over the counter, but the Pharmanex was ordered by the courts to desist from marketing its brand name product, Cholestin, because the original Cholestin contained lovastatin, which was patented by a pharmaceutical company.
      • 600 mg twice a day decreased total cholesterol by 20% and LDL by 26% in an 8 week RCT in 79 adults with hypercholesterolemia (Eur J Cardiovasc Prev Rehab. 2007. 14. 438-440).
      • Red yeast rice (RES-Q LDL-X, N3 Oceanic, 2.53 mg lovastatin per 600 mg capsule) either 1200 mg bid or 1800 mg bid, in conjunction with fish oil and an educational program regarding therapeutic lifestyle changes, was as effective at lowering LDL as simvastatin (Zocor) 40 mg daily, in a 12 week RCT in 74 patients with hypercholesterolemia (Mayo Clin Proc. 2008. 83. 758-764).
      • Xuezhikang (XZK), a partially purified extract of red yeast rice, shown at a dose of 600 mg twice a day to significantly reduce LDL cholesterol (45%) and to reduce the risk of a recurrent event and death (33%)  in a 4.5 year RCT in 4870 Chinese patients. Triglyceride levels fell 12.1% in the treatment group, compared with the placebo group (p=0.003) and the HDL rose 4.1% in the treatment group and was unchanged in the placebo group. The incidence of adverse events (2.1% vs. 1.2%) did not differ between the two groups.  Each 300 mg capsule of XZK contained 2.5 – 3.2 mg of lovastatin, along with other components of the red yeast rice (Am J Cardiol. 2008. 101. 1689-1693 and J Clin Pharmacol. 2009. 49. 957-956).
      • Red yeast rice 1800 mg twice a day associated with a 21.3% decrease in LDL cholesterol and without an increase in CPK or pain levels, in a 24 week RCT in 67 patients with a history of discontinuation of statin therapy due to myalgias (Ann Intern Med. 2009. 150. 830-839).
      • Red yeast rice 1200 mg at bedtime was tolerated by 92% of patients, including 89% of patients with a history of myalgias, and was associated with a 15% decrease in TC (p<0.001), a 21% decrease in LDL (p<0.001), and a 6% decrease in triglycerides (p=0.06), based upon a retrospective chart review of 25 patients identified from a database of 1400 patients. Most patients on red yeast rice had experienced previous intolerance to statin medications (Am J Cardiol. 2010. 105. 664-666).
      • Quality concerns
        1.  Some brands are contaminated with citrinin, a mycotoxin which is nephrotoxic in animals. In a published study, 4 of 12 products tested had elevated levels of citrinin (Arch Intern Med. 2010. 170. 1722-1727).
        2. Variability in total monacolins – these are the compounds which inhibit HMG-CoA reductase, and 14 distinct compounds are present in red yeast rice. In a published study of 12 products, total monacolin content varied from 0.31 to 11.15 mg/600 mg capsule (Arch Intern Med. 2010. 170. 1722-1727).
  • Vitamins, minerals, and non-herbal dietary supplements
    • Activated charcoal - in a 3 week randomized crossover study in subjects with hypercholesterolemia, 20 grams twice a day of activated charcoal reduced plasma cholesterol by 21.8% compared to 8 grams twice a day of Questran, which reduced plasma cholesterol by 16.2% (J Clin Pharmacol. 1988. 28. 416-419). Similar results in a second study comparing activated charcoal with Questran (Eur J Clin Pharmacol. 1989. 73. 225-230).
    • Bifidobacterium – binds cholesterol in the intestine.
    • Calcium citrate – 1000 mg per day of calcium citrate lowered LDL by a mean of 6% and raised the LDL: HDL ratio by 16% in a study in 223 postmenopausal women (Am J Med. 2002. 112. 343-347). Other studies using calcium supplementation have been negative.
    • Chromium (picolinate or GTF) 200 – 1000 mcg/day may raise HDL cholesterol and lower LDL cholesterol, with positive studies (Am J Clin Nutr. 1981. 34. 2670-2678; J Am Coll Nutr. 1982. 1. 263-274; Nutr Res. 1989. 9. 989-998; FASEB. 1989. 3. A761; West J Med. 1990. 152. 41-45) and a negative study (J Gerontol A Biol Sci Med Sci. 2000. 55. M260-M263). May be more effective if combined with niacin 100 mg/day (J Family Pract. 1988. 27. 603-606).
    • Cordyceps sinensis mushroom extract 400 mg hot water extract with 14% beta glucan, 6% cordycepic acid, 0.15% adenosine, 1-3 capsules bid - in a large study of Cordyceps for the treatment of high cholesterol (excluding those patients whose high cholesterol resulted from diabetes mellitus, liver and liver-related diseases, kidney disease, and hypothyroidism) involving 273 patients at nine hospitals in China, patients received 1 gram of Cordyceps three times a day. After 4 to 8 weeks, it was found that their cholesterol levels had dropped by an average of over 17% (http://www.lifestreamgroup.com/Atherosclerosis.html - reference not cited).
    • DHEA (J Clin Endocrinol Metab. 1988. 66. 57-61) and 7-keto-DHEA (Physiol Res. 2001. 50 9-18).
    • Gamma oryzanol (mixture of ferulic acid derivatives found in rice bran) [Curr Ther Res. 1989. 45. 543-552; Curr Ther Res. 1989. 45. 975-982].
    • Grape seed extract (anecdotes)
    • Green tea extract
      • Theaflavin enriched green tea extract beneficial (Arch Intern Med. 2003. 163. 1448-1453).
      • Extract lowered LDL by an average of 9 mg/dl in those subjects with an LDL > 99 mg/dl at baseline in a 3 week RCT in 111 healthy volunteers treated with one capsule twice a day (Nantz MP et al. Nutrition. Epub 10/8/08).
    • Inositol hexaniacinate – less flushing than niacin, but no clinical trials, and some experts say no cholesterol-lowering effect. Suggested dose is 600 mg 1-3 capsules three times a day.
    • Krill oil (NKO)
      • In a 12 week human trial, 1 gram of NKO reduced TC by 13.4%, 2-3 grams of NKO reduced TC 18% and triglycerides 28% (Alternative Medicine Review. 2004. 9. 420-428).
      • In unpublished data from McGill Univ 6/06, 1-1.5 gm/day lowers LDL 34% and raises HDL 43%.
    • L-carnitine 330 mg three times a day based on a trial in 39 patients (but in some patients there is a paradoxical increase in cholesterol and/or triglycerides) [Drugs Exptl Clin Res. 1983. 9. 925-934]. Note L-carnitine 2 grams/day lowers Lp (a).
    • Lactobacillus acidophilus – assimilates cholesterol, inhibiting absorption.
    • Lactobacillus sporogenes – binds cholesterol in the intestine, inhibiting absorption.  May also interfere with cholesterol synthesis.
    • Magnesium - 500 mg daily lowers total cholesterol and raises HDL (Br J Nutr. 1997.78. 737-750).
    • Manganese 4 mg daily (based on anecdotes)
    • Niacin (nicotinic acid) in high doses (3-6 grams per day in divided doses) lowers cholesterol and LDL and raises HDL (Archives of Biochemistry and Biophysics. 1955. 54. 558-559).
      • Inhibits the mobilization of free fatty acids from peripheral tissues, thereby reducing hepatic synthesis of triglycerides.  At high doses also inhibits HDL catabolism.
      • Therapeutic doses (1.5-3 grams) lower LDL by 5-25%, triglycerides by 20-50%, lipoprotein (a) by 34%, and increase HDL by 15-35%.
      • Secondary prevention in those with established atherosclerosis and/or previous MI – go to http://www.acsu.buffalo.edu/~shlevy/preven.htm and scroll down to ‘Secondary Prevention – Supplements.’
      • BEWARE doses this high can cause liver toxicity, can raise blood sugar, and can exacerbate gout. Lecithin 1200 mg twice a day with niacin may decrease the risk of elevated liver function tests.
      • Immediate release niacin costs approximately $7.10 per month for 2000 mg/day.
      • Sustained release niacin costs approximately $9.76 per month for 2000 mg/day, but BEWARE that milligram for milligram, long acting niacin preparations appear to be more hepatotoxic.
      • No flush niacin costs approximately $21.70 per month for 2000 mg/day.
      • In the study which determined the above average costs of OTC products, 10 no-flush products were analyzed and none contained nicotinic acid;  they all contained inositol hexaniacinate, an ester of nicotinic acid (Ann Intern Med. 2003. 139. 996-1002).
      • Inositol hexaniacinate – see separate listing just above in this outline.
    • Pantothenic acid (vitamin B5) - 300 mg three times a day in a trial in 24 patients lowers total cholesterol 17% and triglycerides 49% and raises HDL cholesterol 15% (Clin Ther. 1986. 8. 537-545). Presumed mechanism is reduced hepatic synthesis of cholesterol.
    • Phosphatidylcholine - no clinical trials. Potential to reduce cholesterol by decreasing absorption, decreasing synthesis, initiating conversion into bile salts.
    • Policosanol
      • Product is a mixture of alcohols extracted from either from the wax of sugar cane, honeybees, wheat germ, or rice bran.  Most of the published research has been done with the sugarcane product.
      • Shown in a meta-analysis of 29 RCT's in 1528 individuals to have significant cholesterol lowering effects (Pharmacotherapy. 2005. 25. 171-183). 28 of the 29 studies were done in Cuba by the same research group, and sponsored by Dalmer Laboratories, a commercial enterprise.
      • Studies show a 15% to 25% decrease in total cholesterol, 20% to 30% decrease in LDL cholesterol, and 5% to 15% increase in HDL cholesterol (Alternative Medicine Alert. 2004. 7. 37-41). The lipid lowering effect is believed to be dose-dependent.
      • Seven RCT's comparing policosanol to prescription statins found similar effectiveness.
      • However, a 12 week RCT (following a 6 week open-label placebo and diet run-in phase) in 143 patients with hypercholesterolemia or combined hyperlipidemia randomized to either placebo, 10 mg/day policosanol, 20 mg/day, 40 mg/day, or 80 mg/day found no benefit beyond that of placebo at any dose. This trial was done in Germany, but nonetheless used Cuban policosanol (JAMA. 2006. 295. 2262-2269).
      • Another negative trial was a 12 week trial of 20 mg daily (British J Nutr. 2006. 95. 968-975).
      • In addition to its effects on the lipid profile, policosanol has been shown to decrease platelet aggregation, LDL peroxidation, and smooth muscle peroxidation (Alternative Medicine Alert. 2004. 7. 37-41).
      • The limitation of this data is that all but two studies were done by a single research group in Cuba.
      • Policosanol has been in common use in Cuba since 1991.
      • Dose is 5 - 20 mg a day - effects on the lipid profile are dose dependent.
      • Safety - a total of approximately 80 studies have been done, including approximately 3000 people.  In addition, a post-marketing surveillance study of 27,879 patients from six major Cuban medical centers, followed for as much as 4 years (Curr Ther Res. 1998. 59. 717-722) shows excellent tolerability (only 0.31% of subjects reported adverse effects over a mean of 2.7 years) and safety.
    • Probiotics – see Bifidobacterium and Lactobacillus just above.
    • Pycnogenol (pine bark extract) – 10% decrease in LDL noted in a RCT designed to measure effect of this supplement on menopausal symptoms (Scand J Ob Gyn. 2007).
    • Reishi mushroom extract – appears to inhibit cholesterol synthesis and absorption. Dose is 400 mg hot water extract with 10% beta glucan and 4% triterpenes, 1-5 capsules bid, ideally on an empty stomach.
    • Selenium - - supplementation had modestly beneficial effects on the lipid profile in a 6 month RCT in 501 volunteers. This was a 4 arm trial – placebo, 100 mcg/day high selenium yeast, 200 mcg/day high selenium yeast, and 300 mcg/day high selenium yeast. Total cholesterol and LDL improved, and higher doses raised HDL (Ann Intern Med. 2011. 154. 656-665).
    • Shiitake mushroom extract 400 mg hot water extract with 10% beta glucan, 1-5 capsules bid, ideally on an empty stomach.
    • Vitamin B5 – see pantothenic acid just above
    • Vitamin B6 – theoretical; there is animal data that vitamin B6 deficiency causes high cholesterol level.
    • Vitamin C 2 – 3 grams/day may raise HDL cholesterol levels.
    • Vitamin E – there is some data that tocotrienols, especially gamma and delta, can lower cholesterol by as much as 15-22%, lower triglycerides as much as 28%, and improve LDL/HDL ratios, while preserving CoQ 10 levels (J Atheroscler Thromb. 2010. 17. 1019-1032; Atherosclerosis. 2002.161. 199-207).
  • Medications:
    • Statins (Mevacor, Zocor, Pravachol, Lescol, Lipitor, Crestor) - inhibit HMG-CoA reductase, the rate limiting enzymatic step in the biosynthesis of cholesterol in the liver (also the rate limiting step in the production of Coenzyme Q 10 and other isoprenoids). For information on studies of statins for primary and secondary prevention of heart disease, go to http://www.acsu.buffalo.edu/~shlevy/preven.htm
      • Statins reduce all-cause mortality by decreasing coronary heart disease mortality without increasing nonvascular mortality, based on a meta-analysis of 14 RCTs with 90,056 participants. The relative risk reduction for major coronary events was 23% for each mmol/L reduction in LDL, but the absolute risk reduction decreased from 3.8% for chol > 173 mg/dL to 1.9% for LDL < 135 (Lancet. 2005. 366. 1267-1278 as reviewed in ACP Journal Club. 2006. 144. 62).
    • Potential risks and adverse effects of statins – affect ~5% in published clinical trials, ~20% in clinical practice, with more adverse effects at higher doses, possibly a greater percentage of adverse effects in women and elderly, who tend to be under-represented in clinical trials (Cleve Clin J Med. 2011. 78. 393-403). There is theoretical and anecdotal data that CoQ 10 can reverse some of the adverse effects – dose required may be as high as 200 mg daily of CoQ 10.
      • AA: EPA ratio alteration - simvastatin (Zocor) shown to increase the AA: EPA ratio from 15.5 to 18.8 (p<0.01), an undesirable change in this ratio, in a study in 106 healthy adults with hypercholesterolemia (Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2004. 71. 263-269).

§         Cancer

1.      Meta-analysis of 35 RCTs does NOT show an increased (or decreased) risk of cancer (J Clin Oncol. 2006. 24. 4808-4817).

2.      However, in the PROSPER study of pravastatin in high risk elderly, there was a 25% increase in new cancer incidence (Lancet. 2002. 360. 1623-1630). Furthermore, in pooled analyses of 12 individual trials of pravastatin, there was an increase in the relative risk of cancer in those over age 6, 6% in those 65-69, 13% in those 70-75, and 22% in those > age 75 (CMAJ. 2007. 176. 649-654).

§         Cognitive problems – anecdotes, frequency uncertain

§         Depression – data in 2011 is mixed, with a case control study showing a reduced risk for depression (Arch Intern Med. 2003. 163. 1926-1932) and a small RCT in elderly patients showing an increased risk (J Am Geriatr Soc. 2006. 54. 70-76).

§         Diabetes

1.      A meta-analysis of 13 RCTs including 91,140 participants show that treatment with statins is associated with a 9% increased relative risk of diabetes, corresponding to a 0.4% increased absolute risk. This translates into one new case of diabetes for every 255 patients treated with a statin drug for four years (Lancet. 2010. 375. 735-742).

2.      A second meta-analysis of 17 RCTs also found that treatment with statins is associated with a 9% increased relative risk of diabetes (QJM. 2011. 104. 109-124)

3.      Observational data in 153,840 women in the WHI who did not have diabetes at baseline (7.04% of these women were taking statin medication at baseline) show that statin use at baseline was associated with a RR of diabetes of 1.71 (1.61-1.83) over 1,004,466 years of follow up. This association remained after adjusting for other potential confounders and this association was present for all brands of statin medications (Arch Intern Med. 2012. 172. 144-152).

§         Heart failure - anecdotes, frequency uncertain

§         Liver – occasional elevation of LFTs, often dosee-related

§         Myopathy – typically identified by CPK level > 10 times upper limit of normal, but there are cases in which CPK is normal (Ann Intern Med. 2002. 137. 581-585).

1.      May respond to supplemental Co Q 10

2.      May respond to supplemental creatine (Ann Intern Med. 2010. 153. 690-692).

3.      A small trial showed that those with this condition and vitamin D deficiency diagnosed by blood test experience resolution of symptoms within 3 months of initiation of vitamin D, and most do not have recurrence of symptoms upon re-challenging with the statin (Clin Endocrinol. 2009. 71. 154-156).

§         Parkinson’s disease - anecdotes, frequency uncertain

§         Peripheral neuropathy – (Pharmacotherapy. 2004. 24. 1194-1203). Current use of statins is associated with 16-fold increased risk of idiopathic peripheral neuropathy, in a case control study (Gaist D et al. Neurology. May 14,2002)

§         Weakness – sometimes apparent only after years of treatment; anecdotes, frequency uncertain

    • Pleotropic effects of statins
      • Statins lower hs-CRP
      • Statins reduce the susceptibility of LDL to oxidation
      • Statins shift lipoprotein subtype from pattern B (small, dense LDL) to pattern A (large, buoyant LDL)
      • Statins prevent oxidative stress-mediated endothelial dysfunction in  hypercholesterolemic, hypertensive, and diabetic patients
      • Atorvastatin (Lipitor) raised 25 OH vitamin D levels at 12 months in a study in 83 patients in whom Lipitor was initiated for acute coronary syndrome, with vitamin D increasing from 41 nmol/L to 47 nmol/L (Am J Cardiol. 2007. 99. 903-905).
      • Reduce the expression of adhesion molecules, inflammatory cytokines, and metalloproteinases independent of cholesterol-lowering effect (Thromb Haemost. 2003. 90. 607-610).
      • Statins increase nitric oxide in the endothelium.
    • Bile acid sequestrants (Questran, Colestid, Welchol) - bind to bile acids in the small intestine, which interrupts the enterohepatic circulation of bile acids and increases the conversion of cholesterol to bile acids in the liver.
      • Benefit shown in the LRC-CPPT, with a statistical reduction in CHD death and nonfatal MI in the group receiving cholestyramine 24 grams/day (JAMA. 1984. 251. 351-364).
      • Interfere with absorption of other medications, so must be taken at a different time of the day from other medications.
    • Nicotinic acid - see above under 'vitamins and minerals.'
    • Fibrates (Lopid, Tricor) - PPAR (peroxisome proliferator-activated receptor) alpha-agonists. Statistically significant reduction in major coronary events shown in the Helsinki Heart Study, a primary prevention trial with gemfibrozol (N Engl J Med. 1987. 317. 1237-1245), the VA-HIT Trial, using Lopid 600 mg bid (N Engl J Med. 1999. 341. 410-418), and the Fenofibrate Intervention and Event Lowering in Diabetes trial, using Tricor 200 mg daily (Lancet. 2005. 366. 1849-1861).
    • Ezetimibe (Zetia) - intestinal cholesterol absorption inhibitor.  Can be safely combined with statins.  Inhibits absorption of not just dietary cholesterol but also the cholesterol released into the bowel as part of bile acids.

 

LDL - not all is created equal:

  • Pattern A - large particles.
  • Pattern B - small, dense particles.
  • At any given LDL value, people with pattern B are three times more prone to heart disease than those with pattern A.
  • Hormone replacement therapy in women seems to have a much greater impact on LDL and HDL cholesterol values in those with pattern B.
  • Doctors can order the test which measures LDL particle size from Berkeley Heart Lab at 1-800-HEART-89.
  • Oxidized LDL is the real culprit – there is data that the ratio of oxidized LDL to HDL is a more potent biomarker for discriminating between subjects with and without CAD than the lipid profile (Am J Cardiol. 2006. 97. 640-645).

 

HDL – not all is created equal (Cleve Clin J Med. 2007. 74. 697-705)

  • In most healthy people, HDL has an anti-inflammatory role, facilitates reverse cholesterol transport, and limits the production of oxidized LDL.
  • In the setting of systemic inflammation, HDL can become dysfunctional, and actually have pro-inflammatory effects.
  • A monocytes chemotaxis assay and a cell free assay, not yet commercially available in 2007, can determine the functional characteristics of HDL.
  • Dysfunctional HDL is may be present in the post-operative period after surgery, in individuals consuming a diet high in saturated fat, and in individuals with acute infections such as influenza or sepsis, autoimmune diseases, coronary artery disease, and diabetes.
  • Statins can modify HDL’s properties from pro-inflammatory to anti-inflammatory, based on small clinical trials (Circulation. 2003. 108. 2751-2756; presentation ACC in 2007).
  • BEWARE that pharmacological agents which raise HDL may nonetheless have an adverse effect on its functional characteristics. This may explain why torcetrapib, a cholesteryl ester transfer protein inhibitor which raised HDL 100% in early clinical trials was nonetheless associated with a 61% higher all cause mortality in a subsequent clinical trial, and was thus not brought to market (Arterioscler Thromb Vasc Biol. 2007. 27. 257-260).

 

Triglycerides and heart disease - see ‘Additional Risk factors for coronary heart disease at the bottom of this outline

 

Cost effectiveness of cholesterol lowering with medications (based on modeling):

  • Primary prevention in males and females with cholesterol greater than 300:
    • Age 25-34: $1,000,000 - $10,000,000/year of life saved.
    • Age 55-64: $100,000/year of life saved.
    • Note cardiac transplant only costs an estimate $50,000/year of life saved.
    • For more detailed statistics, see (Ann Intern Med. 2000. 132. 769-779).
  • Secondary prevention
    • In middle aged adults with established coronary artery disease, carotid artery disease, or peripheral vascular disease statins may actually be cost saving, and costs at most $10,000/QALY.
    • In patients over age 75 with a history of myocardial infarction, statins cost anywhere from $5400/QALY to $97,800/QALY, depending on the modeling assumptions (Ann Intern Med. 2000. 132. 780-787).

 

NCEP II - new features (JAMA. 1993.269. 3015-3023):

  • Increased emphasis on total heart disease risk as a guide to treatment.
    • The goal for secondary prevention is LDL < 100, with a recommendation to start medication if LDL > 130 after a trial of lifestyle changes.
    • Age > 45 in males and age > 55 in females is added as a risk factor for heart disease.
    • Recommendation to use an LDL cutoff of 220 instead of 190 with regard to the threshold for starting medication treatment in low risk males under age 35 and low risk females under age 45.
  • Increased emphasis on HDL cholesterol as a heart disease risk factor.
    • Recommend include HDL measurement any time a screening cholesterol is ordered.
    • Designation of HDL > 60 as a negative risk factor for heart disease.
    • Designation of HDL < 35 as an additional positive risk factor for heart disease.
  • Increased emphasis on exercise and weight loss (in addition to diet).
  • Decision tree diagrams.

 

NCEP III - new features (JAMA. 2001. 285. 2486-2497):

  • Focus on multiple risk factors.
    • Persons with diabetes are considered a CHD risk equivalent.
    • Uses Framingham projections of 10 year absolute CHD risk.
    • Identifies persons with multiple metabolic risk factors as candidates for intensified therapeutic lifestyle changes.
  • Modifications of lipid and lipoprotein classification.
    • Identifies LDL cholesterol < 100 mg/dl as optimal.
    • Raises categorical low HDL cholesterol from <35 mg/dl to < 40 mg/dl.
    • Lowers the triglyceride classification cutpoints, such that triglycerides >200 mg/dl are high.
  • Support for implementation.
    • Recommends complete lipoprotein profile instead of just cholesterol and HDL cholesterol for screening.
    • Encourages use of plant sterols/stanols and soluble fiber as therapeutic dietary options to lower LDL cholesterol.
    • Presents strategies for promoting adherence to therapeutic lifestyle changes and drug therapies.
    • Recommends treatment beyond LDL lowering in individuals with triglycerides > 200 mg/dl.

 

Additional risk factors and risk markers for coronary heart disease

Systematic reviews done for the USPSTF concluded that “The current evidence does not support the routine use of any of the 9 risk factors for further risk stratification of intermediate-risk persons.” The 9 risk factors studied are CRP level, CAC score, lipoprotein (a) level, homocysteine level, leukocyte count, fasting glucose concentration, periodontal disease, ankle-brachial index, and carotid IMT (Ann Intern Med. 2009. 151. 496-507).

 

AA/EPA ratio

  • This is a highly sensitive measure of inflammation.
  • Optimal ratio is less than 3.

 

ADMA (asymmetric dimethyl arginine)

  • Naturally occurring compound that inhibits nitric oxide production and impairs endothelial function, and is an important risk factor for coronary artery disease.
  • Initially described in 1992 by Patrick Vallance, an endothelial cell biologist.
  • This is an analog of L-arginine that binds to endothelial nitric oxide synthase (eNOS) and by binding inhibits the conversion of L-arginine to nitric oxide.
  • This compound can be measured in the plasma.  The most meaningful lab value is probably the ratio of L-arginine to ADMA, with 50:1 – 100:1 considered a healthy ratio.
  • If ratio is suboptimal, treatment consists of supplemental L-arginine.

 

Apolipoprotein B: Apolipoprotein A-1 ratio

  • This is a strong risk factor for atherosclerotic cardiovascular disease.
  • Several publications endorsed this ratio as an improved measure of risk (Lancet. 2001. 358. 2026-2033; Lancet. 2004. 364. 937-952; J Intern Med. 2006. 259. 247-258).
  • In a prospective, nested case-control study in which 869 cases of fatal or nonfatal CAD were compared with 1511 controls, in the European Prospective Investigation into Cancer and Nutrition Norfolk Study, this ratio added little to existing measures of CAD risk (Ann Intern Med. 2007. 146. 640-648 and editorial 677-679).
  • In a prospective cohort of 3322 middle-aged white participants in the Framingham Study, after a median follow up of 15 years, this ratio did NOT offer any incremental utility over the chol: HDL ratio (JAMA. 2007. 298. 776-785).

 

Ferritin

  • Measure of iron stores, and high levels are associated with increased oxidative stress.
  • Optimal level is <150 for females and <300 for males.
  • If levels are high, sweating and the supplement inositol hexaphosphate (IP6) facilitate excretion of excess iron

 

Fibrinogen

  • Involved in the formation of a blood clot; high levels increase the risk for formation of blood clots.
  • Optimal levels are 150-299 mg/dl, with levels above 460 mg/dl indicating a high risk.
  • High level might be partially caused by vitamin C insufficiency (BMJ. 1995. 310. 1559-1563).
  • Nattokinase is a plant-derived dietary supplement that can lower fibrinogen levels (J Agric Food Chem. 2000. 48. 3210-3216).

 

GGT (gamma glutamyltransferase)

  • This enzyme which is mainly produced in the liver and catalyzes the antioxidant glutathione is an independent predictor of CVD death, based on data from 164,000 Australian adults followed for up to 17 years (Circulation. 2005. 112. 2130-2137).
  • Hypothetical mechanism – depletion of glutathione.  Thus, hypothetically, supplemental NAC might offset the increased risk associated with high GGT levels.

 

Homocysteine

  • Amino acid derived from methionine which is an independent risk factor for coronary artery disease.  

o       A meta-analysis shows that the hazard ratio for a recurrent event increases by 16% for each increase of 5 micromol/liter in serum homocysteine concentration (BMJ. 2002. 325. 1202).

o       Kilmer McCully first proposed in 1969 that homocysteine causes atherosclerosis.

  • Physiological roles are to regulate bone and tissue formation and to stimulate formation of IGF-1.
  • Homocysteine levels are also correlated with risk of CVA, DVT, and a variety of neurological diseases.  Observational data suggest that homocysteine is neurotoxic.
  • Ideal homocysteine level is probably less than 6 micromol/liter, even though most labs define normal as less than 9 micromol/liter.
  • Factors which raise homocysteine levels

o       Caffeine

o       Chronic high consumption of alcohol

o       Chronic renal failure

o       Diet high in saturated fat (Dr.Perlmutter)

o       Drugs

§         Anticonvulsants

1.      Carbemazepine (Tegretol) and phenytoin (Dilantin) lower folate concentrations

2.      Primidone (Mysoline) and valproate (Depakote) deplete B vitamins too (Dr Perlmutter)

§         Aspirin (Dr Perlmutter)

§         Bezafibrate in combination with niacin via an uncertain mechanism

§         Cholestyramine (Questran) and colestipol (Colestid) impair folate absorption

§         Colestipol in combination with niacin via an uncertain mechanism

§         COX2 inhibitors (i.e. Celebrex) - (Dr Perlmutter)

§         Estrogens (i.e. oral contraceptives, ERT) deplete vitamin B6

§         Fenofibrate in combination with niacin via an uncertain mechanism

§         H2 blockers (Dr Perlmutter)

§         Hydralazine (Dr Perlmutter)

§         Hydrochlorothiazide raises homocysteine level by 16% on average (Metabolism. 2003. 52. 261)

§         Levodopa (Dr Perlmutter)

§         Loop diuretics (Dr Perlmutter)

§         Methotrexate lowers folate levels by depleting folate metabolites

§         NSAIDS - (Dr Perlmutter)

§         Raloxifine (Evista) - (Dr Perlmutter)

§         Steroids, including inhaled and nasal steroids (Dr Perlmutter)

§         Theophylline lowers vitamin B6 levels

§         Trimethoprim (Dr Perlmutter)

o       Hypothyroidism

o       Insufficiency of vitamin B6, B12, or folate - vitamin B12 is a more important determinant of elevated homocysteine concentrations in older people than is folate (Age Ageing. 2004. 33. 34-41).

o       Lead (as per Sherry Rogers, MD)

o       Menopause (Metabolism. 1985. 34. 1073-77).

o       Older age

o       Pernicious anemia

o       Psoriasis (severe)

  • Ways to lower homocysteine levels:

o       Diet – limit coffee consumption, and increase soy consumption. Soy protein with native phytate significantly reduces homocysteine (Am J Clin Nutr. 2006. 84. 774-780).

o       Folate 0.5 – 5 mg/day or 5-MTHF.

o       Vitamin B12 100 - 1000 mcg/day.

o       Vitamin B6 10 – 100 mg/day.

o       Vitamin B2 100 mg/day.

o       Zinc 30 mg/day.

o       If refractory hyperhomocysteinemia (especially postprandial hyperhomocysteinemia) consider betaine 1.5 – 6 grams/day, either anhydrous betaine or betaine hydrochloride.

o       If hyperhomocysteinemia secondary to hemodialysis, consider NAC 1200 mg twice a day.

  • Homocysteine levels are correlated with an increased risk of heart disease

o       A meta-analysis of observational studies showed that a 5 umol/L higher homocysteine level was associated with a 70% increase in the risk of heart disease (JAMA. 1995. 274. 1049-1057).

o       A meta-analysis of both prospective and retrospective studies showed weaker associations of high homocysteine values in prospective studies, such that a 5 umol/L higher homocysteine level was associated with a 30% increase in the risk of heart disease (J Cardiovasc Risk. 1998. 5. 229-232).

  • The data regarding the benefits of lowering homocysteine is mixed, with observational trials showing benefit and most RCTs showing no benefit. The data in aggregate would suggest that homocysteine is a biomarker for cardiovascular risk, rather than a modifiable risk factor.

o       Restenosis post stent placement – one review of published data showed that folate reduced the risk of restenosis after angioplasty from 37.6% to 19.6% (Ann Med. 2003. 35. 156-163), but in a separate study, patients with stents treated with folate, vitamin B12, and vitamin B6 had an increased rate of in-stent restenosis (N Engl J Med. 2004. 350. 2673-2681).

o       In a cohort study of 80,082 nurses in the Nurses’ Health Study followed for 14 years, those women taking a multivitamin and those women with higher dietary folate intake had a lower risk of fatal and nonfatal MI (JAMA. 1998. 279. 359-364).

o       A meta-analysis of prospective observational studies showed that a 25% reduction in homocysteine (approximately 3 umol/L) is associated with an 11% lower risk of heart disease and a 19% lower risk of stroke (JAMA. 2002. 288. 2015-2022).

o       A meta-analysis of case-control studies examining risk of heart disease and stroke as a function of genetic variants in the 5-MTHFR enzyme show that a 3 umol/L difference in homocysteine levels among individuals with the TT genotype as compared with the CC genotype is associated with a 10-15% difference in CHD risk and a 20-25% difference in CVA risk (Lancet. 2005. 365. 224-232).

o       The concordance of the results in prospective and genetic studies provides support for a causal relationship between elevated plasma homocysteine levels and vascular disease risk (BMJ. 2006. 333. 1114-1117).

o       In the CHAOS-2 trial, supplementation with folate, vitamin B12, and vitamin B6 was not associated with a reduction in cardiovascular risk (Circulation. 2002. 106. Suppl II).

o       In the VISP trial in which 3680 patients with stroke were randomized to different daily doses of folate, vitamin B12, and vitamin B6, after two years there was a dose dependent reduction in homocysteine concentration, but no significant difference in the rates of vascular events (JAMA. 2004. 291. 565-575).

o       In the NORVIT trial in 3749 subjects who had had a MI within 7 days before randomization into one of four groups (placebo, folate 0.8 mg + vitamin B12 0.4 mg + vitamin B6 40 mg, folate 0.8 mg + vitamin B12 0.4 mg, or vitamin B6 40 mg), at a mean of 40 months of follow-up, and with 90% compliance, even though the homocysteine level dropped within 2 months an average of 27% in the folate + vitamin B12 group compared to placebo, the incidence of cardiovascular events in all active treatment groups (composite endpoint of recurrent MI, stroke, or sudden death attributed to CAD) was not different from placebo. There was actually a trend toward an increased risk in the composite endpoint in the treatment group administered folic acid, vitamin B6, and vitamin B12 (p=0.050 [N Engl J Med. 2006. 354. 1578-1588].

o       In the HOPE 2 trial in 5222 patients over age 55 with vascular disease or diabetes, those who received 2.5 mg folate daily with 50 mg vitamin B6 daily and 1 mg vitamin B12 daily had a mean decrease in homocysteine of 2.4 micromol/liter, but there was no difference in death from cardiovascular causes, MI, or any of the secondary endpoints. Risk of stroke in the active treatment group was significantly lower (RR=0.75, 0.59-0.97) but the risk of hospitalization for unstable angina was increased in the active treatment group (1.24, 1.04-1.49) [N Engl J Med. 2006. 354. 1567-1577].

o       In a meta-analysis of 12 RCTs, including the above 4 studies and 8 smaller studies, the relative risk for heart disease was 1.04 and the relative risk for stroke was 0.86 (JAMA. 2006. 296. 2720-2726).

o       In the HOST trial in 2056 patients with advanced chronic kidney disease(GFR<30), those who received a daily vitamin capsule containing 40 mg of folate, 100 mg of vitamin B6, and 2 mg of vitamin B12, showed a reduction in homocysteine from a mean of 24 umol/L to 18 umol/L, but there was no significant effect on mortality or any significant effect on any of the secondary outcome measures, including MI, CVA, amputation, time to dialysis, or time to thrombosis in hemodialysis patients (JAMA. 2007. 298. 1163-1170).

o       In the WAFACS study in 5442 high risk women (health professionals) followed for a mean of 7.3 years, a combination pill of 2.5 mg of folate, 50 mg of vitamin B6, and 1 mg of vitamin B12 did not reduce the combined endpoint of total cardiovascular events (JAMA. 2008. 299. 2027 and editorial 2086-2087).

o       In WENBIT, a secondary prevention trial in western Norway using a 2 x 2 factorial design in 3096 patients with coronary artery disease (most patients had stable coronary artery disease), even though mean total homocysteine was lowered 30% after one year, at a median of 38 months of follow up, there was no effect of treatment on total mortality of cardiovascular events. Treatment groups included (1) folate 0.8 mg/day + vitamin B12 0.4 mg/day + vitamin B6 40 mg/day, (2) folate + vitamin B12, (3) vitamin B6 alone, and (4) placebo. Primary endpoint was a composite of all-cause death, nonfatal acute MI, acute hospitalization for unstable angina, and nonfatal thromboembolic stroke (JAMA. 2008. 300. 795-804).

o       In a cohort study of 492 patients with early onset CAD followed for a median of 115 months, folate based vitamin therapy (>400 mcg/day supplemental folate) was associated with lower all cause mortality in those with elevated homocysteine levels at baseline, but not in those with normal homocysteine levels at baseline (Am J Cardiol. 2009. 104. 745-749).

o       In the WAFCAS cardiovascular prevention study, a RCT in ~4200 middle aged female health professionals at risk for cardiovascular disease and type 2 diabetes, a combination pill of 2.5 mg folate, 50 mg B6 and 1 mg B12 was ineffective at reducing the risk of developing diabetes and ineffective at reducing the risk of developing heart disease. Median follow up was 7.3 years, and lack of clinical benefit was in spite of the fact that supplementation did lower homocysteine levels 18.5% (Diabetes. 2009. 58. 1921-1958).

o       In the SEARCH trial, a RCT in 12,064 survivors of MI in secondary care hospitals in the UK between 1998 and 2008, 2 mg folate + 1 mg B12 daily was associated at average follow up of 6.7 years with substantial reductions in blood homocysteine levels, but no beneficial effect on vascular outcomes. There were no associated adverse effects of long term supplementation or adverse effects of supplementation on cancer outcomes (JAMA. 2010. 303. 2486-2494).

o       In the VITATOPS study, a secondary prevention RCT of 8164 patients who experienced a stroke or TIA within the previous 7 months, those who received the combination of folate 2 mg, vitamin B6 25 mg and vitamin B12 0.5 mg daily showed a 9% relative risk reduction and a 1.56% absolute risk reduction in the primary endpoint, a composite of stroke, MI, or vascular death, at a median follow up of 3.4 years (p=0.05). The NNT for 3.4 years to prevent one stroke or MI or vascular death was 64 (Lancet Neurol. 2010. 9. 855-865).

o       A meta-analysis of 8 RCTs of folic acid supplementation, involving 37,485 individuals, showed that despite an average 25% reduction in homocysteine level, during a median follow up of 5 years, there was no significant effect on major vascular outcomes, major coronary events, overall vascular mortality, overall cancer mortality, or all-cause mortality (Arch Intern Med. 2010. 170. 1622-1630).

·        Mechanisms by which folate might offset the homocysteine-lowering benefit, and thus lead to the failure to improve outcomes seen in the above trials include:

o       Folate may promote cell proliferation in atherosclerotic plaque (N Engl J Med. 2006. 354. 1629-1632. Editorial).

o       Folate may alter the methylation potential in vascular cells, promoting the development of plaque (N Engl J Med. 2006. 354. 1629-1632. Editorial).

o       Folate may promote methylation of arginine to ADMA (asymmetric dimethylarginine), a substance which inhibits the activity of nitric oxide synthase (N Engl J Med. 2006. 354. 1629-1632. Editorial).

o       Folate in most supplements (and fortified foods) is pteroylmonoglutamate (PGA), a form that does not occur in nature, may be relevant.  At doses below 0.4 mg daily, all PGA is converted into biologically active methylfolate during absorption.  At higher doses, there is synthetic PGA in the blood and the long term ramifications of this are unknown (BMJ. 2004. 328. 211-214).

o       Folate supplementation may predispose to zinc deficiency, and zinc deficiency might increase the risk of CHD.

·        Possible explanations for the failure of randomized controlled trials to demonstrate reductions in cardiovascular mortality in association with homocysteine lowering include (critique offered by Alan Gaby, MD):

o       Vitamin B6 supplementation may deplete magnesium, and magnesium supplementation was not administered in these trials.

o       Folate supplementation may deplete zinc, and zinc supplementation was not administered in these trials.

o       Magnesium and zinc status are marginal in Western societies. Furthermore, magnesium and zinc deficiencies may be exacerbated in high-risk patients by consumption of atherogenic diets and by the use of zinc-depleting cardiac medications (i.e. diuretics, digoxin, ACE inhibitors).

·        Even if homocysteine lowering does not reduce cardiovascular mortality, there is evidence that homocysteine lowering reduces the risk of osteoporotic fractures and may decrease the risk of Alzheimer’s disease.

 

hs-CRP (high sensitivity C reactive protein)

  • This is a protein synthesized by the liver and it is a marker for inflammation, and an independent risk marker for coronary artery disease (CAD), although the magnitude of the association has been downgraded (N Engl J Med. 2004. 350. 1387-1397).
  • In 2006 it remains unclear whether CRP is causally related to the cardiovascular disease, or just a risk marker.
  • There is ongoing study and debate with regard to the extent to which measurement of hs-CRP alters cardiovascular risk assessment (Editorial. Ann Intern Med. 2006. 145. 70-72).
    • Data at 10 years of follow-up in the Women’s Health Study (an observational cohort study) shows that global risk assessment model that includes hs-CRP improves risk classification in women, particularly amongst those with a 10 year risk of 5-20% (Ann Intern Med. 2006. 145. 21-29).
    • A narrative review of the literature published prior to 1/06 concludes that there is no definitive evidence that adding CRP to models adds substantial predictive value (Ann Intern Med. 2006. 145. 35-42).
    • In an 8 year prospective observational cohort study in 1949 men and 2497 women from the Framingham Heart Study who did not have CAD as baseline, elevated CRP level provided no further prognostic information beyond traditional risk factor assessment (Arch Intern Med. 2005. 165. 2473-2478).
  • CRP can fluctuate as much as 44% over the course of a woman’s menstrual cycle.
  • Factors which raise hs-CRP.
    • High AGE (advanced glycation end products) content of the diet – in a study in which diabetics consumed 2 similar diets that differed 5-fold in their AGE content, achieved by varying the cooking time and temperature, serum AGEs increased by 65% on the high-AGE diet, and C-reactive protein increased by 35% on the high-AGE diet (Proc Natl Acad Sci. 2002;99:15596-15601).
    • High saturated fat intake raises hs-CRP.
    • High trans fat intake raises hs-CRP (J Nutr. 2005. 135. 562-566).
    • High glycemic-index foods raise hs-CRP by promoting excess production of IL-6 (Am J Nutr. 2002. 75. 492-498). Cross-sectional data in 15,033 women in the Women’s Health Study also show this association.
    • Low magnesium intake – those adults who consumed less than the RDA were 1.48-1.75 times more likely to have an elevated CRP (J Am Coll Nutr. 2005. 24. 166-171).
    • Oral estradiol and Premarin raise hs-CRP (topical estradiol does not).
  • Factors which lower hs-CRP
    • Alpha tocopherol and gamma tocopherol
    • Alcohol in moderation lowers hs-CRP, independent of the type of alcoholic beverage consumed, based on data in 11,815 participants in the Women’s Health Study (Am J Cardiol. 2005. 96. 83-88).
    • Co Q 10 (in a study in baboons, in conjunction with vitamin E).
    • Digestive enzymes lower hs-CRP.
    • Diet

§         High antioxidant diet - statistically significant decrease in hs-CRP of questionable clinical significance (3.0 mg/L to 2.5 mg/L) shown in a small clinical trial (Am J Clin Nutr. 2008. 87. 1290-1294).

§         Low AGE (advanced glycation end products) content of the diet – in a study in which diabetics consumed 2 similar diets that differed 5-fold in their AGE content, achieved by varying the cooking time and temperature, serum AGEs decreased by 30% on the low-AGE diet, and C-reactive protein decreased by 20% on the high-AGE diet (Proc Natl Acad Sci. 2002. 99. 15596-15601).

    • Exercise lowers hs-CRP (Epidemiology. 2002. 13. 561-568).
    • Fiber lowers hs-CRP
      • Epidemiologic data comes from NHANES (J Nutr. 2004. 134. 1181-1185).
      • Cross-sectional data in 15,033 women in the Women’s Health Study also show this association, and further link the association to intake of soluble fiber.
      • In a yearlong study in 524 healthy adults, those who ate the most fiber had lower hs-CRP levels (Am J Clin Nutr. 4/06).
      • A randomized crossover intervention trial in 28 women and 7 men showed that fiber intake of 30 gm/day, both from a diet naturally rich in fiber and also from a fiber supplement reduces CRP (Arch Intern Med. 2007. 167. 505-506).
    • Fish oil (J Nutr Biochem. 2003.14. 513-521).
    • L-carnitine lowers hs-CRP.
    • Magnesium might lower hs-CRP (in those who are deficient) based on data that low magnesium intake is associated with high CRP (J Am Coll Nutr. 2005. 24. 166-171).
    • Mediterranean diet lowers hs-CRP (JAMA. 2004. 292. 1440-1446).
    • Multivitamin lowers hs-CRP as much as 32%, based on published data from the Cooper Institute and using “Cooper Complete” (Am J Med. 2003. 115. 702-707).
    • TZD medications lower hs-CRP levels (p<0.0001 in a meta-analysis comparing these medications to placebo) [Am J Cardiol. 2006. 97. 655-658].
    • Vitamin C – in a RCT of 369 healthy nonsmokers, analysis of the subgroup with CRP > 1 mg/L at baseline showed that vitamin C 1 gram daily lowered the median level by 25% (p=0.02). In a second arm of this trial, vitamin E  800 IU per day had not effect (Free Radic Biol Med. 2009. 46. 70-77).
    • Vitamin D3 (QJM. 2002. 95. 787-796).
    • Weight loss lowers hs-CRP, based on a systematic review of 33 studies. For each 1 kg of weight loss, the mean change in CRP level was -0.13 mg/L (Arch Intern Med. 2007. 167. 31-39).
    • Zinc – in a 6 month RCT in 44 seniors, mean age of 66, those taking 45 mg per day of zinc, as zinc gluconate, experienced a drop of CRP from 2.46 mcg/l to 1.90 mcg/l (p=0.015) whereas the placebo patients experienced a nonsignificant increase in CRP level (Am J Clin Nutr. 2010. 91. 1634-1641).
  • Fish oil may or may not lower hs-CRP.

 

Lipoprotein (a)    Cleveland Clinic Journal of Medicine. 1999. 66. 465-466.

  • Independent risk factor for coronary artery disease.
  • Levels are largely genetically determined.
  • Vitamin C deficiency might trigger a rise in Lp (a) as a compensatory mechanism – hypothesis of Thomas Levy, MD (Townsend Letter. May 2011. 46-57)
    • Lp (a) plasma levels increase as vitamin C levels decline (Proc Natl Acad Sci U S A. 1990. 87. 6204-6207).
    • Lp (a) can accelerate wound healing and assist in cellular repair (Nature. 1987. 330. 113-114).
  • Trans fat consumption raises Lp (a).
  • Using 30 mg/dl as the upper limit of normal, it is estimated that 25% of the U.S. population has high levels.
  • Lifestyle modifications such as diet, weight loss, and exercise have no effect on levels.
  • Vitamin C supplementation may protect against Lp (a) induced damage. Fish oil, L-carnitine, L-lysine, and L-proline may also neutralize Lp (a).
  • Estrogen replacement therapy, high dose niacin, and fenofibrate lower Lp (a) but resins (Questran, Colestipol) and statins (Lipitor, Mevacor, etc.) do not.
  • Co Q 10 - 120 mg of Q gel per day decreased values in a trial in 25 patients with coronary artery disease (Int J Cardiol. 1999. 68. 23-29).
  • Ginkgo biloba lowers Lp(a) 23% [P< 0.023] (Atherosclerosis. 2007. 192. 438-444).
  • L-carnitine 2 grams/day lowers Lp (a) 8-12%, based on a RCT in 36 patients (Nutr Metabol Cardiovasc Dis. 2000. 10. 247-251).
  • Niacin 2-3 gm/day can reduce levels by 20-50% after 8 weeks (J Intern Med. 1989. 226. 271-276).
  • Consider measuring the level in patients with premature coronary artery disease or patients with hypercholesterolemia resistant to statin medication.

 

Phosphorous

  • Higher serum phosphorous levels are associated with increased risk of cardiovascular disease in individuals with normal renal function, based on data gathered prospectively in 3368 Framingham Offspring study participants (Arch Intern Med. 2007. 167. 879-885 and editorial 873-874).

 

PLAC

  • This measures lipoprotein phospholipase A2, a compound which occurs only within blood vessels.
  • Levels below 200 ng/ml are optimal; levels above 250 ng/ml indicate a high risk of plaque rupture.

 

RDW (red cell distribution width)

  • This objective measure of heterogeneity in red blood cell size is a powerful independent predictor of future CHD risk, based on data in 7556 participants in NHANES 1999-2006; higher RDW associated with increased risk (Am J Cardiol. 2010. 106. 988-993).
  • NOTE high RDW is also predictive of morbidity and mortality in those with CHF, MI, and stable coronary artery disease (Eur J Heart Fail. 2010. 12. 129-136; Am J Cardiol. 2010. 105. 312-317; Arch Intern Med. 2009. 169. 515-523; Circulation. 2008. 117. 163-168).

 

Triglycerides

  • Triglycerides are fat-like substances in the blood.
  • More than 30 prospective studies involving more than 250,000 participants have demonstrated a correlation between high fasting triglyceride level and higher risk of heart disease, even after controlling for other risk factors (Curr Atheroscler Rep. 2008. 10 386-390).
  • Nonfasting triglycerides are also associated with an increased risk of heart disease

o       In a prospective cohort study of 26,509 initially healthy US women participating in the Women’s Health Study, at median follow up of 11.4 years, nonfasting triglyceride levels were associated with incident cardiovascular events, independent of traditional risk factors, whereas fasting triglyceride levels showed little independent relationship (JAMA. 2007. 298. 309-316).

o       Nonfasting triglyceride level will vary as a function of hour many hours it is drawn postprandially, so while cohort studies show the value of a nonfasting level, applying this data to individuals may require standardization such that the level is drawn 2 hours postprandial, and this can be logistically challenging in the individual (Editorial. JAMA. 2007. 298. 336-338).

  • While fasting and nonfasting triglyceride levels are correlated with an increased risk of heart disease, these elevations are also correlated with low HDL cholesterol, and with small, dense LDL, so it is not clear whether high triglycerides are truly an independent risk factor for heart disease versus a risk marker for heart disease (Editorial. JAMA. 2007. 298. 336-338).
  • Optimal triglyceride level is < 150 mg/dl and acceptable triglyceride level is < 200 mg/dl. Data for 5610 participants in NHANES 199-2004 shows that 1/3 have a triglyceride level >150 mg/dl and 1/5 have a triglyceride level > 200 mg/dl (Arch Intern Med. 2009. 169. 572-578).
  • Treatment for high triglycerides

o       Lifestyle

§         Alcohol in moderation – excess alcohol can cause very high triglyceride levels.

§         Blood sugar control – uncontrolled diabetes can cause very high triglyceride levels. 

§         Exercise – both aerobic and resistance exercises are beneficial

§         Nutrition – reduce intake of high-fructose corn synrup, and reduce intake of high glycemic index foods (i.e. pretzels, bagels, breakfast cereals)

§         Stress reduction

o       Supplements

§         Niacin - no effect on cardiovascular mortality, noncardiovascular mortality, or total mortality, based on a meta-analysis (Arch Intern Med. 2005. 165. 725-730).

§         Omega 3 fats – 2-4 grams of EPA + DHA per day recommended by the American Heart Association.

o       Medications

§         Statins - lower cardiovascular events, cardiovascular mortality, and total mortality.

§         Fibrates - decrease risk of cardiovascular events, but increase noncardiovascular mortality, and no documented benefit in 2009 with regard to cardiovascular mortality or total mortality.

 

Uric acid

  • Hyperuricemia (uric acid > 7.0 mg/dl in men and > 6.5 mg/dl in women) is a risk marker for cardiovascular disease, hypertension, kidney disease, metabolic syndrome, and obesity (Hypertension. 2005. 45. 18-20). Preliminary data suggests that uric acid is a risk factor, not just merely a risk marker.
  • Uric acid is an antioxidant.
  • Fructose is the only sugar that raises uric acid levels (Ann Rheum Disease. 1974. 33. 276-280).
  • Uric acid levels in the U.S. have steadily increased over the past 60 years, possibly due to increased fructose in the diet.
  • Excellent summary article in Cleveland Clinic Journal of Medicine. 2006. 73. 1059-1064.

 

WBC (white blood cell count)

  • Risk marker for coronary artery disease, based on data gathered in 2208 patients in the TACTICS-TIMI 18 trial (J Am Coll Cardiol. 2002. 40. 1761-1768).
  • Specifically, based on a study in which 3227 consecutive patients without a MI who had baseline angiography and were followed prospectively, a high neutrophil count and a low lymphocyte count were predictive of risk of MI and death (J Am Coll Cardiol. 2005. 45. 1638-1643).
  • Hypothetical mechanism – elevations occur in conjunction with inflammation.

 

[Last Updated January 28, 2012] [Return to List of Topics]