CHOLESTEROL (and other cardiovascular risk
What is cholesterol and what are
is a waxy, fat-like substance that is present in all animals, but not in
plants (phytosterols are present in plants instead).
cell in our body contains cholesterol; we cannot live without it.
is a vital component of cell membranes.
a key role in membrane fluidity, thus influencing transmembrane
to the Weston Price Foundation, it is a potent antioxidant that protects
against free radical damage to the cell membrane.
is also in many of the cellular organelles.
in the brain promotes myelin formation (insulates neurons) and neuronal
plasticity (Prog Neurobiol.
2006. 80. 165-176).
is the biochemical precursor to all steroid hormones, vitamin D, and bile
- 93% of
cholesterol in the body is found in the cells of the body, 7% in the
alone is not very soluble in blood, so it is carried in the bloodstream by
molecules called lipoproteins.
are named based on their density.
know from the careful study of cholesterol metabolism that high density
lipoprotein (HDL) is "good" - it transports cholesterol to the
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?
liver makes cholesterol.
general, the higher the saturated fat content of the diet, the more
cholesterol made by the liver.
80% of total body cholesterol is synthesized in the liver – we typically
consume 200-300 mg daily of cholesterol, and the liver typically
synthesizes 800 mg daily of cholesterol.
cells can make cholesterol – high insulin levels signal cells to
synthesize cholesterol instead of taking up cholesterol from 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?
evidence links increased cholesterol levels to an increased risk of
coronary heart disease (CHD)
gathered in The Seven Countries Study linked blood cholesterol levels to
coronary mortality (Keys A, et al. Acta Med Scand. 1966. 460 [suppl].
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).
data from the Framingham
study confirms the link between cholesterol levels and CHD risk (Ann Epidemiol.
1992. 2. 23-28).
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)
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
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).
The total cholesterol level in the blood is not as important as the ratio
of total cholesterol (TC) to HDL cholesterol.
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.
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
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?
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
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?
general, the lower the better, at least down to a cholesterol level of
normal LDL cholesterol amongst hunter-gatherers, healthy human neonates,
and free living primates is 50-70 (J
Am Coll Cardiol.
2004. 43. 2142-2146).
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.
on this definition, only 5% of the population had an abnormal cholesterol
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.
should be greater than 35 - this can be measured along with total
cholesterol in a nonfasting state.
should be less than 130 - a valid measurement requires a 12 hour fast.
diabetics, or in people with a previous history of heart attack, stroke,
or peripheral vascular disease, LDL should be less than 100.
should be less than 150 - a valid measurement requires a 12 hour fast.
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
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%.
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).
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).
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
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.
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.
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.
lowering cholesterol can cause memory impairment.
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?
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.
lowering cholesterol in seniors may cause memory impairment.
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?
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.
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).
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
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
cholesterol is measured for screening purposes, HDL should also be
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.
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.
should be rechecked after 6-8 weeks in somebody on treatment (either
lifestyle changes or medications).
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?
- 1-2 drinks per day raises HDL cholesterol as much as 9-13 mg/dL (Am Heart J.
2004. 147. S29-S35; Am J Clin Nutr. 2002. 75.
aerobic exercise lowers the cholesterol: HDL cholesterol ratio by 15% (Circulation.
1995. 92. 773-777).
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).
is associated with a healthier lipid profile, based on data in 990 adults
in the Midlife in the United States Study. Some of the association of
optimism with healthier lipid profile is attributable to the association
of optimism with healthier lifestyle. However, optimism is associated
with a higher HDL and a lower triglyceride level, independently, after
adjustment for covariates (Am J Med.
2013. 111. 1425-1431).
techniques (meditation, yoga) lower cholesterol and LDL cholesterol.
cessation lowers cholesterol and LDL cholesterol, and raises HDL
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).
loss raises HDL cholesterol.
trans fats with polyunsaturated fats from unhydrogenated oils is the most effective dietary
measure for improving lipid profiles, based on a meat-analysis of 60
controlled trials (Am J Clin Nutr. 2003. 77.
diet low in saturated fat lowers cholesterol and LDL cholesterol.
show that a population based educational approach is associated with a
1-11% reduction in cholesterol levels.
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).
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).
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).
of soluble fiber – a
meta-analysis of 67 controlled trials of dietary soluble fiber as a
single intervention shows only a modest effect on TC and LDL (i.e.
decrease of 5 mg/dL) [Am J Clin Nutr.
1999. 69. 30-42].
information below under the heading of herbs – see konjac
root and psyllium.
is some data that rye fiber lowers cholesterol and blood sugar more than
wheat fiber (Am J Clin Nutr. 2003. 77.
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 of
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.
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
- Polymeal (also referred to as Portfolio Diet) – reduces LDL by
29-35% (Endocrinol Metab Clin North Am. 2009. 38. 45-78).
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.
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).
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
– see ‘tree nuts’ just below
(Am J Clin
Nutr. 2004. 80. 1185-1193)
(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%.
(soluble fiber) [Am J Clin Nutr. 1979. 32.
(dark) improves the HDL: LDL cholesterol ratio (Brit J Nutr. 2002. 88. 479-488). For additional citations in
regard to the cardiovascular benefits of dark chocolate consumption, go
to the Nutrition page of this website, and scroll about 1/3 of the way
down the page to the section on ‘chocolate.’
- Cordyceps sinensis
mushrooms lower cholesterol
fish (salmon, sardines, herring, mackerel, whitefish, and bluefin tuna) raise HDL and lower
triglycerides. Fish oil capsules do the same.
meal or flax oil
seed oil raises HDL.
tea lowers serum cholesterol – a meta-analysis of 14 RCTs (n=1136) of
green tea beverages and extracts showed that green tea significantly
lowered total cholesterol by 7.2 mg/dl (p<0.001) and LDL by 2.19 mg/dl
(p<0.001) with no effect on HDL (Am
J Clin Nutr.
2011. 94. 601-610).
nuts – see ‘tree nuts’ just below
nuts – see ‘tree nuts’ just below
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
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).
oil raises HDL, lowers LDL, and interferes with the oxidation of LDL
(half a raw onion/day) may raise HDL as much as 30%.
– see ‘tree nuts’ just below
– see ‘tree nuts’ just below
sterols and stanols (Am J Cardiol. 2005. 96 [supplement])
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."
intake - 150-350 mg/day of plant sterols and 15-50 mg/day of plant
stanols, so achieving therapeutic intake for purposes of LDL lowering
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
– no justification for using < 1 gram/day or > 3 gram/day. Optimal
LDL lowering is achieved at a dose of approximately 2 grams/day.
of dosing – most studies have dosed 2-3 times per day, based on the
supposition that stanols or sterols need to be present in the intestinal
lumen postprandially to displace cholesterol
from mixed micelles. HOWEVER, there is data that a single daily dose is
as effective as 3 divided doses (Eur J Clin Nutr. 2000. 54.
– plant sterols and stanols need to be in ester form to be effective at
lowering cholesterol, as esterification increases lipid solubility.
After ingestion, the ester bond is hydrolyzed by acid in the stomach.
than 40 phytosterols – sitosterol, campesterol, and stigmasterol
are most abundant
major phytostanols are sitostanol and campestanol
– seems to be free from any symptomatic side effects, and generally
regarded as safe (GRAS) by US and European Union regulatory bodies.
meta-analysis of 41 trials shows that 2 grams per day of either sterols
or stanols reduces LDL cholesterol levels 10% (Mayo Clin Proceed. 2003. 78.
965-978). Maximum effect seen after 16-24 weeks on treatment. Additive
effect in those also on statins, and/or also following a low saturated
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).
of action (presumed) – 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
of plant sterols are absorbed into the bloodstream; 1-5% of plant
stanols are absorbed into the bloodstream – clinical significance
sterols increase plasma plant sterol levels whereas plant stanols
decrease plasma plant sterol levels – clinical significance uncertain.
is a theoretical concern that regular long-term consumption may
interfere with absorption of vitamins and nutrients. Data is as follows
Proceed. 2003. 78. 965-978):
tocopherol - 15 trials; mean change in is minus 5.9%, and this can be
explained by a reduction in cholesterol
carotene - 13 trials; mean change in is minus 8.7%, and this can be
explained by a reduction in cholesterol
carotene - 15 trials; mean change in is minus 19.9%, corrected to
minus 12.1% (significant decrease at p<0.001) when adjusted for
change in serum cholesterol.
– 13 trials; mean change in is minus 7.3 %, and this can be explained
by a reduction in cholesterol
(vitamin A) – 14 trials; mean change in is minus 0.1%.
D – 10 trials; mean change in is positive 0.5%.
K dependent clotting factors – no change in 1 trial in which subjects
were fed stanols
that dietary intake of cholesterol is only 50-750 mg/day, biliary
cholesterol input to the intestine is 500-2400 mg/day.
at cholesterol lowering is additive to that of prescription statins.
- 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).
seeds (40 grams/day ground seeds) based on a trial in 21 patients (Nutr Res. 2005. 25. 559-567).
mushrooms lower cholesterol – also available as a dietary supplement (see
dosing information below).
(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.
- 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.
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
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%.
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.
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
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).
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).
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).
mechanism of action – reduced hepatic cholesterol synthesis.
nuts – reviews conclude that consumption of tree nuts can reduce LDL
cholesterol by 2-19% as compared with lower-fat and Western diets (Br J Nutr.
2006. 96[Suppl 2]. S68-S78; J Nutr.
2005. 135. 2082-2089). Tree nut consumption also associated in some
studies with a reduced risk of MI. For
details on the results of individual studies of various tree nuts
(almonds, hazel nuts, macadamia nuts, pecans, pistachios, and walnuts),
go to the –‘Prevention of MI’ page of this website, Primary Prevention
section, and scroll down to “Nuts”).
– see ‘tree nuts’ just above
herbs (Herbs for serum cholesterol reduction: a systematic review. J Fam Pract. 2003. 52. 468-478). Detailed info is
proprietary; shared at the time of an office visit.
vitamins, minerals, and dietary supplements – additional detailed info is
proprietary; shared at the time of an office visit..
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. 30-40).
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.
(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).
the mobilization of free fatty acids from peripheral tissues, thereby
reducing hepatic synthesis of triglycerides. At high doses also
inhibits HDL catabolism.
doses (1.5-3 grams) lower LDL by 5-25%, triglycerides by 20-50%,
lipoprotein (a) by 34%, and increase HDL by 15-35%.
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.’
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
release niacin costs approximately $7.10 per month for 2000 mg/day.
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.
flush niacin costs approximately $21.70 per month for 2000 mg/day.
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).
hexaniacinate – see separate listing just
above in this outline.
(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 result of individual studies of statins for
primary and secondary prevention of heart disease, as well as
meta-analyses and Cochrane Review conclusions, go to http://www.acsu.buffalo.edu/~shlevy/preven.htm
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). A
Cochrane review of statins for primary prevention identified 18 RCTs
(n=56,934, mean age 57, age range 40-75) and found that while statins do
increase the risk for diabetes, they are not associated with an increased
risk of cancer, myalgia, rhabdomyolysis, liver enzyme elevation, renal
dysfunction, or arthritis; discontinuation rate was 12% in the active
treatment group, and 12% in the placebo group. (Cochrane Database Syst Rev. 2013.
CD004816, as cited in ACP Journal
Club. 2013. 159. JC2, and as cited in a JAMA Clinical Evidence
Synopsis and accompanying editorial. JAMA.
2013. 310. 2451-2452 and 2405-2406). There is theoretical and anecdotal
data that Co Q 10 can reverse some of the adverse effects of statins.
Alternate day dosing with statins with nearly the same magnitude of
cholesterol and LDL reduction, and possibly with a reduced incidence of
adverse effects. The effect of every other day dosing on the pleotropic
effects of statins is unknown (Am J
Med. 2012. 126. 99-104).
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).
of 35 RCTs does NOT show an increased (or decreased) risk of cancer (J Clin Oncol. 2006. 24. 4808-4817).
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).
– see ‘Heart Failure’ just below.
frequency uncertain (Ann Pharmacother. 2012. 46. 549-557).
systematic analysis and meta-analysis concludes “In patients without baseline
cognitive dysfunction, short-term data are most compatible with no adverse
effects of statins on cognition, and long term data may support a beneficial
role for statins in prevention of dementia.” The long term cognition studies
included 25,443 patients with a mean duration of statin treatment of 3 to 24.9
years (Mayo Clin
Proceed. 2013. 88. 1213-1221).
second systematic review concludes that “Published data do not suggest an
adverse effect of statins on cognition; however, the strength of the available
evidence is limited, particularly with regard to high dose statins” (Ann Intern Med. 2013. 159. 688-697).
– 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).
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).
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)
meta-analysis found the rate of excess new-onset diabetes to be dose related (JAMA. 2011. 305. 2556-2564).
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).
data would suggest that this is a class effect, and that the effect is
dose-dependent, with a greater risk of diabetes associated with dose-intensive
therapy (Perspective. N Engl J Med. 2012. 366. 1752-1755).
meta-analysis of 2 RCTs of high dose atorvastatin showed an increased risk of
new onset diabetes, with a number needed to harm comparable with the NNT to
prevent one additional CV event (J Am Coll Cardiol. 2013. 61.
148-152 as cited in ACP Journal Club.
2013. 159. JC3).
7. A Cochrane review of statins for
primary prevention identified 18 RCTs (n=56,934, mean age 57) and found that
“statins reduce mortality and major vascular events and increase the risk for
diabetes without increasing other adverse events.” (Cochrane Database Syst Rev. 2013.
CD004816, as cited in ACP Journal Club.
2013. 159. JC2).
Heart failure - Diastolic dysfunction present in
2/3 of patients after 6 months (Am J Cardiol. 2004. 94. 1306-1310), frequency of symptomatic
heart failure uncertain
– occasional elevation of LFTs, often dose-related
– 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). Common (Ann Intern Med. 2009. 150. 858-868)
May respond to supplemental Co Q 10, but in a meta-analysis of 6 studies (n=302), heterogeneous
and small, no benefit of Co Q 10 was identified (Mayo Clin Proc. 2015. 90. 24-34).
May respond to supplemental creatine (Ann Intern Med. 2010. 153. 690-692).
May respond to Vitamin D supplementation
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).
trial in 150 hypercholesterolemic patients who had a
25 OH vitamin D level < 32 ng/ml and needed to discontinue statin treatment
because of myositis or myalgias showed that vitamin
D3 50,000 IU twice a week for then 50,000 IU weekly allowed successful
resumption of the statin medication in 87% (i.e. no recurrent symptoms during
the 8.1 month median duration of the trial) [Curr Med Res Opin. 2011. 27. 1683-1690].
disease - anecdotes, frequency uncertain
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)
– sometimes apparent only after years of treatment; anecdotes, frequency
factors for adverse effects (Pizzorno J.
Editorial – Table 1. IMCJ.
2014. 13. 8-14).
or small body frame
or renal insufficiency
of elevated CPK
or personal history of muscle disorders
effects of statins
reduce the susceptibility of LDL to oxidation
shift lipoprotein subtype from pattern B (small, dense LDL) to pattern A
(large, buoyant LDL)
prevent oxidative stress-mediated endothelial dysfunction in hypercholesterolemic,
hypertensive, and diabetic patients
(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).
the expression of adhesion molecules, inflammatory cytokines, and metalloproteinases independent of
cholesterol-lowering effect (Thromb Haemost. 2003. 90. 607-610).
increase nitric oxide in the endothelium.
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.
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).
with absorption of other medications, so must be taken at a different
time of the day from other medications.
acid - see above under 'vitamins and minerals.'
(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:
A - large particles.
B - small, dense particles.
any given LDL value, people with pattern B are three times more prone to
heart disease than those with pattern A.
replacement therapy in women seems to have a much greater impact on LDL
and HDL cholesterol values in those with pattern B.
can order the test which measures LDL particle size from Berkeley Heart
Lab at 1-800-HEART-89.
- Oxidized LDL is the real culprit
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).
of oxidized cholesterol include food preparation (i.e. scrambling eggs
rather than preparing sunny side up or hard-boiling) and oxidation of
cholesterol in the body.
Q 10 protects against oxidation of cholesterol.
in virgin olive oil protect against oxidation of cholesterol J Nutr.
2010. 140. 501-508).
of oxidation of cholesterol (Pizzorno J.
Editorial – Table 1. IMCJ.
2014. 13. 8-14).
foods with high cholesterol content at high temperatures
of antioxidant nutrients
metal body burden
blood glutathione levels
HDL – not all is created equal (Cleve Clin J Med. 2007. 74. 697-705)
most healthy people, HDL has an anti-inflammatory role, facilitates
reverse cholesterol transport, and limits the production of oxidized LDL.
the setting of systemic inflammation, HDL can become dysfunctional, and
actually have pro-inflammatory effects.
monocytes chemotaxis assay and a cell free assay, not yet commercially
available in 2007, can determine the functional characteristics of HDL.
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.
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).
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): Note, with availability of generic statins,
cost effectiveness is currently much greater.
prevention in males and females with cholesterol greater than 300:
25-34: $1,000,000 - $10,000,000/year of life saved.
55-64: $100,000/year of life saved.
cardiac transplant only costs an estimate $50,000/year of life saved.
more detailed statistics, see (Ann
Intern Med. 2000. 132. 769-779).
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.
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).
JAMA. 2014. 311. 461-462)
Cholesterol identified as a treatable risk
factor for heart disease based on data from the Lipid Research Clinics Program
trial which showed that cholestyramine treatment of high cholesterol in men was
associated with a reduction in risk of CHD (JAMA.
1984. 251. 351-364).
Data from epidemiological studies, animal
studies, and family studies all supported cholesterol as a treatable risk
NCEP/ATP I (Arch
Intern Med. 1988. 148. 36-69)
LDL level of 160 selected as abnormal in part
because it was the value above which the risk of CHD increased more rapidly and
in part because at the time it represented approximately the 75th
percentile for the US population.
These recommendations thus declared one quarter
of the adult population as having a treatable risk factor for CHD (at a time
when few safe and effective therapies were available).
This report specified whether or not each
recommended drug treatment had been shown to reduce clinical events.
NCEP/ATP II (JAMA.
1993. 269. 3015-3023)
emphasis on total heart disease risk as a guide to treatment.
goal for secondary prevention is LDL < 100, with a recommendation to
start medication if LDL > 130 after a trial of lifestyle changes.
> 45 in males and age > 55 in females is added as a risk factor for
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.
emphasis on HDL cholesterol as a heart disease risk factor.
include HDL measurement any time a screening cholesterol is ordered.
of HDL > 60 as a negative risk factor for heart disease.
of HDL < 35 as an additional positive risk factor for heart disease.
emphasis on exercise and weight loss (in addition to diet).
NCEP/ATP III (JAMA.
2001. 285. 2486-2497) and update (Circulation.
2004. 110. 227-239).
on multiple risk factors.
with diabetes are considered a CHD risk equivalent.
projections of 10 year absolute CHD risk.
persons with multiple metabolic risk factors as candidates for
intensified therapeutic lifestyle changes.
of lipid and lipoprotein classification.
LDL cholesterol < 100 mg/dl as optimal.
categorical low HDL cholesterol from <35 mg/dl to < 40 mg/dl.
the triglyceride classification cutpoints, such
that triglycerides >200 mg/dl are high.
complete lipoprotein profile instead of just cholesterol and HDL
cholesterol for screening.
use of plant sterols/stanols and soluble fiber as therapeutic dietary
options to lower LDL cholesterol.
strategies for promoting adherence to therapeutic lifestyle changes and
treatment beyond LDL lowering in individuals with triglycerides > 200
statins as the ‘usual drug’ for starting therapy, but did not in the
report clearly identify which of the recommended drugs had been shown to
reduce clinical events.
ACC/AHA (American Heart Association and American College of
Cardiology) Guideline on the Treatment of Blood Cholesterol to Reduce
Atherosclerotic Cardiovascular Risk in Adults” (Stone NJ et al. Circulation. Epub
11/12/2013; Stone NJ et al. Ann Intern
Med. 2014. 160. 339-343).
aspect of this guideline receiving the most publicity is the
recommendation for moderate or high intensity statin therapy for the
primary prevention of atherosclerotic cardiovascular disease in
individuals with 7.5% or greater 10 year atherosclerotic cardiovascular disease
risk, and consideration of moderate-intensity statin treatment for
individuals with a 5% to 7.5% 10 year risk. Risk calculator at http://tools.cardiosource.org/ascvd-risk-estimator/
are adults with New York Heart Association heart failure class II – IV and
those receiving maintenance hemodialysis, as statins have not been shown to
reduce risk in trials performed in these populations.
o NOTE that 32.9 % of individuals aged
40-75 fall into the risk category for which prescription statin treatment is
emphasizes shared decision making, and emphasizes adherence to ha healthy diet.
with NCEP/ATP III, this guideline creates 4 categories of adults, with
distinct recommendations for each group:
with atherosclerotic cardiovascular disease (includes ACS, MI, stable angina,
coronary or other arterial revascularization, stroke, TIA, PVD of
atherosclerotic origin – initiate high
intensity statin treatment.
with LDL cholesterol levels of 190 mg/dl or higher – initiate high intensity statin treatment.
with diabetes, aged 40-75 with LDL between 70 and 189 mg/dl – initiate moderate or high intensity statin
age 40-75 with LDL between 70 and 189 mg/dl and a 7.5% or greater 10 year risk
of atherosclerotic cardiovascular disease – initiate moderate or high intensity statin treatment.
moderate, and low intensity statin treatment
(>50% lowering of LDL cholesterol): atorvastatin 40-80 mg daily,
rosuvastatin 20 mg daily
(30-50% lowering of LDL cholesterol): atorvastatin 10 mg daily, rosuvastatin 10
mg daily, simvastatin 20-40 mg daily, pravastatin 40 mg daily, lovastatin 40 mg
daily, fluvastatin 40 mg twice a day
(20-30% lowering of LDL cholesterol): pravastatin 10-20 mg daily, lovastatin 20
New in these guidelines
task force found no scientific evidence to support specific treatment goals for
LDL or HDL cholesterol. Thus the LDL and HDL treatment targets which
characterized the first 3 reports have been abandoned.
monitoring of ALT, AST, and CPK is not recommended – measurement is recommended
only in those with symptoms.
contrast with NCEP/ATP III, this guideline focuses on major disease endpoints
(rather than surrogate markers) in regard to assessment of efficacy of
different classes of medications, and concludes based on the evidence that
statins should be first line (rather than fibrates, niacin, bile acid sequestrants, ezetimibe, or omega
3 fatty acids).
core of the guidelines depends on a new risk score, referred to as the “Pooled
Cohort Equations,” using data from 5-NHLBI-sponsored longitudinal, population
based cohorts African Americans and non-Hispanic white men and women. There is
some data that this score may overestimate risk, but there is much uncertainty
regarding the extent of any overprediction
(Viewpoint. Ioannidis JPA. JAMA.
2014. 311. 463-464). Risk calculator
and process of creation of this guideline
on these guidelines began in 2008, and the panel adhered to the standards of the
IOM study committee, which published in 2011 “Clinical Practice Guidelines We
process involves focusing on select clinical questions (3 questions relevant to
clinical care and 5 additional critical questions) which are to be answered in
the guideline based entirely upon RCT evidence.
panel included cardiologists, epidemiologists, primary care physicians, and
meta-analyses of up to 27 RCTs were available as evidence.
recommendations were reviewed by 23 experts and representatives of federal
agencies identified by the NHLBI.
2013, the NHLBI announced its plan to turn over guideline development to the
– 8 of the 15 panelists had current or recent industry ties (BMJ. 2013. 347. f6989).
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).
is a highly sensitive measure of inflammation.
ratio is less than 3.
ADMA (asymmetric dimethyl arginine)
occurring compound that inhibits nitric oxide production and impairs
endothelial function, and is an important risk factor for coronary artery
described in 1992 by Patrick Vallance, an
endothelial cell biologist.
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.
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.
ratio is suboptimal, treatment consists of supplemental L-arginine.
Apolipoprotein B: Apolipoprotein A-1 ratio
is a strong risk factor for atherosclerotic cardiovascular disease.
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.
of iron stores, and high levels are associated with increased oxidative
level is <150 for females and <300 for males.
levels are high, sweating and the supplement inositol hexaphosphate
(IP6) facilitate excretion of excess iron
in the formation of a blood clot; high levels increase the risk for
formation of blood clots.
levels are 150-299 mg/dl, with levels above 460 mg/dl indicating a high
level might be partially caused by vitamin C insufficiency (BMJ. 1995. 310. 1559-1563).
is a plant-derived dietary supplement that can lower fibrinogen levels (J Agric Food Chem. 2000. 48.
C – recommended by Thomas E Levy (Stop
America’s #1 Killer! 2006. Pg 112).
GGT (gamma glutamyltransferase)
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).
mechanism – depletion of glutathione.
Thus, hypothetically, supplemental NAC might offset the increased
risk associated with high GGT levels.
acid derived from methionine which is an independent risk factor for
coronary artery disease.
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).
McCully first proposed in 1969 that homocysteine
roles are to regulate bone and tissue formation and to stimulate formation
levels are also correlated with risk of CVA, DVT, and a variety of
neurological diseases. Observational data suggest that homocysteine
homocysteine level is probably less than 6 micromol/liter,
even though most labs define normal as less than 9 micromol/liter.
which raise homocysteine levels
high consumption of alcohol
high in saturated fat (Dr.Perlmutter)
Carbemazepine (Tegretol) and
phenytoin (Dilantin) lower folate concentrations
Primidone (Mysoline) and
valproate (Depakote) deplete B vitamins too (Dr Perlmutter)
Bezafibrate in combination with niacin via an uncertain
(Questran) and colestipol (Colestid) impair folate absorption
Colestipol in combination with niacin via an uncertain
inhibitors (i.e. Celebrex) - (Dr Perlmutter)
(i.e. oral contraceptives, ERT) deplete vitamin B6
Fenofibrate in combination with niacin via an uncertain
blockers (Dr Perlmutter)
Hydrochlorothiazide raises homocysteine level by
16% on average (Metabolism. 2003. 52.
Levodopa (Dr Perlmutter)
diuretics (Dr Perlmutter)
lowers folate levels by depleting folate metabolites
- (Dr Perlmutter)
Raloxifine (Evista) - (Dr Perlmutter)
including inhaled and nasal steroids (Dr Perlmutter)
lowers vitamin B6 levels
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).
Lead (as per Sherry Rogers, MD)
(Metabolism. 1985. 34. 1073-77).
to lower homocysteine levels:
– limit coffee consumption, and increase soy consumption. Soy protein with
native phytate significantly reduces homocysteine (Am J Clin Nutr. 2006. 84. 774-780).
B9 (folate) 0.5 – 5 mg/day or 5-MTHF.
B12 100 - 1000 mcg/day.
B6 10 – 100 mg/day.
B2 (riboflavin) 100 mg/day (may be beneficial for those with MTHFR 677TT
refractory hyperhomocysteinemia (especially
postprandial hyperhomocysteinemia) consider betaine
1.5 – 6 grams/day, either anhydrous betaine (TMG) or betaine hydrochloride.
hyperhomocysteinemia secondary to hemodialysis,
consider NAC 1200 mg twice a day.
levels are correlated with an increased risk of heart disease
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).
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).
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.
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).
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).
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).
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.
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.
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).
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).
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].
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].
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.
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.
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).
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).
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).
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).
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).
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).
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:
may promote cell proliferation in atherosclerotic plaque (N Engl J Med. 2006. 354. 1629-1632.
may alter the methylation potential in vascular cells, promoting the
development of plaque (N
Engl J Med. 2006. 354. 1629-1632. Editorial).
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).
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).
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):
B6 supplementation may deplete magnesium, and magnesium supplementation was not
administered in these trials.
supplementation may deplete zinc, and zinc supplementation was not administered
in these trials.
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
hs-CRP (high sensitivity C reactive protein)
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).
2006 it remains unclear whether CRP is causally related to the
cardiovascular disease, or just a risk marker.
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).
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).
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).
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).
can fluctuate as much as 44% over the course of a woman’s menstrual cycle.
which raise hs-CRP.
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
saturated fat intake raises hs-CRP.
trans-fat intake raises hs-CRP (J Nutr. 2005. 135. 562-566).
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.
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).
estradiol and Premarin raise hs-CRP (topical
estradiol does not).
which lower hs-CRP
tocopherol and gamma tocopherol
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).
Q 10 (in a study in baboons, in conjunction with vitamin E).
- conjugation with cyclodextrin increases
absorption, increasing peak plasma concentration
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).
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).
(Epidemiology. 2002. 13.
data comes from NHANES (J Nutr. 2004. 134. 1181-1185).
data in 15,033 women in the Women’s Health Study also show this
association, and further link the association to intake of soluble
a yearlong study in 524 healthy adults, those who ate the most fiber had
lower hs-CRP levels (Am J Clin Nutr. 4/06).
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).
on a total of 11,113 subjects in NHANES 2005-2010 suggest that “A
greater amount of dietary fiber intake might be associated with lower
C-reactive protein levels” (Am J Cardiol. 2014. 113. 287-291).
oil (J Nutr
Biochem. 2003.14. 513-521).
seed extract 300 mg/day
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).
diet lowers hs-CRP (JAMA. 2004.
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).
– conjugation with cyclodextrin increases
absorption, increasing peak plasma concentration
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).
D3 (QJM. 2002. 95. 787-796).
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.
– 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).
oil may or may not lower hs-CRP.
Lipoprotein (a) Cleveland Clinic Journal of Medicine. 1999. 66.
risk factor for coronary artery disease, risk marker for aortic sclerosis.
are largely genetically determined.
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
30 mg/dl as the upper limit of normal, it is estimated that 25% of the U.S.
population has high levels.
modifications such as diet, weight loss, and exercise have no effect on
C supplementation may protect
against Lp (a)
induced damage. Fish oil, L-carnitine, L-lysine, and L-proline
may also neutralize Lp
replacement therapy, high dose niacin, and fenofibrate
lower Lp (a) but resins
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).
biloba lowers Lp(a) 23% [P< 0.023] (Atherosclerosis. 2007. 192.
2 grams/day lowers Lp
(a) 8-12%, based on a RCT in 36 patients (Nutr Metabol Cardiovasc
Dis. 2000. 10. 247-251).
– Linus Pauling hypothesized that this would decrease Lp
(a) binding to the arterial wall and might even dislodge Lp (a) bound to the wall (Thomas E Levy Stop America’s #1 Killer! 2006. Pg
2-3 gm/day can reduce levels by 20-50% after 8 weeks (J Intern Med. 1989. 226. 271-276).
may lower Lp (a).
C – recommended by Thomas E Levy (Stop
America’s #1 Killer! 2006. Pg 112).
measuring the level in patients with premature coronary artery disease or
patients with hypercholesterolemia resistant to statin medication.
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).
measures lipoprotein phospholipase A2, a compound which occurs only within
below 200 ng/ml are optimal; levels above 250 ng/ml indicate a high risk
of plaque rupture.
RDW (red cell distribution width)
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).
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.
are fat-like substances in the blood.
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
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).
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.
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).
for high triglycerides
in moderation – excess alcohol can cause very high triglyceride levels.
sugar control – uncontrolled diabetes can cause very high triglyceride levels.
– both aerobic and resistance exercises are beneficial
– reduce intake of high-fructose corn synrup, and
reduce intake of high glycemic index foods (i.e. pretzels, bagels, breakfast
- no effect on cardiovascular mortality, noncardiovascular
mortality, or total mortality, based on a meta-analysis (Arch Intern Med. 2005. 165. 725-730).
3 fats – 2-4 grams of EPA + DHA per day recommended by the American Heart
C – recommended by Thomas E Levy (Stop
America’s #1 Killer! 2006. Chapter 6).
- lower cardiovascular events, cardiovascular mortality, and total mortality.
oil – prescription Lovaza or Vascepa
- decrease risk of cardiovascular events, but increase noncardiovascular
mortality, and no documented benefit in 2009 with regard to cardiovascular
mortality or total mortality.
– off-label use
- 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.
acid is an antioxidant.
is the only sugar that raises uric acid levels (Ann Rheum Disease. 1974. 33. 276-280).
acid levels in the U.S.
have steadily increased over the past 60 years, possibly due to increased
fructose in the diet.
summary article in Cleveland Clinic
Journal of Medicine. 2006. 73. 1059-1064.
WBC (white blood cell count)
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).
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).
mechanism – elevations occur in conjunction with inflammation.
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