To assess risk of heart attack and stroke, and to prevent heart attack and stroke, the following evaluations should be
done. This is the assessment carried out at the Cholesterol Center, Jewish Hospital, Cincinnati, OH 45229
We will send you and your physicians a letter which includes the results of the tests, our interpretations, and our
directions for therapy with diet and (if necessary) medication.
Lovastatin (Mevacor):
In the EXCEL study, the efficacy and safety of Mevacor was assessed in 8,245 patients with moderate
hypercholesterolemia. The major results were as follows:
1. Mevacor produced sustained, dose-related reductions of LDL cholesterol of 24 to 40%, increased
the good, high density lipoprotein cholesterol 7 to 10%, decreased total cholesterol 17-29%, and decreased triglycerides 10-19%.
2. The National Cholesterol Education Program low density lipoprotein cholesterol level goal of <130 mg/dl was achieved by 38 to 83% of patients.
3. Safety was excellent. Modest, easily reversible increases in liver function tests detectable
in the blood were observed in 0.1% of patients receiving 20 mg of Mevacor (the same as the placebo, interestingly), 0.9% of those receiving 40 mg
per day, and 1.5% in those receiving 80 mg per day. These tests normalized quickly when Mevacor was discontinued or the dose was reduced.
The safety of the drug during pregnancy is not known (for the fetus), and the drug should never be taken
if there is a chance of pregnancy.
4. Muscle aches, cramps and tenderness with a severe elevation of the muscle enzyme CPK were
found in only one patient (0.1%) receiving 40 mg per day, and 4 patients (0.2%) receiving 80 mg per day.
The authors concluded that "Mevacor, when added after an adequate trial of a prudent diet, is a highly effective
and generally well tolerated treatment for patients with moderate hypercholesterolemia (Archives of Internal Medicine, 1991;151:43-49).
Our Cholesterol Center experience has been very comparable to the excellent experience reported in the EXCEL study (as
above). We have never had to discontinue Mevacor in any patient because of problems with liver function tests, muscle problems, or eye problems. Generally,
Mevacor alone or Mevacor in conjunction with other drugs serves to reduce total and LDL cholesterol into ranges where we expect confidently to stop
the progress of atherosclerosis and/or to reverse it.
Important new information has also been obtained about the safety of Mevacor in regards to eyes. In the EXCEL study,
there was absolutely no evidence when compared to placebo that Mevacor had any adverse effect on the eyes, and no effect on the lens. Our experience
has been exactly the same. We have never seen a problem developing in the eyes attributable to Mevacor.
Summary:
Both in the major EXCEL study and in our studies here, Mevacor has been remarkably successful in normalizing total
and LDL cholesterol and its safety record has been excellent.
Outcome Studies:
This primary prevention study "extends the envelope" of treatment because "healthy" patients with
average cholesterol levels benefited from treatment to LDL levels that are lower than those currently recommended by NCEP. Target LDL-C
levels for this trial were # 110 mg/dL vs. the NCEP recommendation for this population of <130 mg/dL or 160 mg/dL. Additionally, benefit was seen
in patients, who under current guidelines, would not have been indicated for drug therapy. Based on NCEP guidelines, only 17% of patients in this
study would qualify for drug therapy. The primary endpoint for the trial was a composite of unstable angina, fatal and nonfatal myocardial
infarction, and sudden cardiac death. The study was not powered to look at reduction in cardiovascular or total mortality.
Study Characteristics:
- 6605 men and women
- no evidence of CHD
- treatment: Lovastatin 20-40 mg; mean dose 30 mg/day
- men 45-73 years of age; women 55-73; mean age 58
- 12 % smokers
- 22% hypertensive
- baseline total cholesterol: mean 221 mg/dL
- baseline LDL-C range 130 - 190 mg/dL; mean LDL 150 mg/dL
- baseline HDL-C: Below 50 mg/dL; mean 37 mg/dL
Results:
- reduced the risk of first acute coronary event by 36%
- reduced the risk of first coronary events in women by 54%, men 34%, hypertensive patients 43%, diabetic patients
43% and elderly 29%
- reduced procedures, such as bypass and angioplasty by 33%
- reduced admissions to hospital due to unstable angina by 34%
- cardiovascular risk reduction was seen across all tertiles of baseline LDL levels (83-142, 143-157, 158-235)
- risk reduction was seen early on (first 6-12 months), indicating plaque stabilization or vasodilatation via
increased nitric oxide release
- long-term safety confirmed
Impact on Lipids:
- total cholesterol - down 18.4%
- LDL-C - down 25%
- triglycerides - down 15%
- HDL-C- up 6%
Why is this study important?
Benefit was demonstrated in patients not currently "indicated" for statin drug therapy by NCEP guidelines.
Benefit was seen across all baseline LDL-C levels (there was no "floor" as in the CARE trial at 125 mg/dL). Irrespective of how low the LDL-C was at baseline (even in the group with baseline 83-142) the patients had benefit from lipid lowering.
There are now two agents (Lovastatin & Pravastatin) that have been shown to prevent first myocardial infarction.
The curves separated early, within the first year, demonstrating that time to benefit depends on the population
studied and are not an attribute unique to Pravachol.
Pravastatin (Pravachol):
Pravachol is a safe, potent HMG-COA reductase inhibitor. This compound, from the statin family of compounds, is an
effective and safe cholesterol lowering drug, demonstrated to reduce risk of coronary heart disease and ischemic stroke in both primary and secondary
prevention (West of Scotland, Plac I, Plac II, Care, Lipid studies). In multi-center studies (Clinical Cardiology 1991;14:146-151), Pravachol was
effective in lowering the "bad"cholesterol, LDL cholesterol, slightly elevated the "good" cholesterol, HDL-C, and, at the highest
dose, lowered triglycerides:
Pravachol LDL-C reduction HDL-C increase TG decrease
5 mg/day -19.2% 5.2% -14.1%
10 mg/day -22.4% 6.6% -14.9%
20 mg/day -32.4% 2.4% -11.4%
40 mg/day -34.1% 11.7% -23.9%
Like Mevacor, the drug acts predominantly to lower LDL cholesterol. At higher doses (40 mg/day), it moderately lowers
triglycerides, and increases HDL-C modestly.
The drug works by reducing synthesis of cholesterol in the liver and the
intestine, and thus forces the liver to catabolize (chop up) more LDL cholesterol to provide adequate cholesterol for
the liver cells. Because the body makes most of its cholesterol at night, the drug works best if taken with the evening meal or at bedtime. The
maximal effect is seen quickly, within 4 weeks.
Side Effects:
Like Mevacor, since this drug works in the liver, a small number of patients (<1%) will develop asymptomatic
increases in liver enzymes (>3 times the laboratory upper normal limit). These resolve quickly when the drug is discontinued, and are not
serious. There is a very small likelihood (<0.02%) of increased risk of muscle pain or tenderness with CK >10 times the upper normal limit)
When given in conjunction with Gemfibrozil (Lopid), there is a small likelihood of increased risk of muscle pain or
tenderness with CK >10 times the upper normal limit, and if this happens, the one of the two drugs should be immediately stopped.
Compared to the other statin drugs, Pravachol is not metabolized by the CYP 3A4 pathway of cytochrome P450 oxidase,
and has few drug-drug interactions. Pravachol should, however, probably not be given along with the following drugs because of increased likelihood
of adverse reactions (myopathy, liver):
1. The antibiotic Erythromycin or any erythromycin derivative.
2. Nicotinic Acid
3. Cyclosporine (may possibly be used, but only with very close follow-up)
The safety of the drug during pregnancy is not known (for the fetus), and the drug should never be taken if there is
any chance of pregnancy.
Outcome Studies:
The West of Scotland Study, a primary prevention study, has shown that Pravachol significantly reduces the
risk of non fatal myocardial
infarction,(31%), and the risk of death from all cardiovascular causes by 32%, while reducing all cause mortality
significantly (21%).
Plac I and Plac II studies, secondary prevention studies with Pravachol
have shown up to 60% reduction in CHD events.
CARE Study. New Eng J Med 1996;335:1001-9
I. Patients: 4,159 (14% women), studied for 5 years
II. Pre-treatment cholesterol levels: Total cholesterol 180-239 mg/dl
(average 209); LDL cholesterol 115-174 mg/dl (average 139 mg/dl)
III. Treatment: Diet plus placebo vs Diet plus Pravachol (LDL cholesterol
lowering, "statin" drug).
IV. Outcome: Reduction in nonfatal myocardial infarction 24%,p=.002
Reduction in fatal/non-fatal myocardial infarct 25%,p=.007
Reduction in need for cardiac bypass/angioplasty 27%,p=.0001
Benefit observed across all patient subgroups including women, hypertensives, diabetics, smokers, patients
over age 60.
V. Major Conclusions:
1. In secondary prevention (after myocardial infarction, ischemic stroke, coronary artery bypass,
angioplasty, etc), Lower LDL cholesterol below 100 mg/dl and optimally below 80 mg/dl.
2. Most patients who have had an atherosclerotic event, even those with conventionally "normal" total and LDL cholesterol (less than 200 mg/dl, less than 100 mg/dl), will benefit from further substantial LDL cholesterol lowering.
3. Primary prevention (before myocardial infarction), with Pravachol, reduces cardiac events 31%, reduces
all cause mortality 21%.
VI. Previous Data On Pravachol
In 1,891 patients:
1. Reduction in fatal/nonfatal MI 62%, p=.001
2. Reduction in nonfatal MI or death 53%, p=.003
3. Reduction in non fatal MI or CHD death 51%, p=.006
4. Reduction in combined cardiovascular disease 30%, p=.02
Publications:
1. Circulation 1995;92:2419-2425
2. Am J Cardiol 1995;75:455-459
3. Circulation 1995;91:2528-2540
4. Journal Amer Col Cardiol 1995;26:1133-9
5. Circulation 1995;92:1758-1764
Lipid
This secondary prevention study is significant in that it was a large trial of over 9,000 patients which showed
that cholesterol reduction in patients with average cholesterol levels saves lives. The trial showed significant reductions in all primary
endpoints and benefit was seen across all tertiles of baseline LDL-C. The trial adds to the overall evidence that lowering cholesterol reduces
coronary events and that virtually all patients with previous Ml or unstable angina should be considered for cholesterol-lowering therapy. Key
components of the study include the following:
Study Characteristics:
- 9014 men + women, 83% men, l7% women, 31 -75 yrs age; mean age 53
- treatment: pravastatin 40 mg
- 10% smokers
- 42% hypertensive
- total cholesterol range 155-221 mg/dL; mean 213 mg/dL
- triglycerides: <=440 mg/dL; >=193 mg/dL
Results:
- reduced the risk of death from coronary heart disease by 24%
- reduced the risk of total mortality by 23%
- reduced the risk of death from heart disease and nonfatal heart attack by 23%
- reduced the need for bypass by 24%
- long-term safety confirmed
Impact on Lipids:
- total cholesterol - down 19%
- LDL-C - down 25%
- Triglycerides - down 12%
- HDL-C- up 6%
Why is this study important?
Benefit was seen across all baseline LDL-C levels (there was no "floor" as reported in the CARE trial at
125 mg/dL)
There are now two agents (Pravastatin & Simvastatin) that have been shown to reduce mortality in patients with
coronary artery disease.
The influence on coronary events of lipid therapy during treatment with pravastatin: The CARE trial
A post-hoc, subgroup analysis of the secondary prevention CARE trial showed that the relationship between LDL levels
on treatment and coronary events was not linear. LDL levels achieved on treatment with pravastatin were associated with reduction in coronary events
down to the level of 125 mg/dL. LDL levels below 125 mg/dL during treatment were not associated with further decreases in the event rate. This "floor" effect was not seen in the secondary prevention LIPID trial with pravastatin. When carrying out this type of post-hoc, subgroup
analysis, it is important to know whether the sample sizes in the groups being compared (LDL-C on therapy >125 mg/dl, LDL-C <125 mg/dl)
were large enough to know whether the lack of significant difference between the two groups was real, or whether no conclusions could confidently be
drawn because the sample size was too small, a Type II statistical error. Not enough of this data has been presented yet to allow firm conclusions
in this regard.
Relationship between LDL-C changes and CHD event reduction with pravastatin in WOSCOPS
In a post-hoc, subgroup analysis of the primary prevention, West of Scotland Study, subjects who achieved an LDL,
reduction of 20-25% experienced the same risk reduction as those who lowered their LDL by 35-40%. Analysis of patients achieving specific
cholesterol levels as a result of pravastatin therapy compared to patients on placebo who had the same cholesterol level demonstrated greater
reduction in CHD events in pravastatin treated patients. It was concluded that the CHD event reduction seen with pravastatin could not be explained
solely by LDL reduction, and that additional mechanisms might be responsible for the benefit seen in this primary prevention trial.
In the West of Scotland trial, the sample size needed to show a difference between pravastatin and placebo was 6500
patients. The West of Scotland trial was not designed to show differences in event reduction based on LDL-C reduction. In order to show a
statistical difference between 2 patient groups on pravastatin would require a much larger patient population.
In clinical trials, when no significance is shown between treatment groups, this does not mean they are equal in
effect. If there are too few patients in the sample to detect a difference the test will show "no significance," a type II error in
statistical terms.
Baseline HDL-C and TG as predictors of progression of atherosclerosis in SVG: NHLBI Post-CABG trial
The increased risk associated with low HDL-C or high triglycerides was significantly reduced with aggressive
treatment of LDL-C in the Post CABG study. Patients treated to an average LDL-C of 93 mg/dL had significantly greater benefit than those treated to
an LDL-C of 136 mg/dL, and the aggressiveLDL-C reduction offset the additional risk associated with high triglycerides or low HDL.
There has only been one large clinical trial designed to show a difference in event reduction between levels of LDL-C
reduction. This is the Post-CABG trial that had 2 groups; one treated to an LDL-C of 93 and the other treated to an LDL-C of 136. The results of
this trial demonstrated that the group with the greater reduction experienced less plaque progression and fewer PTCAs and CABGs.
Overall, major epidemiological and clinical trial evidence (including 4S,
West of Scotland, CARE, LlPlD, CLAS [an earlier trial using Colestid and Nicotinic Acid] and AFCAPS) support the NCEP guideline recommendations. In
primary and secondary prevention of coronary artery disease and ischemic stroke, it appears that the lower the LDL cholesterol, the better the
outcome. However, it will be very important to continue to get more data on this crucial question.
Simvastatin (Zocor):
Zocor is a safe, potent, HMG-COA reductase inhibitor. This compound, from the same family of compounds as Mevacor, is
an effective and safe cholesterol lowering drug. In recent multi-center studies Zocor was effective in lowering the "bad" cholesterol, LDL
cholesterol, slightly elevated the "good" cholesterol, HDL-C, and, at the highest dose, lowered triglycerides:
Zocor LDL-C reduction HDL-C increase TG decrease
5 mg/day -22% 8% -6%
10 mg/day -27% 9% -10%
20 mg/day -34% 12% -14%
40 mg/day -40% 13% 20%
Like Mevacor, the drug acts predominantly to lower LDL cholesterol. At higher doses (40 mg/day), it moderately lowers
triglycerides, and increases HDL-C modestly. The triglyceride lowering and HDL-C elevating effects may be most marked in patients who have
triglycerides >250 mg/dl, and HDL-C <35 mg/dl.
The drug works by reducing synthesis of cholesterol in the liver and possibly in the intestine, and thus forces the
liver to catabolize (chop up) more LDL cholesterol to provide adequate cholesterol for the liver cells. Because the body makes most of its
cholesterol at night, the drug works best if taken with the evening meal. The maximal effect is seen quickly, within 4 weeks.
Side Effects:
Since this drug works in the liver, a small number of patients will develop
asymptomatic increases in liver enzymes. These resolve quickly when the drug is discontinued, and are not serious. In
about 0.6% of patients, the drug needs to be discontinued because of drug-related clinical adverse events, and in about 0.8% for drug-related
laboratory adverse events, usually liver function tests persistently greater than 3 times the upper normal limit. About 5% of patients will develop
elevations of the skeletal muscle enzyme, CPK, but only very rarely does this drug, when given by itself, produce muscle pain, weakness, or
tenderness (myopathy).
The compound may be rarely associated with increased likelihood of headache. When given in conjunction with
Gemfibrozil (Lopid), there is an increased, but still small likelihood of muscle pain, weakness, or tenderness, and if this happens, both Zocor and
Lopid should be immediately stopped, and a call be made immediately to us (513-924-8250).
Zocor should not be given along with the following drugs because of increased likelihood of adverse reactions
(myopathy, liver):
1. The antibiotic Erythromycin or any erythromycin derivative.
2. Nicotinic Acid
3. Cyclosporine (may possibly be used, but only with very close follow-up)
The safety of the drug during pregnancy is not known (for the fetus), and the drug should never be taken if there is
any chance of pregnancy.
Outcome Studies:
In the 4 S study, a secondary prevention study in patients with pre-existing coronary artery disease, Simvastatin
therapy reduced the risk of having any coronary event 27%,and reduced all-cause mortality by 30%. Coronary mortality was reduced by 42%.
The 4S trial was a trial of Zocor vs placebo in patients who had already had a coronary event, hence a "Secondary Prevention" trial. A reanalysis showed that patients in the quartile that had the least reduction in LDL-C had the highest rate
of major coronary event, and those with the greatest reductions in LDL-C had the lowest event rate. Looking at actual LDL-C levels achieved; the 4
year event rate was:
- 10.8% with LDL-C levels of 58 to 104 mg/dL
- 13.3% with LDL-C level of 105 to 126 mg/dL
- 18.9% with LDL-C levels of 127 to 266 mg/dL
This subanalysis shows a near linear relationship (p<.0001) between LDL-C achieved and the rate of coronary
events.
Significance:
This subanalysis was rigorous because it included all patients and had adequate power for statistical analysis.
Atorvastatin (Lipitor):
Lipitor is a newly released synthetic lipid lowering agent. This
compound is a member of the "Statin" family of drugs, a family which includes Mevacor, Zocor, Pravachol, and
Lescol. In this family, Zocor and Pravachol have been shown to reduce the risk of heart attack and stroke in patients who have had previous heart
attack or stroke, and, Pravachol and Mevacor, to have the same protective effect in patients who had not had previous heart attack or stroke.
Like the other statins, Atorvastatin works in the liver, reducing synthesis of LDL cholesterol in the liver, and
forcing the liver to chop up (catabolize)LDL cholesterol (which is what we want it to do).
ATORVASTATIN-DOSE RESPONSE, % CHANGE
DOSE LDL-C TG HDL-C
10 -39 -19 6
20 -43 -26 9
40 -50 -29 6
80 -60 -37 5
ATORVASTATIN (A) VS OTHER STATINS, % CHANGE
A10 -36 -17 7
L20 -27 -6 7 Lovastatin
A10 -35 -17 6
P20 -23 -9 8 Pravastatin
A10 -37 -23 7
Z10 -30 -15 7 Simvastatin
Commment: LDL lowering excellent; triglyceride lowering best of the Statins
Side Effects:
A small percentage (0.2%, O.6%, 0.6%, and 2.3%) of patients on 10,20,40,
and 80 mg/day get changes in liver function tests > 3 times the upper normal limit, requiring that the
Atorvastatin be stopped. When the drug is stopped, then the liver tests come back to normal.
Very rarely, patients can develop muscle aches, cramps, or tenderness on
Atorvastatin. If this happens, stop the drug and call us (513-924-8250).
Pregnancy: The Atorvastatin might be toxic to the fetus. If Atorvastatin
is taken by patients who have the capability of becoming pregnant, then they need bomb-proof contraception to avoid
pregnancy while taking the drug.
Drug-Drug Interactions: Atorvastatin is metabolized by cytochrome P450 3A4,
which means that it should never be taken with the antibiotic Erythromycin, the antidepressant Serzone, or the Ketoconazole drugs for fungus, three
drugs which are metabolized in the same cytochrome system.
Outcomes in the Prevention of Heart Attack and Stroke: Because this is a
newly released drug, to date there are no published controlled clinical trials which shown that Atorvastatin, when compared to placebo, reduces the
risk of heart attack or stroke. For the "older" statin drugs, such data has been published for Mevacor, Pravachol, and Zocor. The best
current evidence suggests that when LDL cholesterol is lowered, optimally below 130 mg/dl in patients without atherosclerotic vascular disease
(ASCVD), or below 100 mg/dl in those with ASCVD, risk of heart attack and stroke is reduced 30 to 60% and all cause mortality (everything which
kills people) is reduced 22 to 34%. It is a reasonable assumption that Atorvastatin will have the same beneficial effects, but it will take time for
the ongoing studies to be completed.
Fluvastatin (Lescol):
1. A new, synthetic third generation "statin" drug. To be used in primary hypercholesterolemia after
ruling out secondary hypercholesterolemia (hypothyroidism, liver disease, etc), and after dietary intervention has failed to lower LDL
cholesterol (LDL-C) to target levels (<130, <100 mg/dl). Not the drug of choice when the primary lipid disorder is high triglyceride with high
VLDL cholesterol.
2. Synthetic
3. Metabolized by cytochrome P450 CYP 3A4; should not be given concurrently with erythromycin,
cyclosporine, or azole antifungals which compete for the CYP 3A4 pathway. Should be given cautiously, if at all, concurrently with fibric acids or
niacin because of increased risk of myopathy.
4. Efficacy: At recommended doses of 20 and 40 mg, in primary hypercholesterolemia, mean percent reduction was
19 and 24% in LDL, 4.5% and 4% increment in HDL.
5. Safety: Comparable to other synthetic statins. Less than 1% of patients with persistent elevations of
transaminases > 3 times the usual upper normal limit, < 1% with myalgias.
Do not use:
In patients with active liver disease or persistent elevations in liver transaminases (> 3 times the upper normal
limit), during pregnancy or lactation, in sexually active women in the childbearing age unless they are following effective contraceptive
programs.
6. Monitoring: Before starting therapy, rule out secondary hypercholesterolemia (hypothyroidism, liver disease,
etc) and measure CK and liver function tests. Repeat liver function tests 6 and 12 weeks after starting therapy, and at 4 month intervals
subsequently.
7. Outcome: Less progression of coronary artery disease.
LCAS study:
2.5 year randomized, double blind, placebo controlled.
Fluvastatin 40 mg vs placebo; adjunctive cholestyramine resin in all patients with LDL-C > 160 mg/dl after
diet.
Primary endpoint: Change in minimum lumen diameter of coronary arteries.
Patients: Primary hypercholesterolemia, age 35-75, LDL between 115-190 on
diet. At least 1 coronary artery lesion causing 30-75% occlusion, and not 100 % occluded. At baseline, mean total cholesterol 222, LDL cholesterol
146. At end of trial, 24% reduction in LDL cholesterol, 8.5% increase in HDL cholesterol, 10.1% decrease in triglycerides.
Outcome: Coronary arteries and CHD: Reduced progression of atherosclerosis,
with less progression of coronary artery occlusion, and fewer new lesions. Fewer patients had progression, and more had regression.
1. Background, Population Studies:
a. Low HDL cholesterol is a major, common, independent risk factor for coronary heart disease (CHD) and ischemic
stroke, even when total cholesterol levels are normal. Low HDL cholesterol is often associated with high triglyceride levels, but isolated low HDL
cholesterol is common in patients with CHD.
b. Triglycerides are predominantly carried in the blood stream by very low density lipoproteins (VLDL). There
is, however, considerable heterogeneity of triglyceride-rich particles. Triglyceride-rich particles derived from dietary fat, chylomicrons, are not
themselves associated with CHD, but, when very high (>1,000 mg/dl) can cause pancreatitis. However, these chylomicron particles are gradually
reduced in size by lipoprotein lipase to intermediate density lipoproteins (IDL) which are atherogenic. Similarly, VLDL from the liver is reduced in
size by lipoprotein lipase, producing atherogenic IDL. VLDL predicts progression of coronary artery disease and CHD events. Because of the close
relationship of high triglycerides with low HDL cholesterol, triglycerides have not uniformly been shown to be independent risk factors for CHD and
ischemic stroke. However, in a meta-analysis of 14 population-based studies, triglycerides were an independent risk factor for CHD independent of HDL
cholesterol (Arteriosclerosis 1991;11:2-14). In a meta-analysis of 17 population-based studies, elevated triglycerides were associated with a 30%
increase in CHD risk in men and a 75% increase in women (J Cardiovasc Risk 1996;3:213-219). Triglycerides are a major, independent risk factor
for CHD in women (ages 50-69 years) in 14 year follow-up in the Framingham Heart Study (Am J Cardiol 1992;70:3-9).
c. When triglyceride levels are very high (>1,000 mg/dl), then they commonly cause pancreatitis (severe
inflammation of the pancreas), increase the risk of blood clotting, and can cause acute heart attack and stroke.
d. Montreal Heart Study (Circulation 1993;88:2762-2770): VLDL cholesterol, but not LDL cholesterol
predicted progression of coronary artery disease and CHD events.
e. Boston Heart Study (Circulation 1997;96:2520-2525): CHD risk factors in 340 cases with heart attack
and 340 matched community controls. Significant association of elevated triglycerides with CHD, which remained significant after adjustment for HDL
cholesterol. Fasting triglycerides were a significant independent risk factor, particularly when HDL cholesterol levels were also considered.
f. Honolulu Heart Study (Circulation 1995;93:1430-1436): CHD risk was elevated in subjects with low HDL
cholesterol and high triglyceride levels when total cholesterol was borderline high or high, independent of other CHD risk factors.
g. Prospective Munster Study (Am J Cardiol 1996:77:1179-1184): Of >4000 subjects studied
prospectively, 5% of the subjects with triglyceride >200 mg/dl and LDL cholesterol/HDL cholesterol ratio >5.0 had 25% of CHD events.
h. Copenhagen Male Study (Circulation 1998;97:1029-1036): In 8 year follow-up of middle aged and elderly
men, there was a gradient of CHD risk which accompanied increasing triglycerides, even when adjusting for HDL cholesterol.
2. Targets for optimal triglycerides and HDL cholesterol levels:
Triglyceride <250 mg/dl, very low density lipoprotein cholesterol <50 mg/dl.
HDL cholesterol >35 in men, > 40 in women.
3. Causes of High Triglycerides:
a. Genetic. About 1/500 people have an inherited tendency towards high plasma
triglycerides. These inherited hypertriglyceridemias are autosomal dominant traits, so that when high triglycerides are diagnosed and acquired causes
are ruled out (as below), then all first degree family members (parents, siblings, children) should be checked. Triglycerides are predominantly
transported by very low density lipoproteins (VLDL) and by larger, predominantly diet-derived particles, chylomicrons. The majority of people with
inherited high triglycerides have triglycerides carried predominantly by VLDL, and usually have triglycerides <750 mg/dl. When people with
inherited high triglycerides have both high VLDL and chylomicron triglycerides, then the triglyceride levels are often >1,000.
b. Acquired. The five most common causes of acquired high triglycerides are excessive alcohol intake, exogenous
estrogens or estrogen agonists, poorly controlled diabetes, beta blocker drugs, and corticosteroids. Very often when triglycerides are >1,000 mg/dl, these very high levels reflect an acquired cause for high triglycerides superimposed on a genetic cause. Less common causes of
acquired high triglycerides include kidney failure, nephrotic syndrome, albuminuria, hypothyroidism, many liver diseases, hemochromatosis,
hyperparathyroidism, and glycogen storage disease.
4. Causes of low HDL cholesterol:
a. Genetic. About 1/500 people have an inherited tendency towards isolated
low HDL cholesterol, usually with normal total cholesterol, triglycerides, and LDL cholesterol. The inherited low HDL is mostly transmitted as an
autosomal dominant trait, so that when low HDL cholesterol is diagnosed and acquired causes are ruled out (as below), then all first degree family
members (parents, siblings, children) should be checked.
b. Acquired. Anything which causes acquired high triglycerides will usually
also cause low levels of HDL cholesterol. Isolated low HDL cholesterol can be acquired secondary to cigarette smoking (or exposure to secondhand
smoke), to severe physical inactivity, or to excessive zinc intake.
5. Interventions to lower triglyceride levels:
a. Triglyceride >1,000 mg/dl: Dangerous, high risk of pancreatitis, venous and arterial blood clots,
acute heart attack and stroke. Requires immediate intervention with fat-free diet (<5% of calories as fat), alcohol-free diet, medications (Lopid
1.5 g/day or Fenofibrate 200-300 mg/day), omega-3 fatty acids (8-12 g/day), and control of secondary factors (alcohol, exogenous estrogens, estrogen
agonists, corticosteroids, etc).
b. Triglyceride 750-1,000 mg/dl. Dangerous, requires immediate intervention with low fat diet (<20% of
calories as fat), alcohol-free diet, medications (Lopid 1.2 g/day or Fenofibrate 200-300 mg/day), omega-3 fatty acids (4-8 g/day), and control of
secondary factors (alcohol, exogenous estrogens, estrogen agonists, corticosteroids, etc).
c. Triglyceride 500-750 mg/dl. Requires intervention with low fat diet <25% of calories), alcohol-free
diet, medications (Lopid 1.2 g/day or Fenofibrate 200-300 mg/day), omega-3 fatty acids (4-6 g/day), and control of secondary factors (alcohol,
exogenous estrogens, estrogen agonists, corticosteroids, etc).
d. Triglyceride 250-500 mg/dl. Requires intervention with diet and, if values do not fall below 250 mg/dl
on diet alone, medications (Lopid 1.2 g/day or Fenofibrate 200-300 mg/day or, particularly if LDL cholesterol is >130 mg/dl, Lipitor 10-40 mg/day,
or Zocor 10-40 mg/day), omega-3 fatty acids (2-4 g/day), and control of secondary factors (alcohol, exogenous estrogens, estrogen agonists,
corticosteroids, etc).
General Comment: Weight loss, avoidance of alcohol, and tight control of
diabetes (fasting blood sugar <130, HgAIC <7.1) are very important in control of high plasma triglycerides, in addition to other therapies noted
above.
6. Interventions to raise HDL cholesterol levels
a. Cessation of smoking, weight loss, tight control of diabetes (fasting blood glucose <130 mg/dl, HgAIC
<7.1%), increased aerobic exercise (usually requires 5 sessions/week, 30 minutes/session).
b. Gemfibrozil 1.2 g/day, micronized Fenofibrate 200 mg/day, NiaSpan 1.5 g/day.
c. If HDL cholesterol levels cannot be elevated, then vigorous lowering of LDL cholesterol with statin drugs (as
recently shown in the Afcaps/Texcaps study), by improving the ratio of total cholesterol/HDL cholesterol, will reduce CHD events.
7. Controlled clinical trials:
a. Helsinki Heart Study (Circulation 1992;85:37-45): Primary prevention (patients had no previous CHD).
Five year randomized, double-blind, placebo-controlled study in 4081 middle aged men. Total CHD endpoints fell by 34% in the Gemfibrozil treatment
group compared to placebo (p<.05). In patients with HDL cholesterol < 35 mg/dl, there was a 62% reduction in CHD. Gemfibrozil (Lopid, 1.2 g/day)
reduced CHD in patients with triglyceride >200 mg/dl (2.3 mmol/L) and a LDL cholesterol/HDL cholesterol ratio >5. The change in HDL cholesterol
alone was a significant, independent variable for reduction of CHD events (p<.01). Gemfibrozil reduced triglyerides 62%, and increased HDL
cholesterol 25%. Gemfibrozil's effect on CHD events was most pronounced in those with low initial HDL cholesterol (<42 mg/dl).
b. Bezafibrate Coronary Atherosclerosis Intervention Trial (Lancet 1996;347:849-853): Secondary
prevention in 92 young (<45 years old) survivors of myocardial infarction. Randomized to Bezafibrate or placebo, followed for 5 years. In treated
group, there was a 26% reduction in VLDL triglyceride, a 9% increase in HDL-C; LDL cholesterol was not changed. Bezafibrate slowed progression of
coronary artery stenosis (blockage) and reduced CHD events by 72%.
c. Lipid Coronary Angiography Trial (LOCAT) (Circulation 1997;96:2137-2143):
Studies done in 372 patients, randomized to Gemfibrozil or placebo, with 2 angiograms separated by 32 months. Patients
with LDL cholesterol >174 mg/dl, triglycerides > 354, or HDL cholesterol >43 mg/dl were excluded, so that the study was done in a low HDL,
mildly hypertriglyceridemic population. Coronary artery disease progression was reduced in native vessels and in grafts. Compared to placebo, VLDL
triglycerides fell 40% and HDL cholesterol rose 15%. The treatment benefit in LOCAT was related to reduced VLDL, alterations in size and
characteristics of LDL, and increased HDL.
General: Fibrates lower triglyceride-rich lipoproteins, and increase HDL
cholesterol, while reducing levels of dense LDL. There is usually an increase in lipolysis of triglyceride-rich lipoproteins and reduction of hepatic
triglyceride production. Third generation fibrates like Fenofibrate also may moderately lower the atherogenic Lp(a), and also lower fibrinogen.
