Introduction — Lipids, such as cholesterol and triglycerides, are fats that are an integral part of cells, and that may dissolve in alcohol, but are insoluble in water. They are thus insoluble in the blood. In order for lipids to be transported in blood, they are packaged as lipoprotein. Lipoproteins have a shell of phospholipids and proteins that allow them to dissolve in blood. The lipids, transported as lipoprotein, are transported to various tissues for energy utilization, lipid deposition, steroid hormone production, and bile acid formation.
High
cholesterol is a major modifiable risk factor for cardiovascular diseases, and
it is essential that the informed consumer understand the importance of an
elevated cholesterol, as a risk factor for cardiovascular diseases; target
levels of cholesterol that may necessitate treatment of high cholesterol
levels; and treatments available to lower blood cholesterol levels. In this
High Cholesterol Knol these topics will be reviewed.
TWO PATHWAYS CONTRIBUTE TO BLOOD CHOLESTEROL LEVELS —
Lipoprotein metabolism
involves two pathways: exogenous, or originating outside of the blood system,
and endogenous, referring to those originating within the blood system.
EXOGENOUS
PATHWAY OF LIPID METABOLISM — The exogenous pathway starts with the intestinal
absorption of dietary cholesterol and fatty acids (1).
Within the intestinal cell, free fatty acids combine with glycerol to form triglycerides (and cholesterol is esterified), to form cholesterol esters. Triglycerides and cholesterol are packaged intracellularly as chylomicrons. The main apolipoprotein is B-48, but C-II and E are acquired as the chylomicrons enter the circulation. Apolipoprotein B-48 permits lipid binding to the chylomicron.
ENDOGENOUS
PATHWAY OF LIPID METABOLISM — The endogenous pathway starts with the synthesis
of VLDL by the liver. (1)
Figure 1
Cholesterol
Levels Are Affected by Multiple Organ Systems:
Net
Cholesterol Balance in Humans
VLDL
particles contain a core of triglycerides (60 percent by mass) and cholesterol
esters (20 percent by mass). The surface apolipoproteins for VLDL include
apolipoprotein C-II which acts as an activator or cofactor for lipoprotein
lipase, apolipoprotein C-III which inhibits the LPL enzyme, and apolipoprotein
B-100 and E which serve as recognition sites or ligands for the apolipoprotein
B/E (LDL) receptor.
Low
density lipoprotein — LDL particles contain a core of cholesterol esters,
lesser amounts of triglyceride, and are enriched in apolipoprotein B-100, which
is the ligand for binding to the apolipoprotein B/E (LDL) receptor. LDL can be
internalized by hepatic and nonhepatic tissues. Hepatic LDL cholesterol can be
converted to bile acids and secreted into the intestinal lumen. LDL cholesterol
internalized by nonhepatic tissues can be used for hormone production, cell
membrane synthesis, or stored in the esterified form.
Circulating
LDL can also enter macrophages and some other tissues through the unregulated
scavenger receptor. This pathway can result in excess accumulation of
intracellular cholesterol and the formation of cholesterol-enriched cells
(called foam cells) that contribute to the formation of fatty deposits,
inflammatory cells and smooth muscle cells in the lining of the arteries,
called atheromatous plaques.
Lipoprotein(a)
— Lipoprotein(a) or Lp(a) is a specialized form of LDL that is assembled
extracellularly from apolipoprotein (a) and LDL. Apolipoprotein (a) is bound to
apolipoprotein B-100 on the surface of LDL by disulfide bridges.
LIPOPROTEINS
AND ATHEROSCLEROSIS — Abnormal lipoprotein metabolism is a major predisposing
factor to atherosclerosis. Atherosclerosis is one form of hardening of the
arteries that involves large arteries. This disorder of large arteries is
responsible for most arterial disease in industrialized societies. The clinical
complications of atherosclerosis may lead to heart attack, stroke, lower
extremity arterial disease and aneurysms.
Low
density lipoprotein —Elevated plasma concentrations of apolipoprotein B-100
containing lipoproteins can induce the development of atherosclerosis even in
the absence of other risk factors.
When
LDL-cholesterol (LDL-C) levels are increased, unregulated uptake via the
scavenger pathway leads to excess accumulation of modified LDL within
macrophages [1]. Foam cells can rupture, releasing oxidized LDL, intracellular
enzymes, and oxygen free radicals that can further damage the vessel wall.
Oxidatively
modified LDL can cause disruption of the endothelial cell surface and impairs
endothelial function, reducing the release of nitric oxide (NO), which is a
major mediator of endothelium-dependent vasodilation. In addition, oxidized LDL
induces programmed cell death of vascular smooth muscle and endothelial cells.
High levels of cholesterol also increase endothelial production of oxygen free
radicals, which may bind to and inactivate NO.
DISORDERS
OF CHOLESTEROL METABOLISM — There are a variety of different lipid disorders
(dyslipidemias) that can occur as either a primary event or secondary to some
underlying disease. The primary dyslipidemias are associated with overproduction
and/or impaired removal of lipoproteins. The latter defect can be induced by an
abnormality in either the lipoprotein itself or in the lipoprotein receptor.
There are a number of different disorders of LDL metabolism, which vary
according to the underlying defect and the clinical presentation.
IDENTIFICATION OF PATIENTS AT RISK FOR CORONARY HEART DISEASE
ATP III
recommendations for risk assessment — The Third Report of the Expert Panel on
Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel III, or ATP III) recommendations for the treatment of
hypercholesterolemia are based upon the LDL-C fraction and are influenced by
the presence of Coronary Heart Disease (CHD) and the number of cardiac risk
factors [2]. There are five major steps to determining an individual's risk
category, which serves as the basis for the treatment guidelines.
Step 1
—Obtain a fasting lipid profile. The lipid profile is ordered by the health
care practitioner. The lipid profile should be obtained in the fasting state or
a minimum of 12 hours after the last meal. The measurement of blood lipids on
fasting samples minimizes the acute effects of diet on increasing blood
triglyceride levels that may distort the LDL-C calculation. Other important
considerations that ensure accuracy of the lipid profile should minimize
changes in blood volume that result from vigorous exercise before the test,
excess dehydration that may occur on a hot humid day, and prolonged standing as
you wait for the test. The last consideration is the effects of inflammation on
the blood lipids and lipoproteins. If you have an infection (cold virus,
bacterial or fungal infection), surgery, major physical trauma or a recent
heart attack, the fasting lipid profile should be deferred until six weeks
after those conditions have resolved.
From the
measured total cholesterol, triglycerides and HDL cholesterol, calculate the
LDL-C fraction according to the formula:
LDL-C =
Total cholesterol – VLDL-C (estimated as 0.2x triglyceride) – HDL-C
The
formula is considered valid when levels are less than 400mg/dL (4.52mmol/L);
when the fasting triglyceride levels are >400mg/dL (4.52mmol/L) the LDL-C
may be measured by direct methods.
Step 2
—Establish the presence of CHD equivalents. These CHD risk factors that place
the patient at similar risk for CHD events as a history of CHD itself. These
risk equivalents include [2]:
• Diabetes mellitus
• Symptomatic carotid artery disease
• Peripheral arterial disease
• Abdominal aortic aneurysm
• Multiple risk factors that confer a
10-year risk of CHD >20 percent (refer to “Step 4”.
Although
not specifically identified by ATP III as CHD equivalents, chronic renal
insufficiency (defined by a plasma creatinine concentration that exceeds 1.5
mg/dL [133 µmol/L] or an estimated glomerular filtration rate that is < 60
mL/min per 1.73 m2) is considered to be a CHD equivalent by other professional
societies.
Step 3 —
Major CHD factors other than LDL-C are identified:
• Age (men ≥45 years, women ≥55
years)
• Cigarette smoking
• Hypertension (BP ≥140/90 or taking
antihypertensive medication)
• Low HDL-cholesterol (HDL-C) (<40
mg/dL [1.03 mmol/L])
• Family history of premature CHD (in
males first degree relatives <55 years, in females first degree relative
<65 years)
HDL-C
≥60 mg/dL (1.55 mmol/L) counts as a "negative" risk factor; its
presence removes one risk factor from the total count. (see HDL Knol)
Step 4 —
If two or more risk factors other than LDL-C (as defined in step 3) are present
in a patient without CHD or a CHD equivalent (as defined in step 2), the
10-year risk of CHD is assessed using the ATP III modification of the
Framingham risk - (www.nhlbi.nih.gov). The risk score does not need to be
assessed in people without CHD who have 0 to 1 risk factors since individuals
in this category have a 10-year risk of CHD that is <10 percent.
The
Framingham CHD predictor has been validated for prediction of CHD events in
white men and women and black men and women, but it overestimated risk among
Japanese American, Hispanic men, and Native American women [3]. Several studies
have suggested that the Framingham criteria also overestimated the risk in
European and Asian populations [4,5].
Step 5
—The last step in risk assessment is to determine the risk category that
establishes the LDL-C goal, when to initiate therapeutic lifestyle changes, and
when to consider drug therapy as shown in - 1 and 2.
- 1
ATP III
LDL-C goals and cutpoints for therapeutic lifestyle changes and drug therapy in
different risk categories [2]
* CHD
risk equivalents defined in text. Ten-year risk is defined by Framingham risk
score (see text).
•Some
authorities recommend use of LDL-C lowering drugs in this category if LDL-C
<100 mg/dL (2.58 mmol/L) cannot be achieved by therapeutic lifestyle
changes. Others prefer use of drugs that primarily modify triglycerides and
HDL-C (e.g., nicotinic acid or fibrate). Clinical judgment may also call for
deferring drug therapy in this subcategory.
†Risk
factors that modify LDL-C goals include cigarette smoking; hypertension (BP
140/90 mmHg or on antihypertensive medication); low HDL-C mg/dL [1.03 mmol/L]);
family history of premature CHD (CHD in male first degree relative <55 years
or CHD in female first degree relative <65 years); age (men 45 years; women
55 years). HDL-C >60 mg/dL (>1.55 mmol/L) counts as a negative risk
factor; its presence removes one risk factor from the total count.
◊Almost
all people with 0 to 1 risk factor have a 10-year risk <10 percent; thus,
10-year risk assessment in people with 0 to 1 risk factor is not necessary.
- 2
Proposed
modification of ATP III LDL-C goals and cutpoints for therapeutic lifestyle
changes and drug therapy in different risk categories [6]
* When
LDL-C lowering drug therapy is given, it is advised that the intensity of
therapy be sufficient to achieve at minimum a 30 to 40 percent reduction in
LDL-C level.
•CHD
risk equivalents include noncoronary forms of atherosclerotic disease (peripheral
arterial disease, abdominal aortic aneurysm, and carotid artery disease), and
diabetes. Ten-year risk defined by modified Framingham risk score.
†Very
high risk favors the optional LDL-C goal of <70 mg/dL (1.82 mmol/L) and, in
patients with high triglycerides, non-HDL-C goal of <100 mg/dL.
◊Any
individual at high or moderately high risk who has lifestyle-related risk
factors (eg, obesity, physical inactivity, hypertriglyceridemia, low HDL-C
[<40 mg/dL (1.04 mmol/L)], or metabolic syndrome is a candidate for
therapeutic lifestyle changes to modify these risk factors independent of LDL-C
level.
§ If
baseline LDL-C is <100 mg/dL (2.58 mmol/L), institution of an LDL-C lowering
drug is an option. This can be combined with a fibrate or nicotinic acid if a
high-risk person has hypertriglyceridemia or low HDL-C (<40 mg/dL (1.04
mmol/L).
¥ Risk
factors that modify LDL-C goals include cigarette smoking; hypertension (BP
140/90 mmHg or on antihypertensive medication)s; low HDL-C (<40 mg/dL [1.03
mmol/L]); family history of premature CHD (CHD in male first degree relative
<55 years or CHD in female first degree relative <65 years); age (men 45
years; women 55 years). HDL-C- 60 mg/dL (>1.55 mmol/L) counts as a negative
risk factor; its presence removes one risk factor from the total count.
Optional
LDL-C goal <100 mg/dL (2.58 mmol/L).
¦ For
moderately high risk persons with LDL-C of 100 to 129 mg/dL (2.58 to 3.35
mmol/L) at baseline or after lifestyle changes, initiation of an LDL-C lowering
drug to achieve an LDL-C <100mg/dL is an option.
**
Almost all people with 0 to 1 risk factor have a 10-year risk <10 percent;
thus, 10-year risk assessment in people with 0 to 1 risk factor is not
necessary.
Therapeutic
lifestyle changes refer to the adaptation of a healthy lifestyle. The main
features of therapeutic lifestyle changes include:
• Reduced intake of saturated and
trans fats to less than 7 percent of total calories and cholesterol to less
than 200 mg daily.
• Increased intake of LDL-C lowering
dietary fibers as found in plant stanols and sterols (2 grams daily) and
viscous soluble fiber (10-25 grams daily)
• Weight reduction in overweight
individuals
• Increased physicial activity.
The
approximate effects of dietary modification on LDL-C reduction are described in
- 3.
- 3
Approximate
and Cumulative LDL Cholesterol Reduction Achievable By Dietary Modification [2]
A more
detailed description of the nutrient content of the therapeutic lifelstyle
changes diet is provided in - 5.
Importance
of other risk factors — A number of other risk factors for CHD have been
suggested by population data, such as obesity, physical inactivity, impaired
fasting glucose, markers for inflammation, and abnormalities of blood clotting
or thrombosis. Since there has been no evidence from controlled trials that
targeting these risk factors improves outcomes, their presence does not
influence current guidelines for cholesterol lowering. Nonetheless, ATP III
suggests that these factors can be used to modify clinical decision-making in
some circumstances [2].
Non-HDL-C
— Non-HDL-C is defined as the difference between the total cholesterol and
HDL-C. Non-HDL-C includes all cholesterol present in lipoprotein particles that
is considered atherogenic, including LDL-C, lipoprotein(a),
intermediate-density lipoprotein, and very-low-density lipoprotein. It has been
suggested that the non-HDL-C fraction may be a better tool for risk assessment
than LDL-C.
ATP III
identifies the non-HDL-C concentration as a secondary target of therapy in
people who have high triglycerides (≥200 mg/dL [2.26 mmol/L]) [2]. The goal for
situation is a concentration that is 30 mg/dL (0.78 mmol/L) higher than that
for LDL-C as show in - 4.
- 4
Non-HDL-C
goals [2]
THERAPIES
— All patients with high LDL-C should undergo lifestyle modifications in an
effort to reduce the serum cholesterol. Many will not reach the goal level of
cholesterol with these measures and will require drug therapy.
Lifestyle
modifications —All patients with high LDL-C should undergo lifestyle
modifications (therapeutic lifestyle changes as stated in ATP III) such as
reductions in dietary total fat and saturated fat as shown in - 5, weight loss
in overweight patients, aerobic exercise, and plant stanols/sterols.
- 5
Nutrient composition of the therapeutic lifestyle changes diet
The
United Kingdom Lipid Clinics Program of 2508 subjects found that, with diet
alone, 60 percent of subjects had a mean reduction in body weight of 1.8
percent, which was associated with 5 to 7 percent reductions in serum total and
LDL-C [7]. Other diets can lower LDL-C by as much as 30 percent.
The
benefits of LDL-C lowering on coronary atherosclerosis may be evident within 6
to 12 months. The individual response to a cholesterol-lowering diet depends
upon many factors that may be genetically determined; an increased body mass
index is associated with less response to dietary change. Patients who are
referred to a dietitian may have greater success in the short term with
lowering LDL-C compared with patients who receive dietary counseling by
physicians, although long-term compliance with dietary therapy is inadequate
for both groups. As a result, there should be no hesitation in beginning a
hypolipidemic drug regimen in patients who fulfill the criteria described
above.
Drug
therapy — Lipid-altering agents encompass several classes of drugs that include
statins, fibric acid derivatives, bile acid sequestrants, nicotinic acid, and
cholesterol absorption inhibitors (eg, ezetimibe). These drugs differ with
respect to mechanism of action and with respect to the degree and type of lipid
lowering. Thus, the indications for a particular drug are influenced by the
underlying lipid abnormality. Conventional dosing regimens and common adverse
reactions are described in - 6.
- 6
Dose,
side effects, and drug interactions of lipid lowering drugs
*BID:
twice daily; QD: daily; TID: three times daily; SR: sustained release; CrCl:
creatinine clearance.
**A
micronized formulation of fenofibrate (145mg daily) may be taken without meals.
The
range of expected changes in the lipid profile are listed in - 7.
- 7
Average
effects of different classes of lipid lowering drugs on serum lipids
↑:
Increase; ↓: Decrease.
* Serum
triglyceride levels may increase in patients with preexisting
hypertriglyceridemia (triglycerides 200mg/dL or 2.26mmol/L).
The
statins are the only class of drugs to demonstrate clear improvements in
overall mortality in primary and secondary prevention; follow-up from a
clinical trial of niacin suggested some mortality benefits in secondary
prevention [8]. Large trials of cholestyramine, clofibrate, and gemfibrozil in
primary prevention not only failed to show mortality benefits but showed worrisome
trends toward an increase in non-cardiac deaths. A large trial of fenofibrate
in patients with diabetes (some of whom had known cardiovascular disease) found
a non-significant increase in overall mortality [9]. A large trial of
gemfibrozil in secondary prevention also failed to show any improvement in
overall mortality, although cardiac mortality was reduced [10].
As such,
statins are the first choice in virtually all patients with
hypercholesterolemia in whom the goal is reduction of primary or secondary
cardiovascular risk. If goal LDL-C levels cannot be attained with the use of a
statin alone, it is uncertain whether the addition of other agents such as
ezetimibe provides additional clinical benefit, even though LDL-C levels can be
reduced further. This issue is discussed in detail separately.
Statins
— Statins inhibit the rate limiting step in cholesterol production,
hydroxyl-methyl-coenzyne A (HMG-CoA) reductase, and through negative feeback
loops secondarily increase expression of LDL receptors on hepatic cells. The
LDL particles are recognized by LDL receptors that allows for their uptake by
the liver, exretion into bile and subsequently stool.The statins are the most
commonly used drugs in the treatment of hypercholesterolemia. They are the most
powerful drugs for lowering LDL-C, with reductions in the range of 20 to 60
percent.
Fibrates
— Fibrates have modest effects on LDL-C that is considered to occur from a
shift in the distribution of small dense LDL particles to large buoyant LDL
particles that are more easily taken up by the LDL receptors. The major effects
of the fibrates are to lower plasma triglyceride and raise HDL-C levels. They
are effective for the treatment of hypertriglyceridemia and combined
hyperlipidemia with or without low HDL-C or hypoalphalipoproteinemia. There is
an increased risk of muscle toxicity in patients t aking a fibrate and a
statin.
Nicotinic
acid — Nicotinic acid acts in the liver to reduce production of VLDL
apolipoprotein B and VLDL triglyceride. These VLDL components are processed to
LDL particles as desribed earlier in the section Exogenous pathways of
cholesterol metabolism. Nicotinic acid is effective in patients with
hypercholesterolemia and in combined hyperlipidemia associated with normal and
low levels of HDL-C (hypoalphalipoproteinemia). Modest VLDL-C and LDL-C
lowering effects can occur at doses of 1.5 to 2.0 g/day, while doses above this
amount (3 g/day) often produce greater effects. The HDL-C raising properties of
nicotinic acid occur with dosages as low as 1 to 1.5 g/day.The use of nicotinic
acid is often limited by poor tolerability.
Ezetimibe
— Ezetimibe blocks a intestinal transporter responsible for active transport of
dietary cholesterol across the wall of the intestine Ezetimibe modestly lowers
the LDL-C when used alone but may have its greatest use in combination with
statins, particularly when high-dose statins are not tolerated or the maximal
tolerated dosage of the statin does not adequately allow the individual to
achieve their minimal accep- LDL-C target as described in - 1 and 2.
Bile
acid sequestrants — Bile acid sequestrants bind the cholesterol enriched bile
acids in the large intestine. Bile acid sequestrants are effective in patients
with mild to moderate elevations of LDL-C. Low doses (8 g/day of cholestyramine
or 10 g/day of colestipol) can reduce LDL-C by 10 to 15 percent. A more
pronounced reduction (about 24 percent) is seen with colesevelam (6 -ts with
dinner). Bile acid sequestrants are also effective when used in combination
with a statin or nicotinic acid in patients with markedly elevated plasma
levels of LDL-C. The use of a bile acid sequestrant is often limited by side
effects.
Monitoring
therapy — There are no reliable data on the optimal method of monitoring the effects
of lipid-lowering therapy. ATP III recommends that the LDL-C be monitored every
six weeks after the initiation of treatment until the LDL-C target is achieved.
Thereafter, measurement every 6 to 12 months is reasonable in patients adherent
to lifestyle modifications.
EFFECTS
OF THERAPY — Cardiovascular benefits of cholesterol lowering with statin drugs
have been demonstrated in various groups, including:
• Patients with CHD, with or without
hyperlipidemia
• Men with hyperlipidemia but no
known CHD
• Men with hypertension and multiple
cardiac risk factors but without hyperlipidemia
• Men and women with average total
and LDL-C levels and no known CHD
The
statins are the only class of drugs to demonstrate clear reductions in overall
mortality in primary (patients with risk factors, but no clinical
manifestations of cardiovascular disease) and secondary prevention (patients
with clinical manifest of cardiovascular disease or anatomical evidence of
atherosclerotic vascular disease). Long-term follow-up from a clinical trial of
niacin suggested some mortality benefits in secondary prevention.
Secondary
prevention — Current ATP guidelines for LDL-C lowering in patients with
existing CHD are more aggressive than those issued previously. This reflects a
better understanding of both the high risk conferred by the presence of CHD and
the impact of cholesterol lowering in these patients. Men and women with CHD
patients have a risk of myocardial infarction that is 20 times higher than
those without CHD [figure 2].
Figure 2
[11]
Rate of
Myocardial Infarction Among Patients With and Without CHD Stratified by Total
Cholesterol Concentration
Large
trials have demonstrated that lipid lowering is beneficial in patients with
CHD. A meta-analysis of 34 trials that looked at the use of statins and other
therapies to reduce cholesterol levels in approximately 25,000 subjects with
CHD found that cholesterol-lowering therapy was associated with a 13 percent
reduction in mortality risk but no change in non-cardiovascular deaths [12].
Lipid
lowering therapy reduced coronary revascularization events by 24 percent
(Figure 3), stroke events were reduced by 19 percent [13] (Figure 4).
Figure 3
Association
Between Reductions in LDL-C and CHD Events
Figure 4
Association
Between Reductions in LDL-C and Stroke
Timing
of therapy — Drug therapy should not be postponed if the target for LDL-C
lowering is unlikely to be achieved in the near term by nonpharmaceutical
approaches [2]. A proposal from the Coordinating Committee of the National
Cholesterol Education Program (NCEP) makes a similar recommendation to initiate
drug therapy at the same time as lifestyle changes whenever the LDL-C is ≥100
mg/dL (2.6 mmol/L) [6]. The statin dose should be adjusted every four to six
weeks to achieve the goal.
Patients
with an acute myocardial infarction should be started on a statin during
hospitalization [14].
Intensity
of therapy — The appropriate goal LDL-C in patients with CHD or CHD equivalents
being treated for secondary prevention has been debated and the recommendations
were made for more aggressive LDL-C target for certain subsets of very high
risk patients as shown in - 8.
- 8
Definition
of "very high risk" in NCEP guidelines [6]
Subsequently,
there has been emergent clinical trial evidence to support a more intensive
LDL-C lowering with statin agents in s- CHD patients with the metabolic
syndrome and type 2 diabetes as shown in figure 5 [15]. The metabolic syndrome
is a constellation of risk markers that are associated with high future risk of
type 2 diabetes and cardiovascular disease. The diagnosis of the metabolic
syndrome requires the presence of at least 3 of the the following 5 risk
markers: central obesity (waist circumference ≥40 inches(104 cm) in men or ≥35
inches (90 cm) in women; elevated fasting triglyceride ≥150 mg/dL (1.69
mmol/L); low HDL cholesterol (<35 mg/dL in men or <40 mg/dL in women); elevated
blood pressure (systolic blood pressure ≥135 and/or diastolic blood pressure
≥85 mm Hg or treatment with blood pressure lowering medications); elevated
fasting blood glucose ≥100 mg/dL (5.55 mmol/L). [16] The recommendation for
more intensive LDL-C lowering in smokers cannot be supported by available
randomized clinical trials.
Figure 5
Prevalence
of Patients with Major Cardiovascular Events in S- CHD Patients Stratified by
Metabolic Syndrome and Diabetes Status [14]
Intensive
statin therapy with atorvastatin 80 mg daily reduces mortality in patients with
an acute coronary syndrome and is recommended as initial therapy. Given the
early benefits, patients should be started on atorvastatin 80 mg daily early in
their hospital course (Figure 6) [17].
The American
Heart Association/American College of Cardiology guidelines for management of
patients with uns- angina/non-ST-elevation myocardial infarction recommends
diet modification and statin therapy in all patients, including post
revascularization, regardless of baseline LDL-C [18].
Figure 6
All-Cause
Death or Major CV Events in All Randomized Subjects [18]
Patients
at very high risk for CHD events such as those in the proposed NCEP guidelines
might also be expected to benefit from more intensive lipid lowering therapy.
We recommend that such patients be treated with the lowest dose of a statin
that reduces their LDL-C below 70 mg/dL (2.5 mmol/L). If such patients cannot
achieve an LDL-C below 100 mg/dL (2.6 mmol/L) with a statin alone, the addition
of a second lipid-lowering agent is conventionally implemented. Clinical trial
evidence that provides support for the use of two lipid lowering agents to
lower LDL-C below 100 mg/dL (2.6mmol/L) despite high-dose statin therapy is
under investigation.
Among
patients with s- CHD who do not tolerate a statin at the lowest available
dosage, treatment with another class of lipid-lowering agents should be
instituted even in the absence of clinical trial data. Side effects of statins
that would prompt selection of a different class of lipid lowering therapy
include muscle aches, weakness or damage or a more than 3 fold elevation in
liver enzymes verified on repeat testing. Other common side effects of statins
are described in - 7. Further in patients with s- CHD who have not been able to
adhere to their goal LDL-C with a statin alone, the use of a second agent in
such patients is recommended.
The
serum LDL-C concentration and risk factor status determine the suggested
approach under ATP-III guidelines. Cardiovascular risk assessment is an
essential requirement for the judicious use of cholesterol-lowering therapies
in primary prevention of CHD. As mentioned above, diabetes mellitus is
considered a CHD equivalent and therefore patients with diabetes do not fall
within the category of primary prevention as described in - 1 and 2.