DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

risk factors. This pivotal role of hypercholesterolemia in
atherogenesis gave rise to the almost universally
accepted cholesterol-diet-CHD hypothesis: elevated
plasma cholesterol levels cause CHD; diets rich in saturated
(animal) fat and cholesterol raise cholesterol levels;
and lowering cholesterol levels reduces CHD risk.
Although the relationship between cholesterol, diet, and
CHD was recognized nearly 50 years ago, proof that
cholesterol lowering was safe and prevented CHD
death required extensive epidemiological studies and
clinical trials.
Epidemiological Studies. Epidemiological studies have demonstrated
the importance of the relationship between excess saturated fat consumption
and elevated cholesterol levels. Reducing the consumption
of dietary saturated fat and cholesterol is the cornerstone of population-based
approaches to the management of hypercholesterolemia.
In addition, it is clearly established that the higher the cholesterol level,
the higher the CHD risk. However, very high cholesterol levels (values
>300 mg/dL) account for only 5-10% of CHD events. In fact, onethird
of CHD events occur in persons with total cholesterol levels
between 150 and 200 mg/dL (Castelli, 2001). The challenge is how to
identify and treat the 20% of individuals with cholesterol levels
between 150 and 200 mg/dL who will develop CHD.
Clinical Trials. Studies of the efficacy of cholesterol lowering began
in the 1960s, and the results of the earliest trials showed that modest
reductions in total cholesterol and LDL-C were associated with
reductions in fatal and nonfatal CHD events but not total mortality.
It was not until the advent of a more efficacious class of cholesterollowering
drugs, the statins, that cholesterol-reduction therapy was
finally proven to prevent CHD events and reduce total mortality.
Patients benefit regardless of gender, age (above or below 75 years
of age), baseline lipid values, or whether they have a prior history of
vascular disease or type 2 diabetes mellitus (Cholesterol Treatment
Trialists’ Collaborators, 2008; Cholesterol Treatment Trialists’
Collaborators, 2005). Stroke risk is reduced by statin therapy, too,
despite the rather weak relationship between total cholesterol and
LDL-C levels. Statin therapy is effective in preventing first and subsequent
atherothrombotic strokes. Evidence of a benefit or harm of
statin therapy in patients with a prior hemorrhagic stroke is sparse
and requires additional studies. Available studies suggest caution
when considering statin therapy for a patient with hemorrhagic
stroke (Amarenco and Labreuche, 2009).
Results of the clinical trials employing statins demonstrate benefit
without offsetting adverse effects, and the benefit is proportionate
to the extent of the reduction of LDL-C level. Moderate doses of
statins that lower LDL-C levels by about 40% reduce cardiovascular
events by about one-third (Cholesterol Treatment Trialists’
Collaborators, 2005). More intensive regimens that lower LDL-C by
45-50% reduce CVD events by as much as 50% (Cannon et al., 2006).
National Cholesterol Education Program
(NCEP) Guidelines for Assessing Risk
The existing NCEP Adult Treatment Panel (ATP) III
guidelines were formulated in 2001 and updated in
2004 (Grundy et al., 2004b). The key features of the
update include abandoning the concept of a threshold
LDL-C level that must be exceeded before initiating
cholesterol-lowering drug therapy in CHD or CHD
equivalent patients; adopting a new target LDL-C level
(<70 mg/dL) for very high-risk patients; and employing
a “standard statin dose” (a dosage sufficient to lower
LDL-C by 30-40%) as a minimum therapy when initiating
cholesterol-lowering therapy with statins (Grundy
et al., 2004b) (Table 31–3). Subsequently, new information
from clinical trials and new information about
risk assessment has led to a need for a new revision,
ATP IV, which is currently in progress. The new ATP
IV guidelines are expected to be published in 2010.
Revisions that are likely to be included in the ATP IV
guidelines are described in the following discussion.
Risk Assessment. The intensity of treatment of dyslipidemia
is based on the severity of a patient’s risk. The
risk of sustaining a heart attack or stroke or of developing
heart failure in the U.S. is striking. Before death,
two-thirds of men and one-half of all women will be
affected (Lloyd-Jones et al., 2009). Because of this very
high prevalence, it is important that all adults ≥20 years
and high-risk children undergo an assessment of their
risk of developing CVD (Daniels et al., 2008; The
Expert Panel, 2002).
Patients at greatest risk of developing an atherothrombotic
CVD event are those who have had a prior event (myocardial infarction,
acute coronary syndrome, transient ischemic attack, stroke, or
claudication) or who are at high risk because of type 2 diabetes mellitus.
These subjects are at very high risk and require intensive management
of plasma lipids (Table 31–3). Other subjects who have not
had a prior CVD event require assessment of plasma lipid levels and
the other major CVD risk factors to determine if treatment to reduce
lipid-related risk is necessary.
Lipid levels (total cholesterol, triglycerides, LDL-C, HDL-
C, and non-HDL-C) and glucose concentration should be measured
following a fasting period of 10-12 hours. The LDL-C should be calculated
[total cholesterol – (HDL-C) – (triglycerides/5) = LDL-C]
and not measured by any of the “direct” techniques (Mora et al.,
2009). Non-HDL-C is derived as follows: total cholesterol – HDL-C
= non-HDL-C. The classification of plasma lipid values is shown in
Table 31–4.
Measurement of apoA-I and apoB afford better risk prediction
of lipid-related risk than LDL-C and HDL-C. However, lack of
an established national reference laboratory for quality control of
these apolipoprotein assays has precluded formal adoption of apoA-
I and apoB measurements by the NCEP thus far (Contois et al.,
2009; Sniderman, 2009; Sniderman and Marcovina, 2006). Despite
this, targets for apoB levels have been established by the American
Diabetes Association for the management of patients with type 2
diabetes mellitus (Brunzell et al., 2008).
Measurements of lipoprotein fraction concentrations, their
subfractions, and lipoprotein particle diameters also are widely available,
but it is not clear that these tests add to the ability to predict risk
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CHAPTER 31
DRUG THERAPY FOR HYPERCHOLESTEROLEMIA AND DYSLIPIDEMIA