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

Drug Therapy for
Hypercholesterolemia
and Dyslipidemia
Thomas P. Bersot
Hyperlipidemia is a major cause of atherosclerosis and
atherosclerosis-induced conditions, such as coronary
heart disease (CHD), ischemic cerebrovascular disease,
and peripheral vascular disease. Although the incidence
of these atherosclerosis-related cardiovascular disease
(CVD) events has declined in the U.S., these conditions
cause morbidity or mortality in a majority of middleaged
or older adults and account for about one-third of
all deaths of persons in this age range. The incidence
and absolute number of annual events will likely
increase over the next decade because of the epidemic
of obesity and the aging of the U.S. population.
Dyslipidemias, including hyperlipidemia (hypercholesterolemia)
and low levels of high-density-lipoprotein
cholesterol (HDL-C), are major causes of increased
atherogenic risk; both genetic disorders and lifestyle
(sedentary behavior and diets high in calories, saturated
fat, and cholesterol) contribute to the dyslipidemias
seen in countries around the world. For many individuals,
alterations in lifestyle have a far greater potential
for reducing vascular disease risk and at a lower cost
than drug therapy. When pharmacotherpy is indicated,
providers can choose from multiple agents with proven
efficacy.
Recognition that dyslipidemia is a risk factor has
led to the development of drugs that modify cholesterol
levels. This chapter focuses on the following classes of
drugs:
• 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-
CoA) reductase inhibitors—the statins
• Bile acid–binding resins
• Nicotinic acid (niacin)
• Fibric acid derivatives
• The cholesterol absorption inhibitor ezetimibe
These drugs provide benefit in patients across the
entire spectrum of cholesterol levels, primarily by
reducing levels of low-density-lipoprotein cholesterol
(LDL-C).
In early well-controlled clinical trials employing
drug regimens that reduce LDL-C levels moderately
(30-40%), fatal and nonfatal CHD events and strokes
were reduced by as much as 30-40% (Grundy et al.,
2004b). Clinical trial data support extending lipidmodifying
therapy to high-risk patients whose major
lipid risk factor is a reduced plasma level of HDL-C,
even if their LDL-C level does not meet the existing
threshold values for initiating hypolipidemic drug therapy
(Grundy et al., 2004b). In patients with low HDL-
C and average LDL-C levels, appropriate drug therapy
reduced CHD endpoint events by 20-35% (Heart
Protection Study Collaborative Group, 2002). Because
two-thirds of patients with CHD in the U.S. have low
HDL-C levels (<40 mg/dL in men, <50 mg/dL in
women), it is important to include low-HDL-C patients
in management guidelines for dyslipidemia, even if
their LDL-C levels are in the normal range (Bersot
et al., 2003).
Severe hypertriglyceridemia (i.e., triglyceride levels
of >1000 mg/dL) requires therapy to prevent pancreatitis.
It is unclear whether hypertriglyceridemia is an
independent risk factor for developing atherothrombotic
CVD (Sarwar et al., 2007). Moderately elevated triglyceride
levels (150-400 mg/dL) are of concern because
they often occur as part of the metabolic syndrome,
which includes insulin resistance, obesity, hypertension,
low HDL-C levels, a procoagulant state, and substantially
increased risk of CVD. The atherogenic dyslipidemia
in patients with the metabolic syndrome also is
characterized by lipid-depleted LDL (sometimes referred