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

Can Cholesterol Levels Be Lowered Too Much? Are there total and
LDL cholesterol levels below which adverse health consequences
begin to increase? Observational studies initially were confusing. In
the U.S. and western Europe, low cholesterol levels were associated
with an increase in noncardiac mortality from chronic pulmonary
disease, chronic liver disease, cancer (many primary sites), and hemorrhagic
stroke; subsequent data indicate that it is the noncardiac
diseases that cause the low plasma cholesterol levels and not the
reverse. One exception may be hemorrhagic stroke. In the Multiple
Risk Factor Intervention Trial (MRFIT), hemorrhagic stroke
occurred more frequently in hypertensive patients with total cholesterol
levels <160 mg/dL; however, the increased incidence of hemorrhagic
stroke was more than offset by reduced CHD risk due to
the low cholesterol levels. A recent meta-analysis of statin efficacy
in preventing recurrent stroke found an increase in the risk of subsequent
hemorrhagic stroke among patients with a prior hemorrhagic
stroke who also received a statin. However, the risk of atherothrombotic
stroke was reduced in proportion to the degree of cholesterol
lowering by statin therapy (Amarenco and Labreuche, 2009).
Abetalipoproteinemia and hypobetalipoproteinemia, two rare
disorders associated with extremely low total cholesterol levels, are
instructive because affected individuals have reduced CHD risk and
no increase in noncardiac mortality. Patients who are homozygous
for the mutations that cause these disorders have total cholesterol
levels <50 mg/dL and triglyceride levels <25 mg/dL. With the
advent of more efficacious cholesterol-lowering agents, it has been
possible to test the benefits and risks of lowering LDL-C levels
<50 mg/dL (Ridker et al., 2008). Lower LDL-C levels translate into
greater reductions in clinical events without any increase in adverse
events.
Treatment of Type 2 Diabetes Patients
Diabetes mellitus is an independent predictor of high
risk for CHD. CHD morbidity is two to four times
higher in patients with diabetes than in nondiabetics.
Glucose control is essential but provides only minimal
benefit with respect to CHD prevention. Aggressive
treatment of diabetic dyslipidemia through diet, weight
control, and drugs is critical in reducing risk.
Diabetic dyslipidemia usually is characterized by high
triglycerides, low HDL-C, and moderate elevations of total cholesterol
and LDL-C. In fact, diabetics without diagnosed CHD have the
same level of risk as nondiabetics with established CHD. Thus, the
dyslipidemia treatment guidelines for diabetic patients are the same
as for patients with CHD, irrespective of whether the diabetic patient
has had a CHD event (The Expert Panel, 2002). The American
Diabetes Association recommends new lipid therapy targets for diabetics.
In addition to targets for LDL-C and non-HDL-C, two targets
for total plasma apoB were established based on the level of
CVD risk (Brunzell et al., 2008).
Clinical trials with statins have clearly established that total
and vascular disease mortality are reduced in diabetics as a consequence
of prevention of CVD events (Cholesterol Treatment
Trialists’ Collaborators, 2008). A recently completed trial comparing
statin therapy to statin plus fenofibrate therapy will provide the first
outcome data for statin plus fibrate combination therapy in type 2
diabetes patients (Ginsberg et al., 2007).
Metabolic Syndrome
There is an increased CHD risk associated with the
insulin-resistant, prediabetic state described under the
rubric of “metabolic syndrome.” This syndrome consists
of a constellation of five CHD risk factors (Table 31–8).
Of the five risk factors, abdominal obesity is defined by ethnicspecific
values of abdominal waist circumference (Alberti et al.,
2009). An alternative to assessing the five criteria that identify the
metabolic syndrome is to determine the ratio of the concentrations
of fasting triglycerides divided by the HDL-C. Values >3.5 predict
insulin resistance as effectively as meeting the criteria for diagnosing
metabolic syndrome (McLaughlin et al., 2005). The prevalence
of metabolic syndrome among patients with premature vascular disease
may be as high as 50%. Treatment should focus on weight loss
and increased physical activity, because being overweight or obese
usually precludes optimal risk factor reduction. Specific treatment of
increased LDL-C, non-HDL-C, and triglyceride levels and low
HDL-C levels also should be undertaken.
Table 31–8
Clinical Identification of the Metabolic Syndrome
RISK FACTOR
Abdominal obesity a
Men
Women
Triglycerides
HDL-C
Men
Women
Blood pressure
Fasting glucose
DEFINING LEVEL
Waist circumference b
>102 cm (>40 in)
>88 cm (>35 in)
≥150 mg/dL
<40 mg/dL
<50 mg/dL
≥130/≥85 mm Hg
>100 mg/dL b
The 2001 National Cholesterol Education Program (NCEP) guidelines
define the metabolic syndrome as the presence of three or more
of these risk factors.
a
Overweight and obesity are associated with insulin resistance and
the metabolic syndrome. However, the presence of abdominal obesity
is more highly correlated with the metabolic risk factors than is
an elevated body mass index. Therefore, the simple measurement of
waist circumference is recommended to identify the body weight
component of the metabolic syndrome.
b
Some male patients can develop multiple metabolic risk factors
when the waist circumference is only marginally increased (e.g.,
94-102 cm [37-39 inches]). Such patients may have a strong genetic
contribution to insulin resistance, and like men with categorical
increases in waist circumference, they should benefit from changes in
life habits. There is ethnic variation in the values of waist circumference
that define abdominal obesity (Alberti et al., 2009). HDL-C,
high-density-lipoprotein cholesterol. From The Expert Panel, 2002.
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CHAPTER 31
DRUG THERAPY FOR HYPERCHOLESTEROLEMIA AND DYSLIPIDEMIA