The AHA Guidelines and Scientifi c Statements Handbook
absolute risk of the patient. Guidelines are designed to
provide an appropriate balance among effi cacy,
safety, and cost-effectiveness of therapies, but beyond
this principle, effi cacy for particular subgroups of the
population is not questioned. Not all investigators are
in agreement with this approach. Some would require
that effi cacy and safety be proved for every subgroup
- men and women, younger and older, non-diabetic
and diabetic, each ethnic groups, etc. – before recom-
mendations can be extended to particular subgroups.
This of course is an impossible demand because of
high costs and lack of funding commitment. As a
middle ground, clinical-management recommenda-
tions could be based on either smaller clinical trials,
from subgroup analyses from larger trials, from epi-
demiological evidence, or from many years of clinical
experience in the lipid fi eld. This problem for specifi c
recommendations goes beyond current guidelines for
evidence-based medicine because no rules have ever
been established for applying clinical-trial evidence to
many different subgroups of the population. A rea-
sonable compromise may be to reduce the Level of
Evidence by one grade to an untested subgroup
where evidence is fi rm in a mixed cohort of tested
subjects. The following addresses some of the press-
ing questions about cholesterol management for
which clinical-trial evidence is limited.
Management of specifi c dyslipidemias
Very high LDL cholesterol (≥190 mg/dL)
Persons with very high LDL-C usually have genetic
forms of hypercholesterolemia, i.e., monogenic
familial hypercholesterolemia, familial defective
apolipoprotein B, or polygenic hypercholesterol-
emia. Early detection of these disorders through
cholesterol testing in young adults is needed to
prevent premature CHD [12]. When hypercholes-
terolemic individuals are identifi ed, family testing is
important to detect similarly affected relatives.
These disorders often require combined drug
therapy (statin + bile acid sequestrant) to achieve the
goals of LDL-lowering treatment [1].
Elevated serum triglycerides
Elevated triglycerides have been identifi ed as inde-
pendent risk factor for CHD [13,14].
This fi nding supports the concept that VLDL is
an atherogenic lipoprotein. Beyond an indication of
elevated VLDL-C, high triglycerides raise the possi-
bility of a variety of metabolic disorders or meta-
bolic consequences of drug therapy. Examples
include obesity and overweight, physical inactivity,
cigarette smoking, excess alcohol intake, type 2 dia-
betes, chronic renal failure, nephrotic syndrome,
certain drugs (e.g., corticosteroids, estrogens, reti-
noids, higher doses of beta-adrenergic blocking
agents), and genetic disorders (familial combined
hyperlipidemia, familial hypertriglyceridemia, and
familial dysbetalipoproteinemia). In clinical prac-
tice, elevated serum triglycerides are most often
observed in persons with the metabolic syndrome,
although secondary or genetic factors can heighten
triglyceride levels. ATP III [1] adopts the following
classifi cation of serum triglycerides:- Normal triglycerides: <150 mg/dL
- Borderline-high triglycerides: 150–199 mg/dL
- High triglycerides: 200–499 mg/dL
- Very high triglycerides: ≥500 mg/dL
When triglycerides are in the range of 150 to 499 mg/
dL, they are especially useful as an indicator of a
metabolic disorder. For lipid-management pur-
poses, triglycerides can be subsumed within non-
HDL-C and do not require special clinical attention
as a separate lipid target of therapy. When triglycer-
ides are ≥500 mg/dL, they pose a potential risk for
acute pancreatitis; the higher the triglycerides, the
greater the risk. Most patients with a very high tri-
glyceride will require therapy with a triglyceride-
lowering drug (e.g., fi brate, nicotinic acid, or high
doses of N-3 fatty acids). The goal is to reduce the
level to <500 mg/dL, which will largely eliminate the
risk for pancreatitis. Patients with very high triglyc-
erides should be counseled to consume a very
low-fat diet (<15% of calories as fat). In hypertri-
glyceridemic patients with diabetes, improvement of
glycemic control will facilitate reduction of triglyc-
eride levels, but an underlying genetic dyslipidemia
is commonly present as well.
Low HDL-C
Low levels of HDL-C are strongly associated with risk
for CHD [15]. ATP III guidelines, low HDL-C both
modifi es the goal for LDL-lowering therapy and is
used as a risk factor to estimate 10-year risk for CHD.
Low HDL-C levels have several causes, many of which
are associated with insulin resistance, i.e., elevated tri-
glycerides, overweight and obesity, physical inactivity,
and type 2 diabetes. Other causes are cigarette