Hyperlipidemia

General Outline
• Definition of hyperlipidemia
• Pathophysiology
• Clinical presentation
• Diagnosis
• Desired outcomes
• Treatment
Non-pharmacologic therapy
Pharmacologic therapy
Treatment recommendations
Treatment of hypertriglyceridemia, low HDL, and diabetic dyslipidemia
• Evaluation of therapeutic outcomes
 Definition
• Elevated total cholesterol, low-density lipoprotein(LDL)
cholesterol, or triglycerides
• A low high-density lipoprotein(HDL) cholesterol
• or A combination of these abnormalities.
• describes an increased concentration of the lipoprotein
macromolecules that transport lipids in the plasma.
• Abnormalities of plasma lipids can result in a
predisposition to coronary, cerebrovascular, and
peripheral vascular arterial disease.
 pathophysiology
• Cholesterol, triglycerides, and phospholipids are transported
in the bloodstream as complexes of lipid and proteins known
as lipoproteins.
• Elevated total and LDL cholesterol and reduced HDL
cholesterol are associated with the development of coronary
heart disease (CHD).
• The response-to-injury hypothesis states that risk factors such
as oxidized LDL, mechanical injury to the endothelium,
excessive homocysteine, immunologic attack, or infection-
induced changes in endothelial and intimal function lead to
endothelial dysfunction and a series of cellular interactions
that culminate in atherosclerosis. The eventual clinical
outcomes may include angina, myocardial infarction,
arrhythmias, stroke, peripheral arterial disease, abdominal
 Clinical presentation
• Familial hypercholesterolemia is characterized by a selective elevation in plasma LDL and deposition of LDL-derived cholesterol
in tendons (xanthomas) and arteries (atheromas).
• Familial lipoprotein lipase deficiency is characterized by a massive accumulation of chylomicrons and a corresponding increase
in plasma triglycerides or a type I lipoprotein pattern. Presenting manifestations include repeated attacks of pancreatitis and
abdominal pain, eruptive cutaneous xanthomatosis, and hepatosplenomegaly beginning in childhood. Symptom severity is
proportional to dietary fat intake, and consequently to the elevation of chylomicrons. Accelerated atherosclerosis is not
associated with this disease.
• Patients with familial type III hyperlipoproteinemia develop the following clinical features after age 20: xanthoma striata
palmaris (yellow discolorations of the palmar and digital creases); tuberous or tuberoeruptive xanthomas (bulbous
cutaneous xanthomas); and severe atherosclerosis involving the coronary arteries, internal carotids, and abdominal aorta.
• Type IV hyperlipoproteinemia is common and occurs in adults, primarily in patients who are obese, diabetic, and hyperuricemic
and do not have xanthomas. It may be secondary to alcohol ingestion and can be aggravated by stress, progestins, oral
contraceptives, thiazides, or β-blockers.
• Type V is characterized by abdominal pain, pancreatitis, eruptive xanthomas, and peripheral polyneuropathy. These patients are
commonly obese, hyperuricemic, and diabetic; alcohol intake, exogenous estrogens, and renal insufficiency tend to be
exacerbating factors. The risk of atherosclerosis is increased with this disorder.
 Diagnosis
• A fasting lipoprotein profile including total cholesterol, LDL, HDL, and triglycerides should be
measured in all adults 20 years of age or older at least once every 5 years.
• Measurement of plasma cholesterol (which is about 3% lower than serum determinations),
triglyceride, and HDL levels after a 12-hour or longer fast is important, because triglycerides
may be elevated in nonfasted individuals; total cholesterol is only modestly affected by
fasting.
• Two determinations, 1 to 8 weeks apart, with the patient on a stable diet and weight, and in the
absence of acute illness, are recommended to minimize variability and to obtain a reliable
baseline. If the total cholesterol is >200 mg/dL, a second determination is recommended, and
if the values are more than 30 mg/dL apart, the average of three values should be used.
• After a lipid abnormality is confirmed, major components of the evaluation are the history
(including age, gender, and, if female, menstrual and estrogen replacement status), physical
examination, and laboratory investigations.
• A complete history and physical examination should assess (1) presence or absence of
cardiovascular risk factors or definite cardiovascular disease in the individual; (2) family
history of premature cardiovascular disease or lipid disorders; (3) presence or absence of
secondary causes of hyperlipidemia, including concurrent medications; and (4) presence or
absence of xanthomas, abdominal pain, or history of pancreatitis, renal or liver disease,
peripheral vascular disease, abdominal aortic aneurysm, or cerebral vascular disease (carotid
bruits, stroke, or transient ischemic attack).
 Desired outcome
• The goals of treatment are to lower total and
LDL cholesterol in order to
• reduce the risk of first or recurrent events
such as myocardial infarction,
• angina, heart failure, ischemic stroke, or other
forms of peripheral arterial
• disease such as carotid stenosis or abdominal
aortic aneurysm.
 Treatment
General approach:
• TABLE 9-1
Classification of Total, LDL, and HDL
Cholesterol and Triglycerides

• TABLE 9-2
Major Risk Factors (Exclusive of LDL Cholesterol)
That Modify LDL Goals
 Non pharmacologic therapy:

• Therapeutic lifestyle changes are begun on the first visit and include
dietary therapy, weight reduction, and increased physical activity. Inducing
a weight loss of 10% should be discussed with patients who are
overweight. In general, physical activity of moderate intensity 30 minutes
a day for most days of the week should be encouraged. All patients should
be counseled to stop smoking and to meet the Seventh Joint National
Committee on the Detection, Evaluation, and Treatment of High Blood
Pressure guidelines for control of hypertension.
• TABLE 9-4
Macronutrient Recommendations for
the Therapeutic Lifestyle Change Diet
Pharmacologic therapy
 Treatment recommendations
• Treatment of type I hyperlipoproteinemia is directed toward reduction of chylomicrons derived
from dietary fat with the subsequent reduction in plasma triglycerides. Total daily fat intake
should be no more than 10 to 25 g/day, or approximately 15% of total calories. Secondary
causes of hypertriglyceridemia should be excluded, and, if present, the underlying disorder
should be treated appropriately.
• Primary hypercholesterolemia (familial hypercholesterolemia, familial combined
hyperlipidemia, type IIa hyperlipoproteinemia) is treated with BARs, statins, niacin, or
ezetimibe.
• Combined hyperlipoproteinemia (type IIb) may be treated with statins, niacin, or gemfibrozil to
lower LDL-C without elevating VLDL and triglycerides. Niacin is the most effective agent and
may be combined with a BAR. A BAR alone in this disorder may elevate VLDL and
triglycerides, and their use as single agents for treating combined hyperlipoproteinemia
should be avoided.
• Type III hyperlipoproteinemia may be treated with fibrates or niacin. Although fibrates have
been suggested as the drugs of choice, niacin is a reasonable alternative because of the lack
of data supporting a cardiovascular mortality benefit from fibrates and because of their
potentially serious adverse effects. Fish oil supplementation may be an alternative therapy.
• Type V hyperlipoproteinemia requires stringent restriction of dietary fat intake. Drug therapy
with fibrates or niacin is indicated if the response to diet alone is inadequate. Medium-chain
triglycerides, which are absorbed without chylomicron formation, may be used as a dietary
 Combination Drug Therapy

• Combination therapy may be considered after adequate trials of

monotherapy and for patients documented to be adherent to the
prescribed regimen. Two or three lipoprotein profiles at 6-week intervals
should confirm lack of response prior to initiation of combination therapy.
• Contraindications to and drug interactions with combined therapy should
be screened carefully, and the extra cost of drug product and monitoring
should be considered.
• In general, a statin plus a BAR or niacin plus a BAR provide the greatest
reduction in total and LDL cholesterol.
• Regimens intended to increase HDL levels should include either gemfibrozil
or niacin, bearing in mind that statins combined with either of these
drugs may result in a greater incidence of hepatotoxicity or myositis.
• Familial combined hyperlipidemia
 Treatment of high triglyceridemia
• Lipoprotein pattern types I, III, IV, and V are associated with hypertriglyceridemia, and these primary
lipoprotein disorders should be excluded prior to implementing therapy.
• A family history positive for CHD is important in identifying patients at risk for premature atherosclerosis. If a
patient with CHD has elevated triglycerides, the associated abnormality is probably a contributing factor to
CHD and should be treated.
• High serum triglycerides (see Table 9-1) should be treated by achieving desirable body weight, consumption
of a low saturated fat and cholesterol diet, regular exercise, smoking cessation, and restriction of alcohol
(in selected patients).
• ATP III identifies the sum of LDL and VLDL (termed non-HDL [total cholesterol – HDL]) as a secondary
therapeutic target in persons with high triglycerides (≥200 mg/dL). The goal for non-HDL with high serum
triglycerides is set at 30 mg/dL higher than that for LDL on the premise that a VLDL level of 30 mg/dL or
less is normal.
• Drug therapy with niacin should be considered in patients with borderline- high triglycerides but with
accompanying risk factors of established CHD, family history of premature CHD, concomitant LDL elevation
or low HDL, and genetic forms of hypertriglyceridemia associated with CHD. Niacin may be used cautiously
in persons with diabetes because a clinical trial found only a slight increase in glucose and no change in
hemoglobin A1C. Alternative therapies include gemfibrozil, statins, and fish oil. The goal of therapy is to
lower triglycerides and VLDL particles that may be atherogenic, increase HDL, and reduce LDL.
• Very high triglycerides are associated with pancreatitis and other adverse consequences. Management
includes dietary fat restriction (10% to 20% of calories as fat), weight loss, alcohol restriction, and
treatment of coexisting disorders (e.g., diabetes). Drug therapy includes gemfibrozil, niacin, and higher-
potency statins (atorvastatin, rosuvastatin, and simvastatin).
 Treatment of low HDL
• Low HDL cholesterol is a strong independent risk
predictor of CHD. ATP
III redefined low HDL cholesterol as <40 mg/dL but
specified no goal for
HDL cholesterol raising. In low HDL, the primary target
remains LDL, but
treatment emphasis shifts to weight reduction, increased
physical activity,
smoking cessation, and to fibrates and niacin if drug
therapy is required.
Treatment of diabetic dyslipidemia
• Diabetic dyslipidemia is characterized by hypertriglyceridemia, low HDL,
and minimally elevated LDL. Small, dense LDL (pattern B) in diabetes is
more atherogenic than larger, more buoyant forms of LDL (pattern A).
• ATP III considers diabetes to be a CHD risk equivalent, and the primary
target is to lower the LDL to <100 mg/dL. When LDL is >130 mg/dL, most
patients require simultaneous therapeutic lifestyle changes and drug
therapy.
When LDL is between 100 and 129 mg/dL, intensifying glycemic
control, adding drugs for atherogenic dyslipidemia (fibrates, niacin), and
intensifying LDL-lowering therapy are options. Statins are considered by
many to be the drugs of choice because the primary target is LDL.
 Evaluation of therapeutic outcomes
• Short-term evaluation of therapy for hyperlipidemia is based on response to diet and drug treatment as
measured in the clinical laboratory by total cholesterol, LDL-C, HDL cholesterol, and triglycerides.
• Many patients treated for primary hyperlipidemia have no symptoms or clinical manifestations of a genetic
lipid disorder (e.g., xanthomas), so monitoring is solely laboratory based.
• In patients treated for secondary intervention, symptoms of atherosclerotic cardiovascular disease, such as
angina or intermittent claudication, may improve over months to years. Xanthomas or other external
manifestations of hyperlipidemia should regress with therapy.
• Lipid measurements should be obtained in the fasted state to minimize interference from chylomicrons.
Monitoring is needed every few months during dosage titration. Once the patient is stable, monitoring at
intervals of 6 months to 1 year is sufficient.
• Patients on BAR therapy should have a fasting panel checked every 4 to 8 weeks until a stable dose is reached;
triglycerides should be checked at a stable dose to ensure they have not increased.
• Niacin requires baseline tests of liver function (alanine aminotransferase), uric acid, and glucose. Repeat tests
are appropriate at doses of 1,000 to 1,500 mg/day. Symptoms of myopathy or diabetes should be
investigated and may require creatine kinase or glucose determinations. Patients with diabetes may
require more frequent monitoring.
• Patients receiving statins should have a fasting panel 4 to 8 weeks after the initial dose or dose changes. Liver
function tests should be obtained at baseline and periodically thereafter based on package insert
information. Some experts believe that monitoring for hepatotoxicity and myopathy should be triggered
by symptoms.
• Patients with multiple risk factors and established CHD should also be monitored and evaluated for progress
in managing their other risk factors such as blood pressure control, smoking cessation, exercise and weight
control, and glycemic control (if diabetic).
References