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Chapter: Basic & Clinical Pharmacology : Agents Used in Dyslipidemia

The Primary Hypertriglyceridemias

Hypertriglyceridemia is associated with increased risk of coronary disease. VLDL and IDL have been found in atherosclerotic plaques.


Hypertriglyceridemia is associated with increased risk of coronary disease. VLDL and IDL have been found in atherosclerotic plaques. These patients tend to have cholesterol-rich VLDL of small-particle diameter and small, dense LDL. Hypertriglyceridemic patients with coronary disease or risk equivalents should be treated aggressively. Patients with triglycerides above 700 mg/dL should be treated to prevent acute pancreatitis because the LPL clearance mechanism is saturated at about this level.

Hypertriglyceridemia is an essential component of the meta-bolic syndrome, which also includes low levels of HDL-C, insulin resistance, hypertension, and abdominal obesity. Hyperuricemia is also frequently present. Insulin resistance appears to be central to this process. Management of these patients frequently requires, in addition to a fibrate or niacin, the use of metformin or a peroxi-some proliferator-activated receptor-gamma (PPAR-γ) agonist or both . In the latter case, pioglitazone is the drug of choice because it reduces triglycerides and does not increase levels of LDL. The severity of hypertriglyceridemia of any cause is increased in the presence of the metabolic syndrome or type 2 diabetes.

Primary Chylomicronemia

Chylomicrons are not present in the serum of normal individuals who have fasted 10 hours. The recessive traits of deficiency of LPL or its cofactor, apo C-II, are usually associated with severe lipemia (2000–3000 mg/dL of triglycerides when the patient is consum-ing a typical American diet). These disorders might not be diag-nosed until an attack of acute pancreatitis occurs. Patients may have eruptive xanthomas, hepatosplenomegaly, hypersplenism, and lipid-laden foam cells in bone marrow, liver, and spleen. The lipemia is aggravated by estrogens because they stimulate VLDL production, and pregnancy may cause marked increases in trigly-cerides despite strict dietary control. Although these patients have a predominant chylomicronemia, they may also have moderately elevated VLDL, presenting with a pattern called mixed lipemia (fasting chylomicronemia and elevated VLDL). LPL deficiency isdiagnosed by assay of lipolytic activity after intravenous injection of heparin. A presumptive diagnosis is made by demonstrating a pronounced decrease in triglycerides a few days after reduction of daily fat intake below 15 g. Marked restriction of total dietary fat is the basis of effective long-term treatment. Niacin, a fibrate, or marine omega-3 fatty acids may be of some benefit if VLDL levels are increased. Genetic variants at other loci that participate in intravascular lipolysis, including LMF1, apo A-V, GPI-HDL BP1, and apo C-III, can have profound effects on triglyceride levels.

Familial Hypertriglyceridemia

A. Severe (Usually Mixed Lipemia)

Mixed lipemia usually results from impaired removal of triglyceride-rich lipoproteins. Factors that increase VLDL production aggravate the lipemia because VLDL and chylomicrons are competing sub-strates for LPL. The primary mixed lipemias probably reflect a vari-ety of genetic determinants. Most patients have centripetal obesity with insulin resistance. Other factors that increase secretion of VLDL also worsen the lipemia. Eruptive xanthomas, lipemia retinalis, epi-gastric pain, and pancreatitis are variably present depending on the severity of the lipemia. Treatment is primarily dietary, with restriction of total fat, avoidance of alcohol and exogenous estrogens, weight reduction, exercise, and supplementation with marine omega-3 fatty acids. Most patients also require treatment with a fibrate or niacin.

B. Moderate

Primary increases of VLDL also reflect a genetic predisposition and are worsened by factors that increase the rate of VLDL secretion from liver, ie, obesity, alcohol, diabetes, and estrogens. Treatment includes addressing these issues and the use of fibrates or niacin as needed. Marine omega-3 fatty acids are a valuable adjuvant.

Familial Combined Hyperlipoproteinemia

In this common disorder associated with an increased incidence of coronary disease, individuals may have elevated levels of VLDL, LDL, or both, and the pattern may change with time. Familial combined hyperlipoproteinemia involves an approximate dou-bling in VLDL secretion and appears to be transmitted as a semi-dominant trait. Triglycerides can be increased by the factors noted above. Elevations of cholesterol and triglycerides are generally moderate, and xanthomas are usually absent. Diet alone does not normalize lipid levels. A reductase inhibitor alone, or in combina-tion with niacin or fenofibrate, is usually required to treat these patients. When fenofibrate is combined with a reductase inhibitor, either pravastatin or rosuvastatin is recommended because neither is metabolized via CYP3A4.

Familial Dysbetalipoproteinemia

In this disorder, remnants of chylomicrons and VLDL accumulate and levels of LDL are decreased. Because remnants are rich in cholesteryl esters, the level of cholesterol may be as high as that of triglycerides. Diagnosis is confirmed by the absence of the ε3 and ε4 alleles of apo E, the ε2/ε2 genotype. Patients often developtuberous or tuberoeruptive xanthomas, or characteristic planar xanthomas of the palmar creases. They tend to be obese, and some have impaired glucose tolerance. These factors, as well as hypothy-roidism, can aggravate the lipemia. Coronary and peripheral ath-erosclerosis occurs with increased frequency. Weight loss, together with decreased fat, cholesterol, and alcohol consumption, may be sufficient, but a fibrate or niacin is usually needed to control the condition. These agents can be given together in more resistant cases, or a reductase inhibitor may be added.Apo E is also secreted by glia in the central nervous system and plays a role in sterol transport. The ε4 allele is associated indose-dependent manner with early-onset Alzheimer’s disease .

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