Hyperlipoproteinemias, treatment

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. 

Carnitine Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH]... 

Treatment Various drugs are available that have different mechanisms of action and effects on LDL (cholesterol) and VLDL (triglycerides) (A). Their use is indicated in the therapy of primary hyperlipoproteinemias. In secondary hyperlipoproteinemias, the immediate goal should be to lower lipoprotein levels by dietary restriction, treatment of the primary disease, or both. 

The bile acid sequestering resins lower elevated LDL cholesterol and therefore are useful in the treatment of type Ila hyperlipoproteinemia. However, because the resins can raise plasma VLDL in some patients, they are not recommended for treatment of combined hyperlipidemias (type Ilb) when both LDL cholesterol and VLDL triglycerides are high or in other conditions of elevated triglycerides. 

According to our present knowledge, there are several ways to treat disorders (referred to as hypercholesterolemias or hyperlipoproteinemias) that enhance cholesterol-containing atheroma formation. The class of compounds referred to as statins dominates the treatment of these disorders. 

Table 35-2 The Primary Hyperlipoproteinemias and Their Drug Treatment.

As described, some persons with familial combined hyperlipoproteinemia have only an elevation in LDL. Serum cholesterol is usually less than 350 mg/dL. Dietary and drug treatment, usually with a reductase inhibitor, is indicated. It may be necessary to add niacin or ezetimibe to normalize LDL. 

This synergistic combination is useful in the treatment of familial hypercholesterolemia but may not control levels of VLDL in some patients with familial combined hyperlipoproteinemia. Statins should be given at least 1 hour before or 4 hours... 

This regimen is more effective than either agent alone in treating hypercholesterolemia. Experience indicates that it is an efficacious and practical combination for treatment of familial combined hyperlipoproteinemia. 

Fenofibrate appears to be complementary with certain statins in the treatment of familial combined hyperlipoproteinemia and other conditions involving elevations of both LDL and VLDL. The combination of fenofibrate with rosuvastatin is particularly effective. Some other statins may interact unfavorably owing to effects on cytochrome P450 metabolism. 

In kindreds with this disorder, individuals may have elevated levels of VLDL, LDL, or both, and the pattern may change with time. Familial combined hyperlipoproteinemia involves an approximate doubling in VLDL secretion. It seems to be transmitted as a semidominant trait. Triglycerides can be increased by the factors noted above. Elevations of cholesterol and triglycerides are generally moderate, and xanthomas are usually absent. Drug treatment is warranted because the risk of coronary atherosclerosis is increased and diet alone does not normalize lipid levels. A reductase inhibitor or ezetimibe in combination with niacin is usually required to treat these patients. 

The Lipid Research Clinics Coronary Primary Prevention Trial (L16, L17) is a landmark double-blind study in which cholestyramine, a bile acid se-questrant that is not absorbed from the gut, was used to lower plasma cholesterol. The investigators recruited 3806 men, with a Type II hyperlipoproteinemia phenotype and in good health, into the study. All were prescribed a cholesterol-lowering diet. Subjects were randomly assigned to a treatment group (who were prescribed 24 g cholestyramine daily) and a group with similar baseline characteristics who received an inactive placebo. A 19% lower incidence of coronary heart disease over a mean of 7.4 years in... 

Therapeutic uses Niacin lowers plasma levels of both cholesterol and triacylglycerol. Therefore, it is particularly useful in the treatment of Type lib and IV hyperlipoproteinemia, in which both VLDL and LDL are elevated. Niacin is also used to treat other severe hypercholesterolemias, often in combination with other antihyperlipidemic agents (see p. 215). In addition, it is the most potent antihyperlipidemic agent for raising plasma HDL levels. 

Puls, W, Keup, U, Krause, H P, Thomas, G, Hoffmeister, E, Glucosidase inhibition. A new approach to the treatment of diabetes, obesity, and hyperlipoproteinemia, Naturwissenschaften, 64, 536-537, 1977. 

In addition, the receptor-binding activity of the apoE2 can be modulated by the lipid composition of lipoprotein particles (Innerarity et ai, 1986). The binding activity of the d < 1.006 lipoproteins (j8-VLDLs) of a type III subject with this variant was tested before and after dietary intervention. Before intervention, the subject expressed the clinical features of type III hyperlipoproteinemia plasma triglycerides and cholesterol were elevated (670 and 725 mg/dl, respectively). After dietary intervention (a common treatment for this disorder, to which patients often respond satisfactorily), the subject lost 34 lbs. and his... 

Lipid transport mechanisms exist that shuttle cholesterol and triglycerides among the liver, intestine, and other tissues. Normally, plasma lipids, including lipoprotein cholesterol, are cycled into and out of plasma and do not cause extensive accumulation of dcpo.sits in the walls of arteries. Genetic factors and changes in hormone levels affect lipid transport by altering enzyme concentrations and apoprotein content, as well us the number and activity of lipoprotein receptors. This complex relationship makes the treatment of all hyperlipoproteinemias by a singular approach difficult, if not impractical. 

Clofibrate is the drug of choice in the treatment of type III hyperlipoproteinemias and may also be useful, to a lesser tent. in types lib and IV hyperlipoproteinemias. The drug is not effective in types I and Ila. 

IVicofrn/c Acid. Nicotinic acid. 3-pyridinccarboxylic Kid (Niacin), is effective in the treatment of ali types nf hyperlipoproteinemia except type I, at dnses abnve thnse given as a vitamin supplement. The drug reduces VLDL... 

Diagnosis of the Type III Lipoprotein Pattern. The ratio of VLDL cholesterol to plasma triglyceride, expressed in terms of mass, is 0.2 or lower in normal samples and in those from patients with lipoprotein disorders other than type III hyperlipidemia. In type III hyperlipoproteinemia, the ratio is 0.3 or higher because of the presence of p-VLDL, and the elevated ratio can persist even after treatment. 

B-Sitosterol - Recent reports demonstrated the efficacy of P-sitosterol in lowering plasma LDL-C in patients with Type II hyperlipoproteinemia. "" 3-Sitosterol obtained from tall oil was found to be effective at 3 g/day, a dose substantially lower than that required with older preparations. However, in juvenile Type II hyperlipoproteinemia, 3-sitosterol lowered LDL-C by only 6% but, in addition, decreased HDL-C by 15% thus, 3-sitosterol was not recommended for the treatment of hypercholesterolemia in children." A potential problem with 3-sitosterol is the increased risk of gallstone formation, in view of the finding of Increased saturation index of bile in patients given 3 g/day of plant sterols. ... 

Since hypercholesterolemia (in particular, LDL cholesterol) increases the risk of CHD, it seems reasonable to lower cholesterol levels in patients whose levels put them at risk. Before treatment, other risk factors such as hypertension, cigarette smoking, obesity, and glucose intolerance need to be evaluated and corrected. Disorders that exacerbate hyperlipoproteinemia (e.g., chronic ethanol abuse, hypothyroidism, diabetes mellitus) need to be treated before lipid-lowering measures are taken (discussed earlier. Table 20-7). 

If dietary therapy is unsuccessful, drug therapy should be employed. Five classes of drugs are available for treatment of hyperlipoproteinemias their effects are due to decreased production or enhanced removal of lipoprotein from plasma. 

Table 35-2. The primary hyperlipoproteinemias and their drug treatment. ...

Bile acid sequestrants are indicated for the treatment of hypercholesterolemia in patients who do not adequately respond to dietary modifications. They may be used either alone or in combination with HMGRIs or niacin. These combinations often can achieve a 50% reduction in plasma LDL levels. Cholestyramine, but neither colestipol nor colesevelam, also is approved for the relief of pruritus associated with partial biliary obstruction. Bile acid sequestrants should not be used to treat hypertriglyceridemias or mixed hyperlipoproteinemias in which hypertriglyceridemia is the primary concern. These compounds also are contraindicated in patients with cholelithiasis or complete biliary obstruction because of the impaired secretion of bile acids caused by these conditions. Finally, cholestyramine and colestipol are contraindicated in patients with primary biliary cirrhosis, because this can further raise serum cholesterol (7,15,21). 

Nicotinic acid is a B-complex vitamin that is converted to nicotinamide, NAD, and NADP. The latter two compounds are coenzymes and are required tor oxidation/reduction reactions in a variety of biochemical pathways. Additionally, nicotinic acid is metabolized to a number of inactive compounds, including nicotinuric acid and N-methylated derivatives. Normal biochemical regulation and feedback prevent large doses of nicotinic acid from producing excess quantities of NAD and NADP. Thus, small doses of nicotinic acid, such as those used tor dietary supplementation, will be primarily excreted as metabolites, whereas large doses, such as those used tor the treatment of hyperlipoproteinemia, will be primarily excreted unchanged by the kidney (15). 

Drood JM, Zimetbaum PJ, Frishman WH. Nicotinic acid for the treatment of hyperlipoproteinemia. J Clin Pharmacol 1991 31 641-650. ... 

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