Reversible elevations in aminotransferases up to twice normal may occur, usually not associated with liver toxicity. However, liver function should be monitored at baseline and at appropriate intervals. Rarely, true hepatotoxicity may occur, and the drug should be discontinued. The association of severe hepatic dysfunction, including acute necrosis, with the use of over-thecounter sustained-release preparations of niacin has been reported. This effect has not been noted to date with an extended-release preparation, Niaspan, given at bedtime in doses of 2 g or less. Carbohydrate tolerance may be moderately impaired, especially in obese patients. Niacin may be given to diabetics who are receiving insulin and to some receiving oral agents but it may increase insulin resistance. This can be addressed by increasing the dose of insulin or the oral agents. Hyperuricemia occurs in some patients and occasionally precipitates gout. Allopurinol can be given with niacin if needed. Red cell macrocytosis can occur and is not an indication for discontinuing treatment. Significant platelet deficiency can occur rarely and is reversible on cessation of treatment. Rarely, niacin is associated with arrhythmias, mostly atrial, and with macular edema, both requiring cessation of treatment. Patients should be instructed to report blurring of distance vision. Niacin may potentiate the action of antihypertensive agents, requiring adjustment of their dosages. Birth defects have been reported in offspring of animals given very high doses.
Colestipol, cholestyramine, and colesevelam are useful only for isolated increases in LDL. In patients who also have hypertriglyceridemia, VLDL levels may be further increased during treatment with resins.
The bile acid-binding agents are large polymeric cationic exchange resins that are insoluble in water. They bind bile acids in the intestinal lumen and prevent their reabsorption. The resin itself is not absorbed.
Mechanism of Action
Bile acids, metabolites of cholesterol, are normally efficiently reabsorbed in the jejunum and ileum (Figure 35–2). Excretion is increased up to tenfold when resins are given, resulting in enhanced conversion of cholesterol to bile acids in liver via 7α-hydroxylation, which is normally controlled by negative feedback by bile acids. Decreased activation of the FXR receptor by bile acids may result in a modest increase in plasma triglycerides but can also improve glucose metabolism in patients with diabetes. The latter effect is due to increased secretion of the incretin glucagon-like peptide-1 from the intestine, thus increasing insulin secretion. Increased uptake of LDL and IDL from plasma results from upregulation of LDL receptors, particularly in liver. Therefore, the resins are without effect in patients with homozygous familial hypercholesterolemia who have no functioning receptors but may be useful in those with some residual receptor function and in patients with receptor-defective combined heterozygous states.
The resins are used in treatment of patients with primary hypercholesterolemia, producing approximately 20% reduction in LDL cholesterol in maximal dosage. If resins are used to treat LDL elevations in persons with combined hyperlipidemia, they may cause an increase in VLDL, requiring the addition of a second agent such as a fibrate or niacin. Resins are also used in combination with other drugs to achieve further hypocholesterolemic effect (see below). They may be helpful in relieving pruritus in patients who have cholestasis and bile salt accumulation. Because the resins bind digitalis glycosides, they may be useful in digitalis toxicity.