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Agents Used in Dyslipidemia
Plasma lipids are transported in complexes called lipoproteins. Metabolic disorders that involve elevations in any lipoprotein spe-cies are termed hyperlipoproteinemias or hyperlipidemias. Hyperlipemia denotes increased levels of triglycerides.
The two major clinical sequelae of hyperlipidemias are acute pancreatitis and atherosclerosis. The former occurs in patients with marked hyperlipemia. Control of triglycerides can prevent recurrent attacks of this life-threatening disease.
Atherosclerosis is the leading cause of death for both genders in the USA and other Western countries. Lipoproteins that contain apolipoprotein (apo) B-100 convey lipids into the artery wall.These are low-density (LDL), intermediate-density (IDL),very-low-density (VLDL), and lipoprotein(a) (Lp[a]). Remnantlipoproteins formed during the catabolism of chylomicrons that contain the B-48 protein (apo B-48) can also enter the artery wall, contributing to atherosclerosis.
Cellular components in atherosclerotic plaques include foam cells, which are transformed macrophages, and smooth muscle cells filled with cholesteryl esters. These cellular alterations result from endocytosis of modified lipoproteins via at least four species of scavenger receptors. Chemical modification of lipoproteins by free radicals creates ligands for these receptors. The atheroma grows with the accumulation of foam cells, collagen, fibrin, and frequently calcium. Whereas such lesions can slowly occlude coro-nary vessels, clinical symptoms are more frequently precipitated by rupture of unstable atheromatous plaques, leading to activation of platelets and formation of occlusive thrombi.
Although treatment of hyperlipidemia can cause slow physical regression of plaques, the well-documented reduction in acute coro-nary events that follows vigorous lipid-lowering treatment is attribut-able chiefly to mitigation of the inflammatory activity of macrophages and is evident within 2–3 months after starting therapy.
High-density lipoproteins (HDL) exert severalantiatherogeniceffects. They participate in retrieval of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins. Low levels of HDL (hypoalphalipoproteinemia) are an independent risk factor for atherosclerotic disease and thus are a target for intervention.
Cigarette smoking is a major risk factor for coronary disease. It is associated with reduced levels of HDL, impairment of cholesterol retrieval, cytotoxic effects on the endothelium, increased oxidation of lipoproteins, and stimulation of thrombogenesis. Diabetes, also a major risk factor, is another source of oxidative stress.
Normal coronary arteries can dilate in response to ischemia, increasing delivery of oxygen to the myocardium. This process is mediated by nitric oxide, acting on smooth muscle cells of the arte-rial media. This function is impaired by atherogenic lipoproteins, thus aggravating ischemia. Reducing levels of atherogenic lipopro-teins and inhibiting their oxidation restores endothelial function.
Because atherogenesis is multifactorial, therapy should be directed toward all modifiable risk factors. Atherogenesis is a dynamic process. Quantitative angiographic trials have demon-strated net regression of plaques during aggressive lipid-lowering therapy. Primary and secondary prevention trials have shown sig-nificant reduction in mortality from new coronary events and in all-cause mortality.
RL, a 42-year-old man with moderately severe coronary artery disease, has a body mass index (BMI) of 29, increased abdomi-nal girth, and hypertension that is well controlled. In addition to medicine for hypertension, he is taking 40 mg atorvastatin. Current lipid panel (mg/dL): cholesterol 184, triglycerides 200, low-density lipoprotein cholesterol (LDL-C) 110, HDL-C 34, non–HDL-C 150. Lipoprotein(a) (Lp[a]) is twice normal. Fasting glucose is 102 mg/dL, and fasting insulin is 38 μU/mL.Liver enzymes are normal. Creatine kinase level is mildly ele-vated. The patient is referred for help with management of his dyslipidemia. You advise dietary measures, exercise, and weight loss. Which additional drugs would help him achieve his lipo-protein treatment goals: LDL-C 60–70 mg/dL; triglycerides120 mg/dL; HDL-C > 45 mg/dL; and reduced level of Lp(a)? Would this patient also benefit from a drug to manage insulin resistance? If so, which drug?
CASE STUDY ANSWER
This patient has combined hyperlipidemia. The statin should be continued. A drug that reduces VLDL produc-tion would be beneficial (niacin or fenofibrate). Niacin is the preferred agent to increase HDL-C and to reduce tri-glycerides and Lp(a). However, increased insulin resistance may occur, necessitating frequent monitoring and, if necessary, the addition of metformin. If the LDL-C goal is not reached with the addition of niacin (or fenofibrate), the statin dose should be increased. Creatine kinase should be monitored. Marine omega-3 fatty acids will help to reduce triglycerides.
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