Lipid Disorders-3

Lipid Disorders
CURRENT Diagnosis & Treatment in Cardiology

Lipid Disorders

Peter C. Chien, MD & William H. Frishman, MD

Treatment (cont'd)

D. PHARMACOLOGIC TREATMENT

1. Lipid-lowering drugs—
a. Bile acid sequestrants—The bile acid-binding resins cholestyramine, colestipol, and colesevelam are primarily used as second-line therapy and in combination with other agents to treat hypercholesterolemia without concurrent hypertriglyceridemia (Table 2–9 and Table 2–10). The Lipid Research Clinics Coronary Primary Prevention Trial demonstrated a reduction in myocardial infarctions and CAD deaths in hypercholesterolemic men without CAD using cholestyramine.

Table 2–9. The four major classes of lipid-modifying drugs.

Table 2–10. Therapeutic options for treatment of primary dyslipidemias.

(1) Mode of action—These agents bind bile acids in the intestinal lumen, interrupting the enterohepatic circulation of bile acids, which are subsequently excreted in the feces. Increased synthesis of bile acids from endogenous cholesterol is then stimulated, resulting in the depletion of the hepatic cholesterol pool. This, in turn, leads to a compensatory increase in the biosynthesis of cholesterol and in the number of specific high-affinity LDL receptors on the liver cell membrane. The increased number of high-affinity LDL receptors expressed on hepatocytes stimulates an enhanced rate of LDL catabolism from plasma and thereby lowers the concentration of this lipoprotein.
(2) Clinical use—With their interruption of the enterohepatic circulation of bile acids and consequent stimulation of endogenous LDL biosynthesis, bile acid resins may have a synergistic effect with concomitant administration of HMG-CoA reductase inhibitors. They are indicated as adjunct therapy to reduce serum cholesterol in patients with primary hypercholesterolemia. Their use should be preceded by dietary therapy, which should address both the specific type of hyperlipoproteinemia in the patient and the patient's body weight, because obesity has been shown to be a contributing factor in hyperlipoproteinemia. Resin use can cause a 5–20% increase in VLDL levels, hence, it should be restricted to hypercholesterolemic patients with only slightly increased triglyceride levels. The increase in VLDL seen with resin use usually starts during the first few weeks of therapy and disappears 4 weeks after the initial rise. It is thought that excessive increases in the VLDL particles may blunt the LDL-lowering effect of the drug by competitively binding the upregulated LDL receptors on the hepatocyte. The resins should, therefore, not be used in patients whose triglyceride levels exceed 3.5 mmol/L unless they are accompanied by a second drug with triglyceride-lowering effects; some suggest not using resins if the triglyceride level exceeds 2.5 mmol/L. A general rule of thumb is that the LDL concentration is seldom raised if the triglyceride level exceeds 7 mmol/L, and bile acid resin treatment would not be effective in this setting.
Cholestyramine and colestipol are powders that must be mixed with water or fruit juice before ingestion and are taken in two or three divided doses with or just after meals. Colestipol is also available in tablet form for greater ease of administration. Colesevelam is a newer bile acid resin, which may have fewer adverse effects and drug interactions than older resins due to its novel structure and higher affinity for bile acids. It should be noted that bile acid sequestrants can decrease absorption of some antihypertensive agents, including thiazide diuretics and propranolol. As a general recommendation, all other drugs should be administered either 1 h before or 4 h after the bile acid sequestrant. The cholesterol-lowering effect of 4 g of cholestyramine appears to be equivalent to 5 g of colestipol. The response to therapy is variable in each individual, but a 15–30% reduction in LDL cholesterol may be seen with colestipol (20 g/day), cholestyramine (16 g/day), or colesevelam (3.8 g/day) treatments. The fall in LDL concentration becomes detectable 4–7 days after the start of treatment, and approaches 90% of maximal effect in 2 weeks. The initial dose should be 4 g of cholestyramine, 5 g of colestipol, or 1.88 g of colesevelam twice a day, and if there is an inadequate response, the dosage can be titrated upward accordingly. Using more than the maximum dosage does not increase the antihypercholesterolemic effect of the drug appreciably, but because it does increase side effects, it decreases compliance. Because resins are virtually identical in action, the choice is based on potential drug interactions and patient preference, specifically taste and the ability to tolerate the ingestion of bulky material.
If resin treatment is discontinued, cholesterol levels return to pretreatment levels within a month. In patients with heterozygous hypercholesterolemia who have not achieved desirable cholesterol levels on resin-plus-diet therapy, the combination therapy of bile acid resins and HMG-CoA reductase inhibitors or nicotinic acid can further lower serum cholesterol, triglyceride, and LDL levels and increase serum HDL concentration.
(3) Side effects—The side effects of bile acid resins include constipation, gastrointestinal irritation or bleeding, cholelithiasis, liver function test abnormalities, myalgias, dizziness, vertigo, and anxiety.
b. Fibric acid derivatives—Fibric acid derivatives are a class of drugs that inhibit the production of VLDL while enhancing VLDL clearance, as a result of the stimulation of lipoprotein lipase activity. These drugs reduce plasma triglycerides and concurrently raise HDL-C levels. Their effects on LDL-C are less marked and more variable. The Helsinki Heart Study demonstrated not only decreased triglycerides, decreased LDL-C and increased HDL-C in men treated with gemfibrozil, but also a decrease in the number of myocardial infarctions compared with placebo.
(1) Mode of action—These drugs increase the activity of the enzyme lipoprotein lipase, enhancing the catabolism of VLDL and triglycerides and promoting the transfer of cholesterol to HDL. VLDL production also appears to be decreased. Gemfibrozil has a more pronounced inhibiting effect on VLDL synthesis than clofibrate. Because gemfibrozil and clofibrate reduce LDL-C concentrations by less than 10%, they cannot be considered first-line agents for the treatment of hypercholesterolemia.
(2) Clinical use—It is well established that fibric-acid derivatives are first-line therapy to reduce the risk of pancreatitis in patients with very high levels of plasma triglycerides. Results from the Helsinki Heart Study have also suggested that hypertriglyceridemic patients with low HDL values can derive a cardioprotective effect from gemfibrozil. A Veterans Administration study found that gemfibrozil confers a significant risk reduction in major cardiovascular events in patients with established CAD and low HDL levels as their primary lipid disorder. However, it is not currently recommended to treat isolated low HDL levels with pharmacologic intervention.
The newer generation of fibric acid derivatives, such as fenofibrate, may decrease total cholesterol and LDL levels to a greater extent than gemfibrozil or clofibrate. Fenofibrate also reduces lipoprotein(a) levels and increases LDL size and buoyancy, as does nicotinic acid. These drugs should not be used as first-line therapy for hypercholesterolemic patients unless hypertriglyceridemia is present; type IIb hyperlipidemic patients would benefit from this therapy. HMG-CoA reductase inhibitors combined with fibric acid derivatives are excellent therapy for severe type IIb hyperlipidemia, however, creatine phosphokinase (CPK) values must be closely monitored. Nicotinic acid or bile acid resins plus gemfibrozil are also a reasonable combination for type IIb disease, but HDL levels may drop slightly with the latter combination.
(3) Side effects—The Side effects of fibric acid derivatives include cholelithiasis, gastrointestinal disturbance, myalgias from myositis, and liver function test abnormalities.
c. Nicotinic acid—Nicotinic acid, a water-soluble vitamin that, at doses much higher than those at which its vitaminic actions occur, lowers VLDL and LDL levels and increases HDL levels. It has been shown to reduce overall morbidity and mortality caused by coronary heart disease and to produce regression of some of the signs of atheroma.
(1) Mode of action—The mode of action of nicotinic acid is unknown and appears to be independent of the drug's role as a vitamin. One of its important actions is believed to be partial inhibition of free fatty acid release from adipose tissue. Experiments show that nicotinic acid inhibits the accumulation of cyclic-adenosinemonophosphate (AMP) stimulated by lipolytic hormones; the cAMP concentration controls the activity of triglyceride lipase and thus lipolysis. Nicotinic acid decreases the synthesis of VLDL and LDL by the liver and has been reported to increase the rate of triglyceride removal from the plasma as a result of increased lipoprotein lipase activity.
(2) Clinical use—Through its beneficial effects on VLDL-TG, LDL-C and HDL-C levels, nicotinic acid is indicated for most forms of hyperlipoproteinemia (types II, III, IV, and V) and for patients with depressed HDL. It is the most potent medication among lipid-lowering agents for the augmentation of HDL levels. It is also particularly useful for patients who have elevated plasma VLDL-TG levels as a part of their lipid profile. It is important to remember, however, that a diet low in cholesterol and saturated fats is the foundation of therapy for hyperlipoproteinemia.
Nicotinic acid is available in 100-, 125-, 250-, and 500-mg tablets as well as in a time-release form. The typical dosage is 3–7 g/day given in three divided doses. Therapeutic effects of the drug are usually not seen until the patient reaches a total daily dose of at least 3 g. A greater response may be attained with periodic increases to a maximum of 7–8 g/day, although the incidence of adverse effects also increases with higher doses. In general, it is best to use the lowest dose that will achieve the desired alterations in plasma lipoprotein levels.
(3) Side effects and contraindications—Unfortunately, many patients cannot tolerate therapeutic doses of nicotinic acid, whose primary side effects are cutaneous flushing and gastrointestinal disturbance, and appropriate steps should be taken to minimize these untoward effects. Taking two aspirins 30 min before the nicotinic acid will reduce flushing; taking the nicotinic acid with meals can ameliorate dyspepsia.
Regardless of the dose, it is important to draw laboratory test samples at regular intervals to monitor potential adverse effects. These include assessment of liver function (bilirubin, alkaline phosphatase, and transaminase levels), uric acid levels, and serum glucose levels.
Nicotinic acid is contraindicated in patients with active peptic ulcer disease. Because the drug may also impair glucose tolerance, it is contraindicated in patients with poorly controlled diabetes. Nicotinic acid is also associated with reversible elevations of liver enzymes and uric acid and should not be used in patients with hepatic disease or a history of symptomatic gout.
Patients taking a time-release form of nicotinic acid have a lower incidence of flushing than do patients with unmodified nicotinic acid (this side effect is thought to be related to the rate of gastrointestinal absorption). This is outweighed, however, by the far greater incidence of gastrointestinal and constitutional symptoms experienced by patients on the time-release form. These include nausea, vomiting, diarrhea, fatigue, and impaired male sexual function. In addition, even with low doses, the time-release preparation may be associated with more hepatotoxicity, entailing greater alkaline phosphatase and transaminase elevations.
Other adverse effects of nicotinic acid include pruritus (which responds to aspirin), acanthosis nigricans, cardiac arrhythmias, gout, and myopathy.
d. Hepatic 3-methylglutaryl coenzyme A reductase inhibitors—These inhibitors (HMG-CoA) inhibit the conversion of HMG-CoA to mevalonic acid, a rate-limiting step in the synthesis of cholesterol in the liver and intestines, the two main sites for production of cholesterol in the body.
HMG-CoA reductase inhibitors produce the greatest reduction in levels of LDL cholesterol, the primary atherogenic lipoprotein, along with ameliorating HDL and triglyceride levels to a lesser extent. In modest daily doses, HMG-CoA reductase inhibitors reduce total and LDL-C at a rate of 15–50% and may reduce triglycerides by 10–30%. Although effective as monotherapy, HMG-CoA reductase inhibitors can be combined to good effect with bile acid sequestrants when a greater effect on cholesterol is required, or with fibric acid derivatives when an additive effect on triglyceride levels is desired. These combinations may, however, increase the risk of rhabdomyolysis.
(1) Mode of action—Most cholesterol that is endogenously produced is synthesized in the liver. HMG-CoA reductase inhibitors interrupt an early rate-limiting step in cholesterol synthesis: the conversion of HMG-CoA to mevalonic acid. Because the synthesis rates of LDL receptors are inversely related to the amount of cholesterol in cells, the action of HMG-CoA reductase inhibitors reduces cholesterol synthesis and cellular concentrations of cholesterol and increases the expression of LDL receptors in the liver. Furthermore, because LDL receptors are responsible for clearing about two thirds to three quarters of plasma LDL (and associated cholesterol), HMG-CoA reductase inhibitors may promote the clearance of LDL as well as VLDL remnants. By reducing cholesterol synthesis, they may also interfere with the hepatic formation of lipoproteins. As cholesterol synthesis is maximal at night, it is recommended that HMG-CoA reductase inhibitors be given at bedtime.
(2) Clinical use—HMG-CoA reductase inhibitors have revolutionized the treatment of hyperlipidemia by their potency, efficacy, and tolerability and have evolved into first-line therapy for most forms of hyperlipidemia. Numerous studies with reductase inhibitors involving primary and secondary prevention of CAD have demonstrated a reduction in CAD events, CAD mortality, cerebrovascular events, and mortality from all other causes. Increased LDL receptor activity and decreased LDL synthesis are responsible for the hypocholesterolemic effect of the drug. This increase in LDL receptor activity occurs in response to a decrement in cholesterol synthesis by HMG-CoA reductase inhibition. LDL may be reduced by either its increased clearance from the plasma or its decreased production.
Reductase inhibitors exhibit pleiotropic effects beyond the lowering of LDL cholesterol levels. The reduction in coronary events and mortality rates is not solely attributable to the attenuation of atherosclerosis and improvement in vessel patency. They are postulated to possess antiinflammatory properties, contribute to coronary plaque stabilization, and improve endothelial cell function, conditions that are increasingly recognized as emerging areas of therapy for the treatment of coronary artery disease. They also reduce C-reactive protein levels, which are markers of inflammation and strong predictors of coronary events. One primary prevention trial suggested that pravastatin use may delay or prevent the development of diabetes mellitus, which is intimately linked to a constellation of multiple CAD risk factors known as the metabolic syndrome. Some studies have indicated that reductase inhibitors may prevent the onset of congestive heart failure, osteoporosis, and Alzheimer's disease as well.
(3) Side effects, drug interactions, and contraindications—HMG-CoA reductase inhibitors are contraindicated in pregnancy, lactation, hypersensitivity to the drugs, and active liver disease.
Immunosuppressive drugs, fibric acid derivatives, nicotinic acid, and erythromycin all may increase the risk of rhabdomyolysis. Concurrent use with warfarin (Coumadin) may potentiate the anticoagulant effect. Bile acid sequestrants decrease the bioavailability of the drug. ACE inhibitors may cause hyperkalemia when used with HMG-CoA reductase inhibitors. Digoxin tends to raise simvastatin levels.
Although the HMG-CoA reductase inhibitors are well tolerated, 10% of patients experience unwanted side effects. Although liver enzymes are elevated in 0.5–2% of patients, the patients are asymptomatic, and values may revert to normal on discontinuation of treatment. It is recommended that treatment be stopped if enzymes increase to a level three times that of normal.
Myositis, myalgia, and myopathy have been reported with increased creatine kinase levels in 5% of patients. Creatine kinase may increase further with the combined use of HMG-CoA reductase inhibitors with fibrates or nicotinic acid. Cerivastatin has been discontinued from production due to a high incidence of rhabdomyolysis and death, especially when combined with gemfibrozil. Although the question of cataract induction has been brought up with the use of these agents, clinical studies with lovastatin have not shown an increase in lens opacity. Recently cases of peripheral neuropathy have been described with these agents.
e. Estrogens and progestogens—Women are at increased risk of atherosclerosis after menopause. This is thought to be due to the lack of the protective effect of estrogen on lipoproteins. In this connection, several investigators have observed reductions in total-C and LDL in women taking exogenous estrogens compared with women not receiving any estrogen supplements. Exogenous estrogens can also produce modest elevations in HDL cholesterol (Table 2–11). There is, however, an increased risk of endometrial hyperplasia, possibly leading to endometrial cancer, with unopposed estrogen therapy. Therefore, in treating a postmenopausal woman with an intact uterus, it is advisable to add progesterone to offset the possible carcinogenic effect of estrogen on the uterus. By doing so, however, the beneficial effects on the lipoprotein profile induced by estrogens tend to be lost (Table 2–12).

Table 2–11. Possible beneficial effects of estrogens in reducing the risk of coronary artery disease in postmenopausal women.

Table 2–12. Effects of estrogens and progestogens on lipids and lipoproteins.

The Heart Estrogen/Progestin Replacement Study concluded that hormone replacement therapy (HRT) for the secondary prevention of CAD did not confer a reduction in CAD events or CAD mortality rates overall in the 4.1-year average follow-up period. In addition, a higher rate of venous thromboembolism and gallbladder disease was noted in the patients taking HRT. A subsequent angiographic end-point study demonstrated no benefit with estrogen or the combination of estrogen and medroxyprogesterone on the progression of coronary atherosclerosis compared with placebo in postmenopausal women with established CAD. The Women's Health Initiative trial recently showed that the combination of a conjugated estrogen with methoxyprogesterone increased the rate of coronary events, strokes, breast cancers, and thromboembolic diseases despite significant reductions in LDL-C and HDL-C levels.
2. Combination drug therapy—When treating patients with most severe genetic dyslipidemias, such as heterozygous familial hypercholesterolemia or familial combined hyperlipidemia, it is common for single-drug therapy to fail to achieve satisfactory plasma lipoprotein levels, even with HMG-CoA reductase inhibitors. In this setting, combination drug therapy is often successful in controlling plasma lipid levels (see Table 2–10). With less severe disorders, it is beneficial sometimes to use a combination of low-dose therapeutic agents with complementary effects rather than high doses of either agent alone in order to minimize their individual dose-related toxicities.
Common lipid-modifying agents to be used in combination regimens are the bile acid resins cholestyramine, colestipol, and colesevelam. They have the advantage of not being absorbed and thus cause fewer drug interactions. When the resins are used in full doses in combination with niacin, LDL-C levels are reduced 32–55% in patients with familial hyperlipidemia. Niacin is poorly tolerated by some patients, however, particularly because of its side effects. Recently a combination niacin–lovastatin formulation has become available for use in the treatment of hyperlipidemia.
Bile acid sequestrants can also be used in combination with fibric acid derivatives; some studies have shown an LDL-C reduction of 36–42%. Bile acid sequestrants and HMG-CoA reductase inhibitors used together are highly effective in lowering plasma LDL-C concentrations. A study of cholestyramine and lovastatin use in 62 patients showed a mean reduction in total-C of 48% and LDL-C levels of 59%.
The antifungal agent ketoconazole has an inhibitory effect on several enzymes linked to cytochrome P450. Large doses of this compound have been demonstrated to reduce total-C and LDL-C levels substantially, probably through inhibition of cholesterol synthesis at the demethylation-of-lanosterol step. The effects of low-dose ketoconazole (400 mg) alone and in combination with cholestyramine (12 g/day) have led to reductions in LDL-C levels of 22% and 31-41%, respectively.
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