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`A correction has been published: N .Engl J Med 1999;341(26):2020.
`
`REVIEW ARTICLE
`
`DRUG THERAPY
`Alastair J.J. Wood, M.D., Editor
`Voluine 341:498-511
`August 12, 1999
`
`Number 7
`
`.- Previous
`
`Drug Treatment of Lipid Disorders
`Robert H. Knopp, MD.
`
`Arteriosclerosis of the coronary and peripheral vasculature is the leading
`cause of death among men and women in the United Statesl and
`worldwide}- In 1992, for example, cardiovascular disease accounted for
`38 percent of deaths from all causes among men and 42 percent of all
`deaths among women in Washington Statel; nationwide, the mortality
`rate for cardiovascular disease is approximately 50 percent.1
`
`Mechanisms of A therogenesis
`
`Central to the pathogenesis of arteriosclerosis is the deposition of
`cholesterol in the arterial wall . .5.,Q. Nearly all lipoproteins are involved in
`this process, including cholesterol carried by very-low-density
`lipoprotein (VLDL),Lli remnant lipoprotein,~ and low-density
`lipoprotein (LDL), particularly the small, dense form.2 Conversely,
`cholesterol is carried away from the arterial wall by high-density
`lipoprotein (HDL).l.Q,il
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`In healthy persons, these lipoproteins function to distribute and recycle cholesterol (figure I_). 12 Hepatic
`overproduction ofVLDL can lead to increases in the serum concentrations ofVLDL, remnant
`lipoprotein, and LDL, I J,J.:I. depending on the ability of the body to metabolize each of these types or
`lipoprotein . .Ll.,.!Q,!1 The most common and important lipid disorder involving this mechanism is fam :ilial
`combined hyperlipidemia (also referred to as mixed hyperlipemia). 13·.1! The primary disorders of
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`lipoprotein metabolism. are described in Table l and have been reviewed elsewhere.2-.~.20
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`I
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`Figure 1. Pathways of Lipid Transport.
`
`Cholesterol is absorbed from the intestine and transported to the
`liver by chylomicron remnants, which are taken up by the low- ·
`density lipoprotein (LDL)-receptor-related protein (LRP). Hepatic
`cholesterol enters the circulation as yery-low-density lipoprotein
`(VLDL) and is metabolized to remnant lipoproteins after
`lipoprotein lipase removes triglyceride. The remnant lipoproteins
`are removed by LDI,, receptors (LDL-R) or further metabolized to
`LDL and then removed by these receptors. Cholesterol is
`transported from peripheral cells to the liver by high-density
`lipoprotein (HDL). Cholesterol is recycled to LDL and VLDL by
`cholesterol-ester transport protein (CETP) or is taken up in the liver
`by hepatic lipase. Cholesterol is excreted in bile. The points in the
`process that are affected by the five primary lipoprotein disorders
`-
`familial hypertriglyceridemia· (FHTG), familial combined
`hyperlipidemia (FCHL), remnant removal disease (RRD, also
`known as familial dysbetalipoproteinemia), familial
`hypercholesterolemia (FH), and hypoalphalipoproteinemia -
`shown.
`·
`
`are
`
`The effects of drug therapy can also be understood from these
`pathways. Statins decrease the synthesis of cholesterol and the
`secretion ofVLDL and increase the activity ofLDL receptors.
`Bile-acid-binding resins increase the secretion of bile acids.
`Nicotinic acid decreases the secretion ofVLDL and the formation
`ofLDL and increases the formation ofHDL. Fibrates decrease the
`secretion of VLDL and increase the activity of lipoprotein lipase,
`thereby increasing the removal of triglycerides. Adapted from
`Knopp.11
`
`View this table: Table 1. Primary Lipoprotein Disorders Amenable to Treatment with Diet and
`[in this window]. Drug Therapy .
`.[in a new window·!
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`The chief risk factors for cardiovascular disease are listed in Table 2.§.lQ.lL21 ·ll..23 •24·f2.26 When these
`risk factors occur in combination with hyperlipidemia and low serum HDL concentrations, early
`cardiovascular disease i~ commohplace.ll Keys to prevention and treatment are the elimination or
`modific~tion of risk factors, if possible, in conjunction with treatment of the specHic lipid disorder.
`
`View this table: Table 2. Risk Factors for Cardiovascular Disease Identified by the National
`{in this window]. Cholesterol Education Program and Others.
`·
`[in a new window]
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`Secondary Causes of Hyperlipidemia
`
`Closely related to the numerous risk factors for cardiovascular disease are conditions that cause
`hyperlipidernia,27 including obesity, diabetes mellitus, hypothyroidism, and the nephrotic syndrome;
`alcohol ingestion; and therapy with oral estrogen, isotretinoin, sertraline hydrochloride, human
`immunodeficiency virus (HIV}-protease inhibitors, B-adrenergic antagonists, glucocorticoids,
`cyclosporine, and thiazide diuretics. In general, each condition should be treated and any offending
`medications discontinued before a program to lower _serum lipid concentrations is initiated. Patients with
`severe hyperlipidemia usually have two disorders -
`for example, diabetes mellitus and familial
`combined hyperlipidemia, familial hypertriglyceridemia, or remnant removal disease . .l.2.,2.Q..28
`
`Target Serum Lipoprotein Concentrations
`
`The threshold serum total cholesterol and LDL cholesterol concentrations above which diet and drug
`therapy should be initiated, as well as the goals of therapy, have been defined by the National
`Cholesterol Education Program (Iable ..3.).Il The target serum LDL cholesterol concentration is less than
`160 mg per deciliter ( 4.3 mmol per liter) for patients with no risk factors for heart disease or only one
`risk factor, less than 130 mg per deciliter (3.4 mmol per liter) for patients with two or more risk factors,
`and less than 100 mg per deciliter (2.6 mmol per liter) for those with cardiovascular disease (Table
`.J.).ll.29,30,3 "I Persons with diabetes also fall in this third category, even those with no apparent
`cardiovascular disease. 21 •32•33 Reducing serum LDL cholesterol concentrations below the target levels
`does not necessarily result in a proportional reduction in the risk of cardiovascular
`·disease, 34,3 5,3G,3 7 ,3s,39 because of the 'attenuation of the cholesterol-heart disease relation at lower
`serum cholesterol concentrations.40 Drug therapy is not recommended for premenopausal women and
`men under 35 years of age unless they have serum LDL cholesterol concentrations of more than 220 mg
`per deciliter (5.7 mmol per liter), because their immediate risk of heart disease is low.21 The presenc'e of
`risk factors and a family history of the disease could lower this threshold.
`
`View this table: Table 3. Threshold Serum Total and Low-Density Lipoprotein (LDL) Cholesterol
`{in this wi ndowJ Concentrations for the Initiation of Dietary and Drug Treatment, According to the
`[in a new window] Number of Risk Factors for Cardiovascular Disease and the Presence or Absence of
`Cardiovascular Disease.
`
`A serum triglyceride concentration of more than 200 mg per deciliter (2.3 mmol per liter; approximately
`the 90th percentile for older men and women)!]_ is considered somewhat elevated, and a concentration of
`more than 400 mg per deciliter (4.5 mmol per liter; >95th percentile) is considered high according to the
`National Cholesterol Education Program guidelines.Il A reasonable target is a triglyceride concentration
`of 200 mg per deciliter or less, bec.ause higher values are associated with a doubling of the risk of
`cardiovascular disease when serum total cholesterol concentrations exceed 240 mg per deciliter (6.2
`mmol per liter) or the ratio of serum LDL cholesterol to HDL cholesterol exceeds 5:1.42•43 Reasonable
`targets for serum HDL cholesterol concentrations are 45 mg per deciliter (1.2 mmol per liter) in men and
`55 mg per deciliter (1.4 rnmol per liter) in women -
`the respective means in these populations.11
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`Dietary Treatment of Hyperlipidemia
`
`Dietary treatment of hyperlipidemia is a necessary foundation for drug treatment. Depending on the
`degree of hyperlipide:rn. ia, the Step I and Step II diets can be introduced sequentially ,Zl or the Step II diet
`can be begun immedia..tely (or when drug therapy is begun) if the patient is a.lready restricting his or her
`intake of saturated fa tty acids to less than 10 percent of total calories or if the risk of cardiovascular
`disease is high. The Step I diet contains no more than 30 percent of calories from fat, less than 10
`percent of calories from saturated fatty acids, and less than 300 mg of cholesterol (7 .8 mmol) per day.
`The Step II diet contains no more than 30 percent of calories from fat, less than 7 percent of calories
`from saturated fatty acids, and less than 200 mg of cholesterol per day.
`
`In long-term studies the Step II diet decreased serum LDL cholesterol concentrations 8 to 15
`percent.44•45•46 In addition, diet can help to reduce weight to an ideal level, increase the intake of
`vitamins, and reduce blood pressure and insulin resistance.44•45•46•47•48 Diets more restricted in fat than
`the Step II diet result in little additional reduction in serum LDL cholesterol concentrations, raise serum
`triglyceride concentrations, and lower serum HDL cholesterol concentrations.44 The risk of heart disease
`can also be reduced with the use of some diets that include a moderate intake of monounsaturated and
`polyunsaturated fat, such as the Mediterranean diet.49
`
`Sta tins
`
`Drugs of the statin class are structurally similar to hydroxymethylglutaryl-coenzyme A (HMG-CoA), a
`precursor of cholesterol, and are competitive inhibitors of HMG-CoA reductase, the last regulated step
`in the synthesis of cho lesterot.50 These drugs lower serum LDL cholesterol concentrations51 •52 by up(cid:173)
`regulating LDL-recept:or activity as well as reducing the entry ofLDL into the circulation.~ 53•54 Given
`alone for primary or secondary prevention of heart disease, these drugs can reduce the incidence of
`coronary artery disease by 25 to 60 percent34·~36• 55•56•57• 58 and reduce the risk of death from any cause
`by about 30 percent. 35 •56•58 Therapy with a statin also reduces the risk of angina pectoris and
`cerebrovascular accidents and decreases the need for coronary-artery bypass grafting and
`angioplasty .11.34,35,3 6 ,~55,56,57 ,58,i2,60
`
`Lipid-Altering Effects
`
`The characteristics of the six currently available statins are listed'in Table 4. The dose required to lower
`serum LDL cholesterol concentrations to a similar degree varies substantially among the statins. In
`addition, the response to increases in the dose is not proportional, because the dose-response relation for
`all six statins is curvilinear (Figure 2). In general, a doubling of the dose above the minimal effective
`dose decreases serum LDL cholesterol concentrations by an additional 6 percent. The maximal reduction
`in serum LDL cholesterol concentrations induced by treatment with a statin ranges froll'! 24 to 60 percent
`(Table 4).
`
`View this table: Table 4. Characteristics of Statins.
`[in this window].
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`Figure 2. Effects of Treatment with Statin and Bile-Acid-Binding Resin,
`Alone or in Combination, on Serum High-DensityLipoprotein (HDL) and
`Low-Density Lipoprotein (LDL) Cholesterol Concentrations.
`
`The effects of both drugs decline exponentially with increasing doses.
`Resin denotes bile-acid-binding resin given as cholestyramine. Data were
`obtained from the Pravastatin Multicenter Study Group II.62
`
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`View larger version (7K):
`[in this window].
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`All the statins lower serum triglyceride concentrations, with atorvastatin64 and sirnvastatin65 having the
`greatest effect. In general, the higher the base-line serum triglyceride concentration, the greater the
`decrease induced by statin therapy.65 Statinsare a useful adjunct in the treatmentofmoderate
`hypertriglyceridemia in patients with familial combined hyperlipidemia, but they are often insufficient.
`Statins are ineffective in the treatment of patients with chylomicronemia.
`
`•67 include decreased fibrinogen levels and viscosity, 66 increased
`Other benefits of some statins66
`immune tolerance after transplantation,68•69 diminished uptake of aggregated LDL by vascular smooth(cid:173)
`muscle cells,70 increased free cholesterol and decreased cholesterol ester concentrations within
`macrophages,11 suppression of the release of tissue factor, 72 and activation of endothelial nitric oxide
`synthase. 73
`
`Absorption and Metabolism
`
`Since lovastatin is better absorbed when taken with food, it should be taken with neals (Table 4). On the
`other hand, pravastatin is best taken on an empty stomach or at bedtime.61 Food ha.s less of an effect on
`the absorption of the other statins. Because the rate of endogenous cholesterol synthesis is higher at
`night, all the statins are best given in the evening.
`
`The statins are eliminated in part by the kidneys (Table 4), and serum concentratioDs may be higher in
`patients with renal disease. The predominant route of excretion 'is through the bile, after hepatic
`transformation. Patients with hepatic disease should be given lower doses or treated with another type of
`drug.fil,74 None of the statins should be given to pregn~t women because they are teratogenic at high
`dos~s in animals. Statin t~erapy does not affect adrenal or gonadal steroidogenesis- 75
`
`Adverse Effects
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`.
`.
`The most common adverse effects of statins are gastrointestinal upset, muscle aches, and hepatitis. Rarer
`problems are myopathy (defined as muscle pain with serum creatine kinase concentrations of more than
`1000 u per liter), rash, peripheral·neuropathy, insomnia, bad or vivid dreams, and difficulty sleeping or
`concentrating (Table 5).~77• 78• 79 For patients who have adverse central nervous system effects, a statin
`with no penetration of the central nervous system, such as pravastatin, can be tried. Cataracts have
`occurred in animals treated with high doses of lovastatin, simvastatin, and fluvastatin, but not in humans
`given these or any other statin. 80,fil
`
`View this table: Ta hie 5. Side Effects of Lipid-Lowering Drugs .
`.[in this window].
`.[in a new window].
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`Hepatotoxicity occurs in less than 1 percent of patients given high doses, and it is very rare during
`treatment with low doses. Myotoxicity is even rarer. 82 Hepatotoxicity and myotoxicity are both more
`common among patient:s who are receiving drugs that are metabolized by cytochrome P-450 enzyme
`systems. Four of the six statins are metabolized by the cytochrome P-450 3A4 system, fluvastatin is
`metabolized by the cytochrome P-450 2C9 system, and pravastatin is metabolized by sulfation and
`possibly other mechanisms. Drugs that inhibit cytochrome P-450 3A4 or 2C9 retard the metabolism of
`statins and include antibiotics, antifungal drugs, HIV-protease inhibitors, and cyclosporine (Table 6). 83
`Drugs that induce cytochrome P-450 3A4, such as barbiturates and carbamazepine, reduce serum statin
`concentrations. For patients who are receiving either type of drug, pravastatin, which is not metabolized
`by any cytochrome P-450 enzyme, provides an alternative. Warfarin and fluvastatin are common
`substrates for cytochrome P-450 2C9, and warfarin levels inay increase if the two drugs are given
`concomitantly. 83
`
`View this table: Table 6. Drugs and Substances That Interfere with the Metabolism of Statins.
`[in this window]
`[in a new window]
`
`fatigue, sluggishness, anorexia, and weight loss -
`The symptoms of hepatitis induced by statins -
`resemble those of an influenza-like syndrome. Serum aminotransferase concentrations are usually only
`moderately elevated (e.g., two to three times the upper limit of the normal range). Serum LDL
`cholesterol concentrations are often much lower than expected, and serum HDL cholesterol
`concentrations are low. The symptoms subside almost overnight after the drug is discontinued, but
`serum aminotransferase concentrations may not return to normal for several weeks, depending on the
`degree of the elevation. On the other hand, minor, isolated elevations in serum aminotransferase
`concentrations (such as increases to 1.5 times the upper limit of the normal range) can be ignored in the
`absence of symptoms. The recommended intervals for the measurement of serum aminotransferases vary
`among the drugs; the initial measurements should be done 2 to 12 weeks after treatment is started and
`every 6 months during long-term treatment.82
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`When lovastatin is given with nicotinic acid or with derivatives of fibric acid (commonly referred to as
`fibrates), rnyopathy and myositis occur in approximately I percent of patients.M.85 •86•87•88 Patients vvho
`are at higher risk for myositis when they receive combined treatment with a statin and a fibrate are
`small-framed, older persons with impaired renal function. 89 As a general rule, high doses of statin
`should not be given to patients who are taking a fibrate. The frequency of myopathy among patients who
`are taking lovastatin alone at a dose of 80 mg per day is reported to be 0.2 percent, 82 but it is higher
`among patients who are also taking cyclosporine or erythromycin.84
`
`Indicatio:ns
`
`Statins are useful in treating most of the major types of hyperlipidemia. The classic indication is
`heterozygous familial or polygenic hypercholesterolemia, in which LDL-receptor activity is reduced.
`S~atins increase LDL-receptor activity by inhibiting the synthesis of cholesterol. 53 They also reduce the
`formation of apolipoprotein B-containing lipoproteins and their entry into the circulation50·~90 and can
`reduce high serum concentrations of triglycerides and remnant lipoproteins.64•91 •92•93 As a result, statin
`therapy is also indicated in patients with combined or familial combined hyperlipidemia, remnant
`removal disease, and the hyperlipidemia of diabetes94 and renal failure.2J.
`
`Bile-Ac id-Binding Resins
`
`Once a mainstay of lipid-lowering therapy, bile-acid-binding resins are now largely used as adjuncts to
`statin therapy for patients in whom further lowering of serum cholesterol concentrations is indicated.
`The available bile-acid-binding resins are cholestyramine and colestipol. A 5-g dose of colestipol is
`approximately equivalent to a 4-g dose of cholestyrarnine. When given in doses of'4 to 8 g or 5 to l 0 g
`twice daily with meals as a suspension in juice or water, these resins decrease serum LDL cholesterol
`concentrations by IO to 20 percent.62•96 Recently, 1-g tabletsofcolestipol have become available. No
`one formulation of cholestyramine or colestipol is consistently preferred by patients.
`
`Lipid-AI•ering Effects
`
`Resins bind bile acids (not cholesterol) in the intestine, thereby interrupting the enterohepatic circulation
`of bile acids and increasing the conversion of cholesterol into bile acids in the liver. Hepatic synthesis of
`chqlesterol is also increased, which in turn increases the secretion of VLDL into the circulation, raises
`serum triglyceride concentrations, and limits the effect of the drug on LDL cholesterol concentrations.
`The increase in serum triglyceride concentrations can represent a major complication in patients who are
`prone to hypertriglyceridemia.
`
`The chief' indication for therapy with a bile-acid-binding resin is to reduce serum LDL cholesterol
`concentra.tions in patients who are already receiving a statin (Figure 2).62 The statin-induced inhibition
`of cholest~rol synthesis increases the efficacy of the bile-acid-binding resin. In addition, serum HDL
`cholesterol concentrations increase by about 0.5 mg per deciliter (0.04 mmol per liter) when a bile-acid(cid:173)
`binding resin is added to the treatment regimen of patients who are already receiving a statin. 96•97
`Combinat:ion therapy can potentially reduce the risk of events related to heart disease by more than 50 .
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`percent.31
`
`Adverse Effects
`
`.,,.
`Bile-acid-binding resins cause abdominal fullness, gas, and constipation in 30 percent of patients (Table
`'j_).62,96,97 The dose can. be adjusted to minimize these symptoms, and fiber (such as 3 tsp [10.2 g] of
`psyllium-husk fiber) or a glass of prune juice can be added to the daily diet, especially when treatment is
`started, to help avoid constipation. Stool softeners are less useful for this purpose.
`·
`
`Cholestyramine can cause hyperchloremic acidosis in children or in patients with renal failure because
`chloride ions are released in exchange.for bile acid. 98 Colestipol may not have this effect. Both resins
`may reduce the absorption of vitamin D and other fat-soluble vitamins, but this effect is negligible,
`except possibly in children.98 Bile-acid-binding resins can b~nd polar compounds, including warfarin,
`digoxin, thyroxine, thia.zide diuretics, folic acid, and statins. To avoid such an effect, these substances
`should be given one hour before or four hours after the resin.
`
`Indications
`
`Treatment with bile-acid-binding resins should be restricted to patients who have hypercholesterolernia
`but not hypertriglyceridemia. This group includes patients with polygenic or heterozygous familial
`hypercholesterolemia and those with the hypercholesterolemic form of familial combined
`hyperlipidemia.
`
`Nicotinic Acid
`
`Lipid-Altering Effects
`
`The cholesterol.-loweri:ng effect of nicotinic acid was first reported in 1955.99 Its primary action is to
`inhibit the mobilization. of free fatty acids from peripheral tissues, thereby reducing hepatic synthesis of
`triglycerides and secret: ion of VLDL (Figure 3). lQQ Nicotinic acid may also inhibit the conversion of
`VLDL into LDL. lfil The ability of nicotinic acid to increase serum HDL concentrations, by up to 30
`percent at the maximal dose, exceeds that of all other drugs. 1 oo In addition, nicotinic acid causes a shift
`in the form of LDL fro Ill small, dense particles to large, buoyant particles and lowers serum Lp(a)
`lipoprotein concentrations by about 30 percent. fil
`
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`Figure 3. Mechanisms of ~ction ofNicotinic Acid.
`
`Nicotinic acid inhibits the mobilization of free fatty acids (FF A)
`from peripheral adipose tissue to the liver. As a consequence of this
`decrease or an additional hepatic effect, the synthesis and secretion
`of very-low-density lipoprotein (VLDL) are reduced, and the
`conversion of VLDL to low-density lipoprotein (LDL) is
`decreased. 96 Nicotinic acid can also increase serum high-density
`lipoprotein (HDL) cholesterol concentrations by up to 30 percent;
`the mechanism responsible for this effect is unknown. Reproduced
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`from Knopp et al. 100 with the permission of the publishers.
`
`Nicotinic acid has proved most effective in preventing heart disease when it is given in combination
`with other drugs, such as a bile-acid-binding resin30,J..L 103 or a fibrate. 104 Treatment with nicotinic acid
`has also been reported t:o reduce the rates of nonfatal and fatal myoc~dial infarction and the total 15-
`year mortality rate. 105• 106 The ability of combination therapy with nicotinic acid and a statin to prevent
`cardiovascular disease has not been studied, but the combination lowers serum LDL cholesterol
`concentrations more than treatment with either drug alone, without increasing adverse effects'. 1o7,108
`Combination therapy also reduces serum triglyceride and remnant lipopr_otein concentrations, raises
`serum HDL cholesterol concentrations, and improves the LDL-subclass profile 109 more than does
`monotherapy. 107•108
`
`Adverse Effects
`
`The predominant adverse effect of nicotinic acid is flushing of the skin, an effect that about 10 percent
`of patients find intolerable (Table 5). The administration of 325 mg of aspirin 30 to 60 minutes before
`each dose of nicotinic acid reduces the severity of flushing, and the aspirin can often be discontinued
`after a few days as tachyphylaxis develops in response to the prostaglandin-mediated flush. Patients can
`also minimize flushing by taking nicotinic acid at the end of a meal and by not taking it with hot liquids.
`With the use of these precautionary measures, nicotinic acid can be started at a moderate dose, such as
`250 to 500 mg twice daily, depending on the patient's size. The daily dose can be increased at monthly
`intervals by 500 or 1000 mg, to a maximum of 3000 mg, if serum aminotransferase, glucose, and uric
`acid concentrations do not increase excessively. With each increase in the dose, flushing may recur.
`
`Other adverse effects include conjunctivitis, nasal stuffiness, loose bowel movements or diarrhea,
`acanthosis nigricans, and ichthyosis (Table S). Hepatitis is more frequent in patients who are taking
`nicotinic acid than in those who are taking statins, especially at doses of more than 2000 to 3000 mg of
`nicotinic acid daily. The symptoms and time course of nicotinic-acid-induced hepatitis are similar to
`those associated with statins.
`
`Timed-release formulations of nicotinic acid are designed to minimize cutaneous flushing. However, the
`absence of flushing may indicate poor gastrointestinal absorption. 1OO,J 02 Other drawbacks of such
`formulations are hepatotoxicity at doses of2000 mg per day or higher 100,llQ and smaller decreases in
`serum triglyceride concentrations anq smaller increases in serum HDL cholesterol concentrations than
`are induced with plain nicotinic acid. 1 OQ,llQ Nonetheless, some timed-release formulations are useful in
`patients who cannot tolerate plain nicotinic acid and are equivalent to plain nicotinic acid with respect to
`the effects on serum lipid and aminotransferase concentrations.lfil.
`
`Indications
`
`The changes in serwn triglyceride and HDL cholesterol concentrations that are induced by nicotinic acid
`are curvilinear, whereas the changes in serum LDL cholesterol concentrations are linear (~).ill
`Thus, a daily dose of 1500 to 2000 mg ofnicotinic acid will substantially change the serum triglyceride
`
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`and HDL cholesterol concentrations without causing many of the mucocutaneous and hepatic adverse
`effects seen with higher doses. This dose is often ideal for patients with familial combined
`hyperlipidemia. These patients usually need to take a statin as well, and because it is tolerated better, the
`statin should be given first. The patients may then be more receptive to moderate doses of plain or
`timed-release nicotinic acid. Higher doses of nicotinic acid (3000 to 4500 mg daily) may be needed to
`reduce serum LDL choleste~ol concentrations substantially in patients with familial
`hyperchoJesterolemia even when statins and a bile-acid-binding resin are given concomitantly.
`
`Figure 4. Effects of Plain and Timed-Release Nicotinic Acid on
`Serum Lipoprotein Concentrations.
`
`Low doses of plain nicotinic acid have more favorable effects than
`most timed-release forms on serum triglyceride and high-density
`lipoprotein (HDL) cholesterol concentrations. The plain and timed(cid:173)
`release forms have similar effects at any given dose on serum low(cid:173)
`density lipoprotein (LDL) cholesterol concentrations. The majority
`of the effects on serum triglyceride and HDL cholesterol
`concentrations occur with lower doses of nicotinic acid.
`
`0
`
`3000
`2000
`1000
`Doosa of Nlmtinic Add lmQl!byl
`
`.._
`
`View larger version (9K):
`[in this window].
`[in a new window].
`
`Fib rates
`
`Lipid-Altering Effects
`
`The prototypical fibric acid is clofibrate (ethylp-chlorophenoxyisobutyrate). Clofibrate and related
`drugs resemble, in part,. short-chain fatty acids and increase the oxidation of fatty acids in both liver and
`muscle (Figure 5). The increase in fatty-acid oxidation in the liver is associated with increased formation
`of ketone bodies (an effect that is not clinically important)112 and decreased secretion oftriglyceride(cid:173)
`rich lipoproteins. In muscle, the increase. in fatty-acid oxidation is associated with an increase in both
`lipoprotein lipase activity and the uptake of fatty acids. 113 These drugs act by activating the nuclear
`transcription factor peroxisome proliferator-activated receptor a (PPARa-), up-regulating the expression
`of the LDL cholesterol and apolipoprotein AI genes, and down-regulating the expression of the
`apolipopr~tein en gene.ill.ill
`
`-...::-.~
`
`'I.
`
`~\···~· .. ·;-.... tt··-··~r7~7ff
`·~...
`·-·~ ··~ -~~ -
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`~~·· .... ~~ .. --::-. =·
`-~. _)/#
`. ·-~ ~ _·/'
`
`View larger version (5 lK):
`[in this window].
`[in a new window]
`
`Figure 5. Metabolic Effects of Fibrates.
`
`Bold lines indicate increased transport, and dashed lines
`diminished transport. Fibrates enhance the oxidation of fatty acids
`(FA) in liver and muscle and reduce the rate of lipogenesis in t:he
`liver, thereby reducing hepatic secretion of very-low-density
`lipoprotein (VLDL) triglycerides (TG). The increased uptake of
`triglyceride-derived fatty acids in muscle cells results from an
`increase in lipoprotein lipase (LPL) activity in adjacent capillaries
`and a decrease in the apolipoprotein CIII (Apo CIII) concentration
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`mediated transcriptionally by peroxisome proliferator-:activated
`receptor er (PP ARa). The decrease in apolipoprotein CHI reduces
`the inhibition of LPL activity. The enhanced catabolism ofVLDL
`generates surface remnants, which are transferred to high-density
`lipoprotein (HDL). HDL concentrations are further augmented by
`an increase in PP ARa-mediated transcription of apolipoprotein AI
`(Apo Al) and apolipoprotein All (Apo All). Ultimately, the rate of
`HDL-mediated reverse cholesterol transport may increase. Fibrates
`activate PP ARcr, which binds to a PPARcr response element in
`conjunction with the retinoid X receptor. Other effects of fibrates
`include an increase in the size ofLDL particles, increased removal
`ofLDL, and a reduction in the levels of plasminogen activator
`inhibitor type I.
`
`The fibrates are the most effective triglyceride-lowering drugs.28 Patients with very high serum
`triglyceride concentraticms have low serum LDL cholesterol concentrations, and these may increase
`during treatment with a fibrate. If the increase is substantial, a low-dose statin may be added to the
`regimen. Conversely, in patients with high