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that is formed by HMG-CoA reductase in the synthesis of mevalonate. These analogs cause partial inhibition of the enzyme and thus may impair the synthesis of isoprenoids such as ubiquinone and dolichol and the prenylation of proteins. It is not known whether this has biologic significance. However, the reductase inhibitors clearly induce an increase in high-affinity LDL receptors. This effect increases both the fractional catabolic rate of LDL and the liver’s extraction of LDL precursors (VLDL remnants) from the blood, thus reducing LDL (Figure 35–2). Because of marked first-pass hepatic extraction, the major effect is on the liver. Preferential activity in liver of some congeners appears to be attributable to tissue-specific differences in uptake. Modest decreases in plasma triglycerides and small increases in HDL also occur.

Clinical trials involving many of the statins have demonstrated significant reduction of new coronary events and atherothrombotic stroke. Mechanisms other than reduction of lipoprotein levels appear to be involved. The availability of isoprenyl groups from the HMG-CoA pathway for prenylation of proteins is reduced by statins, resulting in reduced prenylation of Rho and Rab proteins. Prenylated Rho activates Rho kinase, which mediates a number of mechanisms in vascular biology. The observation that reduction in new coronary events occurs more rapidly than changes in morphology of arterial plaques suggests that these pleiotropic effects may be important. Likewise, decreased prenylation of Rab reduces the accumulation of

Aβ protein in neurons, possibly mitigating the manifestations of Alzheimer’s disease.

Therapeutic Uses & Dosage

Reductase inhibitors are useful alone or with resins, niacin, or ezetimibe in reducing levels of LDL. Women with hyperlipidemia who are pregnant, lactating, or likely to become pregnant should not be given these agents. Use in children is restricted to selected patients with familial hypercholesterolemias.

Because cholesterol synthesis occurs predominantly at night, reductase inhibitors—except atorvastatin, rosuvastatin, and pitavastatin—should be given in the evening. Absorption generally (with the exception of pravastatin and pitavastatin) is enhanced by food. Daily doses of lovastatin vary from 10 to 80 mg. Pravastatin is nearly as potent on a mass basis as lovastatin with a maximum recommended daily dose of 80 mg. Simvastatin is twice as potent and is given in doses of 5–80 mg daily. Because of increased risk of myopathy with the 80-mg/d dose, the U.S. Food and Drug Administration (FDA) issued labeling for scaled dosing of simvastatin and combined ezetimibe/simvastatin in 2011. Pitavastatin is given in doses of 1–4 mg daily. Fluvastatin appears to be about half as potent as lovastatin on a mass basis and is given in doses of 10–80 mg daily. Atorvastatin is given in doses of 10–80 mg/d, and rosuvastatin at 5–40 mg/d. The dose-response curves of pravastatin and

especially of fluvastatin tend to level off in the upper part of the dosage range in patients with moderate to severe hypercholesterolemia. Those of other statins are somewhat more linear.

Toxicity

Elevations of serum aminotransferase activity (up to three times normal) occur in some patients. This is often intermittent and usually not associated with other evidence of hepatic toxicity. Therapy may be continued in such patients in the absence of symptoms if aminotransferase levels are monitored and stable. In some patients, who may have underlying liver disease or a history of alcohol abuse, levels may exceed three times normal. This finding portends more severe hepatic toxicity. These patients may present with malaise, anorexia, and precipitous decreases in LDL. Medication should be discontinued immediately in these patients and in asymptomatic patients whose aminotransferase activity is persistently elevated to more than three times the upper limit of normal. These agents should be used with caution and in reduced dosage in patients with hepatic parenchymal disease, north Asians, and the elderly. Severe hepatic disease may preclude their use. In general, aminotransferase activity should be measured at baseline, at 1–2 months, and then every 6–12 months (if stable). Monitoring of liver enzymes should be more frequent if the patient is taking other drugs that have potential interactions with the statin. Excess intake of alcohol tends to aggravate hepatotoxic effects of statins. Fasting plasma glucose levels tend to increase 5–7 mg/dL with statin treatment. Long-term studies have shown a small but significant increase in the incidence of type 2 diabetes in statin-treated patients, most of whom had findings of prediabetes before treatment.

Minor increases in creatine kinase (CK) activity in plasma are observed in some patients receiving reductase inhibitors, frequently associated with heavy physical activity. Rarely, patients may have marked elevations in CK activity, often accompanied by generalized discomfort or weakness in skeletal muscles. If the drug is not discontinued, myoglobinuria can occur, leading to renal injury. Myopathy may occur with monotherapy, but there is an increased incidence in patients also receiving certain other drugs. Genetic variation in an anion transporter (OATP1B1) is associated with severe myopathy and rhabdomyolysis induced by statins. Variants in the gene (SLCO1B1) coding for this protein can now be assessed (see Chapter 5).

The catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through CYP3A4, whereas that of fluvastatin and rosuvastatin, and to a lesser extent pitavastatin, is mediated by CYP2C9. Pravastatin is catabolized through other pathways, including sulfation. The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These include the macrolide antibiotics, cyclosporine, ketoconazole and its congeners, some HIV protease inhibitors, tacrolimus, nefazodone, fibrates, paroxetine, venlafaxine, and others (see Chapters 4 and 66). Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy.

Conversely, drugs such as phenytoin, griseofulvin, barbiturates, rifampin, and thiazolidinediones increase expression of CYP3A4 and can reduce the plasma concentrations of the 3A4-dependent reductase inhibitors. Inhibitors of CYP2C9 such as ketoconazole and its congeners, metronidazole, sulfinpyrazone, amiodarone, and cimetidine may increase plasma levels of fluvastatin and rosuvastatin. Pravastatin and rosuvastatin appear to be the statins of choice for use with verapamil, the ketoconazole group of antifungal agents, macrolides, and cyclosporine. Doses should be kept low and the patient monitored frequently. Plasma levels of lovastatin, simvastatin, and atorvastatin may be elevated in patients ingesting more than 1 liter of grapefruit juice daily. All statins undergo glycosylation, thus creating an interaction with gemfibrozil.

Creatine kinase activity should be measured in patients receiving potentially interacting drug combinations. In all patients, CK should be measured at baseline. If muscle pain, tenderness, or weakness appears, CK should be measured immediately and the drug discontinued if activity is elevated significantly over baseline. The myopathy usually reverses promptly upon cessation of therapy. If the association is unclear, the patient can be rechallenged under close surveillance. Myopathy in the absence of elevated CK can occur. Rarely, hypersensitivity syndromes have been reported that include a lupus-like disorder, dermatomyositis, peripheral neuropathy, and autoimmune myopathy. The latter presents as severe pain and weakness in proximal muscles that does not remit when the statin is discontinued. It is HMG-CoA reductase antibody positive and requires immunosuppressive treatment.

Reductase inhibitors may be temporarily discontinued in the event of serious illness, trauma, or major surgery to minimize the potential for liver and muscle toxicity.

Use of red yeast rice, a fermentation product that contains statin activity, is not recommended because the statin content is highly variable and some preparations contain a nephrotoxin, citrinin. The long-term safety of these preparations, which often contain a large number of poorly studied organic compounds, has not been established.

FIBRIC ACID DERIVATIVES (FIBRATES)

Gemfibrozil and fenofibrate decrease levels of VLDL and, in some patients, LDL as well. Another fibrate, bezafibrate, is not yet available in the USA.

Chemistry & Pharmacokinetics

Gemfibrozil is absorbed quantitatively from the intestine and is tightly bound to plasma proteins. It undergoes enterohepatic circulation and readily passes the placenta. The plasma half-life is 1.5 hours. Seventy percent is eliminated through the kidneys, mostly unmodified. The liver modifies some of the drug to hydroxymethyl, carboxyl, or quinol derivatives. Fenofibrate is an isopropyl ester that is hydrolyzed completely in the intestine.

Its plasma half-life is 20 hours. Sixty percent is excreted in the urine as the glucuronide, and about 25% in feces.

CH3

CH3

Mechanism of Action

Fibrates function primarily as ligands for the nuclear transcription receptor PPAR-α. They transcriptionally upregulate LPL, apo A-I, and apo A-II, and they downregulate apo C-III, an inhibitor of lipolysis. A major effect is an increase in oxidation of fatty acids in liver and striated muscle (Figure 35–4). They increase lipolysis of lipoprotein triglyceride via LPL. Intracellular lipolysis in adipose tissue is decreased. Levels of VLDL decrease, in part as a result of decreased secretion by the liver. Only modest reductions of LDL occur in most patients. In others, especially those with combined hyperlipidemia, LDL often increases as triglycerides are reduced. HDL cholesterol increases moderately. Part of this apparent increase is a consequence of lower triglyceride in plasma, resulting

CHAPTER 35 Agents Used in Dyslipidemia 635

in reduction in the exchange of triglycerides into HDL in place of cholesteryl esters.

Therapeutic Uses & Dosage

Fibrates are useful drugs in hypertriglyceridemias in which VLDL predominate and in dysbetalipoproteinemia. They also may be of benefit in treating the hypertriglyceridemia that results from treatment with antiviral protease inhibitors. The usual dose of gemfibrozil is 600 mg orally once or twice daily. The dosage of fenofibrate as Tricor is one to three 48-mg tablets (or a single 145-mg tablet) daily. Dosages of other preparations vary. Absorption of gemfibrozil is improved when the drug is taken with food.

Toxicity

Rare adverse effects of fibrates include rashes, gastrointestinal symptoms, myopathy, arrhythmias, hypokalemia, and high blood levels of aminotransferases or alkaline phosphatase. A few patients show decreases in white blood count or hematocrit. Both agents may potentiate the action of anticoagulants, and doses of these agents should be adjusted. Rhabdomyolysis has occurred rarely. Risk of myopathy increases when fibrates are given with reductase inhibitors. Fenofibrate is the fibrate of choice for use in combination with a statin. Fibrates should be avoided in patients with hepatic or renal dysfunction. There appears to be a modest increase in the risk of cholesterol gallstones, reflecting an increase in the cholesterol content of bile. Therefore, fibrates should be used with caution in patients with biliary tract disease or in those at higher risk such as women, obese patients, and Native Americans.

NIACIN (NICOTINIC ACID)

Niacin (but not niacinamide) decreases triglycerides and LDL levels, and Lp(a) in most patients. It often increases HDL levels significantly. Historically, combination therapy including niacin has been associated with regression of atherosclerotic coronary lesions in three angiographic trials and with extension of lifespan in one large trial in which patients received niacin alone.

Chemistry & Pharmacokinetics

In its role as a vitamin, niacin (vitamin B3) is converted in the body to the amide, which is incorporated into niacinamide adenine dinucleotide (NAD), which in turn has a critical role in energy metabolism. In pharmacologic doses, it has important effects on lipid metabolism that are poorly understood. It is excreted in the urine unmodified and as several metabolites. One, N-methyl nicotinamide, creates a draft on methyl groups that can occasionally result in erythrocyte macrocytosis, similar to deficiency of folate or vitamin B12.

Mechanism of Action

Niacin inhibits VLDL secretion, in turn decreasing production of LDL (Figure 35–2). Increased clearance of VLDL via the LPL pathway contributes to reduction of triglycerides. Excretion of neutral sterols in the stool is increased acutely as cholesterol is mobilized from tissue pools and a new steady state is reached. The catabolic rate for HDL is decreased. Fibrinogen levels are reduced, and levels of tissue plasminogen activator appear to increase. Niacin inhibits the intracellular lipase of adipose tissue via receptor-mediated signaling, possibly reducing VLDL production by decreasing the flux of free fatty acids to the liver. Sustained inhibition of lipolysis has not been established, however.

Therapeutic Uses & Dosage

In combination with a resin or reductase inhibitor, niacin normalizes LDL in most patients with heterozygous familial hypercholesterolemia and other forms of hypercholesterolemia. These combinations are also indicated in some cases of nephrosis. In severe mixed lipemia that is incompletely responsive to diet, niacin often produces marked reduction of triglycerides, an effect enhanced by marine omega-3 fatty acids. It is useful in patients with combined hyperlipidemia and in those with dysbetalipoproteinemia. Niacin is clearly the most effective agent for increasing HDL and reduces Lp(a) in most patients.

For treatment of heterozygous familial hypercholesterolemia, 2–6 g of niacin daily is usually required; more than this should not be given. For other types of hypercholesterolemia and for hypertriglyceridemia, 1.5–3.5 g daily is often sufficient. Crystalline niacin should be given in divided doses with meals, starting with 100 mg two or three times daily and increasing gradually.

Toxicity

Most persons experience a harmless cutaneous vasodilation and sensation of warmth after each dose when niacin is started or

the dose increased. Taking 81–325 mg of aspirin 30 minutes beforehand blunts this prostaglandin-mediated effect. Naproxen, 220 mg once daily, also mitigates the flush. Tachyphylaxis to flushing usually occurs within a few days at doses above 1.5–3 g daily. Patients should be warned to expect the flush and understand that it is a harmless side effect. Pruritus, rashes, dry skin or mucous membranes, and acanthosis nigricans have been reported. The latter requires the discontinuance of niacin because of its association with insulin resistance. Some patients experience nausea and abdominal discomfort. Many can continue the drug at reduced dosage, with inhibitors of gastric acid secretion or with antacids not containing aluminum. Niacin should be avoided in patients with significant peptic disease.

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-the- counter 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.

BILE ACID–BINDING RESINS

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.

Chemistry & Pharmacokinetics

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.

Therapeutic Uses & Dosage

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.

Colestipol and cholestyramine are available as granular preparations. A gradual increase of dosage of granules from 4 or 5 g/d to 20 g/d is recommended. Total dosages of 30–32 g/d may be needed for maximum effect. The usual dosage for a child is 10–20 g/d. Granular resins are mixed with juice or water and allowed to hydrate for 1 minute. Colestipol is also available in 1-g tablets that must be swallowed whole, with a maximum dose of 16 g daily. Colesevelam is available in 625-mg tablets and as a suspension (1875-mg or 3750-mg packets). The maximum dose is six tablets or 3750 mg as suspension, daily. Resins should be taken in two or three doses with meals.

Toxicity

Common complaints are constipation and bloating, usually relieved by increasing dietary fiber. Resins should be avoided in patients with diverticulitis. Heartburn and diarrhea are occasionally reported. In patients who have preexisting bowel disease or cholestasis, steatorrhea may occur. Malabsorption of vitamin K occurs rarely, leading to hypoprothrombinemia. Prothrombin time should be measured frequently in patients who are taking resins and anticoagulants. Malabsorption of folic acid has been reported rarely. Increased formation of gallstones, particularly in obese persons, was an anticipated adverse effect but has rarely occurred in practice.

Absorption of certain drugs, including those with neutral or cationic charge as well as anions, may be impaired by the resins. These include digitalis glycosides, thiazides, warfarin, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, ezetimibe, folic acid, phenylbutazone, aspirin, and ascorbic acid, among others.

CHAPTER 35 Agents Used in Dyslipidemia 637

In general, additional medication (except niacin) should be given 1 hour before or at least 2 hours after the resin to ensure adequate absorption. Colesevelam does not bind digoxin, warfarin, or reductase inhibitors.

INHIBITORS OF INTESTINAL STEROL ABSORPTION

Ezetimibe inhibits intestinal absorption of phytosterols and cholesterol. Added to statin therapy, it provides an additional effect, decreasing LDL levels and further reducing the dimensions of atherosclerotic plaques.

Chemistry & Pharmacokinetics

Ezetimibe is readily absorbed and conjugated in the intestine to an active glucuronide, reaching peak blood levels in 12–14 hours. It undergoes enterohepatic circulation, and its half-life is 22 hours. Approximately 80% of the drug is excreted in feces. Plasma concentrations are substantially increased when it is administered with fibrates and reduced when it is given with cholestyramine. Other resins may also decrease its absorption. There are no significant interactions with warfarin or digoxin.

OH

OH

N F

O

F

Ezetimibe

Mechanism of Action

Ezetimibe selectively inhibits intestinal absorption of cholesterol and phytosterols. A transport protein, NPC1L1, is the target of the drug. It is effective in the absence of dietary cholesterol because it also inhibits reabsorption of cholesterol excreted in the bile.

Therapeutic Uses & Dosage

The effect of ezetimibe on cholesterol absorption is constant over the dosage range of 5–20 mg/d. Therefore, a daily dose of 10 mg is used. Average reduction in LDL cholesterol with ezetimibe alone in patients with primary hypercholesterolemia is about 18%, with minimal increases in HDL cholesterol. It is also effective in patients with phytosterolemia. Ezetimibe is synergistic with reductase inhibitors, producing decrements as great as 25% in LDL cholesterol beyond that achieved with the reductase inhibitor alone.

Toxicity

Ezetimibe does not appear to be a substrate for cytochrome P450 enzymes. Experience to date reveals a low incidence of reversible impaired hepatic function with a small increase in incidence when given with a reductase inhibitor. Myositis has been reported rarely.

INHIBITION OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN

Microsomal triglyceride transfer protein (MTP) plays an essential role in the addition of triglycerides to nascent VLDL in liver, and to chylomicrons in the intestine. Its inhibition decreases VLDL secretion and consequently the accumulation of LDL in plasma. An MTP inhibitor, lomitapide, is available but is currently restricted to patients with homozygous familial hypercholesterolemia. It causes accumulation of triglycerides in the liver in some individuals. Elevations in transaminases can occur. Patients must maintain a low fat diet to avoid steatorrhea and should take steps to minimize deficiency of essential fat-soluble nutrients. Lomitapide is given orally in gradually increasing doses of 5- to 60-mg capsules once daily 2 hours after the evening meal. It is available only through a restricted (REMS) program for patients with homozygous familial hypercholesterolemia.

ANTISENSE INHIBITION OF APO B-100 SYNTHESIS

Mipomersen is an antisense oligonucleotide that targets apo B-100, mainly in the liver. It is important to note that the apo B-100 gene is also transcribed in the retina and in cardiomyocytes. Subcutaneous injections of mipomersen reduce levels of LDL and Lp(a). Mild to moderate injection site reactions and flu-like symptoms can occur. The drug is available only for use in homozygous familial hypercholesterolemia through a restricted (REMS) program.

PCSK9 INHIBITION

Development of inhibitors of proprotein convertase subtilisin/ kexin type 9 (PCSK9) followed on the observation that loss of function mutations result in very low levels of LDL and no apparent morbidity. Therapeutic agents currently available in this class are humanized antibodies to PCSK9 (evolocumab, alirocumab). LDL reductions of up to 70% at the highest doses have been achieved with these agents when administered subcutaneously every two weeks. (Evolocumab can also be given monthly at a higher dose). Triglycerides and apo B-100 are reduced, and Lp(a) levels decrease by about 25%. Rarely, hypersensitivity reactions have occurred. Local reactions at the injection site, upper respiratory and flu-like symptoms have been observed more frequently. Use of these agents is restricted to patients who have familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional reduction of LDL. They are given with diet and maximal tolerated statin and/or ezetimibe. Development of small molecules and antisense oligonucleotides to inhibit PCSK9 is underway. Studies of PCSK9 inhibition should be approached with caution because of its established role in normal cell biology. These agents are very expensive.

AGENTS UNDER DEVELOPMENT

CETP INHIBITION

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from mature, large diameter HDL particles to triglyceriderich lipoproteins that ultimately deliver the esters to liver whence both cholesterol and bile acids can be eliminated into the intestine. Inhibition of CETP leads to accumulation of mature HDL particles and diminution of the transport of cholesteryl esters to liver. The accumulation of large HDL particles does not have the cardioprotective effect anticipated on the basis of epidemiologic studies. Some reduction of LDL-C can be achieved and cholesterol efflux capacity enhanced. Thus far no drug (eg, torcetrapib, anacetrapib) in this class has been approved.

AMP KINASE ACTIVATION

AMP-activated protein kinase acts as a sensor of energy status in cells. When increased ATP availability is required, AMP kinase increases fatty acid oxidation and insulin sensitivity, and inhibits cholesterol and triglyceride biosynthesis. Although the trials to date have been directed at decreasing LDL-C levels, AMP kinase activation may have merit for management of the metabolic syndrome and diabetes. An agent combining AMP kinase activation and ATP citrate lyase inhibition is in clinical trials.

CYCLODEXTRINS

These are circular sugar polymers that can solubilize hydrophobic drugs for delivery and are approved for this purpose. They can also solubilize cholesterol from tissue sites such as arteriosclerotic plaque. Early stage animal studies on this potential therapeutic activity are in progress.

TREATMENT WITH DRUG COMBINATIONS

Combined drug therapy is useful (1) when VLDL levels are significantly increased during treatment of hypercholesterolemia with a resin; (2) when LDL and VLDL levels are both elevated initially;

(3) when LDL or VLDL levels are not normalized with a single agent, or (4) when an elevated level of Lp(a) or an HDL deficiency coexists with other hyperlipidemias. The lowest effective doses should be used in combination therapy and the patient should be monitored more closely for evidence of toxicity. In combinations that include resins, the other agent (with the exception of niacin) should be separated temporally to ensure absorption.

FIBRIC ACID DERIVATIVES & BILE ACID BINDING RESINS

This combination is sometimes useful in treating patients with familial combined hyperlipidemia who are intolerant of niacin or statins. However, it may increase the risk of cholelithiasis.

HMG CoA REDUCTASE INHIBITORS &

BILE ACID BINDING RESINS

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.

NIACIN & BILE ACID BINDING RESINS

This combination effectively controls VLDL levels during resin therapy of familial combined hyperlipoproteinemia or other disorders involving both increased VLDL and LDL levels. When VLDL and LDL levels are both initially increased, doses of niacin as low as 1–3 g/d may be sufficient in combination with a resin. The niacin-resin combination is effective for treating heterozygous familial hypercholesterolemia.

NIACIN & REDUCTASE INHIBITORS

If the maximum tolerated statin dose fails to achieve the LDL cholesterol goal in a patient with hypercholesterolemia, niacin may be helpful. This combination may be useful in the treatment of familial combined hyperlipoproteinemia.

REDUCTASE INHIBITORS & EZETIMIBE

This combination is synergistic in treating primary hypercholesterolemia and may be of use in the treatment of patients with homozygous familial hypercholesterolemia who have some receptor function.

CHAPTER 35 Agents Used in Dyslipidemia 639

REDUCTASE INHIBITORS &

FENOFIBRATE

Fenofibrate appears to be complementary with most statins in the treatment of familial combined hyperlipoproteinemia and other conditions involving elevations of both LDL and VLDL. The combination of fenofibrate with rosuvastatin appears to be especially well tolerated. Some other statins may interact unfavorably owing to effects on cytochrome P450 metabolism. In any case, particular vigilance for liver and muscle toxicity is indicated.

COMBINATIONS OF RESINS, EZETIMIBE, NIACIN, & REDUCTASE INHIBITORS

These agents act in a complementary fashion to normalize cholesterol in patients with severe disorders involving elevated LDL. The effects are sustained, and little compound toxicity has been observed. Effective doses of the individual drugs may be lower than when each is used alone; for example, as little as 1–2 g of niacin may substantially increase the effects of the other agents.

COMBINATIONS OF PCSK9 ANTIBODY WITH STATIN AND EZETIMIBE

These agents can be used together to achieve maximal reduction of LDL. Because of the need for parenteral administration of PCSK9 antibody and its expense, this therapy is reserved for patients with familial hypercholesterolemia or atherosclerotic vascular disease who do not respond adequately to other regimens.

P R E P A R A T I O N S

A V A I L A B L E

REFERENCES

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Boekholdt SM et al: Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: A meta-analysis. Circulation 2013;128:1504.

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C A S E S T U D Y A N S W E R

The patient’s history of muscle symptoms should be carefully evaluated. The genotype at the SLCO1B1 locus might be obtained to determine whether myositis is due to impaired metabolism of statins. If you agree that her muscle symptoms were clearly associated with statin use but were not particularly severe and not associated with creatine kinase elevations significantly greater than normal, you could prescribe any one the agents she tried in the past or select a different statin. The starting dose should be low and the drug given on alternate days, increasing the dose and frequency to achieve the

LDL-C goal. If this is not tolerated or the goal is not reached, alternate drugs can be used, including a bile acid binding resin, intestinal sterol absorption inhibitor, or niacin (monitoring uric acid, glucose, and liver enzymes). These can be used in combinations with each other or with a low dose statin. If all else fails, use of a PCSK9 monoclonal antibody should be considered. Her homocysteine level should be measured because of the synergy between that amino acid and Lp(a) with respect to thrombotic risk. Also, because of her elevated Lp(a), she should be evaluated for aortic stenosis.

A 48-year-old man presents with complaints of bilateral morning sti ness in his wrists and knees and pain in these joints on exercise. On physical examination, the joints are slightly swollen. e rest of the examination is unremarkable. His laboratory ndings are also negative except for slight anemia, elevated erythrocyte sedimentation rate, and positive rheumatoid factor. With the diagnosis of rheumatoid arthritis, he is started on a regimen of naproxen, 220 mg twice daily. A er 1 week, the dosage is increased to 440 mg

twice daily. His symptoms are reduced at this dosage, but he complains of signi cant heartburn that is not controlled by antacids. He is then switched to celecoxib, 200 mg twice daily, and on this regimen his joint symptoms and heartburn resolve. Two years later, he returns with increased joint symptoms. His hands, wrists, elbows, feet, and knees are all now involved and appear swollen, warm, and tender. What therapeutic options should be considered at this time? What are the possible complications?