Statins are currently the most prescribed lipid-altering drugs because of their efficacy in favorably altering blood lipid levels, safety and tolerability, and proven benefits on reducing atherosclerotic coronary heart disease (CHD) events. Combination lipid-altering drug therapy with statins is often indicated for patients: (1) who are unable to achieve recommended treatment goals with statin monotherapy, (2) who may be at risk for intolerance, toxicity, or adverse drug interactions with higher-dose statin monotherapy, or (3) who may benefit from the use of one or more lipid-altering drugs in combination with statins resulting in complementary benefits towards further reduction in CHD risk. Some of the lipid-altering agents most commonly used in combination with statins include ezetimibe, bile acid sequestrants, peroxisome proliferator-activated receptor (PPAR) agonists, fish oils, and niacin. A potentially important investigational lipid-altering drug combination is statin in combination with a cholesteryl ester transport inhibitor.

The National Cholesterol Education Program Adult Treatment Panel III (ATP III) defines high-risk patients as those who have CHD or atherosclerotic disease of the blood vessels to the brain or extremities, or diabetes, or multiple (2 or more) risk factors (e.g., smoking, hypertension) that give them a >20% chance of having a heart attack within 10 years. Very high risk patients are those who have cardiovascular disease together with (1) multiple risk factors (especially diabetes), or severe and poorly controlled risk factors (e.g., continued smoking), (2) metabolic syndrome (a constellation of risk factors associated with obesity including high triglycerides and low high-density lipoprotein cholesterol [HDL-C]) and/or (3) acute coronary syndromes such as heart attack. For high-risk patients, the overall goal is to achieve a low-density lipoprotein cholesterol (LDL-C) level of <100 mg/dL. But for patients at very high risk, a group that is considered a "subset" of the high-risk category, a therapeutic option is to decrease LDL-C levels to <70 mg/dL. For very high risk patients whose LDL-C levels are already <100 mg/dL, there is also an option to use drug therapy to reach the <70-mg/dL treatment goal.

For moderately high risk patients, the goal is to achieve an LDL-C level <130 mg/dL, but it is a therapeutic option to set a lower LDL-C goal of <100 mg/dL and to use drug therapy for LDL-C levels of 100–129 mg/dL to achieve this lower goal. For high-risk or moderately high risk patients, the report advises that LDL-C–lowering drug therapy be sufficient to achieve at least a 30–40% reduction in LDL-C levels. This can be accomplished by taking statins or by combining lower doses of statins with other drugs (bile acid resins, nicotinic acid, or ezetimibe) or with food products containing plant stanols/sterols. For moderately high risk patients with LDL-C levels of 100–129 mg/dL at baseline or on lifestyle therapy, LDL-C–lowering therapy to reach a goal of <100 mg/dL is recommended, and lipid-altering drug therapy to achieve this goal is a therapeutic option. By definition, almost all people with 0–1 risk factor have a 10-year risk <10%. Drug therapy for primary prevention in this patient population is recommended only for those with higher LDL-C levels. Major CHD risk factors include cigarette smoking, blood pressure >140/90 mm Hg or on antihypertensive medication, HDL-C <40 mg/dL (1.0 mmol/L), family history of premature CHD (CHD in male first-degree relative aged <55 years; CHD in female first-degree relative aged <65 years), and age (men >45 years; women >55 years). HDL-C >60 mg/dL (>1.6 mmol/L) counts as a "negative" risk factor; its presence removes 1 risk factor from the total count. Framingham risk score may also be used to determine 10-year CHD risk.

1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-3421.
2. Grundy SM, Cleeman JI, Bairey Merz CN, et al., for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-239.
3. Bays H, Shepherd J. Diabetes, metabolic syndrome and dyslipidemia. In: Management Strategies in Diabetes. Hackensack, NJ: Cambridge Medical Publications, 2004:1-28.

Over the years, various surveys have documented that the very patients who are at highest CHD risk appear to be the least likely to achieve lipid treatment goals. One such survey was the Lipid Treatment Assessment Project (L-TAP). This analysis evaluated 4,888 patients (4,137 treated with drug therapy and 751 treated with diet and exercise) from 5 regions of the United States who were being treated for hypercholesterolemia in a primary care setting from August 1996 to February 1997. Of these patients, 30% had established CHD, 47% had >2 risk factors without evidence of CHD (high-risk group), and 23% had <2 risk factors (low-risk group). Although current achievement of lipid treatment goals may be improved over what may have been achieved in 1996–1997 (based upon this L-TAP analysis), it continues to be true that many of those patients at highest CHD risk often do not achieve lipid treatment goals.

1. Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000;160:459-467.

Many potential reasons exist as to why patients do not achieve lipid treatment goals. For example, some patients are never treated with any lipid-altering drug. Patient noncompliance may also be a factor. Known, potential, or perceived issues of tolerability and safety of high-dose statins among clinicians and patients may pose therapeutic challenges.

However, the resistance among many clinicians to use the highest doses of statins alone is due to not only concerns about toxicity and intolerability (which most often occur at higher doses), but also the recognition that most LDL-C reduction with statins occurs at the lower doses. In fact, each doubling of the statin dose produces an average additional decrease in LDL-C levels of about 5–6%, based upon the baseline LDL-C value ("rule of 6"). In the example above, atorvastatin 10 mg/day lowered mean LDL-C levels by 38%. Upon titration to 20 mg, 40 mg, and 80 mg, LDL-C levels were lowered only an additional 8%, 5%, and 3% respectively (based upon the baseline, pretreatment LDL-C level) for a total further reduction of 16% with these three titrations. In other words, starting with a mean baseline LDL-C level of 211 mg/dL, atorvastatin 10 mg/day would be expected to lower LDL-C levels to about 131 mg/dL (38% reduction). A three-step doubling of the dose to atorvastatin 80 mg/day would lower the baseline mean LDL-C levels an additional 16% to about 97 mg/dL (38% + 16% = 54% total reduction). The modest percent reduction after the lowest doses is also seen with the above simvastatin example, in which simvastatin 10 mg lowered mean LDL-C levels by 28%, while titration to 20 mg and 40 mg resulted in only an additional 7% and 6% reduction in LDL-C compared with the baseline value.

Finally, many patients with more severe dyslipidemias and/or in need of the most aggressive lipid therapy may not achieve lipid treatment goals even when the highest dose of statin is used. For all of these reasons, combination lipid-altering drug therapy is often indicated to avoid known or potential toxicity with higher doses of statin alone, or when statin monotherapy is insufficiently effective at the higher doses.

1. Illingworth DR. Management of hypercholesterolemia. Med Clin North Am 2000;84:23-42.
2. Bays H. Ezetimibe. Expert Opin Investig Drugs 2002;11:1587-1604.
3. Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVES Investigators. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998;81:582-587.

Conceptually, it might be argued that circulating cholesterol originates from predominantly two sources: synthesis (from liver and peripheral tissues) and absorption (from the intestine). Irrespective of the origins of cholesterol, it is the liver that normally serves as the main regulatory organ that determines LDL-C blood levels. (Cholesterol from endothelial macrophages associated with arterial cholesterol plaques are clinically important, but only a very minor contributor to total circulating cholesterol.)

Animal data suggest that most cholesterol synthesis in the body is from peripheral tissues such as intestine, muscle, and skin. The greatest amount of cholesterol produced per gram of tissue is from endocrine organs such as the ovary, adrenal glands, and gastrointestinal tract. This is because cholesterol is the "backbone" precursor for many hormones.

The relative contribution of cholesterol from any of these sources is dependent upon genetic predisposition, diet, drug therapies, interplay of enzymatic up- and down-regulations, and other potential factors. Decreased cholesterol contribution to the liver may increase hepatic LDL receptor activity and thus reduce circulating LDL-C blood levels, which in turn is associated with reduced risk for CHD. Thus, different lipid-altering drugs whose mechanism of action reduces different sources of cholesterol may have complementary actions in lowering LDL-C.

Additional abbreviation on slide: SR-B1 = scavenger receptor class B, type 1.

1. Bays H, Dujovne C. Colesevelam HCl: a non-systemic lipid-altering drug. Expert Opin Pharmacother 2003;4:779-790.
2. Dietschy JM, Turley SD, Spady DK. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res 1993;34:1637-1659.
3. Spady DK, Dietschy JM. Sterol synthesis in vivo in 18 tissues of the squirrel monkey, guinea pig, rabbit, hamster, and rat. J Lipid Res 1983;24:303-315.

Intestinal cholesterol absorption is an important origin of circulating LDL-C. Although dietary cholesterol does contribute, the majority (2/3 to 3/4) of cholesterol delivered to the intestine is derived from biliary cholesterol excretion. Intestinal cholesterol undergoes micellar adaptation by bile acids and is then absorbed into the intestinal cells. The ensuing free cholesterol may subsequently be "pumped" back into the intestine through adenosine triphosphate–binding cassette (ABC) transporters ABCG5 and ABCG8. Alternatively, intestinal free cholesterol may be esterified through acyl-coenzyme A:cholesterol acyltransferase (ACAT), and then packaged into chylomicrons (CMs) in the intestinal epithelial cell by microsomal triglyceride transfer protein (MTP). As CMs leave the intestine, their cholesterol is transported through the lymphatic system to the liver.

1. Bays H, Dujovne C. Colesevelam HCl: a non-systemic lipid-altering drug. Expert Opin Pharmacother 2003;4:779-790.
2. Bays H. Ezetimibe. Expert Opin Investig Drugs 2002;11:1587-1604.

Ezetimibe is the first in the class of cholesterol absorption inhibitors, whose mechanism of action is consistent with the binding to and blockade of a sterol transporter on the brush border membrane of intestinal epithelial cells. Radiolabeled ezetimibe is clearly found on the brush border where a transporter would be expected to reside. While a specific cholesterol transporter remained elusive for years, a Niemann-Pick C1 Like 1 Protein transporter has been discovered that appears to be critical for intestinal cholesterol absorption.

Through inhibition of intestinal cholesterol absorption, ezetimibe effectively reduces the amount of biliary/dietary cholesterol delivered to the liver (via chylomicrons and chylomicron remnants) and reduces the cholesterol content of atherogenic particles (chylomicrons/chylomicron remnants, VLDL, LDL). The reduced delivery of intestinal cholesterol to the liver increases hepatic LDL receptor activity and increases clearance of circulating LDL-C. LDL-C levels and LDL particles are thereby reduced.

1. Catapano AL. Ezetimibe: a selective inhibitor of cholesterol absorption. Eur Heart J Suppl 2001;3:E6-E10.
2. Bays H. Ezetimibe. Expert Opin Investig Drugs 2002;11:1587-1604.
3. Altmann SW, Davis HR Jr, Zhu LJ, et al. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science 2004;303:1201-1204.

The pharmacokinetic properties of ezetimibe make it suitable for once-daily administration. The time to maximum ezetimibe concentration is 4–12 hours.

1. Zaks A, Dodds DR. Enzymatic glucuronidation of a novel cholesterol absorption inhibitor, SCH 58235. Appl Biochem Biotechnol 1998;73:205-214.
2. Bays H. Ezetimibe. Expert Opin Investig Drugs 2002;11:1587-1604.
3. van Heek M, Farley C, Compton DS, et al. Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663. Br J Pharmacol 2000;129:1748-1754.

In two 12-week studies, ezetimibe monotherapy significantly decreased plasma LDL-C levels and increased plasma HDL-C levels, with a tolerability profile similar to that of placebo. The 10-mg dose of ezetimibe provided greater benefit on blood LDL-C level reduction compared with 5 mg, without affecting tolerability and without any significant increase in adverse events. Therefore, the 10-mg dose of ezetimibe was chosen as the only dose for phase III clinical trials. The 10-mg dose of ezetimibe was subsequently submitted to the FDA for approval in December 2001 and was approved for clinical use in November 2002.

1. Bays HE, Moore PB, Drehobl MA, et al., for the Ezetimibe Study Group. Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. Clin Ther 2001;23:1209-1230.

In this practical and clinically relevant randomized placebo-controlled trial, the efficacy and safety of ezetimibe "added on" to ongoing statin therapy was evaluated in 769 patients with hypercholesterolemia, CHD, and/or multiple risk factors. All subjects continued on stable doses of whatever statin had been prescribed by their treating clinician. They were eligible to enter the study if they had not achieved their NCEP ATP II LDL-C treatment goal with statin alone. After a 6-week run-in, about half of subjects were randomized to ezetimibe 10 mg once a day plus their statin, and the other half were randomized to placebo plus their statin. The primary endpoint was the percent LDL-C reduction at 8 weeks.

1. Gagné C, Bays HE, Weiss SR, et al, for the Ezetimibe Study Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002;90:1084-1091.

After 8 weeks in the "Add on" study, the addition of ezetimibe to ongoing statin therapy significantly reduced LDL-C, increased HDL-C, and decreased triglyceride levels compared with placebo plus statin.

1. Gagné C, Bays HE, Weiss SR, et al, for the Ezetimibe Study Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002;90:1084-1091.

Ezetimibe added to stable statin dose was markedly superior to placebo added to stable statin dose in achievement of NCEP ATP II LDL-C treatment goals.

1. Gagné C, Bays HE, Weiss SR, et al, for the Ezetimibe Study Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002;90:1084-1091.

In a study of 628 patients with primary hypercholesterolemia, ezetimibe plus 10 mg of atorvastatin was more effective than atorvastatin 10 mg, 20 mg, or 40 mg in lowering LDL-C levels. In fact, the LDL-C–lowering efficacy of 10 mg of ezetimibe plus 10 mg of atorvastatin was similar to 80 mg of atorvastatin. One method used to remember this clinical finding is the "formula" of "10 + 10 = 80."

1. Ballantyne CM, Houri J, Notarbartolo A, et al., for the Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003;107;2409-2415.

Three hours after intravenous administration to rats, the majority of radioactively labeled ezetimibe localized to the intestinal lumen and some of it was associated with the intestinal wall. In contrast, minute ezetimibe-derived radioactivity was found in plasma, liver, or bile. Therefore, although ezetimibe is technically a "systemic" drug because of its enterohepatic circulation and recirculation, the low systemic exposure of ezetimibe may help reduce its potential for systemic adverse effects and for drug interactions.

1. van Heek M, Farley C, Compton DS, et al. Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663. Br J Pharmacol 2000;129:1748-1754.

At least in part because of its limited systemic exposure, ezetimibe has limited drug interactions. Although colesevelam may have less potential for adverse drug interactions with ezetimibe than cholestyramine, the potential efficacy and drug interactions of the combination of colesevelam and ezetimibe have not been evaluated and/or reported. Mild increases in ezetimibe (less than a factor of 2) have been found with concomitant fibrate administration (gemfibrozil and fenofibrate). However, information on the safety and effectiveness of ezetimibe and fibrates awaits the results of ongoing studies.

1. Kosoglou T, Meyer I, Veltri EP, et al. Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin. Br J Clin Pharmacol 2002;54:309-319.
2. Bays H. Ezetimibe. Expert Opin Investig Drugs 2002;11:1587-1604.
3. Kosoglou T, Guillaume M, Sun S, et al. Pharmacodynamic interaction between fenofibrate and the cholesterol absorption inhibitor ezetimibe [abstract]. Atheroscler Suppl 2001;2:38.
4. Zhu Y, Statkevich P, Kosoglou T, et al. Effect of SCH 58235 on the activity of drug metabolizing enzymes in vivo [abstract]. Clin Pharmacol Ther 2000;67:152.
5. Stein E. Results of phase I/II clinical trials with exetimibe, a novel selective cholesterol absorption inhibitor. Eur Heart J Suppl 2001;3:E11-E16.

Ezetimibe is indicated for use as monotherapy and combination therapy with statins in patients with hypercholesterolemia.

1. Bays H. Ezetimibe. Expert Opin Investig Drugs 2002;11:1587-1604.
2. Dujovne CA, Ettinger MP, McNeer JF, et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol 2002;90:1092-1097.
3. Gagné C, Bays HE, Weiss SR, et al, for the Ezetimibe Study Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002;90:1084-1091.
4. Gagné C, Gaudet D, Bruckert E, et al. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002;105:2469-2475.
5. Salen G, von Bergmann K, Kweiterovich P, et al. Ezetimibe is an effective treatment for homozygous sitosterolemia [abstract]. Circulation 2002;106:II-185.

Ezetimibe is also indicated for treatment of homozygous sitosterolemia, a very rare inherited genetic disorder of the ABCG5/ABCG8 transporter protein. Phytosterols (such as sitosterol and campesterol) are not synthesized in humans and are derived entirely from the diet. Once absorbed by intestinal cells, ABCG5/ABCG8 transporters normally pump these potentially atherogenic phytosterols back into the intestinal lumen, normally resulting in <5% net absorption. Dysfunctional ABCG5/ABCG8 sterol transporters result in a net hyperabsorption of phytosterols, leading to tendinous and tuberous xanthomas and premature atherosclerosis that may or may not be accompanied by elevations in blood cholesterol levels. Ezetimibe inhibits net phytosterol absorption in these patients and is the only drug with an indication for treatment of homozygous sitosterolemia.

ABC transporters function to translocate or "pump" various compounds (such as sugars, amino acids, metal ions, peptides, proteins, and a large number of hydrophobic compounds and metabolites) across the membranes of cells and tissues. The ABC transporter superfamily is the largest transporter gene family and is typically classified into subfamilies of A–G.

Tangier disease is an inherited recessive disorder resulting from a defect in the ABCA1 transporter, which is responsible for the transport of cholesterol from peripheral tissues to HDL particles. No normal HDL exists in this disorder, and patients have very low levels of an abnormal HDL variant. Clinically, patients have yellow-orange tonsils, peripheral neuropathy, and hepatosplenomegaly thought to be related to the accumulation of cholesteryl esters in body tissues and macrophages.

Sitosterolemia is an inherited autosomal recessive disorder resulting from a defect in enterocyte ABCG5 and/or ABCG8, responsible for the transport of intestinally absorbed cholesterol and plant sterols/stanols back to the intestinal lumen. Clinically, patients express tendinous and tuberous xanthomas and premature atherosclerosis without necessarily having elevations in blood cholesterol levels.

1. Bodzioch M, Orso E, Klucken J, et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 1999;22:347-351.
2. Bays HE, Stein EA. Pharmacotherapy for dyslipidemia: current therapies and future agents. Expert Opin Pharmacother 2003;4:1901-1938.
3. Rust S, Rosier M, Funke H, et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 1999;22:352-355.

Ezetimibe is contraindicated in patients with moderate or severe hepatic insufficiency. The combination of ezetimibe and statins is contraindicated in patients with active liver disease or unexplained persistent elevations in liver transaminases. When ezetimibe is administered with a statin in a woman of child-bearing potential, it is recommended that the prescribing clinician refer to the pregnancy category and product labeling for the statin. However, since statins are not indicated for use in pregnant women (pregnancy X category), the combined use of ezetimibe with statins is also not indicated during pregnancy. The use of ezetimibe alone is in the pregnancy C category, as no adequate studies have demonstrated safety in pregnant women. Thus, the use of ezetimibe alone in pregnant women should be used only if the potential benefit justifies the risk to the fetus.

1. Bays H. Ezetimibe. Expert Opin Investig Drugs 2002;11:1587-1604.

None of the individual trials of ezetimibe monotherapy have demonstrated significant increases in liver enzymes compared with placebo. In the clinical trials of combination therapy with ezetimibe plus statin versus placebo plus statin, the incidence of consecutive transaminase elevations 3 or more times the upper limit of normal was <2% in either group. However, the incidence of such liver enzyme elevations was slightly higher (1.3%) in the ezetimibe plus statin group than the placebo plus statin group (0.4%). These liver enzyme elevations were asymptomatic and often transient, with resolution on discontinuation of therapy or sometimes with continued therapy. For this reason, it is recommended that if ezetimibe is to be used in combination with a statin, liver enzyme monitoring should occur at initiation of therapy and then according to the recommendations for the statin. Some clinicians have interpreted this to mean that with regard to liver enzyme monitoring, the addition of ezetimibe to a statin might be considered analogous to increasing the dose of the statin. Ezetimibe is not associated with increased myalgias or myopathy.

1. Bays H. Ezetimibe. Expert Opin Investig Drugs 2002;11:1587-1604.

As with the use of other lipid-altering drugs, the administration of ezetimibe should occur with appropriate management of potential secondary causes of dyslipidemia, such as diabetes mellitus, hypothyroidism, certain types of liver and kidney diseases, and drug-induced dyslipidemia as might occur with various steroids, ethanol, protease inhibitors, isotretinoin, etc.

1. Bays H. Ezetimibe. Expert Opin Investig Drugs 2002;11:1587-1604.

The combination of ezetimibe and simvastatin is available in a single tablet (Vytorin™). The rationale behind this lipid-altering therapy is to harness the dual inhibition of hepatic cholesterol synthesis (with simvastatin) and intestinal cholesterol absorption (with ezetimibe). A typical starting dose of 10 mg ezetimibe/20 mg simvastatin lowers LDL-C levels by about 50% or more, although an optional starting dose of 10 mg ezetimibe/40 mg simvastatin is available for patients in need of more immediate and greater LDL-C lowering. At the top dose of 10 mg/80 mg, LDL-C levels are reduced by about 60%. In the study described above, the mean LDL-C at baseline was 178 mg/dL, and LDL-C levels were lowered to 70 mg/dL, which is of potential therapeutic importance given the aggressive LDL-C treatment goals recommended for patients at highest CHD risk.

1. Bays HE, Ose L, Fraser N, et al. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy, safety, and tolerability profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther 2004;26:1758-1773.

The lipid-altering efficacy of the coadministration of ezetimibe and simvastatin to bioequivalent doses of ezetimibe/simvastatin in a single tablet has been studied and compared to atorvastatin. At relative starting doses, 10 mg ezetimibe/20 mg simvastatin once per day has been shown to lower LDL-C levels more than atorvastatin at its starting doses of 10 mg or 20 mg once a day. At the highest doses, 10 mg ezetimibe/80 mg simvastatin lowers LDL-C more than atorvastatin 80 mg per day.

1. Ballantyne CM, Blazing MA, King TR, et al. Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. Am J Cardiol 2004;93:1487-1494.

Ezetimibe/simvastatin also provided persistent and consistent elevations in HDL-C levels from the starting dose of 10 mg/20 mg up to the top dose of 10 mg/80 mg. In multiple other clinical trials of atorvastatin, further increases in HDL-C levels typically do not occur with titration to the higher doses of atorvastatin. In fact, many clinical trials have shown an attenuated effect upon HDL-C raising with the higher 80-mg dose of atorvastatin (although the clinical significance of this is unknown). As the result of the increase of HDL-C levels with increasing doses of ezetimibe/simvastatin, coupled with the attenuated effects upon HDL-C levels with increasing doses of atorvastatin, the greatest differences in HDL-C levels in this comparative study was at the top dose of ezetimibe/simvastatin (10 mg/80 mg) versus the top dose of atorvastatin (80 mg).

1. Ballantyne CM, Blazing MA, King TR, et al. Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. Am J Cardiol 2004;93:1487-1494.

The triglyceride-lowering effects of ezetimibe/simvastatin versus atorvastatin was roughly the same at starting doses, and at the highest doses of each.

1. Ballantyne CM, Blazing MA, King TR, et al. Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. Am J Cardiol 2004;93:1487-1494.

Bile acid sequestrants (resins) were among the first lipid-altering drugs to show an ability to reduce the risk for CHD. Unfortunately, the clinical use of bile acid resins such as cholestyramine and colestipol has been limited because of common gastrointestinal side effects and potential drug interactions with commonly prescribed concomitant drugs. Colesevelam is a unique bile acid sequestrant polymer that has been shown to have favorable lipid effects, better tolerability, and fewer potential drug interactions than other bile acid sequestrants. Because it is considered to be truly a nonsystemic drug, colesevelam would not be expected to add adverse systemic effects when used in combination with statins.

The efficacy of colesevelam has been evaluated in combination with statins. In comparison to what would be expected with statins alone, the administration of 4 tablets of colesevelam with statins has been shown to result in an approximate 8–12% further reduction in LDL-C levels, with variable effects on HDL-C and triglyceride levels. Similarly, the administration of 6 tablets of colesevelam with statins has been shown to result in an approximate 10–16% further reduction in LDL-C levels, favorable effects upon HDL-C levels, and mild to moderate elevations in triglyceride levels.

1. Bays H, Dujovne C. Colesevelam HCl: a non-systemic lipid-altering drug. Expert Opin Pharmacother 2003;4:779-790.
2. Davidson MH, Dicklin MR, Maki KC, Kleinpell RM. Colesevelam hydrochloride: a non-absorbed, polymeric cholesterol-lowering agent. Expert Opin Investig Drugs 2000;9:2663-2671.
3. Davidson MH, Toth P, Weiss S, et al. Low-dose combination therapy with colesevelam hydrochloride and lovastatin effectively decreases low-density lipoprotein cholesterol in patients with primary hypercholesterolemia. Clin Cardiol 2001;24:467-474.
4. Knapp HH, Schrott H, Ma P, et al. Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia. Am J Med 2001;110:352-360.
5. Hunninghake D, Insull W Jr, Toth P, et al. Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively. Atherosclerosis 2001;158:407-416.

The total LDL-C lowering with 6 tablets of colesevelam plus 10 mg of atorvastatin is roughly equivalent to what is achieved with 80 mg of atorvastatin. This may have clinical implications for patients who are unable to tolerate higher statin doses or who are at risk for toxicity and drug interactions at higher statin doses.

1. Bays H, Dujovne C. Colesevelam HCl: a non-systemic lipid-altering drug. Expert Opin Pharmacother 2003;4:779-790.
2. Hunninghake D, Insull W Jr, Toth P, et al. Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively. Atherosclerosis 2001;158:407-416.

Each doubling of the statin dose produces an incremental LDL-C reduction of approximately 5–6% of the baseline LDL-C value, resulting in a further LDL-C reduction of 15–18% with a three-step doubling of the statin, compared with the LDL-C reduction achieved with the statin starting dose. The addition of 6 tablets of colesevelam or the addition of 10 mg of ezetimibe to 10 mg of a statin results in about the same level of LDL-C lowering as 80 mg of the statin. The highest doses of statins are most associated with adverse side effects.

1. Bays H, Dujovne C. Colesevelam HCl: a non-systemic lipid-altering drug. Expert Opin Pharmacother 2003;4:779-790.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that, once activated, increase the transcription of target genes. Activation of PPARs occurs through ligand agonists that typically result in the subsequent formation of a heterodimer complex with the nuclear receptor RXR (PPAR/RXR heterodimer), which in turn regulates gene transcription by binding to specific response elements (peroxisome proliferator response element) that promote the activity of target genes. The ligands for the PPAR-α receptor include fatty acids and fibrates. Fibrates have been shown to reduce CHD in both primary and secondary prevention monotherapy clinical trials. The ligands for the PPAR-γ receptor include thiazolidinediones (TZDs), which have been shown to improve glucose control.

Additional abbreviations on slide: BSEP = bile salt export pump; I-BABP = intestinal bile acid–binding protein; FFA: free fatty acid; TG: triglyceride; VLDL: very low density lipoprotein; RXR: retinoid X receptor; LXR: liver X receptor; FXR: farnesoid-activated receptor; SREBP: sterol response element–binding protein.

1. Bays H, Shepherd J. Diabetes, metabolic syndrome and dyslipidemia. In: Management Strategies in Diabetes. Hackensack, NJ: Cambridge Medical Publications, 2004:1-28.
2. Bays HE, Stein EA. Pharmacotherapy for dyslipidemia: current therapies and future agents. Expert Opin Pharmacother 2003;4:1901-1938.

Myalgia is defined as muscle aches with or without muscle enzyme elevation. Myopathy is often defined as creatine kinase levels >10 times the upper limit of normal associated with symptoms (myalgias). Rhabdomyolysis may occur for many reasons, such as alcoholism (with tremors), infection, trauma, marked increase in extraordinary exercise (particularly without adequate hydration), seizures, genetic metabolic abnormalities. Its diagnosis is somewhat subjective, but it is typically characterized by creatine kinase levels >5 times the upper limit of normal, elevations in other muscle enzymes, myoglobinuria, hyperkalemia, hypocalcemia, hyperphosphatemia, hyperuricemia, metabolic acidosis, and possibly renal insufficiency or renal failure. In drug-induced rhabdomyolysis, symptoms of muscle weakness may be present only 50% of the time.

Statin administration alone may cause myalgias and myopathy. Statin monotherapy has even been described to result in rhabdomyolysis in rare cases. One of the main concerns with the combined use of statins with fibrates is the increased risk for myopathy and rhabdomyolysis, particularly when gemfibrozil is the fibrate used.

1. Bays HE, Stein EA. Pharmacotherapy for dyslipidemia: current therapies and future agents. Expert Opin Pharmacother 2003;4:1901-1938.
2. Ballantyne CM, Corsini A, Davidson MH, et al. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med 2003;163:553-564.
3. Bays H. Existing and investigational combination drug therapy for high-density lipoprotein cholesterol. Am J Cardiol 2002;90:30K-43K.

The use of statins and TZDs is common, given that (1) diabetes mellitus is considered a CHD risk equivalent, (2) aggressive LDL-C level lowering is recommended in patients with diabetes mellitus, (3) statins and TZDs are common lipid-altering and antidiabetes agents, respectively, and (4) dyslipidemia and diabetes mellitus often occur in the same patient. One of the most active areas of clinical research for metabolic syndrome and type 2 diabetes mellitus is the development of pharmaceutical agents that possess both PPAR-α and PPAR-γ effects (dual PPAR-α/γ agonists). Another area of research involves development of agents that may affect other nuclear receptors.

1. Bays HE. Atherogenic dyslipidaemia in type 2 diabetes and metabolic syndrome: current and possible future treatment options. British Journal of Diabetes and Vascular Disease 2003;3:356-360.
2. Ginsberg HN. Treatment for patients with the metabolic syndrome. Am J Cardiol 2003;91:29E-39E.

Commercial fish oil preparations are available that contain more than 1000 mg per capsule of omega-3 fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In general, most studies have described benefits on blood triglyceride levels with combined doses of EPA and DHA of at least 4 g, up to 9 g/day. Side effects of fish oils include fishy aftertaste and dyspepsia, which may be improved by refrigeration of agent prior to administration. Reports have inconsistently noted an early, short-lived potential increase in blood glucose levels in patients with diabetes mellitus. Fish oils may impair platelet aggregation and increase bleeding time, potentially reducing the risk for thrombosis. Clinical trials have not demonstrated significantly increased risk of bleeding if used concomitantly with anticoagulants (aspirin or warfarin).

1. Kris-Etherton PM, Harris WS, Appel LJ, et al. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-2757.
2. Bays HE, Stein EA. Pharmacotherapy for dyslipidemia: current therapies and future agents. Expert Opin Pharmacother 2003;4:1901-1938.

The two major sources of circulating cholesterol are (1) synthesis (from peripheral tissues and liver) and (2) absorption (from the intestine). Once synthesized or absorbed, free cholesterol is esterified. Depending upon the location or pathway, cholesteryl ester may then be packaged into apolipoprotein (apo) B–containing lipoproteins. Preferential delivery of cholesterol from peripheral tissues (such as endothelial macrophages associated with arterial cholesterol plaques) to the liver may occur with increased HDL metabolic flux to the liver, which may reduce atherosclerotic plaques. Elevated levels of HDL-C have been associated with a reduced risk for CHD, which may occur by at least three mechanisms: (1) promotion of peripheral cholesterol transport, (2) antioxidant/anti-inflammatory effects, and (3) antithrombotic effects.

1. Bays H. Existing and investigational combination drug therapy for high-density lipoprotein cholesterol. Am J Cardiol 2002;90:30K-43K.
2. Bays H. Ezetimibe. Expert Opin Investig Drugs 2002;11:1587-1604.

Statins and niacin have different mechanisms of action and different favorable effects on lipoprotein levels. Thus, the combined use of statins and niacin may have complementary benefits on multiple lipoprotein parameters.

1. McKenney JM, McCormick LS, Schaefer EJ, et al. Effects of niacin and atorvastatin on lipoprotein subclasses in patients with atherogenic dyslipidemia. Am J Cardiol 2001;88:270-274.
2. Bays H. Existing and investigational combination drug therapy for high-density lipoprotein cholesterol. Am J Cardiol 2002;90:30K-43K.

The ADvicor Versus Other Cholesterol-modulating Agents Trial Evaluation (ADVOCATE) was designed to compare the efficacy of a niacin extended-release (ER)/lovastatin preparation with that of 2 common statin monotherapies, atorvastatin and simvastatin. After 8 weeks' administration at their starting doses, both niacin ER/lovastatin 1,000/40 mg and atorvastatin 10 mg lowered mean LDL-C levels by 38%. After 12 weeks, niacin ER/lovastatin 1,000/40 mg lowered LDL-C levels by 42%, while the 20-mg starting dose of simvastatin lowered LDL-C levels by 35% (p <0.001). Additionally, niacin ER/lovastatin increased HDL-C levels significantly more than either atorvastatin or simvastatin at all compared doses (p <0.001), and provided significant improvements in other lipid parameters such as triglyceride, lipoprotein(a), apo A-I, and apo B levels. Equal or greater reductions in LDL-C levels with greater, more multidimensional improvement in other lipid parameters using combination niacin plus statin therapy reduces CHD lipid risk factors more than the use of either agent alone.

1. Bays HE, Dujovne CA, McGovern ME, et al. Comparison of once-daily, niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin (the ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE]). Am J Cardiol 2003;91:667-672.

This table describes relative terminology among the various commercially available lipoprotein subclass analyses, and is not meant to represent direct comparisons of the various methodologies with respect to lipoprotein particle size and subclass distribution. In general, a decrease in LDL and HDL particle size is most associated with increased CHD risk. The implications of VLDL particle size are less clear. As assessed by nuclear magnetic resonance, larger VLDL particles are thought to be associated with higher CHD risk. Conversely, it has been suggested that with Vertical Auto Profile, it is the small remnant VLDL particles that are stronger predictors of CHD risk than large, buoyant VLDL particles. The slide highlights the complexity of comparing methods that differ substantially in how lipoproteins are measured. There is no federal agency that regulates the accuracy of the measurements, and obviously, there is no set standard as to how results of lipoprotein particle size and subclass distribution are reported.

1. Bays HE, McGovern ME. Once-daily niacin extended release/lovastatin combination tablet has more favorable effects on lipoprotein particle size and subclass distribution than atorvastatin and simvastatin. Prev Cardiol 2003;6:179-188.

In a further review of the ADVOCATE data with a focus on relative effects on lipoprotein subclass distribution, at all doses tested:

- Niacin ER/lovastatin was more effective than either atorvastatin or simvastatin in increasing LDL peak particle diameter.

- Niacin ER/lovastatin was more effective than either atorvastatin or simvastatin in increasing the proportion of HDL in "cardioprotective" 2b subclass (according to segmented gel electrophoresis).

1. Bays HE, McGovern ME. Once-daily niacin extended-release/lovastatin combination tablet has more favorable effects on lipoprotein particle size and subclass distribution than atorvastatin and simvastatin. Prev Cardiol 2003;6:179-188.

In a further review of the ADVOCATE data with a focus on relative effects on lipoprotein subclass distribution, at all doses tested:

- Niacin ER/lovastatin was more effective than either atorvastatin or simvastastin in reducing the proportion of LDL in atherogenic small, dense IIIa/IIIb subclasses.

- Niacin ER/lovastatin was more effective than either atorvastatin or simvastatin in reducing LDL pattern B prevalence.

1. Bays HE, McGovern ME. Once-daily niacin extended-release/lovastatin combination tablet has more favorable effects on lipoprotein particle size and subclass distribution compared to atorvastatin and simvastatin. Prev Cardiol 2003;6:179-188.

Isolated case reports have suggested an increased risk for liver and muscle toxicity with previous niacin preparations used in combination with statins. However, the ADVOCATE trial, using niacin extended-release [ER]/lovastatin in doses ranging from 500 mg/20 mg to 2000 mg/40 mg and atorvastatin or simvastatin monotherapy 10–40 mg, demonstrated that:

- 10 of 157 patients (6%) treated with niacin ER/lovastatin withdrew because of flushing

- Increases in mean alanine aminotransferase (ALT) levels were significantly greater at all doses of atorvastatin and simvastatin compared with niacin ER/lovastatin (although the mean ALT levels did not rise above the upper limit of normal in any treatment group)

- No drug-induced cases of myopathy were observed

- No significant differences were seen in the incidence of rash, hyperglycemia, hyperuricemia, or gastrointestinal complaints between treatment groups.

The risk for flushing with niacin can be reduced with the use of longer acting niacin preparations such as the ER preparation used in this trial, as well as preventive measures such as avoiding spicy or hot foods and drinks, avoiding alcohol while taking niacin, taking aspirin or a nonsteroidal anti-inflammatory drug 30 minutes before niacin, and administration of a small snack with niacin administration. The risk for increased liver toxicity when niacin ER is combined with statins is low if the agents are properly administered and appropriately monitored. An increased risk for myopathy with this combination was not supported by this trial. In fact, there is little evidence from clinical trials that the use of moderate doses of niacin increases muscle toxicity of any kind. However, myalgias and myopathy may occur with statins alone. Finally, although not observed in this trial, other adverse effects such as rash, hyperglycemia, hyperuricemia, and gastrointestinal complaints may occur with niacin and should be appropriately monitored.

1. Bays HE, Dujovne CA, McGovern ME, et al. Comparison of once-daily, niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin (the ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE]). Am J Cardiol 2003;91:667-672.
2. Zhao XQ, Morse JS, Dowdy AA, et al. Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high-density lipoprotein cholesterol (The HDL Atherosclerosis Treatment Study). Am J Cardiol 2004;93:307-312.
3. Bays H. Commentary: Trial finds that simvastatin plus niacin is safe in people with coronary artery disease and low HDL cholesterol. Evidence-based Cardiovascular Medicine 2004;8:173-176.
4. Bays HE. Extended-release niacin/lovastatin: the first combination product for dyslipidemia. Expert Rev Cardiovasc Ther 2004;2:485-501.

A study that has examined the potential CHD outcomes benefit of niacin plus statin combination therapy was the HDL-Atherosclerosis Treatment Study (HATS). In this placebo-controlled secondary prevention study, 160 patients with CHD, low HDL-C (average, 31 mg/dL), and "normal" serum LDL-C levels (average, 125 mg/dL) were administered either niacin (N; slow-release or immediate-release, mean dose 2.4 g/d) plus simvastatin (S; mean dose 13 mg/d) or placebo with or without antioxidant vitamins (AV) for 3 years. In the group receiving niacin plus simvastatin without antioxidants, LDL-C levels were lowered by 42%; the LDL-C levels in the placebo groups were unaltered. HDL-C was increased by 26% in the niacin plus simvastatin group. The combination of niacin and simvastatin reduced CHD events by 60–90%, with about a 90% reduction seen in those subjects who did not take antioxidants, possibly because the treatment-induced increase in HDL particle size was blunted by antioxidants.

HATS was a small trial that clearly needs to be repeated in order to verify the essential "cure" of atherosclerotic CHD with combination niacin plus statin therapy. However, this trial does give hope that the use of combination lipid-altering drugs with complementary actions may not only provide superior effects on multiple lipid parameters as compared with either agent alone, but may also improve CHD outcomes.

Further support for the clinical benefit of niacin in combination with statins was provided by Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2, a 12-month study of 167 statin-treated patients with known CHD and low HDL-C levels (<45 mg/dL) who were also administered extended-release niacin or placebo. Patients receiving statin alone had significant progression in atherosclerosis measured by carotid intima–media thickness (p <0.001) while a nonsignificant tendency toward progression (p=0.23) occurred in the statin-plus-niacin group. Although the study was not powered to show differences in cardiovascular event endpoints, there was a trend towards greater reduction in clinical cardiovascular events in the statin-plus-niacin patients (3.8%, versus 9.6% in the statin-only group; p=0.20).

1. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-1592.
2. Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins.Circulation 2004;110:3512-3517.

Multiple clinical trials of statins have demonstrated significant reductions in CHD events compared to placebo. However, overall, the risk of CHD compared to placebo has "only" been reduced on the order of about 1/4 to 1/3. Thus, in clinical trials of statin monotherapy, the majority of CHD events were not prevented. These data have prompted studies of more aggressive lowering of LDL-C levels, which usually requires combining other lipid-altering drugs with statins. In addition, because of intriguing and provocative outcomes data (such as those described with small CHD outcome studies of statins and niacin), current studies are evaluating other investigational agents in combination with statins that may provide complementary actions beyond LDL-C lowering alone.

Abbreviations: AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT-LLA = Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm; CARE = Cholesterol and Recurrent Events; HPS = Heart Protection Study; LIPID = Long-Term Intervention with Pravastatin in Ischaemic Disease; PROSPER = Prospective Study of Pravastatin in the Elderly at Risk; 4S = Scandinavian Simvastatin Survival Study; WOSCOPS = West of Scotland Coronary Prevention Study.

1. Bays HE. Extended-release niacin/lovastatin: the first combination product for dyslipidemia. Expert Rev Cardiovasc Ther 2004;2:485-501.
2. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389.
3. Shepherd J, Cobbe SM, Ford I, et al., for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-1307.
4. Sacks FM, Pfeffer MA, Moye LA, et al., for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-1009.
5. Downs JR, Clearfield M, Weis S, et al., for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615-1622.
6. Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-1357.
7. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.
8. Shepherd J, Blauw GJ, Murphy MB, et al., on behalf of the PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-1630.
9. Sever PS, Dahlof B, Poulter NR, et al., for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-1158.

In the process of cholesterol transport, apo B–containing VLDL particles are released to the circulation from the liver, and through metabolism by endothelial lipoprotein lipases (LPL) and hepatic lipases (HL), are catabolized into LDL particles. Once these LDL particles have traversed arterial endothelial walls (along with their associated cholesterol), the particles may become modified and undergo uptake by subendothelial macrophages which express specialized or scavenger receptors (SR). The result is the formation of cholesterol-laden macrophages (otherwise known as foam cells) that may produce growth factors (that may promote cell proliferation) and metalloproteinases (that may promote cell matrix degradation)—all resulting in promotion of the vulnerable atherosclerotic plaque that leads to CHD events.

In contrast to simply becoming engorged with cholesterol, arterial-associated macrophages may also interact with HDL particles, and through ABCA1, transport cholesterol to nascent HDL particles. Once in the circulation, apo A-I–associated HDL particles may then be metabolized through uptake at the liver by:

• Scavenger receptors, such as SR B1, that extract cholesterol from HDL particles and then release HDL back into the circulation

• Putative receptors that mediate hepatic uptake and the subsequent catabolism of the entire HDL particle

This transport of cholesterol from peripheral arterial–associated macrophages to the liver (peripheral cholesterol transport) is thought to be an important process in reducing atherosclerotic progression. CETP facilitates the exchange of cholesterol from antiatherogenic apo A-I–containing HDL particles to the atherogenic apo B–containing VLDL and LDL particles. Theoretically, inhibition of CETP, in effect, breaks the bridge between the antiatherogenic and atherogenic pathways, leading to a greater redirection of cholesterol back to the liver for clearance and away from the atherogenic pathway.

1. Brewer HB Jr, Santamarina-Fojo S. Clinical significance of high-density lipoproteins and the development of atherosclerosis: focus on the role of the adenosine triphosphate–binding cassette protein A1 transporter. Am J Cardiol 2003;92:10K-16K.
2. Bays HE, Stein EA. Pharmacotherapy for dyslipidemia: current therapies and future agents. Expert Opin Pharmacother 2003;4:1901-1938.
3. Bays HE. Extended-release niacin/lovastatin: the first combination product for dyslipidemia. Expert Rev Cardiovasc Ther 2004;2:485-501.

In addition to effects upon absolute blood lipid levels, CETP also has a role in promoting abnormalities in lipoprotein particle size and subclass distribution. Adiposity, genetic predisposition, and sedentary lifestyle promote dysfunctional adipose tissue (adiposopathy). Adiposopathy is associated with abnormalities in the release of hormones, cytokines, enzymes, molecules, and other factors from fat cells that may contribute to an array of metabolic abnormalities including dyslipidemia, insulin resistance, and hypertension. For example, the release of free fatty acids from dysfunctional fat cells may contribute to fatty liver and fasting hypertriglyceridemia with increased VLDL particles. CETP facilitates the exchange of triglyceride (for cholesterol) from VLDL particles to HDL particles, which are more readily cleared by the kidneys resulting in lower HDL-C levels. CETP may also facilitate the exchange of triglyceride (for cholesterol) from VLDL particles to LDL particles. The more triglyceride-rich LDL particles undergo metabolism by various lipases resulting in small, dense LDL particles. Thus, CETP contributes to the common lipid profile characterized as "metabolic syndrome," which often includes fatty liver, fasting hypertriglyceridemia, low HDL-C levels, and small, dense LDL particles. This figure does not depict the important contribution of postprandial hypertriglyceridemia, which often occurs in these same patients, wherein elevated postprandial chylomicrons (from the intestine) may also contribute to hypertriglyceridemia, the atherogenic lipid profile described above, and the creation of chylomicron remnant particles, which may be significantly atherogenic.

1. Bays HE. Extended-release niacin/lovastatin: the first combination product for dyslipidemia. Expert Rev Cardiovasc Ther 2004;2:485-501.
2. Bays HE. Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obes Res 2004;12:1197-1211.
3. Bays H, Abate N, Chandalia M.  Adiposopathy: sick fat causes high blood sugar, high blood pressure and dyslipidemia.  Future Cardiology (2005) 1(1), 39-59.

Inhibiting CETP may improve lipoprotein particle size and subclass distribution. For example, centenarians ("probands") and their offspring have been suggested to have larger HDL and LDL particle size (as well as lower prevalence of hypertension, cardiovascular disease, and the metabolic syndrome), which may, at least in part, be due to the presence of a CETP mutation associated with decreased CETP activity. Thus, CETP inhibition may not only improve lipid blood levels, but may also improve HDL and LDL particle sizes. Therefore, inhibiting CETP may be an attractive treatment target for the purpose of CHD risk reduction.

1. Barzilai N, Atzmon G, Schechter C, et al. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 2003;290:2030-2040.

Torcetrapib is a CETP inhibitor that has been shown in monotherapy to result in a dose-dependent increase in HDL-C (15–70%), as well as a modest decrease in LDL-C (up to ~20%) and inconsistent effect on triglyceride (TG) levels.

1. Clark RW, Sutfin TA, Ruggeri RB, et al. Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib. Arterioscler Thromb Vasc Biol 2004;24:490-497.

According to other preliminary data released by the manufacturer (Pfizer), torcetrapib monotherapy has been shown in an 8-week phase II trial to increase HDL-C levels by 55% and lower LDL-C levels by 20%. Across the dose range of atorvastatin (10–80 mg), torcetrapib 90 mg in combination with atorvastatin has the potential to raise HDL-C levels by 50% and lower LDL-C levels by 70–80%. The addition of torcetrapib 90 mg to atorvastatin 20 mg resulted in an additional LDL-C lowering of 15% over atorvastatin alone, which was comparable to the 20% LDL-C lowering found with torcetrapib 120 mg monotherapy.

Torcetrapib is not currently being planned as a monotherapy drug. However, a combination product is in phase III development, including CHD outcomes studies. In one example, the effects of torcetrapib/atorvastatin combination on atherosclerotic progression is being evaluated by intravascular ultrasound in patients with nonobstructive CHD (20–50% stenosis).

1. Bays HE, Stein EA. Pharmacotherapy for dyslipidemia: current therapies and future agents. Expert Opin Pharmacother 2003;4:1901-1938.

Statins are currently the most prescribed lipid-altering drugs because of their efficacy in favorably altering blood lipid levels, safety and tolerability, and proven benefits on reducing atherosclerotic CHD events. Combination lipid-altering drug therapy with statins is often indicated for patients: (1) who are unable to achieve recommended treatment goals with statin monotherapy, (2) who may be at risk for intolerance, toxicity, or adverse drug interactions with higher-dose statin monotherapy, or (3) who may benefit from the use of one or more lipid-altering drugs in combination with statins resulting in complementary benefits towards further reduction in CHD risk. Some of the lipid-altering agents most commonly used in combination with statins include ezetimibe, bile acid sequestrants, PPAR agonists, fish oils, and niacin. A potentially important investigational lipid-altering drug combination is statin in combination with a cholesteryl ester transport inhibitor.