A Novel Therapeutic Approach

Since 1988, the National Cholesterol Education Program has identified low-density lipoprotein cholesterol (LDL-C) as the target of therapy; the new Adult Treatment Panel III (ATP III) guidelines continue the tradition of matching the aggressiveness of LDL-lowering therapy according to the risk of coronary heart disease (CHD). A significant change in the new guidelines is the definition of.CHD risk equivalents. and the inclusion of a modified Framingham global risk score. These revisions significantly raise the number of patients who qualify for lipid-lowering therapy. ATP III recognizes statins as the drug of first choice for LDL-C lowering. Statins are proven to be safe and effective for LDL-C reduction and are proven to reduce CHD event rates and mortality. Some patients are not candidates for statin therapy, however, and must rely on nonstatin agents that are less effective in reducing LDL-C, less safe, or poorly tolerated. Consequently, new cholesterol-lowering therapies are needed. Ezetimibe, approved by the U.S. Food and Drug Administration (FDA) in October 2002, is the first in a new class of selective cholesterol absorption inhibitors and offers a novel approach to the treatment of dyslipidemia. Phase 2 data demonstrated that ezetimibe lowers LDL-C by 18% and has a tolerability and short-term safety profile similar to placebo. This paper reviews the cholesterol metabolic pathways and the mechanism of action of the currently available lipid-modifying agents and introduces ezetimibe, the first selective cholesterol absorption inhibitor.

H ypercholesterolemia is a well-established risk factor for coronary heart disease (CHD). 1,2 The Adult Treatment Panel III (ATP III) emphasis on both aggressive therapy for patients at high risk and long-term, less aggressive therapy for patients at high lifetime risk, contributes to the growing need to identify new approaches to combat lipid abnormalities. Of great interest is the development of new drugs that can favorably alter the lipid profile through mechanisms that differ from currently available drugs. Based on the overwhelming evidence of benefit, statins are currently recommended by ATP III as first-line agents for the reduction of low-density lipoprotein cholesterol (LDL-C). Because of the intensified LDL-C targets recommended by ATP III, combination therapy may be required by significant numbers of patients to achieve goal. Agents that target novel pathways of cholesterol metabolism may enable a greater number of patients to attain these LDL-C targets.
Ezetimibe, approved by the U.S. Food and Drug Administration (FDA) in October 2002, is the first in a new class of selective cholesterol absorption inhibitors. Ezetimibe monotherapy blocks cholesterol and bile acid absorption from the intestine and results in up to an 18% reduction in LDL-C with once-daily dosing and a short-term safety profile similar to placebo. 3 When 10 mg of ezetimibe is combined with a lowdose statin, the complementary mechanisms of action of the 2 agents produces LDL-C reductions typically seen only with high-dose statin therapy. 4,5 ■■ Cholesterol Pathways Developing clinically effective therapies requires an understanding of the basic principles of cholesterol balance. Cholesterol is a ubiquitous sterol that plays a vital role in cell membranes, bile and bile acid production, and steroid hormones. The total body pool of cholesterol is controlled by 3 main factors that determine cholesterol balance. On the input side, cholesterol can be produced endogenously or can be obtained from absorption of dietary or biliary sources of cholesterol. In an otherwise healthy person, endogenous cholesterol synthesis contributes approximately 900 mg of cholesterol to the total cholesterol pool each day, while an additional 300 mg is added by intestinal absorption. Endogenous cholesterol synthesis results from numerous enzymatically mediated reactions, the most important being the conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonic acid. This step is catalyzed by the HMG-CoA reductase enzyme, which is tightly controlled by the flow of intestinal cholesterol to the liver. Newly synthesized hepatic cholesterol is released into the circulation in the form of a triglyceride-rich, very-low-density lipoprotein cholesterol (VLDL-C) particle. Although it was previously suspected that the hepatic production of cholesterol was the primary source

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of endogenously synthesized cholesterol, hepatic production of cholesterol accounts for only 10% of the total daily production. Peripheral tissues synthesize the majority of cholesterol. As VLDL-C circulates in the blood, the triglyceride component is removed and the lipoprotein particle accumulates cholesterol from peripheral tissues, resulting in the formation of intermediate-density lipoproteins (IDL). The IDL, which is depleted of triglycerides but rich in cholesterol, has 2 possible fates: it is either taken up by receptors on the liver or it remains in the circulation and is converted to LDL-C. Ultimately, the IDL-derived LDL-C may be removed from the circulation by hepatic LDL-C receptors or it can penetrate arterial walls to develop atheromas, precursors to atherosclerotic plaques. High-density lipoprotein (HDL-C) cholesterol is an additional carrier lipoprotein for moving peripherally synthesized cholesterol back to the liver for transfer.
The exogenous pathway altering total body cholesterol balance involves a complicated processing of both dietary and biliary cholesterol by the intestine. The first step in this process is the absorption of cholesterol by the enterocytes that line the intestinal lumen. Once inside the enterocyte, cholesterol is ultimately packaged into a triglyceride-rich chylomicron particle. Chylomicrons are released into the circulation, where the triglyceride component is stripped away, resulting in a remnant particle. Chylomicron remnants are cholesterol-rich particles that are removed from the circulation by remnant receptors found on the surface of the liver. In the liver, exogenously derived cholesterol is mixed with the endogenously synthesized cholesterol and used to form bile acids or incorporated into VLDL-C and returned to the circulation.
Cholesterol balance is achieved by regulating the amount of cholesterol synthesis. Reduced delivery of intestinal cholesterol to the liver increases HMG-CoA reductase activity and enhances cholesterol synthesis. whereas high intestinal uptake of cholesterol inhibits HMG-CoA activity, reduces hepatic synthesis, decreases LDL-C uptake, and increases plasma LDL-C. Because the liver and intestine are critical centers for cholesterol balances, they are prime targets for cholesterol modification therapies. Thus, statin therapy, by its action of reducing total body cholesterol synthesis, has a secondary effect of increasing LDL-receptor activity. The liver is the primary target of the secondary effect of statins, as the liver is the organ that contains most of the body' s LDL receptors. The intestine is the target of therapy designed to limit exogenous cholesterol intake (e.g., the novel cholesterol absorption inhibitor, ezetimibe).

■■ Mechanism of Action of Currently Available Drugs
Statins exert their effects largely by inhibiting the activity of the HMG-CoA reductase enzyme. Reduced enzyme activity decreases the amount of free hepatic cholesterol and stimulates an up-regulation of LDL receptors located on the surface of the hepatocytes. Up-regulation of liver LDL-C receptors stimulates an increased LDL-C uptake from the circulation to restore the hepatic cholesterol balance. Thus, statins exert both direct and indirect effects that result in a lowering of LDL-C: they directly decrease cholesterol synthesis, which, in turn, increases the uptake of cholesterol from the blood, thereby decreasing blood LDL-C levels. Statins also have moderate HDL-raising and triglyceride-lowering effects.
A decline in LDL-C levels can also be achieved by directly increasing cholesterol loss from the body. Augmentation of cholesterol loss has been achieved for many years using bile acid sequestrants. A significant portion of the cholesterol entering the liver is eventually converted into bile acids. Bile acids are secreted into the lumen of the small intestine and are responsible for the absorption of dietary fatty acids as well as fat-soluble vitamins. The total body biliary pool is quite small and is rapidly excreted and reabsorbed 2 to 3 times during a single meal and up to 10 times during a typical day. This significant recycling of biliary acids is accomplished by highly specific transporter proteins in the intestinal wall that can rapidly return bile acids back to the liver in the enterohepatic circulation. Bile acid sequestrants prevent this recycling by interfering with the ability of the transporter to move bile acids back to the liver. Sequestrants sequester bile acids so that they cannot be reabsorbed and must be excreted in stool. Because bile acid synthesis requires cholesterol as a precursor, disruption of bile acid reabsorption creates a major perturbation of cholesterol balance, lowering the total body cholesterol pool size.
The effectiveness of this approach is limited because the liver has a remarkable capacity to up-regulate its own rate of cholesterol synthesis in order to produce more bile in the face of a deficit. This compensatory increase in cholesterol synthesis by the liver consequently blunts the cholesterol-lowering action of the sequestrant, limiting its ability to significantly lower plasma LDL-C.
Nicotinic acid is another drug option for the treatment of dyslipidemia; nicotinic acid can produce reductions in LDL-C, as well as reductions in triglycerides and increases in HDL-C. Nicotinic acids work primarily by inhibiting the transport of free fatty acids from the peripheral tissues to the liver. This action reduces both the hepatic synthesis of triglycerides and the hepatic secretion of VLDL-C. Nicotinic acid may also limit the conversion of VLDL-C to LDL-C and initiate a shift in LDL-C from the small, dense, atherogenic type to large, buoyant, less atherogenic LDL-C particles. Fibrates have limited LDL-C-lowering capacity and are most useful in the treatment of isolated hypertriglyceridemia and combined hypercholesterolemia with elevated triglycerides. These agents primarily lower triglycerides and raise HDL-C. Plant stanols and sterols block cholesterol absorption from the intestinal lumen by interfering with the formation of lipid-rich chylomicrons and chylomicron remnants. Although relatively effective in reducing LDL-C, these agents must be taken primarily during meals to be effective.
Given the limitations of currently available lipid-lowering approaches, a therapy or combination of therapies that is tolerable; offers safe, convenient dosing; and removes cholesterol from the body without triggering compensatory hepatic mechanisms may achieve superior LDL-C reductions.

■■ The Novel Cholesterol Absorption Inhibitor: Ezetimibe
Approximately half the total cholesterol found in the gut after a meal is absorbed by the intestinal enterocyte; the remainder is excreted in the stool. Absorbed cholesterol is packaged by the enterocyte into triglyceride-rich chylomicrons. Restricting dietary intake of cholesterol can reduce the pool of cholesterol available for intestinal absorption, but the impact on LDL-C levels is highly variable, with some patients having little or no response to dietary restriction alone. Blocking the absorption of cholesterol from the intestinal lumen has a greater effect on cholesterol balance because the block inhibits not only dietary cholesterol absorption but also biliary cholesterol absorption. The search for an effective, convenient, safe, and better-tolerated drug for the reduction of cholesterol and prevention of CHD has led to the development of a novel class of lipid-reducing agents, the selective cholesterol absorption inhibitors.
Ezetimibe, the first in a new class of selective cholesterol absorption inhibitors, reduces plasma cholesterol by selectively inhibiting the absorption of dietary and biliary cholesterol from the intestine. 3 Early studies in animals show that ezetimibe lowers both serum and liver cholesterol concentrations in a dose-dependent manner. 6 Ezetimibe is rapidly glucuronidated in the gut and liver and the glucuronidated derivative is the active, more potent form of the drug. Both ezetimibe and its glucuronide derivative undergo extensive enterohepatic circulation and are ultimately secreted into the bile. Glucuronidated ezetimibe is returned to the intestinal lumen when bile is secreted in response to a high-fat meal and localizes to the brush border membrane of the intestinal mucosal cell. Glucuronidated ezetimibe appears to specifically inhibit free cholesterol uptake into the enterocyte by interacting with a cholesterol transporter protein, however, its exact mechanism of action remains to be elucidated. 7 Ezetimibe was recently approved by the FDA, and many of the results of the phase 2 development program are available. 8,9 The goals of the phase 2 trials were to describe the dose-response relationship of ezetimibe, investigate the existence of any food interactions, determine if differences existed between morning and evening dosing, and determine dosing regimens for phase 3 trials. The phase 2 trials also investigated the pharmacokinetic and pharmacodynamic interaction between ezetimibe and several statins as well as the magnitude of LDL-C reduction when administered in combination with statins.
Patients included in phase 2 trials are representative of those seen by primary care physicians. Total cholesterol and LDL-C levels at randomization were >250 mg/dL and >130 mg/dL, respectively, and triglycerides were below 300 mg/dL. Patients with diabetes were excluded. The first phase 2 trials were small, placebocontrolled trials that randomized patients into groups that received ezetimibe at doses between 1 mg and 40 mg for approximately 8 weeks. One group received 40 mg lovastatin as a benchmark against which to assess the lipid-lowering actions of ezetimibe. The results of these studies indicated a small, dose-dependent effect for ezetimibe with the maximum LDL-C reduction achieved at once-daily dosing of 10 mg to 20 mg. Tolerability, side effects, and biochemical abnormalities were no different than those seen with placebo. 10 This small pilot trial was followed by a 12-week, placebo-controlled, dose-ranging study. Approximately 50 patients were randomized to each study arm using a dose range of 1 mg to 10 mg of ezetimibe per day. The results confirmed the findings of the smaller dose-ranging trial and demonstrated a peak LDL-C reduction of 18% from baseline at 10 mg/day. 10 To determine if LDL-C reduction was impacted by the timing of dosing or by the presence of food, another phase 2 study evaluated the lipid-lowering effects of 5 mg and 10 mg/day administered to 189 patients in the morning and in the evening, with and without food. These studies found no significant differences between morning and evening dosing with 10 mg of ezetimibe, with LDL-C reductions of 17.5% and 18.2% for morning and evening dosing, respectively. LDL-C reductions were also unaffected by the presence or absence of food. 9,10 In total, the phase 2 monotherapy studies included 124 patients who received 5 mg ezetimibe, 118 who received 10 mg, and 87 who received placebo. Pooling the data reveals a consistent doseresponse effect with a peak LDL-C reduction of 18.5% at 10 mg/day. Ezetimibe showed essentially no effect on triglyceride levels and a small, but statistically significant increase of 3.5% in HDL-C. 9 A second arm of the phase 2 program was designed to test the effectiveness, tolerability, and safety of ezetimibe in combination with currently available agents. Each trial included 32 patients with elevated LDL-C and tested the cholesterol-lowering effect of 10 mg/day of ezetimibe in monotherapy and in combination with atorvastatin 10 mg/day, fluvastatin 20 mg/day, and fenofibrate 200 mg/day. Ezetimibe monotherapy reduced LDL-C cholesterol by 22.7% from baseline compared to 40% with atorvastatin 10 mg/day. Combination therapy with atorvastatin decreased LDL-C by 55%. 4 Ezetimibe, when compared to fluvastatin, reduced LDL-C by 20.2% versus 12.8% for fluvastatin 20 mg/day. When taken together, the combination achieved a reduction of 32% from baseline. 11 The trial that compared ezetimibe with fenofibrate demonstrated that ezetimibe decreased LDL-C by 22.3% from baseline versus 13.5% with the fenofibrate 200 mg/day. The 2 drugs in combination produced a 36.3% reduction in LDL-C. 12 From the results of these small, well-designed studies, it can be concluded that ezetimibe, when used as monotherapy, produces clinically significant reductions in LDL-C. In addition, these trials suggest that combination therapy of ezetimibe with atorvastatin, fluvastatin, or fenofibrate leads to LDL-C reductions greater than that observed when the agents are administered alone. The overall results of the phase 2 development program indicated that the selective cholesterol absorption inhibitor, ezetimibe, is effective both as monotherapy and in combination with several statins. The short-term coadministration trials also found that the combination of ezetimibe with statins or fenofibrate was safe and that ezetimibe did not alter the pharmacokinetics of the other agents or vice versa. The phase 2 trials established that ezetimibe achieved maximum cholesterol lowering at doses between 10 mg and 20 mg/day. These studies also demonstrated that ezetimibe was well tolerated, with a side-effect profile no different from placebo.
Following the completion of the phase 2 trials, it was decided to test the LDL-C-lowering effect of ezetimibe in larger and longer trials. The third phase of the development program was designed to determine whether ezetimibe could provide consistent and predictable reductions in LDL-C when used as monotherapy, to evaluate the drug' s efficacy as an adjunct to dietary therapy, to determine whether the drug could provide consistent LDL-C lowering when coadministered with a statin at any dose, and to further describe its safety and tolerability profile. The purpose of the first phase 3 study was to evaluate the efficacy of ezetimibe versus placebo. This double-blinded, randomized, parallel group trial included 820 patients with LDL-C between 130 mg/dL and 250 mg/dL and triglyceride levels below 350 mg/dL. Prior to randomization, all patients completed 6 to 12 weeks of drug washout and diet, followed by 3:1 randomization and 12 weeks of active treatment. The primary efficacy endpoint was the percentage reduction in LDL-C from baseline, with changes in total cholesterol, triglycerides, and HDL-C as secondary endpoints. Ezetimibe treatment reduced LDL-C by 18%, with a 12% decrease in total cholesterol, a 4.1% decrease in triglycerides, and a 1% increase in HDL-C. The safety profile of ezetimibe was similar to placebo, with no clinically significant changes in creatine kinase or hepatic transaminase levels, and no effect on the absorption of fat soluble vitamins A, D, E, or alpha carotene and beta carotene. The most common side effects in both the active treatment and placebo groups were headache, upper respiratory tract infections, and back pain not believed to be related to either ezetimibe or placebo. 3 At the conclusion of the 12-week study period, all patients were enrolled in an open-label extension trial designed to provide confirmatory data of the stability of the lipid response and to assess long-term safety. In this extension study, the investigators will consider adding a statin to ezetimibe monotherapy in those patients not achieving the LDL-C targets recommended in ATP III.
A series of randomized, double-blind, placebo-controlled, factorial design phase 3 trials investigating coadministration of ezetimibe 10 mg with most available doses of simvastatin, lovastatin, pravastatin, and atorvastatin are ongoing, but are available in abstract form only at the time of preparation of this manuscript. In addition to confirming the efficacy and safety of using ezetimibe 10 mg in combination with currently available statins, these studies are designed to assess whether a 3-step statin titration-from 10 mg to 20 mg, 20 mg to 40 mg, and 40 mg to 80 mg-is better than, as good as, or not as good as a 1-step administration of a lowdose statin and ezetimibe 10 mg in patients classified by ATP III as having a 10-year risk of CHD >10% and with LDL-C >130 mg/dL, despite low-dose statin monotherapy.

■■ Summary and Conclusion
ATP III has increased the number of patients qualifying for aggressive LDL-C reduction, and statins remain the drugs of first choice for LDL-C reduction. Ezetimibe monotherapy at 10 mg/day offers an excellent alternative therapy to statins for patients who require modest LDL-C lowering or patients who are statin-intolerant. Coadministration of ezetimibe and a statin offers additional LDL-C reduction and is associated with an excellent tolerability and safety profile and ease of use. Taken as a whole, the phase 2 and 3 studies indicated that ezetimibe, the first in a new class of selective cholesterol absorption inhibitors, is effective as monotherapy and complements the LDL-C-lowering effects of statins. Ezetimibe at a once-daily dose of 10 mg lowers LDL-C by 18% to 20% as monotherapy, and when coadministered with a low-dose statin, produces LDL-C reductions usually observed only with high doses of statins. Furthermore, the ezetimibe and low-dose statin combination maximizes LDL-C reductions with a safety profile similar to placebo. Although ezetimibe has been shown to reduce LDL-C levels, its effectiveness in reducing cardiovascular morbidity and mortality remains to be proven. It is not certain whether lowering LDL-C by ezetimibe therapy alone versus statin plus ezetimibe will have the same cardiovascular benefits as statin therapy.