The new guidelines issued in PRESENTATIONS... Future Outlook: Changing Perspectives on Best Practice

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Sydney Day
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1 ... PRESENTATIONS... Future Outlook: Changing Perspectives on Best Practice Based on a presentation by Daniel J. Rader, MD Presentation Summary The guidelines recently released by the National Cholesterol Education Program call for more aggressive lowering of the level of low-density lipoprotein (LDL) cholesterol and a significant increase in the number of patients eligible for therapy that lowers the level of LDL. Despite the efficacy of statins in lowering the LDL level and in reducing the risk of a coronary event or stroke, other cholesterol-lowering therapies are needed. Some patients are unable to tolerate statins or are not candidates for statin therapy because of liver enzyme abnormalities, age, a preference for nonsystemic therapy, or a modestly elevated LDL level. For those patients, bile acid sequestrants, intestinal bile acid transport inhibitors, acyl coenzyme A:cholesterol acyltransferase inhibitors, and a number of nonselective cholesterol absorption inhibitors are alternative treatments. However, those agents vary in their effectiveness in reducing the level of LDL. Their use often does not reduce the LDL level to the extent desired or is compromised by patients poor compliance with therapy because of inconvenient dosing or unpleasant side effects. Ezetimibe, the first selective inhibitor of intestinal cholesterol absorption, is a promising alternative to the agents listed above. When ezetimibe is used either as monotherapy or in combination with a statin, once-daily dosing reduces the level of LDL by an average of 18%. The new guidelines issued in 2001 by the National Cholesterol Education Program s (NCEP) Adult Treatment Panel (ATP III) differ in several significant ways from previous recommendations and, if followed by all practicing physicians, would mark a major change in the management of dyslipidemia in the United States. In the new guidelines, type 2 diabetes is classified as a coronary heart disease (CHD) risk equivalent, patients with 2 or more major risk factors for CHD are classified as high risk, and a lower level of low-density lipoprotein (LDL) is recommended as the treatment goal for patients at high, moderate, or low risk for CHD. 1 Those recommendations greatly increase the number of Americans eligible for LDL-lowering therapy. According to the new ATP III guidelines, those with CHD or other clinical forms of atherosclerotic disease, type 2 diabetes, or multiple risk factors that confer a 10-year risk of a coronary event that exceeds 20% should receive the most aggressive therapy, which is that of lowering the level of LDL to < 100 mg/dl. The LDL level recommended for those patients in previous NCEP guidelines was < 130 mg/dl. 1 The new guidelines also indicate that the LDL level should be lowered to < 130 mg/dl (a reduction from the prior cutpoint of < 160 mg/dl) in patients at moderate risk for a coronary event (those with 2 or more risk factors that confer a 10-year risk of 10% to 20% for a coronary event) and that it should be reduced to < 160 mg/dl (rather than the prior cutpoint of < 190 mg/dl) in those with a 10- year risk of less than 10%. 1 The Efficacy of Statins in Preventing a Coronary Event The statins are very effective and relatively safe in reducing the level of LDL and CHD-related morbidity and mortality S40 THE AMERICAN JOURNAL OF MANAGED CARE FEBRUARY 2002

2 Future Outlook: Changing Perspectives on Best Practice rates. That effectiveness has led many physicians to believe that there is little need for other lipid-modifying therapies. Although statins are readily available and effective, they do not meet the needs of many patients who require lipid-lowering therapy. It is essential that effective alternatives to statin therapy be available for those patients. For example, some patients cannot tolerate initial therapy with statins because of adverse side effects; others can tolerate a low dose of statins but not dose escalation. Some patients require a modest reduction in their level of LDL, some prefer nonsystemic therapy, others cannot achieve their target level of LDL as a result of statin monotherapy, and those with an elevated level of liver enzymes are not candidates for statin therapy. Many physicians are reluctant to prescribe statins for younger men and women who will require long-term therapy, and statins should not be prescribed for women who are pregnant or actively trying to become pregnant. Alternatives to Statin Monotherapy and Complementary Therapies Several alternatives and complements to statin monotherapy are currently available, and other potential agents and protocols are being investigated in clinical studies. Alternative agents exert an LDL-lowering effect primarily in the liver or the intestines. Combination therapy with agents that have complementary mechanisms of action can be very efficacious in further reducing LDL cholesterol and improving other aspects of the lipid profile. Niacin and Microsomal Triglyceride Transfer Protein Inhibitors An LDL-lowering effect in the liver is also produced by niacin and inhibitors of microsomal triglyceride transfer protein (MTP), a critical intracellular protein required for the development of nascent very-low-density lipoprotein (VLDL), which is the precursor of LDL. Niacin reduces the hepatic production of VLDL through mechanisms of action that are not completely understood. MTP inhibitors also lower the level of LDL by reducing VLDL secretion from the liver. Although MTP inhibitors have been investigated for some time, it is unclear whether they will ever be used clinically. Niacin is frequently used in combination with statins to lower the level of LDL even further. An observational study of an extended-release form of niacin indicated that 1 g of niacin added to a statin provided an additional 18% to 20% reduction in the level of LDL in patients who could not achieve a target LDL level while receiving statin monotherapy. 2 However, niacin can produce side effects that decrease its tolerability, and it is unlikely to be a long-term solution for patients who require further reduction in their level of LDL. Bile Acid Sequestrants Bile acid sequestrants are among several classes of agents that exert their effects primarily in the intestine, where lipids are packaged into chylomicrons and converted into chylomicron remnants that are ultimately taken up by the liver. Bile acid sequestrants have been available for many years. They bind bile acids, promote their excretion, and reduce their reuptake; reduce the enterohepatic cholesterol pool; upregulate LDL receptor activity in the liver and the clearance of LDL; and ultimately reduce the LDL plasma level. A new bile acid sequestrant, colesevelam, has multiple areas for bile acid binding, and 1 molecule of colesevelam can bind more bile acid than does 1 molecule of cholestyramine. As a result, the pill size of colesevelam is much smaller than that of cholestyramine. However, at least 3.8 g (6 pills per day) of colesevelam are required daily to produce a reasonable decrease in the level of LDL. According to a study in which monotherapy with colesevelam was evaluated, the standard daily dose of 3.8 g lowered the level of LDL in patients with moderate hypercholesterolemia by about 16%, produced a modest increase in the level of high-density lipoprotein (HDL), and VOL. 8, NO. 2, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S41

3 PRESENTATIONS Table 1. Case 1: A Young Man with Hypertension Age 34 years LDL level 176 mg/dl HDL level 34 mg/dl Risk 0 to 1 risk factor Initial therapy: Dietary modification and exercise for 3 months LDL level 162 mg/dl HDL level 36 mg/dl goal of < 160 mg/dl Options: A statin or monotherapy with ezetimibe 10 mg/day Option chosen: Monotherapy with ezetimibe Ezetimibe monotherapy for 3 months LDL level 128 mg/dl HDL level 40 mg/dl HDL = high-density lipoprotein; LDL = low-density lipoprotein. increased the level of triglycerides by about 10%. 3 Bile acid sequestrants such as colesevelam can be used in combination with statins in patients for whom statin monotherapy does not produce the desired level of LDL. Although bile acid sequestrants are relatively safe, the high pill burden of colesevelam and the inconvenient dosing of cholestyramine and colestipol reduce compliance and ultimately limit the effectiveness of those agents in monotherapeutic and combination regimens. Intestinal Bile Acid Transport Inhibitors Another potential approach to lowering the level of LDL is the use of intestinal bile acid transport (ibat) inhibitors, which are molecular compounds that directly inhibit the binding and transport of bile acids from the lumen of the intestine into the enterocyte, inhibit the uptake of bile acids and promote their excretion, and upregulate LDL receptor activity. These effects are conceptually related to those of bile acid sequestrants in that they decrease the enterohepatic circulation of bile acids and their return to the liver. The ibat inhibitors are currently being investigated in clinical trials and may be feasible alternatives to other therapies that lower the level of LDL. Acyl Coenzyme A:Cholesterol Acyltransferase Inhibitors The use of acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitors is also effective in lowering the level of LDL. Because ACAT is required within the intestinal enterocyte to promote the esterification of free cholesterol and the transport of the ester, the inhibition of ACAT would theoretically reduce cholesterol absorption and ultimately reduce the level of LDL. The ACAT inhibitor avasimibe has been investigated in clinical trials. Plant Sterols and Stanols Plant sterols and stanols are functional foods that are available in health food stores and supermarkets. At a relatively high dose, they lower the level of LDL by interfering with the generation of micelles required for efficient cholesterol absorption. According to the results of a meta-analysis of 16 trials evaluating the effects of dietary phytosterols, those compounds reduced the LDL levels in patients with moderate hypercholesterolemia by a mean of 13%. 4 Although plant sterols and stanols are usually well tolerated, they must be taken 3 times per day to be effective. However, they are an alternative to statin therapy for patients who want to avoid systemic therapy and require only a minimal reduction in the level of LDL cholesterol and are willing to comply with the dosing regimen. Selective Cholesterol Absorption Inhibitors Ezetimibe, the first selective cholesterol absorption inhibitor, is now being investigated in clinical trials. At a dose of S42 THE AMERICAN JOURNAL OF MANAGED CARE FEBRUARY 2002

4 Future Outlook: Changing Perspectives on Best Practice Table 2. Case 2: A Postmenopausal Woman with Hypertension and a Family History of Premature Coronary Disease Age 55 years LDL level 202 mg/dl HDL level 39 mg/dl Risk 2+ risk factors Initial therapy: Atorvastatin 10 mg/day for 3 months LDL level 137 mg/dl HDL level 42 mg/dl goal of < 130 mg/dl Options: Escalation of statin dose or combination therapy with starting dose of statin plus ezetimibe 10 mg/day Option chosen: Combination therapy Combination therapy for 3 months LDL level 118 mg/dl HDL = high-density lipoprotein; LDL = low-density lipoprotein. 10 mg/day, it reduces the level of LDL by about 18% in monotherapeutic and combination regimens and is safe and well tolerated. It also increases the level of HDL, modestly lowers the level of triglycerides, and requires only oncedaily dosing. 5 The selective inhibition of cholesterol by ezetimibe suggests that this agent interferes with the transport of cholesterol across the brush border into the intestinal epithelial cell, a key step in the absorption of cholesterol. As a therapeutic alternative to statins, ezetimibe 10 mg/day appears to have great potential for use in clinical practice. As illustrated in the 3 cases described in this presentation (Tables 1 to 3), ezetimibe is suitable as a monotherapy for patients at low risk for CHD who require only a modest reduction in their LDL level, and it can be used in a combination regimen for patients at moderate or high risk for a cardiovascular event. Table 3. Case 3: A Middle-Aged Man with Type 2 Diabetes Age 56 years LDL level 183 mg/dl HDL level 36 mg/dl Risk CHD risk equivalent Initial therapy: Simvastatin 20 mg/day for 3 months LDL level 141 mg/dl HDL level 39 mg/dl goal of < 100 mg/dl Options: Escalation of statin dose or escalation of statin dose plus addition of ezetimibe 10 mg/day Option chosen: Escalation of statin dose Simvastatin 80 mg/day for 3 months LDL level 120 mg/dl HDL level 41 mg/dl Additional therapy still needed to reach LDL goal of < 100 mg/dl Options: Simvastatin 80 mg/day plus addition of ezetimibe 10 mg/day Combined therapy with high-dose simvastatin and ezetimibe for 3 months LDL level < 100 mg/dl CHD = coronary heart disease; HDL = high-density lipoprotein; LDL = low-density lipoprotein. Conclusion Statins are very effective in lowering the level of LDL and reducing the morbidity and mortality caused by CHD. Despite that success, those agents are not appropriate for all patients who must lower their LDL level. Furthermore, not all patients can achieve LDL goals on statin monotherapy. Therefore, alternative and/or additional therapies are needed. Selective cholesterol absorption inhibitors such as ezetimibe appear to be safe, effective, and well tolerated, and can also be used in combination with statins to lower the level of LDL. VOL. 8, NO. 2, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S43

5 PRESENTATIONS... REFERENCES Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol (Adult Treatment Panel III). JAMA 2001;285: Wolfe ML, Vartranian SF, Ross JL, et al. Safety and effectiveness of Niaspan when added sequentially to a statin for treatment of dyslipidemia. Am J Cardiol 2001;87: Insull W Jr, Toth P, Mullican W, et al. Effectiveness of colesevelam hydrochloride in decreasing LDL cholesterol in patients with primary hypercholesterolemia: A 24-week randomized controlled trial. Mayo Clin Proc 2001;76: Moghadasian MH, Frolich JJ. Effects of dietary phytosterols on cholesterol metabolism and atherosclerosis: Clinical and experimental evidence. Am J Med 1999;107: Merck/Schering-Plough Pharmaceuticals; North Wales, PA. Data on file. S44 THE AMERICAN JOURNAL OF MANAGED CARE FEBRUARY 2002

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