- Open Access
The pivotal role of cholesterol absorption inhibitors in the management of dyslipidemia
Lipids in Health and Disease volume 3, Article number: 22 (2004)
Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease. Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors. It impairs the intestinal reabsorption of both dietary and hepatically excreted biliary cholesterol. Ezetimibe is an effective and safe agent for lowering LDL-C and non HDL-C. Short term clinical trials have established the role of ezetimibe monotherapy and its use in combination with statins. Furthermore, ezetimibe and statin combination therapy increased the percentage of patients who achieved their LDL-C treatment goal.
Studies using surrogate markers of atherosclerosis have suggested a possible role of ezetimibe in combating atherosclerosis. Ezetimibe provides an effective therapeutic strategy for the management of homozygous familial hypercholesterolemia (HoFH) and sitosterolemia. The lack of outcomes and long term safety data is attributed to the relatively recent introduction of this medication.
Over 60 million Americans suffer from cardiovascular disease (CHD). The incidence of CHD and stroke has been on the rise partly because of the increase in life expectancy and the explosive epidemic of diabetes and the metabolic syndrome . CHD is responsible for about 38% of the overall mortality in the United States making it the number one killer of Americans .
Animal and human studies have established the role of cholesterol in the development and progression of atherosclerosis. LDL-cholesterol (LDL-C) constitutes approximately 60–70 % of total serum cholesterol. Epidemiological studies directly implicated LDL-C to the development of atherosclerosis and CHD. Furthermore, LDL-C level appears to be directly related to the development and recurrence of CHD .
Animal studies suggested a protective effect of low LDL-C against atherosclerosis . Multiple human trials examining the relationship of LDL-C lowering in primary and secondary prevention of CHD have demonstrated the impact of reducing LDL-C levels on decreasing CHD and CHD related mortality [4–8].
Most of the landmark CHD prevention trials involved the use of statin medications. LDL-C remains the primary target of treatment in most instances, and statins are the mainstay of LDL-C lowering treatment .
The National Cholesterol Education Program/ Adult Treatment Panel III (NCEP/ATP III) updated guidelines (table 1) for detection and treatment of dyslipidemia envisioned LDL-C below 100 mg/dL to be optimal for all patient risk categories. These more aggressive guidelines resulted in doubling of the number of patients that are not at target LDL-C levels as compared to previous guidelines . Recent NCEP/ATP III update data suggested even lower LDL-C levels than previously advocated, making it harder to achieve the treatment in many instances and recommended the use of combination therapy if needed to help achieve the treatment targets. The NCEP/ATP III update emphasized "the lower, the better" hypothesis .
Cholesterol Absorption inhibitors
Ezetimibe, a cholesterol absorption inhibitor, is the first agent of a new class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. Ezetimibe undergoes extensive glucuronidation to an active metabolite in the intestinal mucosa . Ezetimibe acts on brush border of the small intestine and decreases biliary and dietary cholesterol from the small intestine uptake into the enterocytes. Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion . Ezetimibe does not affect the absorption of fat-soluble vitamins, triglycerides, or bile acids .
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide) , the drug and its metabolite have a half-life of approximately 22 hours . Concomitant food administration (high fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered in the 10-mg clinical dose . Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins .
Plasma concentrations for total ezetimibe were about 2-fold higher in older individuals (>65 years), levels were similar in adolescents to healthy adults and may be higher in women than in men . In patients with severe renal disease, ezetimibe level was increased approximately 1.5-fold, compared to healthy controls . Ezetimibe had no significant effects on the bioavailability of warfarin, fenofibrate, HMG CoA reductase inhibitors, or digoxin [16, 18–20].
Adverse experiences were reported in approximately 2% of patients treated with ezetimibe and included fatigue, arthralgia, diarrhea, abdominal pain and back pain. Angioedema and rash were reported after general clinical use of this medication . With co-administration of ezetimibe and statins the adverse event profile was similar to that for statins alone. In a recently published case report, the authors described two patients whose creatinine kinase (CK) increased after the addition of ezetimibe to statin therapy causing one of the patients to experience myalgia and tendinopathy. This finding raises the question of whether ezetimibe can be implicated in precipitating increased risk of stain-associated myopathy .
The Role of Ezetimibe in Clinical Practice
Indications for use
Primary Hypercholesterolemia (heterozygous familial and non-familial), Ezetimibe is indicated in this case for use as both mono and combination therapy.
The reduction of elevated total-C and LDL-C levels in patients with homozygous familial hypercholesterolemia (HoFH) either as primary or as an adjunct to other lipid-lowering treatments.
In patients suffering from Homozygous Sitosterolemia, as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.
Multiple studies conducted to examine the effects of ezetimibe monotherapy have concluded that this drug was effective in lowering LDL-C versus placebo.
Analysis of multicenter, double-blind, placebo-controlled trials demonstrated that ezetimibe at the 10 mg once daily clinically approved dose significantly modified cholesterol and cholesterol subtypes in patients with hypercholesterolemia when compared to placebo. Ezetimibe significantly lowered total-Cholesterol (TC) (12 %), LDL-C (18 %), apolipoprotein B (Apo B) (15 %), and triglycerides (TG) (7%) and increased high density lipoprotein (HDL-C) (3.5%) [22–24]. Lipoprotein (a) [Lp (a)] was not significantly affected by Ezetimibe 10 mg once a day treatment .
In a case series report, we analyzed the effects of Ezetimibe on cholesterol particle size and number using NMR technology (Lipo science, Raleigh, NC). We found that Ezetimibe lowered cholesterol particle number by a mean 26 % and had no significant effect on cholesterol particle size .
The effects of ezetimibe on cholesterol and its subtypes were not influenced by risk-factor status, gender, age, race, time of administration, or baseline lipid profile . The overall incidence of adverse effects with ezetimibe monotherapy was similar to placebo.
The struggle to achieve the NCEP/ATP III guidelines LDL-C goals through primary utilization of statins is often frustrating for the clinician. In a study to examine the efficacy of statin titration on attainment of LDL-C goal, the authors concluded that for high risk patients, approximately half were able to achieve their LDL-C goal at the appropriate statin starting dose, and only one third of the titration group were able to achieve the NCEP/ATP III cholesterol goal . Now with the very recent publication of the update to the NCEP/ATP III, clinicians are faced with even lower goals of LDL-C, Making combination therapy a must in more cases than previously advocated by the NCEP/ATP III .
HMG-CoA reductase inhibitors (statins) act on the rate-limiting step to inhibit HMG-CoA conversion to mevalonate, effectively decreasing LDL-C synthesis. They result in a decrease of LDL-C ranging between 30–60 %, depending on the individual statin and the dose administered. Statin induced LDL-C lowering appears to be effective in reducing CHD and CHD related mortality and morbidity. The extent of CHD and CHD related events reduction is proportionate to the extent of LDL-C reduction [10, 28]. LDL-C reduction trials have demonstrated a reduction in CHD related events by approximately 20–40% [4–8].
Reasons to initiate combination therapy to treat hyperlipidemia include: further LDL-C lowering, reducing side effects related to higher doses of statins, modifying other risk factors besides LDL-C such as HDL-C and TG.
Increasing the dose of statins has a limited effect on reducing LDL-C, as it is well established that doubling the dose of a statins leads to a 5 % more reduction in total TC and 7 % more reduction in LDL-C with each doubling .
Although statins have demonstrated similarity in CHD related events, they are heterogeneous not only in LDL-C lowering efficacy but also in their safety profiles. The bulk of the statins effect on LDL-C occurs at the initial recommended dose and they are safer when used at doses below the maximal recommended dose.
Statins are the most effective drugs known to modify LDL-C, but in terms of HDL-C and TG modifying capacity, other classes of lipid lowering medications used alone or in combination with statins offer higher efficacy.
The metabolism of cholesterol is an intricate process that involves both produced and ingested cholesterol. The mechanism of action of HMG-CoA reductase inhibitors affects the production of cholesterol, whereas that of cholesterol absorption inhibitors affects absorbed cholesterol, thereby offering potential synergism of action when the medication are used in combination. Trials examining the efficacy have demonstrated synergism and consistency in LDL-C lowering in the absence pharmacokinetic interaction between the statins and ezetimibe.
In a relatively large, multicenter study, involving patients with primary hypercholesterolemia already receiving statin monotherapy (but who had not met their NCEP ATP II target LDL-C goal), patients were randomized to receive either ezetimibe or placebo in addition to their current statin therapy. At the conclusion of this 8 week study, the ezetimibe and statin groups were found to have a significantly lower total-C, LDL-C, Apo B, and TG, and increased HDL-C when compared to the statin only and placebo groups. Furthermore, LDL-C reductions induced by ezetimibe were generally consistent across all statins groups .
Another multicenter, double-blind, randomized trial examined the effects of ezetimibe on patients suffering from (HoFH). At the initiation of the trial patients were receiving either atorvastatin or simvastatin. The addition of ezetimibe reduced LDL-C by an additional 20.5 % in contrast to only 6.7 % reduction that resulted from doubling the statin dose . Similar results were demonstrated in high-risk patients with familial heterozygous hypercholesterolemia (HeFH) .
The addition of ezetimibe to statins is superior to treatment with statins alone in lowering non-HDL-C, ezetimibe co-administered with simvastatin lowered non-HDL-C by 47.1% whereas, simvastatin monotherapy lowered non-HDL-C by 33.6% when results were pooled across different doses .
In terms of modifying risk factors other than LDL-C, the co-administration of ezetimibe with statins had a more favorable effect on HDL-C and TG when compared to statins therapy alone . In conclusion, the addition of ezetimibe to statins produced further lowering of LDL-C of approximately 15–20 % with no apparent increase in side effects. This effect was superior to that observed by doubling the dose of the statins. Furthermore, the lowering produced was consistent.
Ezetimibe co-administration with fibric acid derivatives was examined in a randomized, evaluator-blind, placebo-controlled, parallel-group study of 32 healthy hypereholesterolemics. Ezetimibe co-administration with fenofibrate was found to produce clinically significant reductions in LDL-C (36.3%) compared to the fenofibrate group (22.3%) with a more favorable TG and HDL-C profile .
Sitosterolemia is a rare inherited disorder caused by mutation in either the ABCG5 or ABCG8 genes located on chromosome (2p21) . First described by Bhattacharyya and Connor in 1974 in two sisters of German and German-Swiss ancestry with normal mental development. The patients presented with tendinous and tuberous xanthoma and elevation of beta-sitosterol, campesterol and stigmasterol (plant sterols) in the blood . Affected individuals have increased intestinal absorption of plant sterols (mainly sitosterol) that are usually absorbed in minute amounts in normal individuals. Additionally, these patients have diminished clearance of plant sterols, leading to very high levels of plant sterols in the plasma. Patients suffering from sitosterolemia have severely depressed hepatic cholesterol biosynthesis, and decreased levels of HMG-CoA reductase enzyme .
Clinical manifestations include: tendon and tuberous xanthomas, episodes of hemolysis, accelerated atherosclerosis, and premature coronary artery disease. It is important to note that close to 50 % of these patients have normal cholesterol levels [38–41].
A recently reported trial demonstrated that treatment with ezetimibe reduces plant sterol levels in patients with sitosterolemia. The authors reported a decrease in sitosterol concentrations by 21% and campesterol by 24 % .
Ezetimibe and atherosclerosis
It is generally accepted that atherosclerosis is an inflammatory disorder. It is believed that the atherosclerotic process begins with endothelial cell activation, which is triggered by multiple factors such as oxidized lipoproteins. Cholesterol lowering agents as a group have demonstrated great efficacy in prevention and cessation of the progression of atherosclerosis. The efficacy of ezetimibe in monotherapy or in combination on CHD morbidity and mortality has not been well established.
One of the unique features of cholesterol absorption inhibitors is their ability to modify post-prandial hyperlipidemia. There is increasing evidence that post-prandial lipoproteins (particularly cholesterol-rich chylomicron remnant) are atherogenic. Ezetimibe has the potential to reduce the cholesterol content of chylomicrons by up to 60% , which may lead to a lower atherogenic potential of chylomicron remnants .
High-sensitivity C-reactive protein (hs-CRP) is an inflammatory mediator whose levels correlate with increased coronary risk. Ezetimibe co-administered with simvastatin resulted in significant incremental decreases in hs-CRP in patients with primary hypercholesterolemia. Changes in individual lipid parameters did not explain the observed decreases in hs-CRP and were possibly consistent with an additional anti-inflammatory effect compared with simvastatin monotherapy .
In a prospective trial to study effects of ezetimibe co-administered with atorvastatin in patients with primary hypercholesterolemia, ezetimibe plus atorvastatin significantly provided an additional (10%) lowering of hs-CRP versus atorvastatin alone .
The unanswered questions
Ezetimibe and its class of cholesterol absorption inhibitors are new, and there is a lack of outcomes data to explore whether its cholesterol modifying effects will translate to lower CHD mortality and morbidity. The safety of this medication has not yet been established with long term trials data as most of the studies conducted were short term. With the advent and increased utilization of combination therapy in the management of dyslipidemia, further trials are needed to explore the efficacy, indications and safety profile of ezetimibe use in combination with Peroxisome proliferator-activated receptors (PPARs), niacin and bile acid resins.
The increased popularity of special weight loss diets such as the high protein diet, poses questions of whether such diets will alter the efficacy or safety of cholesterol absorption inhibitors.
Finally, the efficacy of statins in reducing CHD related events has lead to the controversial hypothesis regarding whether or not statins poses a pleiotropic (non lipoprotein) effect. If a pleiotropic effect exists, one might argue that a statin at a higher dose might be more beneficial than combination therapy producing the same effect.
Ezetimibe is the first clinically approved cholesterol absorption inhibitor. It is effective in lowering LDL-C as monotherapy or in combination with statins. The use of combination LDL-C lowering medication is expected to become a much more common modality of treatment, especially after the recent NCEP/ATP III update. Ezetimibe offers further lowering of LDL-C and non HDL-C that is consistent and probably safer than increasing the dose of the individual statin. It also provides another effective treatment option for HoFH and sitosterolemia patients. Because of its recent introduction, we still lack both outcomes and long term safety data.
Ford ES, Giles WH, Dietz WH: Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002, 287: 356-9.
American Heart Association: Heart Disease and Stroke Statistics – 2004 Update. Dallas, Tex.: American Heart Association; © 2003 American Heart Association. 2003.
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. 106 (25): 3143-3421. 2002 Dec 17.
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998, 279 (20): 1615-1622.
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ, : Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995, 333: 1301-1307. 10.1056/NEJM199511163332001
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E, : The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996, 335: 1001-1009. 10.1056/NEJM199610033351401
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.
The 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. 10.1056/NEJM199811053391902
Ballantyne CM: Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol. 1998, 82 (9A): 3Q-12Q. 10.1016/S0002-9149(98)00769-3
Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Stone NJ: Coordinating Committee of the National Cholesterol Education Program; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Arterioscler Thromb Vasc Biol. 2004, 24: e149-161. 10.1161/01.ATV.0000133317.49796.0E
Salisbury BG, Davis HR, Burrier RE, Burnett DA, Bowkow G, Caplen MA, Clemmons AL, Compton DS, Hoos LM, McGregor DG: Hypocholesterolemic activity of a novel inhibitor of cholesterol absorption, SCH 48461. Atherosclerosis. 1995, 115: 45-63. 10.1016/0021-9150(94)05499-9
Jeu L, Cheng JW: Pharmacology and therapeutics of ezetimibe (SCH 58235), a cholesterol-absorption inhibitor. Clin Ther. 2003, 25: 2352-87. 10.1016/S0149-2918(03)80281-3
Nutescu EA, Shapiro NL: Ezetimibe: a selective cholesterol absorption inhibitor. Pharmacotherapy. 2003, 23: 1463-1474. 10.1592/phco.23.14.1463.31942
Van Heek M, France CF, Compton DS, McLeod RL, Yumibe NP, Alton KB, Sybertz EJ, Davis HR: In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH5 in the rat and rhesus monkey through the identification of the active metabolites of SCH48461. J Pharmacol Exp Ther. 1997, 283: 157-163.
Courtney RD, Kosoglou T, Statkevich P: Effect of food on the oral bioavailability of ezetimibe. Clin Pharmacol Ther. 2002, 71: 80-Abstract.
Zetia [package insert]. North Wales, Pa: Merck/Schering Plough Pharmaceuticals. 2003.
Manel Barbanoj, Rosa Antonijoan, Adelaida Morte, Josep Ma Grinyó, Ricard Solà, Joaquim Vallès, Concepció Peraire, José Cordero, Ana Muñoz, Francesc Jané, Rossend Obach: Pharmacokinetics of Ezetimibe in subjects with normal renal function or severe chronic renal insufficiency. Clin Pharmacol Ther. 2002, 71: 27-Abstract.
Harumi Takahashi, Shiro Ishikawa, Shinichi Nomoto, Yoshiyuki Nishigaki, Fumitaka Ando, Toshitaka Kashima, Sosuke Kimura, Madoka Kanamori, Hirotoshi Echizen: Ezetimibe does not affect the pharmacokinetics or pharmacodynamics of warfarin. Clin Pharmacol Ther. 2001, 69: 5-Abstract.
Reyderman L, Kosoglou T, Statkevich P: No pharmacokinetic drug interaction between ezetimibe and lovastatin. Clin Pharmacol Ther. 2001, 69: 66-Abstract 10.1067/mcp.2001.112680
Zhu Y, Statkevich F', Kosoglou T: Lack of pharmacokinetic interaction between ezetimibe and atorvastatin. Clin Pharmacol Ther. 2001, 69: 68-Abstract
Fux R, Morike K, Gundel UF, Hartmann R, Gleiter CH: Ezetimibe and statin-associated myopathy. Ann Intern Med. 2004, 140: 671-2.
Bays HE, Moore PB, Drehobl MA, Rosenblatt S, Toth PD, Dujovne CA, Knopp RH, Lipka LJ, Lebeaut AP, Yang B, Mellars LE, Cuffie-Jackson C, Veltri EP, : Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. Clin Ther. 2001, 23: 1209-1230. 10.1016/S0149-2918(01)80102-8
Knopp RH, Dujovne CA, Le Beaut A, Lipka LJ, Suresh R, Veltri EP, : Evaluation of the efficacy, safety, and tolerability of ezetimibe in primary hypercholesterolaemia: a pooled analysis from two controlled phase III clinical studies. Int J Clin Pract. 2003, 57: 363-368.
Dujovne CA, Ettinger MP, McNeer JF, Lipka LJ, LeBeaut AP, Suresh R, Yang B, Veltri EP, : Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol. 90: 1092-1097. 10.1016/S0002-9149(02)02798-4. 2002 Nov 15
Kerzner B, Corbelli J, Sharp S, Lipka LJ, Melani L, LeBeaut A, Suresh R, Mukhopadhyay P, Veltri EP, : Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. Am J Cardiol. 91: 418-424. 10.1016/S0002-9149(02)03236-8. 2003 Feb 15
Al-Shaer MH: The Effects of Ezetimibe on the LDL-Cholesterol Particle Number. Cardiovasc Drugs Ther. 2004, 18: 327-328. 10.1023/B:CARD.0000041253.85861.24
Foley KA, Simpson RJ, Crouse JR, Weiss TW, Markson LE, Alexander CM: Effectiveness of statin titration on low-density lipoprotein cholesterol goal attainment in patients at high risk of atherogenic events. Am J Cardiol. 2003, 92: 79-81. 10.1016/S0002-9149(03)00474-0
The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Group: Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002, 288: 2998-3007.
Roberts WC: The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am J Cardiol. 80: 106-107. 10.1016/S0002-9149(97)00298-1. 1997 Jul 1 10.1016/S0002-9149(97)00298-1
Gagne C, Bays HE, Weiss SR, Mata P, Quinto K, Melino M, Cho M, Musliner TA, Gumbiner B, : Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 90: 1084-91. 10.1016/S0002-9149(02)02774-1. 2002 Nov 15 10.1016/S0002-9149(02)02774-1
Gagne C, Gaudet D, Bruckert E, : Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 105: 2469-2475. 10.1161/01.CIR.0000018744.58460.62. 2002 May 28 10.1161/01.CIR.0000018744.58460.62
Bruckert E, Giral P, Tellier P: Perspectives in cholesterol-lowering therapy: the role of ezetimibe, a new selective inhibitor of intestinal cholesterol absorption. Circulation. 107: 3124-8. 10.1161/01.CIR.0000072345.98581.24. 2003 Jul 1 10.1161/01.CIR.0000072345.98581.24
Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP, Suresh R, Sun S, Veltri EP: Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol. 2002, 40: 2125-2134i. 10.1016/S0735-1097(02)02610-4
Kosoglou T, Statkevich P, Fruchart JC, Pember LJ, Reyderman L, Cutler DL, Guillaume M, Maxwell SE, Veltri EP: Pharmacodynamic and pharmacokinetic interaction between fenofibrate and ezetimibe. Curr Med Res Opin. 2004, 20 (8): 1197-1207.
Lu K, Lee MH, Hazard S, Brooks-Wilson A, Hidaka H, Kojima H, Ose L, Stalenhoef AF, Mietinnen T, Bjorkhem I, Bruckert E, Pandya A, Brewer HB, Salen G, Dean M, Srivastava A, Patel SB: Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by abcg5 and abcg8, respectively. Am J Hum Genet. 2001, 69: 278-290. 10.1086/321294
Bhattacharyya AK, Connor WE: Beta-sitosterolemia and xanthomatosis: a newly described lipid storage disease in two sisters. J Clin Invest. 1974, 53: 1033-1043.
Nguyen LB, Shefer S, Salen G, Ness GC, Tint GS, Zaki FG, Rani I: A molecular defect in hepatic cholesterol biosynthesis in sitosterolemia with xanthomatosis. J Clin Invest. 1990, 86: 923-931.
Wang C, Lin HJ, Chan TK, Salen G, Chan WC, Tse TF: A unique patient with coexisting cerebrotendinous xanthomatosis and beta-sitosterolemia. Am J Med. 1981, 71: 313-319. 10.1016/0002-9343(81)90134-0
Miettinen TA: Phytosterolemia, xanthomatosis and premature atherosclerotic arterial disease: a case with high plant sterol absorption, impaired sterol elimination and low cholesterol synthesis. Europ J Clin Invest. 1980, 10: 27-35.
Kwiterovich PO, Bachorik PS, Smith HH, McKusick VA, Connor WE, Teng B, Sniderman AD: Hyperapobetalipoproteinaemia in two families with xanthomas and phytosterolaemia. Lancet. 1981, I: 466-469. 10.1016/S0140-6736(81)91850-X. 10.1016/S0140-6736(81)91850-X
Salen G, Horak I, Rothkopf M, Cohen JL, Speck J, Tint GS, Shore V, Dayal B, Chen T, Shefer S: Lethal atherosclerosis associated with abnormal plasma and tissue sterol composition in sitosterolemia with xanthomatosis. J Lipid Res. 1985, 26: 1126-1133.
Salen G, von Bergmann K, Lutjohann D, Kwiterovich P, Kane J, Patel SB, Musliner T, Stein P, Musser B, : Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia. Circulation. 109: 966-971. 10.1161/01.CIR.0000116766.31036.03. 2004 Mar 2 10.1161/01.CIR.0000116766.31036.03.
Huff MW: Dietary cholesterol, cholesterol absorption, postprandial lipemia and atherosclerosis. Can J Clin Pharmacol. 2003, Winter; 10 (Suppl A): 26A-32A.
Evans M, Roberts A, Rees A: The future direction of cholesterol-lowering therapy. Curr Opin Lipidol. 2002, 13: 663-669. 10.1097/00041433-200212000-00010
Sager PT, Melani L, Lipka L, Strony J, Yang B, Suresh R, Veltri E, : Ezetimibe Study Group. Effect of coadministration of ezetimibe and simvastatin on high-sensitivity C-reactive protein. American Journal of Cardiology. 2003, 92: 1414-1418. 10.1016/j.amjcard.2003.08.048
Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, Suresh R, Sun S, LeBeaut AP, Sager PT, Veltri EP, : Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003, 107: 2409-2415. 10.1161/01.CIR.0000068312.21969.C8
Authors’ original submitted files for images
Below are the links to the authors’ original submitted files for images.
About this article
Cite this article
Al-Shaer, M.H., Choueiri, N.E. & Suleiman, E.S. The pivotal role of cholesterol absorption inhibitors in the management of dyslipidemia. Lipids Health Dis 3, 22 (2004). https://doi.org/10.1186/1476-511X-3-22
- Cholesterol Absorption Inhibitors
- Pleiotropic Effects of Statins
- homozygous familial hypercholesterolemia