Pharmacology and therapeutics of ezetimibe (SCH 58235), a cholesterol-absorption inhibitor

BACKGROUND: Ezetimibe is the first of a new class of antihyperlipidemic agents, the cholesterol-absorption inhibitors. It is indicated for monotherapy or in combination with 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins) in patients with primary hypercholesterolemia, in combination with simvastatin or atorvastatin in patients with homozygous familial hypercholesterolemia, and as monotherapy in patients with homozygous familial sitosterolemia. OBJECTIVE: This article reviews available data on the clinical pharmacology, clinical efficacy, and tolerability of ezetimibe. METHODS: A literature review was conducted using the search terms ezetimibe and SCH 58235 to identify articles and abstracts indexed in MEDLINE and the Iowa Drug Information Service from 1966 to February 2003. The reference lists of the identified articles were reviewed for additional publications. RESULTS: In adults, ezetimibe 10 mg PO given once daily has been reported to reduce intestinal cholesterol absorption by 54% from baseline in association with a compensatory increase in endogenous cholesterol synthesis. Within 2 weeks of its initiation, ezetimibe monotherapy produced a 17% to 20% reduction from baseline in low-density lipoprotein cholesterol (LDL-C); in combination with statins, ezetimibe produced a reduction in LDL-C of up to 40% over the same period. Based on studies performed to date, ezetimibe appears to be well tolerated, with a safety profile similar to that of placebo. Because ezetimibe is eliminated primarily by glucuronidation and not by cytochrome P450 (CYP) oxidation, it is subject to minimal drug interactions involving the CYP enzyme system. CONCLUSIONS: Ezetimibe is an option for monotherapy in patients with mild hypercholesterolemia or in those requiring adjunctive drug therapy for reduction of LDL-C levels. It may be useful in patients at risk for adverse events (eg, liver toxicity, myopathy) from other hypocholesterolemic agents. Additive LDL-C-lowering effects of ezetimibe may allow use of lower doses of conventional agents (eg, statins, fibric acid derivatives, niacin) to achieve an equivalent effect, thereby reducing the potential for adverse events and drug interactions. However, because trials have lasted no longer than 12 weeks, the long-term effect of ezetimibe on cardiovascular morbidity and mortality remains to be determined.     

Ezetimibe plus simvastatin cardiovascular outcomes study program

Ezetimibe is a drug that impairs intestinal cholesterol absorption and decreases blood cholesterol levels. It has been shown that added to statins it can achieve a further reduction of low-density lipoprotein-cholesterol of 18-20%, overcoming the increase in absorption that follow the reduction in cholesterol synthesis by statins. Four major outcome trials are underway to study the effect of ezetimibe plus simvastatin in different subsets of high-risk patients: familiar hypercholesterolemia, degenerative aortic stenosis, chronic kidney disease and acute coronary syndrome. Hopefully, in the next few years the information provided by these trials will allow us to further reduce the increasing burden of cardiovascular disease.     

Ezetimibe-induced acute pancreatitis

Ezetimibe is a lipid-lowering agent that inhibits the intestinal absorption of cholesterol and other related phytosterols. It is used alone or in combination with other lipid-lowering agents in the treatment of various forms of hypercholesterolemia. Since its FDA approval in 2002, there are no known citations of ezetimibe-induced pancreatitis.     

Effects of plant stanol and sterol esters on serum phytosterols in a family with familial hypercholesterolemia including a homozygous subject

We studied the concentrations and ratios to cholesterol of noncholesterol sterols reflecting absorption (eg, campesterol) or synthesis (eg, lathosterol) of cholesterol off and on plant sterol and stanol ester spreads in serum and in different lipoproteins of a family with familial hypercholesterolemia, including heterozygous parents receiving no treatment and their homozygous offspring undergoing long-term treatment with statins and apheresis. Serum cholesterol levels were similar in the homozygous and heterozygous individuals, but the concentrations of sterols reflecting cholesterol absorption were as much as 10 times greater in the homozygous child than in the heterozygous parents, whereas the respective markers of cholesterol synthesis only tended to be higher. About 70% of squalene in the homozygous individual (60% in the heterozygous family members) and 85% to 90% of noncholesterol sterols (60%-80% in the heterozygous subjects) were transported by low-density lipoprotein. The ratios of absorption sterols to cholesterol were higher in high-density lipoprotein (HDL) than in very low-density lipoprotein (VLDL), whereas those of synthesis markers and plant stanols were highest in VLDL. The ratios of absorption sterols in serum were mostly lower than those in HDL but higher than in VLDL, whereas the ratios of synthesis sterols in serum were lower than they were in VLDL. Both spreads reduced serum total cholesterol by about 14% in the heterozygous family members and 9% in the homozygous individual. The sterol ester spread increased serum plant sterol concentrations (eg, campesterol in the homozygous family member increased from 5 to 9 mg/dL) and the ratios to cholesterol, but the stanol ester spread decreased them. Plant sterol esters seemed to similarly decrease serum cholesterol in this family with familial hypercholesterolemia, but the clinical role of increased plant sterol concentrations, almost doubled in the LDL of homozygous individuals, is not known.     

Ezetimibe: a novel option for lowering cholesterol

Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease but lowering LDL-cholesterol to levels established in current National Cholesterol Education Program (NCEP) guidelines provides significant risk reduction. Nevertheless, many patients receiving lipid-lowering therapy, particularly those at highest coronary heart disease risk, do not reach LDL-cholesterol goals with their current medications. Ezetimibe (Zetia^®, Merck Schering-Plough) is the first of a new class of lipid-lowering drugs known as cholesterol absorption inhibitors. Ezetimibe has a favorable pharmacokinetic profile, which allows it to be administered once daily and to be given in conjunction with statins. In a series of randomized, controlled, multicenter studies, ezetimibe produced significant improvements in levels of LDL-cholesterol and other lipid parameters when used as monotherapy, with a safety profile comparable with that of placebo. Furthermore, coadministration of ezetimibe with a statin (simvastatin, atorvastatin, lovastatin, or pravastatin) was more effective than statin monotherapy in lowering LDL-cholesterol and improving other lipid parameters. Moreover, coadministration of ezetimibe with a statin allowed a greater percentage of patients to achieve treatment goals established in NCEP guidelines. The safety and side-effect profile of ezetimibe plus statin coadministration therapy was generally comparable with that of statin monotherapy. These studies establish ezetimibe as an effective lipid-lowering agent, which will likely be useful in the management of a broad range of patients with hypercholesterolemia. Ezetimibe can be used in conjunction with a statin at the beginning of therapy, or it can be added if patients do not achieve their LDL-cholesterol goal with statins alone.     

Ezetimibe: a novel option for lowering cholesterol

Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease but lowering LDL-cholesterol to levels established in current National Cholesterol Education Program (NCEP) guidelines provides significant risk reduction. Nevertheless, many patients receiving lipid-lowering therapy, particularly those at highest coronary heart disease risk, do not reach LDL-cholesterol goals with their current medications. Ezetimibe (Zetia, Merck Schering-Plough) is the first of a new class of lipid-lowering drugs known as cholesterol absorption inhibitors. Ezetimibe has a favorable pharmacokinetic profile, which allows it to be administered once daily and to be given in conjunction with statins. In a series of randomized, controlled, multicenter studies, ezetimibe produced significant improvements in levels of LDL-cholesterol and other lipid parameters when used as monotherapy, with a safety profile comparable with that of placebo. Furthermore, coadministration of ezetimibe with a statin (simvastatin, atorvastatin, lovastatin, or pravastatin) was more effective than statin monotherapy in lowering LDL-cholesterol and improving other lipid parameters. Moreover, coadministration of ezetimibe with a statin allowed a greater percentage of patients to achieve treatment goals established in NCEP guidelines. The safety and side-effect profile of ezetimibe plus statin coadministration therapy was generally comparable with that of statin monotherapy. These studies establish ezetimibe as an effective lipid-lowering agent, which will likely be useful in the management of a broad range of patients with hypercholesterolemia. Ezetimibe can be used in conjunction with a statin at the beginning of therapy, or it can be added if patients do not achieve their LDL-cholesterol goal with statins alone.     

Efficacy and safety of ezetimibe coadministered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia

We assessed pooled safety and lipid-regulating efficacy data from four similarly designed trials of ezetimibe coadministered with statins in 2382 patients with primary hypercholesterolemia. Patients were randomised to one of the following double-blind treatments for 12 weeks: placebo; ezetimibe 10 mg; statin; or statin + ezetimibe. Statin doses tested were 10, 20, 40 mg/day (atorvastatin, simvastatin, pravastatin or lovastatin) or 80 mg/day (atorvastatin, simvastatin). Treatment with ezetimibe + statin led to significantly greater reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and increases in HDL-C, compared to statin alone. At each statin dose, treatment with ezetimibe + statin led to a greater LDL-C reduction compared to the next highest statin monotherapy dose. Ezetimibe + statin had a safety profile similar to statin monotherapy. Coadministration of ezetimibe + statin offers a well-tolerated, highly efficacious new treatment strategy for patients with hypercholesterolemia.     

Ezetimibe: cholesterol lowering and beyond

Ezetimibe is a cholesterol absorption inhibitor that blocks the intestinal absorption of both biliary and dietary cholesterol. It appears to exert its effect by blocking intestinal sterol transporters, specifically Niemann–Pick C1-like 1 proteins, thereby inhibiting the intestinal absorption of cholesterol, phytosterols and certain oxysterols. Ezetimibe monotherapy and in combination with statin therapy is primarily indicated for lowering LDL-cholesterol levels. In addition, it may favorably affect other parameters that could potentially further reduce atherosclerotic coronary heart disease risk, such as raising HDL-cholesterol and lowering levels of triglycerides, non-HDL-cholesterol, apolipoprotein B and remnant-like particle cholesterol. Further effects of ezetimibe include a reduction in circulating phytosterols and oxysterols and, when used in combination with statins, a reduction in high-sensitivity C-reactive protein. The clinical significance of the LDL-cholesterol lowering and other effects of ezetimibe is being evaluated in clinical outcome studies.     

Ezetimibe: cholesterol lowering and beyond

Ezetimibe is a cholesterol absorption inhibitor that blocks the intestinal absorption of both biliary and dietary cholesterol. It appears to exert its effect by blocking intestinal sterol transporters, specifically Niemann-Pick C1-like 1 proteins, thereby inhibiting the intestinal absorption of cholesterol, phytosterols and certain oxysterols. Ezetimibe monotherapy and in combination with statin therapy is primarily indicated for lowering LDL-cholesterol levels. In addition, it may favorably affect other parameters that could potentially further reduce atherosclerotic coronary heart disease risk, such as raising HDL-cholesterol and lowering levels of triglycerides, non-HDL-cholesterol, apolipoprotein B and remnant-like particle cholesterol. Further effects of ezetimibe include a reduction in circulating phytosterols and oxysterols and, when used in combination with statins, a reduction in high-sensitivity C-reactive protein. The clinical significance of the LDL-cholesterol lowering and other effects of ezetimibe is being evaluated in clinical outcome studies.     

Long-term safety and, tolerability profiles and lipid-modifying efficacy of ezetimibe coadministered with ongoing simvastatin treatment: a multicenter, randomized, double-blind, placebo-controlled, 48-week extension study

BACKGROUND: Ezetimibe (EZE) is a cholesterol-lowering drug that inhibits absorption of dietary and biliary cholesterol across the intestinal wall without affecting absorption of bile acids, fatty acids, fat-soluble vitamins, or triglycerides. It has a complementary mechanism of action to the statins, which inhibit cholesterol synthesis in the liver. Coadministration of EZE and statins provides inhibition of 2 sources of cholesterol, leading to greater reductions in low-density lipoprotein cholesterol (LDL-C) than with either agent alone. OBJECTIVES: This study evaluated the long-term safety and tolerability profiles and lipid-modifying efficacy of treatment with EZE 10 mg/d plus simvastatin (SIMVA) 10, 20, 40, or 80 mg/d for 48 weeks in patients with primary hypercholesterolemia. METHODS: This was an extension of a multicenter, double-blind, placebo (PBO)-controlled base study in which hypercholesterolemic patients were randomized to receive EZE 10 mg/d or PBO in addition to their current statin for 8 weeks. Patients who successfully completed the base study could enter the extension study if they were willing to switch from their current statin to an approximately equipotent dose of SIMVA for the 54-week study period. After a 6-week open-label SIMVA run-in phase, patients were rerandomized to receive EZE 10 mg/d or PBO in a 4:1 ratio, respectively, for 48 weeks. At each clinic visit, beginning at week 12, the dose of SIMVA was titrated upward until patients reached their National Cholesterol Education Program Adult Treatment Panel II LDL-C goal or the maximum SIMVA dose of 80 mg/d. Safety/tolerability and lipid efficacy parameters were assessed at 12-week intervals. RESULTS: Of 433 patients entering the extension study, 355 were randomized to receive EZE and 78 were randomized to receive PBO. Baseline demographic characteristics and lipid levels were similar between treatment groups. Overall, coadministration of EZE + SIMVA was well tolerated. There were no clinically meaningful differences between the EZE and PBO groups with regard to the incidence of treatment-related adverse events (AEs) (19% vs 17%, respectively), discontinuations due to AEs (7% vs 10%), serious AEs (12% vs 17%), consecutive elevations in liver function tests > or =3 times the upper limit of normal (ULN) (0.3% vs 0%), or elevations in creatine kinase > or =10 times the ULN (both, 0%). As in the base study, LDL-C levels were significantly lower with the addition of EZE to SIMVA compared with the addition of PBO (-24% vs 3%; P < 0.001). CONCLUSION: In these patients with primary hypercholesterolemia, EZE 10 mg/d added to ongoing SIMVA treatment for 48 weeks had a favorable safety and tolerability profile and was more efficacious than SIMVA monotherapy.     

Ezetimibe in hypercholesterolaemia

Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors, compounds that effectively block intestinal absorption of dietary and biliary cholesterol, without affecting absorption of fat soluble vitamins or triglycerides. Ezetimibe underwent glucuronidation to a single metabolite and localised at the intestinal wall, where it prevented luminal cholesterol absorption. Pre-clinical studies demonstrated the lipid-lowering and antiatherosclerotic properties of ezetimibe. The efficacy and safety of ezetimibe monotherapy have been determined in phase II/III studies: in phase II studies, the optimal efficacy was reached with ezetimibe 10 mg per day and the pooled efficacy data have shown that ezetimibe 10 mg has a positive effect on the lipoprotein profile with a significant reduction in LDL-cholesterol of 18.5%, an increase in HDL-cholesterol of 3.5% and a trend towards lowering in triglyceride concentrations (-4.9%). The monotherapy phase III studies have confirmed the efficacy with a decrease in LDL-C of 17.4% and have demonstrated an excellent safety and tolerability profile. The potential for a pharmacokinetic and/or pharmacodynamic interaction between ezetimibe and various statins and the efficacy and safety or the co-administration of ezetimibe and statins have been evaluated in different phase I/II studies: ezetimibe had no significant effect on the pharmacokinetics of simvastatin or atorvastatin. Ezetimibe 10 mg co-administrated with the starting dose of any statin induced a mean 18% additive LDL-C lowering effect. This additive 18% reduction in LDL-C is achieved in one step compared with the three steps necessary with statin monotherapy.     

Ezetimibe for management of hypercholesterolemia

OBJECTIVE: To review the primary literature describing the pharmacology of ezetimibe and clinical trials investigating its use in the management of hypercholesterolemia. DATA SOURCES: A MEDLINE search (1966-December 2002) was performed using SCH 48461, SCH 58235, ezetimibe, and 2-azetidinone as key words. English-language articles were identified and the references of these articles were used to further identify pertinent articles and abstracts. Given the paucity of published articles available on ezetimibe, many of the references cited are abstracts. STUDY SELECTION: All acquired articles that discussed the pharmacology, pharmacokinetics, chemistry, and clinical efficacy of ezetimibe were reviewed. DATA EXTRACTION: Articles were selected based on content regarding the medicinal chemistry, pharmacology, and clinical use of ezetimibe. DATA SYNTHESIS: Ezetimibe, approved for use in October 2002, belongs to a new class of antihyperlipidemic agents that uniquely inhibit the absorption of cholesterol by inhibiting the cholesterol transport system located within intestinal cell walls. In humans, ezetimibe reduced cholesterol absorption by >50%. In clinical trials, ezetimibe 10 mg/d reduced low-density lipoprotein cholesterol (LDL-C) by approximately 18% and further enhanced the LDL-C-lowering effect of statin medications by an additional 15-20%. In addition, ezetimibe lowered triglycerides about 5% and increased high-density lipoprotein cholesterol (HDL-C) approximately 3%. Ezetimibe is well tolerated. At present, no serious adverse effects have been directly attributable to ezetimibe. CONCLUSIONS: Based on the data currently available, it appears that ezetimibe has a potential role in the treatment of primary hypercholesterolemia; however further data are needed to determine its long-term tolerability and efficacy. The potential roles for ezetimibe include its concurrent use with a statin to further enhance the lowering of LDL-C. Other possible roles for ezetimibe include its concurrent use with a statin to permit a lowering of statin dosage to avoid statin-related complications or its use as monotherapy to treat hypercholesterolemia when statin use cannot be tolerated or is contraindicated. Outcome data demonstrating that cardiovascular morbidity and/or mortality are reduced by ezetimibe therapy have yet to be generated.     

Selective cholesterol absorption inhibition: a novel strategy in lipid-lowering management

Many individuals throughout Europe have risk factors for coronary heart disease (CHD) and are non-compliant with recommended treatments, despite guidelines for the reduction of low-density lipoprotein cholesterol (LDL-C) and the prevention of CHD. Significant numbers who should receive pharmacotherapy for hypercholesterolaemia do not, and one-third of treated patients do not achieve recommended target LDL-C levels. Optimum doses of statins, which have demonstrated undisputed efficacy in the treatment of hypercholesterolaemia in clinical trials, are seldom used; the inconvenience of dosage adjustments and safety concerns, particularly myalgia, may constitute obstacles to their optimal use for LDL-C reduction in clinical practice. Ezetimibe is the first selective cholesterol absorption inhibitor that has demonstrated clinical benefits when used as either monotherapy or in combination with other lipid-modifying agents.     

Elevated Cholesterol and Bile Acid Synthesis in a Young Patient with Homozygous Familial Hypercholesterolemia

Cholesterol balance studies were carried out twice in a young male patient with homozygous familial hypercholesterolemia. At 13 mo, cholesterol balance in this patient averaged 31.3 mg/kg per d, and bile acid excretion was 12.0 mg/kg per d; at 3 yr, results were similar, 27.3 and 15.5 mg/kg per d for cholesterol balance and bile acids, respectively. A normal boy of 3 yr was also studied for comparison with the second study in our patient. Cholesterol balance and bile acid outputs in the normal child were 11.5 and 3.3 mg/kg per d, respectively. Thus, in comparison with the normal child, the patient with homozygous familial hypercholesterolemia had a marked increase in synthesis of cholesterol and bile acids. Although synthesis of bile acids was high in this patient, the fraction of newly synthesized cholesterol converted into bile acids (40-56%) was in the normal range; this suggests that the enhanced output of bile acids was secondary to an increased synthesis of cholesterol and not to malabsorption of bile acids, which likely would have produced a higher fractional conversion. Although our patient has been studied at a younger age than any reported in the literature, two similar children 5 and 6 yr of age were also observed to have elevated cholesterol synthesis. This finding contrasts with those in older children with the homozygous as well as heterozygous forms of this disease who appear to have normal synthesis of cholesterol and bile acids. Therefore, increased synthesis of cholesterol seems to be characteristic of early homozygous familial hypercholesterolemia, and may be a manifestation of a loss of feedback inhibition of cholesterol synthesis secondary to an absence of specific cell-surface receptors for low density lipoproteins. However, as children with this disease grow older, other mechanisms may come into play to restore cholesterol synthesis to normal levels.     

Effectiveness of ezetimibe added to ongoing statin therapy in modifying lipid profiles and low-density lipoprotein cholesterol goal attainment in patients of different races and ethnicities: a substudy of the Ezetimibe add-on to statin for effectiveness trial

OBJECTIVE: To examine whether the improvements in lipid profiles and low-density lipoprotein cholesterol (LDL-C) goal attainment found in the Ezetimibe Add-On to Statin for Effectiveness trial occurred equally in the black, Hispanic, and white patient populations enrolled in the study. PATIENTS AND METHODS: In this double-blind, placebo-controlled study, patients were recruited from 299 community-based practices across the United States (January to August 2003). Patients with, hypercholesterolemia and LDL-C levels exceeding National Cholesterol Education Program Adult Treatment Panel III goals were randomized (2:1) to receive either ezetimibe (10 mg/d) or placebo in addition to their ongoing statin therapy for 6 weeks. RESULTS: A total of 5802 patients were screened at baseline for the Ezetimibe Add-On to Statin for Effectiveness study. Of these, 2772 were excluded, and the remaining 3030 eligible patients were randomized. Ezetimibe, compared with placebo, added to statin therapy significantly reduced LDL-C levels from statin-treated baseline by 23.0% (white patients), 23.0% (black patients), and 21.0% (Hispanic patients). This effect was consistent across race and ethnicity groups (P > .50 for treatment-by-race interactions). Ezetimibe added to statin therapy also statistically significantly (P < .001) increased the percentage of patients attaining their LDL-C goal for their National Cholesterol Education Program Adult Treatment Panel III risk category in black (63.0%), Hispanic (64.8%), and white (72.3%) patients compared with placebo plus statin (32.9% black patients, 19.0% Hispanic patients, and 19.7% white patients). Ezetimibe treatment improved other lipid parameters across groups, including triglyceride, high-density lipoprotein cholesterol, non-high-density ilpoprotein cholesterol, and total cholesterol levels. Finally, the addition of ezetimibe reduced high-sensitivity C-reactive protein levels overall, and no significant interaction of treatment by race occurred (P = .83), Indicating a consistent effect across races. Ezetimibe was generally well tolerated, and no detectable differences occurred in the adverse event profile by race or ethnicity. CONCLUSION: Ezetimibe added to statin therapy is effective and well tolerated for improving the lipid profile and LDL-C goal attainment of patients regardless of race or ethnicity.     

Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review

Bile acid sequestrants (BAS) continue to command a position in the treatment of dyslipidemias 25 years after their introduction. Partial diversion of the enterohepatic circulation using BAS depletes the endogenous bile acid pool by approximately 40%, thus stimulating an increase in bile acid synthesis from cholesterol, which lowers low-density lipoprotein cholesterol (LDL-C) by 15 to 26%. Three BAS are currently used for treating hypercholesterolemia in the United States: the conventional sequestrants, cholestyramine and colestipol, and the specifically engineered BAS, colesevelam hydrochloride (HCl). Compared with conventional BAS, colesevelam HCl has enhanced specificity, greater affinity, and higher capacity for binding bile acids, due to its polymer structure engineered for bile acid sequestration. BAS are not absorbed by the intestine and thus have no systemic drug-drug interactions, but may interfere with the absorption of some drugs. Although BAS monotherapy effectively lowers LDL-C, combination therapy, especially with BAS and statins, is becoming increasingly common due to complementary mechanisms of action. Low-dose statin plus BAS combinations lead to greater or similar LDL-C reductions compared with high-dose statin monotherapy and may have a better safety profile. Combinations of BAS with nonstatin lipid-lowering agents, including niacin, fibrates, and cholesterol absorption inhibitors, may be useful in those patients who require intensive lipid-lowering, but are statin intolerant. BAS treatment can significantly reduce coronary artery disease (CAD) progression and the risk of CAD-associated outcomes. It is also becoming clear that BAS and other therapies that manipulate the bile acid synthetic pathway may have clinically useful therapeutic effects on other metabolic disorders including type 2 diabetes.     

Statin pleiotropy: fact or fiction?

Accumulating evidence from clinical trials and basic research indicates that statin therapy favorably influences a number of diverse clinical events through both effects related to lowering of LDL cholesterol levels and effects independent of the lowering of LDL cholesterol levels. The latter effects are referred to as pleiotropic. The full potential of this exciting class of drugs in vascular and nonvascular protection is only just being realized. The pleiotropic effects of the statins improve vascular relaxation, promote new vessel formation, and stabilize unstable plaques. Statins reduce glomerular injury, renal disease progression, insulin resistance, and bone resorption. Ezetimibe, a recently approved medication, enhances the lipid-lowering effects of the statins by lowering LDL and increasing HDL levels through its property of inhibiting absorption of cholesterol in the small intestine. These salutary effects of ezetimibe on statin levels presumably enhance the beneficial effects attributed to statin pleiotropy. It is noteworthy that the pleiotropic properties of the statins have been beneficial in a variety of diseases that involve a number of organs and organ systems. No other therapeutic agent can claim equally stellar results in such a wide variety of diseases. The common denominator in all of the diseases that have been shown to improve with statin pleiotropy could be arteriolar pathology due to hyperlipidemia, which improves in response to statins by a return of arteriolar function to normal rather than through statin pleiotropy. Recent reports indicate that higher doses of statins reverse atheromatous changes in the coronary artery when the LDL cholesterol level is lowered to well below 2.59 mmol/L (100 mg/dL). These results lend additional support to the probability that similar pathological changes that may be present in the small arteries and arterioles also can respond to adequate statin therapy. Statin pleiotropy: fact or fiction?     

Rosuvastatin in the management of hyperlipidemia

BACKGROUND: Rosuvastatin is a new statin indicated to reduce elevated levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides and to increase levels of high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia, mixed dyslipidemia, and homozygous familial hypercholesterolemia. OBJECTIVE: The purpose of this article was to review the pharmacology, clinical efficacy, and tolerability of rosuvastatin as monotherapy and combination therapy for patients with hyperlipidemia. METHODS: A literature review was conducted using the search term rosuvastatin to identify English-language peer-reviewed articles and abstracts in the MEDLINE and Current Contents databases (both 1966 to March 2004). Citations from available articles were reviewed for additional references, and selected information from the manufacturer was discussed. RESULTS: Rosuvastatin 10 to 40 mg/d reduced LDL-C by 43% to 63% (P < 0.05). Compared with other statins, rosuvastatin had the highest dose-to-dose potency in lowering LDL-C (reduction of 60% vs 50% with atorvastatin, 40% with simvastatin, 30% with pravastatin or lovastatin, and 20% with fluvastatin) and better efficacy in raising HDL-C (increase of approximately 10% vs approximately 5% with other statins; P < 0.05). Rosuvastatin enabled significantly more patients to achieve the National Cholesterol Education Program (NCEP) goals for LDL-C with lower doses (P < 0.05). Rosuvastatin was well tolerated. Incidences of myopathy and liver function test abnormalities were rare and comparable to those of other statins. Because it is not metabolized by the cytochrome P-450 enzymes, rosuvastatin had fewer clinically significant drug interactions compared with other statins. Studies to assess the effect of rosuvastatin on cardiovascular outcomes are ongoing. CONCLUSIONS: Clinical studies continue to demonstrate that achieving optimal levels of LDL-C is an important goal in reducing cardiovascular events. Recent evidence suggests the need for an even lower LDL-C goal than that being recommended by the NCEP Based on the studies included in this review, rosuvastatin may help patients achieve optimal goals early with lower dosages, thus reducing the need for dose titration or combination therapy.     

Treatment of hypercholesterolemia with heparin-induced extracorporeal low-density lipoprotein precipitation (HELP)

Familial hypercholesterolemia (FH) can cause early disability and death from premature atherosclerotic cardiovascular disease. Patients homozygous for the disease have very high plasma cholesterol, extensive xanthomatosis, and die from atherosclerosis in childhood or early adulthood. Past attempts to improve the prognosis included removal of cholesterol from the circulation by ileal bypass or biliary diversion. Neither treatment was successful. Direct removal by plasmapheresis of low-density lipoprotein (LDL), the primary carrier of cholesterol in plasma, was first performed on an FH homozygous patient in 1966. The treatment was well tolerated and led to rapid diminution of xanthomas. Other experimental treatments included selective LDL apheresis with monoclonal or polyclonal antibody affinity columns. A method for selective LDL apheresis was developed in 1983 by Armstrong, Seidel, and colleagues based on heparin precipitation of LDL at low pH. This method, called HELP, removes all apolipoprotein B-containing lipoproteins including LDL and lipoprotein (a), as well as some fibrinogen. LDL apheresis by HELP is well tolerated; the incidence of side effects is low, and the treatment has been associated with regression of cardiovascular disease. LDL apheresis, rather than liver transplantation, is the treatment of choice for patients with severe, life-threatening hypercholesterolemia which does not respond to diet and drug therapy. © 1996 Wiley-Liss, Inc.