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At least 55 records · Page 3Linked to original sources

PubMed2005

Supratherapeutic response to ezetimibe administered with cyclosporine.

OBJECTIVE: To report the case of a patient who underwent orthotopic heart transplant (OHT) and demonstrated a supratherapeutic response to ezetimibe when administered with cyclosporine. CASE SUMMARY: Ezetimibe 10 mg/day was added to the lipid-lowering regimen (atorvastatin 40 mg/day) of a 64-year-old male patient after OHT to achieve a target low-density lipoprotein cholesterol (LDL-C) level < or = 97 mg/dL, as recommended by national guidelines. After 2 months of ezetimibe, the patient's LDL-C level had decreased by 60% to 51 mg/dL. Subsequently, the dose of ezetimibe was reduced to 5 mg/day and, after another 2 months, a repeat lipid panel revealed LDL-C 57 mg/dL. DISCUSSION: Hyperlipidemia is a common problem among heart transplant recipients. Combination therapy using a statin plus ezetimibe appears to be an attractive option to achieve target lipid levels in this population. However, the manufacturer warns that ezetimibe should be administered cautiously in patients concomitantly receiving cyclosporine. Unpublished data suggest a pharmacokinetic interaction between ezetimibe and cyclosporine that results in a significant 2.3- to 12-fold increase in exposure to total ezetimibe. An objective causality assessment in this case revealed that this supratherapeutic LDL-C reduction was probably related to coadministration of ezetimibe and cyclosporine. A potential mechanism to explain this interaction might be an alteration in glucuronidation induced by cyclosporine. CONCLUSIONS: When ezetimibe is prescribed for patients concomitantly receiving cyclosporine, it should be initiated at a lower than recommended dose (> or = 5 mg/day) and titrated upward. Careful and consistent monitoring of patients on this combination is also advised.

Anticholesteremic Agents↗

PubMed2001

Ezetimibe, a potent cholesterol absorption inhibitor, normalizes combined dyslipidemia in obese hyperinsulinemic hamsters.

Ezetimibe potently and selectively inhibits cholesterol absorption in the intestine, thereby reducing plasma cholesterol in preclinical models of hypercholesterolemia. Clinical trials have demonstrated that ezetimibe lowers LDL cholesterol and raises HDL cholesterol in humans. The effect of ezetimibe on other dyslipidemias, particularly hypertriglyceridemia, is not yet known. In the present studies, we assessed the effect of ezetimibe on combined hypercholesterolemia and hypertriglyceridemia in obese hyperinsulinemic hamsters. Hamsters were fed chow, chow with cholesterol (0.12%), or the same cholesterol diet containing different dietary triglycerides (15%) in the absence or presence of 1 mg/kg ezetimibe (in diet) for up to 84 days. Body weight, serum insulin, leptin, glucose, cholesterol, and triglyceride levels were analyzed. Cholesterol and triglyceride levels were also determined in VLDL+IDL, LDL, and HDL. Hamsters maintained on high-fat diets became obese, hyperinsulinemic, hyperleptinemic, hypercholesterolemic, and hypertriglyceridemic. Ezetimibe did not affect body weight, insulin, or leptin, but ablated the combined hypercholesterolemia and hypertriglyceridemia induced by high-fat diets. Ezetimibe normalized VLDL+IDL cholesterol and triglyceride and significantly decreased LDL cholesterol to below chow-fed levels. The ratio of HDL to LDL cholesterol increased significantly with the addition of ezetimibe. Ezetimibe completely eliminated the accumulation of cholesteryl ester and free cholesterol in liver that was induced under the various dietary conditions in the absence of drug. In conclusion, ezetimibe is very effective in correcting the combined dyslipidemia in diet-induced obese hyperinsulinemic hamsters and may be an effective therapy for ameliorating combined dyslipidemia in obese insulin-resistant and/or type 2 diabetic humans.

Animals↗

PubMed2002

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.

Anticholesteremic Agents↗

PubMed2002

Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia.

The efficacy and safety of ezetimibe, a new cholesterol absorption inhibitor, was evaluated in this randomized, double-blind, placebo-controlled trial of 892 patients with primary hypercholesterolemia. After > or =2 weeks on the National Cholesterol Education Program (NCEP) Step I or a stricter diet and a 4- to 8-week single-blind placebo lead-in, patients with low-density lipoprotein (LDL) cholesterol 130 to 250 mg/dl and triglycerides < or =350 mg/dl were randomized 3:1 to receive ezetimibe 10 mg or placebo orally each morning for 12 weeks. The primary efficacy end point was the percent reduction in direct plasma LDL cholesterol from baseline to end point. A total of 434 men and 458 women (ages 18 to 85 years) received randomized treatment (666 ezetimibe 10 mg, 226 placebo). Demographics and baseline characteristics were similar between treatment groups. Ezetimibe significantly reduced direct LDL cholesterol by a mean of 16.9%, compared with an increase of 0.4% with placebo (p <0.01). Subgroup analysis indicated that response to ezetimibe was generally consistent across all subgroups, regardless of risk-factor status, gender, age, race, or baseline lipid profile. Ezetimibe effects on LDL cholesterol occurred early (2 weeks) and persisted throughout the 12-week treatment period. Compared with placebo, ezetimibe 10 mg also significantly improved calculated LDL cholesterol, apolipoprotein B, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and HDL(3) cholesterol (p <0.01). Ezetimibe was well tolerated. There were no differences in laboratory or clinical safety parameters, or gastrointestinal, liver, or muscle side effects from that of placebo. Ezetimibe 10 mg/day is well tolerated, reduces LDL cholesterol approximately 17%, and improves other key lipid parameters.

Adolescent↗

PubMed2004

Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals.

This study assessed whether the co-administration of ezetimibe and simvastatin would be more effective than simvastatin monotherapy in allowing high-risk patients to achieve a low-density lipoprotein (LDL) cholesterol goal of <100 mg/dl. Men and women with LDL cholesterol >/=130 mg/dl and meeting National Cholesterol Education Program Adult Treatment Panel III criteria for coronary heart disease (CHD) or CHD risk equivalent were randomized to 1 of 4 daily treatments for 23 weeks: simvastatin 20 mg (n = 253), ezetimibe 10 mg plus simvastatin 10 mg (n = 251), ezetimibe 10 mg plus simvastatin 20 mg (n = 109), and ezetimibe 10 mg plus simvastatin 40 mg (n = 97). In all groups, patients not at goal had their simvastatin doses doubled at weeks 6, 12, and/or 18, up to a maximum of 80 mg. The primary efficacy objective was LDL cholesterol goal attainment (<100 mg/dl) after 5 weeks of treatment. Ezetimibe plus any dose of simvastatin produced greater reductions in LDL cholesterol and allowed more patients to achieve goal after 5 weeks (p <0.001) and at the end of the study (p <0.001) than simvastatin 20 mg alone. At 5 weeks, 75%, 83%, and 87% of patients receiving ezetimibe plus simvastatin 10, 20, and 40 mg had LDL cholesterol <100 mg/dl compared with 46% of patients receiving simvastatin 20 mg. In patients who started on ezetimibe plus simvastatin 10, 20 and 40 mg, 33%, 22%, and 12%, respectively, required simvastatin titration during the study compared with 68% of patients who started on simvastatin 20 mg. The corresponding median simvastatin doses used were 10, 20, 40, and 40 mg, respectively. Ezetimibe plus simvastatin was well tolerated, with an overall safety profile similar to that of simvastatin monotherapy. Thus, through the dual inhibition of cholesterol absorption and synthesis, ezetimibe plus simvastatin allowed more patients to reach LDL cholesterol <100 mg/dl at a lower simvastatin dose and with fewer dose titrations than simvastatin monotherapy.

Adult↗

PubMed2006

Intestinal expression of P-glycoprotein (ABCB1), multidrug resistance associated protein 2 (ABCC2), and uridine diphosphate-glucuronosyltransferase 1A1 predicts the disposition and modulates the effects of the cholesterol absorption inhibitor ezetimibe in humans.

BACKGROUND AND AIMS: Ezetimibe is an inhibitor of the cholesterol uptake transporter Niemann-Pick C1-like protein (NPC1L1). Target concentrations can be influenced by intestinal uridine diphosphate-glucuronosyltransferases (UGTs) and the efflux transporters P-glycoprotein (P-gp) (ABCB1) and multidrug resistance associated protein 2 (MRP2) (ABCC2). This study evaluates the contribution of these factors to the disposition and cholesterol-lowering effect of ezetimibe before and after induction of UGT1A1, P-gp, and MRP2 with rifampin (INN, rifampicin). METHODS: Serum concentrations of ezetimibe, as well as its glucuronide, and the plant sterols campesterol and sitosterol (surrogate for cholesterol absorption) were studied in 12 healthy subjects before and after rifampin comedication. In parallel, duodenal expression of UGT1A1, P-gp, MRP2, and NPC1L1 was quantified by use of real-time reverse transcriptase-polymerase chain reaction and quantitative immunohistochemical evaluation. The affinity of ezetimibe and its glucuronide to P-gp and MRP2 was assessed in P-gp- overexpressing Madin-Darby canine kidney II cells and P-gp-containing or MRP2-containing inside-out vesicles. RESULTS: Up-regulation of intestinal P-gp, MRP2, and UGT1A1 (but not of NPC1L1) by rifampin was associated with markedly decreased areas under the curve of ezetimibe and its glucuronide (116 +/- 78.1 ng.h/mL versus 49.9 +/- 31.0 ng.h/mL and 635 +/- 302 ng.h/mL versus 225 +/- 86.4 ng.h/mL, respectively; both P = .002) and increased intestinal clearances (2400 +/- 1560 mL/min versus 5500 +/- 4610 mL/min [P = .003] and 76.6 +/- 113 mL/min versus 316 +/- 457 mL/min [P = .010], respectively) and nearly abolished sterol-lowering effects. Intestinal expression of UGT1A1, ABCB1, and ABCC2 was inversely correlated with the effects of ezetimibe on plant sterol serum concentrations. Parallel in vitro studies confirmed that ezetimibe glucuronide is a high-affinity substrate of MRP2 and has a low affinity to P-gp whereas ezetimibe interacts with P-gp and MRP2. CONCLUSIONS: The disposition and sterol-lowering effects of ezetimibe are modified by metabolic degradation of the drug via intestinal UGT1A1 and either intestinal or hepatic secretion (or both) via P-gp and MRP2.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Effect of co-administering ezetimibe with on-going simvastatin treatment on LDL-C goal attainment in hypercholesterolemic patients with coronary heart disease.

OBJECTIVE: To determine whether co-administering ezetimibe with on-going simvastatin treatment was more effective than placebo plus on-going simvastatin in achieving an LDL-C treatment target of < or = 2.60 mmol/l (100 mg/dl) in hypercholesterolemic patients with coronary heart disease (CHD). METHODS: Men and women (age > or = 18 years) with documented CHD and on a stable dose of simvastatin 10 mg or 20 mg for at least 6 weeks were recruited for this study. After a 4-week simvastatin 10 or 20 mg plus placebo and diet run-in period, patients were eligible for randomization if LDL-C > 2.60 and < or = 4.20 mmol/l and triglycerides (TG) < or = 4.00 mmol/l. Eligible patients were randomized to a double-blind comparative study with ezetimibe 10 mg co-administered with on-going simvastatin 10 mg or 20 mg (n=181) versus placebo to match ezetimibe co-administered with simvastatin 10 mg or 20 mg (n=191) for 6 weeks. RESULTS: At baseline, mean LDL-C was comparable between the ezetimibe (3.14 mmol/l) and placebo (3.19 mmol/l) groups. With the addition of ezetimibe or placebo to on-going simvastatin therapy, the percentage of patients achieving the LDL-C goal of < or = 2.60 mmol/l after 6 weeks of treatment was significantly (p < or = 0.001) greater in the ezetimibe group (74.3%) than in the placebo group (16.7%). The addition of ezetimibe to on-going simvastatin treatment also resulted in a significantly (p < or = 0.001) larger mean percent reduction in LDL-C from baseline (25.2%) compared with placebo (0.9%). Ezetimibe was generally well tolerated compared to placebo when added to on-going simvastatin treatment. CONCLUSIONS: Co-administering ezetimibe with on-going simvastatin 10 or 20 mg treatment allowed more hypercholesterolemic patients with CHD to reach the LDL-C treatment target of < or = 2.60 mmol/l.

Anticholesteremic Agents↗

PubMed2005

A LC-MS/MS method to quantify the novel cholesterol lowering drug ezetimibe in human serum, urine and feces in healthy subjects genotyped for SLCO1B1.

Ezetimibe (Ezetrol) is a novel cholesterol lowering drug which disposition is not fully understood in man. We developed a selective and high-sensitive assay to measure serum concentration-time profiles, renal and fecal elimination of ezetimibe in pharmacokinetic studies. Ezetimibe glucuronide, the major metabolite of ezetimibe was determined by enzymatic degradation to the parent compound. Ezetimibe was measured after extraction with methyl tert-butyl ether using 4-hydroxychalcone as internal standard and liquid chromatography coupled via an APCI interface with tandem mass spectrometry (LC-MS/MS) for detection. The chromatography (column XTerra) MS, C(18), 2.1 mm x 100 mm, particle size 3.5 microm) was done isocratically with acetonitrile/water (60/40, v/v; flow rate 200 microl/min). The MS/MS analysis was performed in the negative ion mode (m/z transition: ezetimibe 408-271, internal standard 223-117). The validation ranges for ezetimibe and total ezetimibe were as follows: serum 0.0001-0.015 microg/ml and 0.001-0.2 microg/ml; urine and fecal homogenate 0.025-10 microg/ml and 0.1-20 mg/ml, respectively. The assay was successfully applied to measure ezetimibe disposition in two subjects genotyped for the hepatic uptake transporter SLCO1B1.

Adult↗

PubMedDate not supplied

Ezetimibe: the first in a novel class of selective cholesterol-absorption inhibitors.

Zetia (ezetimibe) is the first medication in the novel class of selective cholesterol-absorption inhibitors to be released in the United States. Ezetimibe selectively inhibits the uptake of cholesterol from the intestinal lumen at the level of the enterocyte in the intestinal brush border while having no effect on other sterols or lipid-soluble vitamins. Ezetimibe 10 mg daily produces a consistent reduction in low-density lipoprotein cholesterol (LDL-C) by approximately 15 to 20% when used as monotherapy or in combination with 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) or fenofibrate and a 4 to 9% increase in high-density lipoprotein cholesterol. Unlike other lipid-lowering medications that act in the gastrointestinal tract, ezetimibe does not appear to worsen hypertriglyceridemia. Ezetimibe also has an adverse-event profile that is similar to placebo when used as monotherapy or in combination with statins and fenofibrate. Studies of longer duration and with niacin, bile acid sequestrants, and gemfibrozil are warranted to more completely assess the safety of ezetimibe in combination therapy. To date, no clinically significant drug-drug interactions have been noted with the use of ezetimibe; however, further studies are warranted. Ezetimibe will be useful as monotherapy in patients who need modest reductions in LDL-C or are intolerant to other lipid-lowering medication, and in combination with a statin in patients who are unable to tolerate large doses of statins or need further reductions in LDL-C despite maximum doses of a statin. The long-term safety and the effect on cardiovascular morbidity and mortality of ezetimibe are unknown.

Anticholesteremic Agents↗

PubMed2003

Ezetimibe: a first-in-class, novel cholesterol absorption inhibitor.

Significant numbers of patients at risk for coronary heart disease (CHD) fail to reach National Cholesterol Education Program (NCEP)-designated low density lipoprotein cholesterol (LDL-C) goals in spite of the wide range of currently available treatments, including combination therapies. Ezetimibe, the first in a class of novel cholesterol absorption inhibitors, demonstrated lipid-lowering and antiatherosclerotic activity in experimental and clinical hypercholesterolemia. Studies in hypercholesterolemic dogs showed that ezetimibe coadministered with statins caused greater lipid-lowering effects compared to either drug alone. These effects were confirmed in clinical studies of patients with primary hypercholesterolemia where initiation of treatment with ezetimibe plus a statin, or addition of ezetimibe to ongoing statin therapy, produced significant incremental reductions in LDL-C, as well as incremental increases in high-density lipoprotein cholesterol (HDL-C) and reductions in triglyceride levels. Combination therapy also significantly increased the number of patients attaining LDL-C goal at the end of treatment, compared to statin monotherapy. In studies using simvastatin, atorvastatin, pravastatin, and lovastatin, addition of ezetimibe to low dose statin was as effective as a 2- to 3-fold upward titration of the corresponding statin dose. Ezetimibe-statin combination therapy provided similar improvements in patients with primary hypercholesterolemia, as well as with heterozygous and homozygous familial hypercholesterolemia. Ezetimibe monotherapy effectively reduced plasma campesterol and sitosterol in patients with homozygous sitosterolemia. Clinical studies showed that ezetimibe was well tolerated, with a safety profile comparable to placebo when administered as monotherapy and comparable to statin alone when coadministered with a statin. These data provide strong evidence that, through their complementary lipid-lowering mechanisms, ezetimibe coadministered with a statin offers an effective combination treatment option for patients with hypercholesterolemia, including those with genetically inherited disease.

Animals↗

PubMed2006

Effect of ezetimibe and/or simvastatin on coenzyme Q10 levels in plasma: a randomised trial.

BACKGROUND: HMG-CoA reductase inhibitors ('statins') have been associated with a decrease in ubidecarenone (ubiquinone) levels, a lipophilic enzyme also known as coenzyme Q10 (CoQ10), due to inhibition of mevalonate synthesis. There is speculation that a decrease in CoQ10 levels may be associated with statin-induced myopathy. The cholesterol absorption inhibitor ezetimibe increases endogenous cholesterol synthesis. The purpose of this study was to examine (i) the effects of ezetimibe and simvastatin on plasma CoQ10 levels and (ii) whether ezetimibe coadministered with simvastatin abrogates the suggested statin-induced decrease in the CoQ10 plasma levels. METHODS: Seventy-two healthy male subjects were enrolled in a single-centre, randomised, parallel-group study with three arms. Subjects received ezetimibe 10 mg/day, simvastatin 40 mg/day or the combination of ezetimibe 10 mg/day plus simvastatin 40 mg/day for 14 days. RESULTS: Baseline CoQ10 (0.99 +/- 0.30 mg/L) levels for the combined groups remained unchanged in the ezetimibe group (0.95 +/- 0.24 mg/L), and significantly decreased in the simvastatin and combination groups (0.82 +/- 0.18 mg/L, p = 0.0002 and 0.7 +/- 0.22 mg/L, p < 0.0001, respectively). There was a correlation between the percentage change in the levels of low-density lipoprotein-cholesterol (LDL-C) and the percentage change in CoQ10 levels in all treatment groups (correlation coefficient [R] = 0.67, p < 0.0001). The ratios of CoQ10 levels to LDL-C levels were significantly increased in all treatment groups (p < 0.0001). CoQ10 level was independent of cholesterol synthesis or absorption markers. CONCLUSIONS: Simvastatin and the combination of simvastatin and ezetimibe significantly decrease plasma CoQ10 levels whereas ezetimibe monotherapy does not. There is a significant correlation between the CoQ10 level decrease and the decrease in total and LDL-C levels in all three treatment groups, suggesting that the CoQ10 decrease may reflect the decrease in the levels of its lipoprotein carriers and might not be statin-specific. The statin-associated CoQ10 reduction is not abrogated through ezetimibe coadministration. Changes of CoQ10 levels are independent of cholesterol synthesis and absorption.

Adult↗

PubMed2003

Ezetimibe.

Ezetimibe, a synthetic 2-azetidinone, is the first of a new class of compounds that selectively inhibits the absorption of cholesterol and related plant sterols in the intestine. The drug, and its glucuronyl metabolite, are thought to inhibit a putative cholesterol transporter of enterocytes, located within the brush-border membrane of the small intestine. In large, randomized, placebo-controlled, 12-week trials, ezetimibe reduced levels of low density lipoprotein-cholesterol (LDL-C) by approximately 18%; triglyceride levels were reduced by approximately 6% in one trial but not another. Ezetimibe produced a modest increase in levels of high density lipoprotein-cholesterol. Moreover, reductions in LDL-C and triglyceride levels were greater in patients treated with ezetimibe coadministered with a statin (lovastatin, pravastatin, atorvastatin or simvastatin), than with either of those agents given alone. The coadministration of the lowest statin dose and ezetimibe produced similar LDL-C reductions to the administration of the highest statin dose alone. Ezetimibe also provided beneficial effects on plasma lipid levels when administered to patients with hypercholesterolemia already receiving a statin. Ezetimibe plus a statin reduced LDL-C levels more than the maximum statin dose alone in a trial in patients with homozygous familial hypercholesterolemia and was effective in a placebo-controlled trial in patients with homozygous sitosterolemia. The drug was well tolerated in clinical studies conducted to date. In large, randomized, double-blind trials, ezetimibe had a similar tolerability profile to that of placebo. Coadministration of ezetimibe and a statin did not increase the incidence of adverse events related to statin monotherapy.

Animals↗

PubMedDate not supplied

Effectiveness and tolerability of adding ezetimibe to niacin-based regimens for treatment of primary hyperlipidemia.

OBJECTIVE: To determine the effectiveness and tolerability of adding ezetimibe, 10 mg daily, to niacin-based regimens for dyslipidemia. METHODS: We conducted a retrospective review of medical records of 53 patients in 2 lipid clinics who received ezetimibe as add-on therapy to stable doses of niacin and other lipid medications. Mean percentage changes of lipoprotein cholesterol and triglyceride levels were determined. Safety and tolerability measures included adverse events, serum hepatic transaminases, and hemoglobin A1c (in patients with diabetes). RESULTS: Most study subjects (81%) had established atherosclerotic disease. The niacin formulation was extended-release in 31 patients (58%), immediate-release in 17 (32%), and slow-release in 5 (9%). Most patients (75%) were also taking a statin. Add-on ezetimibe therapy yielded mean reductions of 18% for total cholesterol (P<0.001), 25% for low-density lipoprotein (LDL) cholesterol (P<0.001), and 17% for triglycerides (P<0.001). High-density lipoprotein (HDL) cholesterol did not change significantly (+2%). Only 7 patients (13%) met Adult Treatment Panel III (ATP III) LDL cholesterol goals before the addition of ezetimibe, but 24 (45%; P<0.001 compared with baseline) attained these goals after addition of ezetimibe to the therapeutic regimen. Ezetimibe effectiveness did not correlate with the baseline dose of niacin or the dose/efficacy of the statin used. The addition of ezetimibe to niacin-based therapy for dyslipidemia was well tolerated. No patient had clinically significant elevations in hepatic enzyme or hemoglobin A1c levels or discontinued the ezetimibe therapy permanently. CONCLUSION: In our study, the addition of ezetimibe to niacin-based regimens lowered the LDL cholesterol level by 25% and did not change the level of HDL cholesterol. This combination can be useful in multidrug regimens for high-risk patients with dyslipidemia who are not achieving ATP III treatment goals.

Aged↗

PubMed2002

Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia.

Ezetimibe is a lipid-lowering drug that inhibits the intestinal absorption of dietary and biliary cholesterol by blocking passage across the intestinal wall. The efficacy and safety of adding ezetimibe to ongoing statin therapy in patients with primary hypercholesterolemia was evaluated in a randomized, double-blind, placebo-controlled study. The study group included 769 adults (aged > or =18 years) with primary hypercholesterolemia who had not achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel II goals with dietary alteration and statin monotherapy. Patients receiving a stable dose of a statin for > or =6 weeks were randomized to receive concurrent treatment with placebo (n = 390) or ezetimibe (n = 379), 10 mg/day, in addition to continuing their open-label statin for 8 weeks. The primary efficacy variable was the percent change in low-density lipoprotein (LDL) cholesterol from baseline with statin monotherapy to end point after intervention (secondary variables: high-density lipoprotein [HDL] cholesterol and triglycerides). Ongoing statin therapy plus ezetimibe led to changes of -25.1% for LDL cholesterol (HDL cholesterol +2.7%; triglycerides -14.0%) compared with LDL cholesterol -3.7% (p <0.001), HDL cholesterol +1.0% (p <0.05), and triglycerides -2.9% (p <0.001) for placebo added to ongoing statin therapy. Among patients not at LDL cholesterol goal at on-statin baseline, 71.5% receiving statin plus ezetimibe versus 18.9% receiving statin plus placebo reached goal at end point (odds ratio 23.7; p <0.001). The co-administration of statin and ezetimibe was generally well tolerated. Adding ezetimibe to ongoing statin therapy led to substantial additional reduction in LDL cholesterol levels, facilitating attainment of NCEP goals. Ezetimibe offers a new therapeutic option for patients receiving statins who require further reduction in LDL cholesterol.

Adult↗

PubMed2003

Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia.

AIMS: This randomized, double-blind, placebo-controlled, parallel-group study evaluated the safety and efficacy of ezetimibe 10 mg/day in patients with primary hypercholesterolemia. METHODS AND RESULTS: Following dietary stabilization, a 2-12-week washout period, and a 4-week, single-blind, placebo lead-in period, 827 patients with baseline low-density lipoprotein cholesterol (LDL-C) > or =3.36 mmol/l (130 mg/dl) to < or =6.47 mmol/l (250 mg/dl) and triglycerides < or =3.95 mmol/l (350 mg/dl) were randomized 3:1 to receive ezetimibe 10 mg or placebo orally once daily in the morning for 12 weeks. The primary efficacy endpoint was percentage reduction in direct plasma LDL-C. Ezetimibe reduced direct LDL-C by a mean of 17.7% from baseline to endpoint, compared with an increase of 0.8% with placebo (P<0.01). Response to ezetimibe was generally consistent across all subgroups analyzed. Ezetimibe also significantly improved levels of plasma total cholesterol, apolipoprotein B, high-density lipoprotein(2)-cholesterol and lipoprotein(a), and elicited a trend toward lower triglyceride levels. Ezetimibe did not alter the serum concentrations of lipid-soluble vitamins or significantly affect baseline or stimulated cortisol production. Ezetimibe was well tolerated, with a safety profile similar to that of placebo. CONCLUSIONS: Ezetimibe, which significantly reduces LDL-C and favorably affects other lipid variables, may provide a well tolerated and effective new option for lipid management in the future.

Adult↗

PubMed2025

Ezetimibe and the risk of new-onset type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: Statins reduce cardiovascular risk but may increase new-onset type 2 diabetes mellitus (NO-T2DM). Ezetimibe, a cholesterol absorption inhibitor, is often added to statins to improve lipid control, yet its impact on NO-T2DM remains uncertain. OBJECTIVE: This systematic review evaluated moderate-intensity statin plus ezetimibe dual therapy versus high-intensity statin monotherapy for NO-T2DM risk. METHODS: Five databases were searched to identify eligible studies. Random-effects meta-analyses generated pooled relative risks (RR) quantifying the effect of ezetimibe plus moderate-intensity statins on NO-T2DM. The Attributable Risk Fraction (ARF) was quantified utilizing the pooled estimate. RESULTS: Ten observational studies and four clinical trials were included. In four cohort studies, ezetimibe plus moderate-intensity statin compared to high-intensity statin monotherapy was significantly linked to 18% reduced risk of NO-T2DM (pooled RR: 0.82; 95% CI: 0.77-0.87; I2 = 0.0%; p < 0.001). In three methodologically similar studies, compared to moderate-intensity statin monotherapy, adding ezetimibe to moderate-intensity statin dual therapy showed non-statistically (p > 0.05) significant 4% increased risk of NO-T2DM development (pooled RR: 1.04; 95% CI: 0.94-1.14, I2= 0.0%). Compared with patients receiving high-intensity statin therapy, 22% of NO-T2DM cases could potentially be averted with dual therapy (moderate-intensity statin plus ezetimibe). In four studies involving 5,072 patients on high-intensity statins who developed NO-T2DM, 1,115 patients (812-1,420) could have been prevented with ezetimibe plus moderate-intensity statin dual therapy. CONCLUSION: Incorporating ezetimibe with moderate-intensity statins, rather than relying solely on high-intensity statins, may reduce the risk of NO-T2DM in patients with dyslipidemia and elevated cardiovascular disease risk. PROSPERO REGISTRATION NUMBER: CRD42024518630.

Humans↗

PubMed2004

Effects of ezetimibe on plasma lipoproteins in severely hypercholesterolemic patients treated with regular LDL-apheresis and statins.

Ezetimibe, a cholesterol absorption inhibitor, can be combined with statins to lower LDL-cholesterol. We evaluated additional ezetimibe (10 mg/day) in a placebo-controlled, double blind, randomized cross-over study in 20 patients (age 56+/-9 years, m:f 10:10, BMI 27.5+/-4.0 kg/m(2)) suffering from severe hypercholesterolemia and CHD who were treated by statins and regular LDL-apheresis. Lipoproteins (cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, VLDL-cholesterol, VLDL-triglycerides, lipoprotein(a)) were determined twice (before and during ezetimibe/placebo, each given for 5 weeks), dietary behaviour was analyzed once (3-days-protocol) during each treatment period. During ezetimibe the mean (+/-S.D.) preapheresis LDL-cholesterol concentration decreased from 159+/-26 mg/dl (4.11+/-0.67 mmol/l) to 133+/-28 mg/dl (3.44+/-0.72 mmol/l) (-16+/-11%, P<0.0001, Wilcoxon test) and the postapheresis LDL-cholesterol from 51+/-9 mg/dl (1.32+/-0.23 mmol/l) to 43+/-8 mg/dl (1.11+/-0.21 mmol/l) (-14+/-25%, P<0.05), while there was no significant change during placebo. Mean VLDL-cholesterol fell by 18+/-71% (P<0.05) during ezetimibe and was not significantly changed by placebo (+19+/-70%). Furthermore, during ezetimibe less plasma volume was treated (3725+/-1560 versus 3870+/-1549 ml, P<0.05). Ezetimibe had no effect on pre- and postapheresis triglyceride, HDL-cholesterol and lipoprotein(a) levels. The effect of ezetimibe was independent of the statin dose. Dietary behaviour did not change and no side effects were observed. Thus, in patients with severe LDL-hypercholesterolemia and CHD the addition of ezetimibe to intensive lipid lowering therapy (statins and LDL-apheresis) resulted in a further, clinically significant decrease of LDL-cholesterol.

Aged↗

PubMed2006

Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.

We investigated the effect of statins and statins plus ezetimibe in 65 FH heterozygotes carrying LDLR-defective or LDLR-negative mutations as well as the effect of ezetimibe monotherapy in 50 hypercholesterolemic (HCH) patients intolerant to statins. PCSK9 and NPC1L1 genes were analysed to assess the role of genetic variants in response to therapy. In FH patients combined therapy reduced LDL-C by 57%, irrespective of the type of LDLR mutation. The additional decrease of plasma LDL-C induced by ezetimibe showed wide inter-individual variability (from -39% to -4.7%) and was negatively correlated with percent LDL-C decrease due to statin alone (r=-0.713, P<0.001). The variable response to statins was not due to PCSK9 gene variants associated with statin hyper-sensitivity. The highest response to ezetimibe was observed in a carrier of R174H substitution in NPC1L1, which had been found to be associated with high cholesterol absorption. In HCH patients, ezetimibe monotherapy induced a variable decrease of plasma LDL-C (from -47.7% to -13.4%). To investigate this variability, we sequenced NPC1L1 gene in patients with the highest and the lowest response to ezetimibe. This analysis showed a higher prevalence of the G allele of the c.816 C>G polymorphism (L272L) in hyper-responders, an observation confirmed also in FH patients hyper-responders to ezetimibe. In both FH and HCH patients, the G allele carriers tended to have a higher LDL-C reduction in response to ezetimibe. These observations suggest that in FH heterozygotes LDL-C reduction following combined therapy reflects a complex interplay between hepatic synthesis and intestinal absorption of cholesterol.

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