ezetimibe--simvastatin-drug-combination and Hyperlipidemias

In recent years, combination therapy has received growing popularity as a powerful therapeutic tactic for the treatment of diseases. The justifications and benefits of combination therapy are far-reaching, including but not limited to addressing unmet medical needs such as cancer, malaria, and HIV/AIDS, improved clinical efficacy and safety with reduced dosage of a single medication, understanding the underlying science of the disease, alleviating pharmaco-economic impacts, and better drug life-cycle management. Using the ezetimibe/simvastatin combination therapy as a case study, a comprehensive overview of the successful discovery and development of the single-pill combination, Vytorin, is presented in this review. A cursory introduction to combination therapy and the rationale for the ezetimibe/simvastatin combination for the treatment of hyperlipidemia provides an instructive entry point. The discovery and mode of action of simvastatin and ezetimibe monotherapies set the scene for a detailed discussion on the discovery and development of Vytorin, with emphasis on bioequivalency studies, clinical efficacy and safety profile studies, and the economic consequences of the single-pill combination therapy. Large-scale outcome clinical trials are also discussed to demonstrate the long-term effects of Vytorin.

Topics: Animals; Azetidines; Drug Combinations; Drug Discovery; Ezetimibe, Simvastatin Drug Combination; Heart Diseases; Humans; Hyperlipidemias; Hypolipidemic Agents; Simvastatin

Ezetimibe/simvastatin is a combination of a statin and a cholesterol absorption inhibitor. This article reviews current information on the pharmacology, clinical efficacy and safety of ezetimibe/simvastatin combination therapy as a lipid-lowering pharmacologic option. Focus is on the LDL cholesterol-lowering efficacy of ezetimibe/simvastatin. PubMed was searched for english-language articles from January 2005 to 14 April 2010 using the keywords 'ezetimibe and simvastatin' and 'hyperlipidemia'. Reviewers screened all records and only English language papers and human clinical studies were included in the review. References of these papers were reviewed for relevant articles, and retrospective studies were excluded. Limitations include the exclusion of non-English publications, the use of only one data source (PubMed), and the fact that most studies were of short duration and several studies were of low quality (nonrandomized trials or meta-analyses). Ezetimibe and simvastatin has proven to be a well-tolerated, effective lipid-lowering drug combination. It is effective in reducing LDL-cholesterol and triglycerides, and increasing HDL-cholesterol. It also decreases C-reactive protein and exhibits some pleiotropic effects in a variety of patient populations. More data are needed to evaluate its effect on cardiovascular events/outcomes.

Topics: Animals; Anticholesteremic Agents; Azetidines; Drug Combinations; Ezetimibe, Simvastatin Drug Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Simvastatin

Inflammation and postprandial lipemia are associated with increased cardiovascular disease. We investigated whether ezetimibe and simvastatin combination, a lipid lowering combination of simvastatin and ezetimibe, exerts an anti-inflammatory effect in the fasting state and after dairy cream intake.. Twenty obese patients were randomized to either ezetimibe and simvastatin combination or placebo treatment for 6 weeks. All patients were asked to ingest 33 ml of dairy cream (300 Calories) at the beginning and at the end of intervention. Fasting and post-cream blood samples were obtained.. At 0 week, ingestion of cream induced significant increases in MNC expression of IL-1β (105 ± 18%), TNFα (97 ± 12%), CD68 (48 ± 8%), CD16 (141 ± 39%), MMP-9 (122 ± 31%), PECAM (66 ± 10%), TLR-4 (84 ± 11%) and TLR-2 (67 ± 9%) and in endotoxin (LPS) concentrations (49 ± 7%) (p < 0.05). Ezetimibe and simvastatin combination treatment lowered fasting total cholesterol, LDLc and Lp(a) concentrations and Apo B/A1 ratio and suppressed the MNC expression of IL-1β and CD68 (by 21 ± 7 and 24 ± 10, p < 0.05) and the concentrations of LPS, CRP, FFA and IL-18 by 24 ± 7%, 32 ± 11%, 19 ± 8% 15 ± 4%, respectively, (p < 0.05). Cream-induced increases in the expression of IL-1β, CD68, CD16, MMP-9, TNFα and PECAM were reduced in the ezetimibe and simvastatin combination group by 74 ± 15%, 68 ± 13%, 57 ± 13%, 64 ± 16%, 67 ± 14% and 45 ± 9%, respectively, while those of LPS and MMP-9 concentrations were reduced by 53 ± 9% and 38 ± 8%, respectively, compared to the increases at week 0 (p < 0.05). There was a suppression of TLR-2 and TLR-4 expression by 21 ± 8% and 18 ± 7%, respectively, compared to 0-h baseline, after cream intake following ezetimibe and simvastatin combination treatment.. Ezetimibe and simvastatin combination exerts a profound anti-inflammatory effect both in the fasting state and acutely after the ingestion of saturated fat.

Topics: Adult; Anticholesteremic Agents; Biomarkers; Dairy Products; Double-Blind Method; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Inflammation; Inflammation Mediators; Lipids; Male; Middle Aged; New York; Obesity; Postprandial Period; Prospective Studies; Time Factors; Treatment Outcome

Combination therapy with ezetimibe/simvastatin (E/S) and extended-release niacin (N) has been reported to be safe and efficacious in concomitantly reducing low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol in hyperlipidemic patients at high risk for atherosclerotic cardiovascular events. This analysis evaluated the effect of E/S coadministered with N on low-density lipoprotein particle number (LDL-P) and high-density lipoprotein particle number (HDL-P) as assessed by nuclear magnetic resonance (NMR) spectroscopy in patients with type IIa or IIb hyperlipidemia.. This was an analysis of a previously reported 24-week randomized, double-blind study in type IIa/IIb hyperlipidemic patients randomized to treatment with E/S (10/20 mg/day)+N (titrated to 2 g/day) or N (titrated to 2 g/day) or E/S (10/20 mg/day). Samples from a subset of patients (577 of 1220) were available for post hoc analysis of LDL-P and HDL-P by NMR spectroscopy. Increases in HDL-P (+16.2%) and decreases in LDL-P (-47.7%) were significantly greater with E/S+N compared with N (+9.8% for HDL-P and -21.5% for LDL-P) and E/S (+12.8% for HDL-P and -36.8% for LDL-P). In tertile analyses, those with the lowest baseline HDL-P had the greatest percent increase in HDL-P (N, 18.4/7.9/2.1; E/S, 19.3/12.2/5.3; and E/S+N, 26.9/13.8/6.9; all P<0.001). Individuals in the highest tertile of LDL-P had the greatest percent reduction in LDL-P (N, 18.3/23.1/24.6; E/S, 29.7/38.3/41.8; and E/S+N, 44.3/49.0/50.5; all P<0.001).. These results suggest that E/S+N improves lipoprotein particle number, consistent with its lipid-modifying benefits in type IIa or IIb hyperlipidemia patients and may exert the greatest effect in those with high LDL-P and low HDL-P at baseline.

Topics: Aged; Azetidines; Biomarkers; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Lipoproteins, HDL; Lipoproteins, LDL; Magnetic Resonance Spectroscopy; Male; Middle Aged; Niacin; Particle Size; Simvastatin; Time Factors; Treatment Outcome

To determine the effect of niacin on fasting glucose (FG) and new-onset diabetes in statin/ezetimibe-treated patients.. This was a prespecified secondary analysis among 942 hyperlipidemic patients randomized to ezetimibe/simvastatin (E/S; 10/20 mg) or E/S + extended-release niacin (N; titrated to 2 g) over 64 weeks.. FG levels peaked by 8-12 weeks, then declined even without antidiabetic medication. At 64 weeks, 3.5% taking E/S+N versus 2.6% taking E/S met criteria for new-onset diabetes (P = 0.66). An additional 1.4% taking E/S+N versus 0.4% taking E/S transiently met criteria for diabetes and then remitted (P = 0.46). Of 28 new-diabetes diagnoses in the E/S+N group, 25 occurred by 24 weeks. Among patients with baseline diabetes, 13.9% taking E/S+N and 11.6% taking E/S underwent antidiabetic treatment modification.. Increased FG and new-onset diabetes with E/S+N occurred mainly around the time of initial uptitration of N and often improved or remitted without specific treatment.

Topics: Adolescent; Adult; Age of Onset; Aged; Azetidines; Delayed-Action Preparations; Diabetes Complications; Diabetes Mellitus; Drug Combinations; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Niacin; Simvastatin; Time Factors; Young Adult

To assess the efficacy and safety of ezetimibe/simvastatin (E/S) plus extended-release niacin (N) in hyperlipidaemic patients with diabetes mellitus (DM), metabolic syndrome (MetS) without DM (MetS/non-DM) or neither (non-DM/non-MetS).. A subgroup analysis of a double-blind, 64-week trial of 1220 randomized patients who received E/S (10/20 mg) + N (to 2 g) or E/S (10/20 mg) for 64 weeks, or N (to 2 g) for 24 weeks then E/S (10/20 mg) + N (2 g) or E/S (10/20 mg) for 40 additional weeks. The evaluable populations of this analysis included n = 765 patients at 24 weeks and n = 574 at 64 weeks. Among those receiving N, only those who attained the 2-g dose were included in the analysis.. E/S+N improved levels of low-density lipoprotein cholesterol, other lipids and lipoprotein ratios compared with N and E/S at 24 weeks and E/S at 64 weeks. The combination increased high-density lipoprotein cholesterol and apolipoprotein AI comparably to N and more than E/S. E/S+N reduced high-sensitivity C-reactive protein (hsCRP) levels more effectively than N and similarly to E/S. E/S+N was generally well tolerated. Discontinuations due to flushing with N and E/S+N were comparable and greater than E/S in all subgroups. Fasting glucose trended higher for N vs. E/S. Glucose elevations from baseline to 12 weeks were highest for patients with DM (24.9 mg/dl for N, 21.2 mg/dl for E/S+N, 17.5 mg/dl for E/S); fasting glucose then declined to pretreatment levels at 64 weeks in all subgroups. New-onset DM was more frequent among MetS patients than those without MetS during the first 24 weeks and trended higher among those assigned to N-containing regimens [n = 5(5.1%) for N, n = 2(1.7%) for E/S, n = 21(8.8%) for E/S+N]; during the 24-64 week extension study, diabetes was diagnosed in five additional patients in the E/S(cumulative incidence of 5.9%) and one in the E/S+N (cumulative incidence of 9.2%). Treatment-incident elevations in uric acid levels were increased among subjects assigned to N-containing regimens, but there were no effects on symptomatic gout.. Combination E/S+N is a safe treatment option for hyperlipidaemic patients including those with DM and MetS, but requires monitoring of glucose and potentially uric acid levels.

Topics: Anticholesteremic Agents; Azetidines; Cholesterol, LDL; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Combinations; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Hyperlipidemias; Male; Metabolic Syndrome; Middle Aged; Niacin; Simvastatin; Treatment Outcome

Mixed hyperlipidemia is characterized by elevated low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and TG-rich lipoprotein levels.. In a multicenter, randomized, double-blind, placebo-controlled, parallel arm trial, eligible patients were 18 to 79 years of age, with mixed hyperlipidemia (LDL-C 130-220 mg/dL, TG 150-500 mg/dL). Patients with type 2 diabetes were limited to those with LDL-C of 100 to 180 mg/dL. Patients (N = 611) were randomized in a 3:3:3:1 ratio to one of 4 treatment arms for 12 weeks: ezetimibe/simvastatin 10/20 mg (EZE/SIMVA) + fenofibrate 160 mg (FENO), EZE/SIMVA 10/20 mg, FENO 160 mg, or placebo. The primary objective was to evaluate the LDL-C-lowering efficacy of EZE/SIMVA + FENO versus FENO monotherapy.. Low-density lipoprotein cholesterol level was significantly (P < .05) reduced with EZE/SIMVA + FENO (-45.8%) compared with FENO (-15.7%) or placebo (-3.5%), but not when compared with EZE/SIMVA (-47.1%). High-density lipoprotein cholesterol and apolipoprotein A-I levels were significantly increased with EZE/SIMVA + FENO (18.7% and 11.1%, respectively) treatment compared with EZE/SIMVA (9.3% and 6.6%) or placebo (1.1% and 1.6%), but not when compared with FENO (18.2% and 10.8%). Triglyceride, non-high-density lipoprotein cholesterol, and apolipoprotein B levels were significantly reduced with EZE/SIMVA + FENO (-50.0%, -50.5%, and -44.7%, respectively) versus all other treatments. Treatment with EZE/SIMVA + FENO was generally well tolerated with a safety profile similar to the EZE/SIMVA and FENO therapies.. Coadministration of EZE/SIMVA + FENO effectively improved the overall atherogenic lipid profile of patients with mixed hyperlipidemia. Clinical trial registry number: NCT 00093899 (http://www.ClinicalTrials.gov).

Topics: Azetidines; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Ezetimibe, Simvastatin Drug Combination; Female; Fenofibrate; Humans; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Simvastatin

We previously reported that the level of low-density lipoprotein cholesterol (LDL-C) was higher in patients receiving continuous ambulatory peritoneal dialysis (CAPD) than in patients on hemodialysis (HD). One of the problems associated with reaching the LDL-C target during statin treatment of patients on CAPD is the emergence of laboratory or clinical side effects. The present study evaluated the efficacy and tolerability of daily combined treatment with ezetimibe 10 mg and simvastatin 10 mg in patients receiving CAPD. Our study enrolled 12 CAPD patients who were experiencing adverse effects from statin therapy. Their existing statin therapy was suspended for 1 month ("washout period"), and the patients were then shifted to treatment with the ezetimibe-simvastatin combination. The patients were again monitored for adverse events such as asthenia and myalgia during the subsequent 12 months. Body mass index and levels of glycated hemoglobin, fasting plasma glucose, total cholesterol, LDL-C, triglycerides, alanine amino-transferase, aspartate aminotransferase, and creatinine phosphokinase were also assessed. The combination of ezetimibe and low-dose simvastatin significantly reduced levels of total cholesterol (by a mean of 27%), triglycerides (by 9%), and LDL-C (by 33%) and increased levels of high-density lipoprotein cholesterol (by 15%). In 11 patients (92%), the target LDL-C level of less than 100 mg/dL was reached. No significant change in weekly creatinine clearance occurred, and no serious adverse effects were observed. No patient developed muscle pain or weakness, and no increase in creatinine kinase was found. Residual renal function declined, although not significantly when compared with initial values. In conclusion, the present study suggests that combined ezetimibe and low-dose statin treatment is a promising approach for safe and effective primary treatment of dyslipidemia in CAPD patients.

Topics: Anticholesteremic Agents; Azetidines; Cholesterol; Cholesterol, LDL; Drug Combinations; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Hyperlipidemias; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Simvastatin