Effectiveness of simvastatin therapy in raising HDL-C in patients with type 2 diabetes and low HDL-C

OBJECTIVE: To evaluate the efficacy of high and moderate doses of simvastatin (80 and 40 mg), for raising high density lipoprotein-cholesterol (HDL-C), improving HDL sub-fractions, and affecting other parameters, including high sensitivity C-reactive protein (hs-CRP), in patients with type 2 diabetes mellitus (DM) and low HDL-C. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, randomized, 3-period, complete block, 6-week crossover study examined the efficacy of simvastatin in adult men and women (N = 151) with stable type 2 DM (HbA(1C) < 9%), low density lipoprotein-cholesterol (LDL-C) > 100 mg/dL (2.6 mmol/L), HDL-C < 40 mg/dL (< 1 mmol/L), and fasting triglyceride level > 150 (> 1.7 mmol/L) and < 700 mg/dL (< 7.9 mmol/L). This study included adult men (71%) and women (29%) of various races (89% white, 6% black, 1% Asian, 3% other) enrolled from 29 practice-based sites in the United States. MAIN OUTCOME MEASURES: Percentage change in HDL-C from baseline at the end of each 6-week treatment interval. RESULTS: Both simvastatin 80 and 40 mg significantly increased total HDL-C from baseline (mean increases of 8% +/- 1 [SE] and 5% +/- 1, respectively; p < 0.001) compared with placebo, and significantly reduced plasma concentrations of LDL-C (p < 0.001), triglycerides (p < 0.001), apolipoprotein B (p < 0.001), and hs-CRP (p < or = 0.012). Compared with simvastatin 40 mg, the 80 mg dose provided additional efficacy. Simvastatin 80 mg also significantly (p < 0.001) increased HDL(2) from baseline (14% +/- 3[SE]) and placebo phases (10 +/- 3). An exploratory analysis showed 87% (simvastatin 80 mg) and 82% (simvastatin 40 mg) of patients reached the NCEP ATP III treatment goals for LDL-C compared with 14% on placebo. CONCLUSIONS: Both simvastatin 80 and 40 mg raise HDL-C and improve other measures associated with elevated coronary risk in patients with type 2 DM and low HDL-C.     

Niacin extended-release/simvastatin

Niacin extended-release (ER)/simvastatin is a once-daily, fixed-dose combination of the HMG-CoA reductase inhibitor simvastatin and an ER formulation of niacin (a B-complex vitamin). In healthy volunteers who were given niacin ER/simvastatin 2000 mg/40 mg, niacin exposure was similar to that with niacin ER 2000 mg, while simvastatin exposure was increased compared to that with simvastatin 40 mg. In patients with elevated non-high-density lipoprotein cholesterol (non-HDL-C) but with low-density lipoprotein cholesterol (LDL-C) at or below the National Cholesterol Education Program (NCEP) goal after a > or = 2-week simvastatin 20 mg/day run-in period (SEACOAST I), 24 weeks of niacin ER/simvastatin 1000 mg/20 mg or 2000 mg/20 mg per day reduced median plasma non-HDL-C levels to a significantly greater extent than simvastatin 20 mg/day. In patients with elevated non-HDL-C and LDL-C at any level after a > or = 2-week simvastatin 40 mg/day run-in period (SEACOAST II), 24 weeks of niacin ER/simvastatin 1000 mg/40 mg or 2000 mg/40 mg per day was noninferior to simvastatin 80 mg/day in reducing median plasma non-HDL-C levels. Compared with simvastatin monotherapy, there was no significant difference in reduction in plasma LDL-C levels with niacin ER/simvastatin in SEACOAST I, and the noninferiority criterion for LDL-C was not met in SEACOAST II. However, plasma HDL-C levels increased more and triglyceride levels were lowered more than with simvastatin monotherapy (SEACOAST I and II). Niacin ER/simvastatin was generally well tolerated, with flushing being the most common adverse reaction.     

Long-Term Safety and Efficacy of a Combination of Niacin Extended Release and Simvastatin in Patients with Dyslipidemia

INTRODUCTION: High-dose HMG-CoA reductase inhibitors (statins) fail to prevent approximately two-thirds of cardiovascular events. This fact has focused increased attention on treating abnormalities of non-high-density lipoprotein-cholesterol (non-HDL-C), HDL-C, and triglycerides in national guidelines and has intensified interest in combination therapy. METHODS: The OCEANS study (Open-label evaluation of the safety and efficacy of a Combination of niacin ER and simvAstatin in patieNts with dySlipidemia; ClinicalTrials.gov identifier: NCT00080275) evaluated the safety and efficacy of a combination of niacin extended release and simvastatin (NER/S; SIMCOR) over 52 weeks in 520 patients with mixed dyslipidemia. After a >or=4-week run-in phase of diet modification and simvastatin 40 mg/day, median baseline values (mg/dL) were: non-HDL-C = 141, low-density lipoprotein-cholesterol (LDL-C) = 110, HDL-C = 45, and triglyceride = 151. Patients were randomized to an 8- or 12-week niacin titration scheme to a maximum NER/S dosage of 2,000/40 mg/day. RESULTS: Differences between titration groups in tolerability, safety, and efficacy were minimal; therefore, all results are for pooled titration groups. The safety of NER/S was consistent with the safety profile of each individual component. Treatment with NER/S was well tolerated: 71% of patients experienced flushing and 92% of flushing episodes were mild or moderate in intensity. Overall, 61% of patients experienced flushing episodes that were rated as mild or moderate in intensity. Flushing decreased over time: <40% of those who had flushing during titration experienced flushing during the final 12 weeks. A total of 20% of patients discontinued treatment because of a treatment-related adverse event, including 7% who discontinued because of flushing. Median changes from baseline (following the simvastatin 40 mg/day run-in phase) to 24 weeks were: non-HDL-C = -27.3%, LDL-C = -25.0%, HDL-C = +23.9%, and triglycerides = -35.9% (all p < 0.0001 vs baseline). In lipid-treatment-naive patients, NER/S 2,000/40 mg/day decreased non-HDL-C, LDL-C, and triglycerides by approximately 50% and increased HDL-C by approximately 25% when week-24 lipid values were compared with lipid values obtained prior to the simvastatin 40 mg/day run-in. All three therapeutic lipid targets (LDL-C [risk-adjusted goal], HDL-C >or=40 mg/dL, and triglycerides <150 mg/dL) were achieved concurrently by 65% of patients treated with NER/S. CONCLUSION: Treatment with NER/S 2,000/40 mg/day is well tolerated, has no unanticipated adverse events, and provides additional, clinically relevant improvements in multiple lipid parameters beyond statin monotherapy.     

Cost-effectiveness analysis of simvastatin and lovastatin/extended- release niacin to achieve LDL and HDL goal using NHANES data

OBJECTIVE: The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, Adult Treatment Panel III (ATP III) encouraged reduced low-density lipoprotein (LDL) cholesterol levels for a greater number of patients and reemphasized the benefits of high-density lipoprotein (HDL) cholesterol. The purpose of this study was to compare 2 regimens achieving simultaneous LDL and HDL goals. METHODS: A decision-analytic model compared the cost-effectiveness of simvastatin and lovastatin/extended-release niacin. The perspective of the analysis was that of a health system. Product labeling was used to determine changes in cholesterol concentrations and frequencies of clinically important adverse events. The Third National Health and Nutrition Examination Survey (NHANES III) adult data were used for baseline cholesterol levels. Each product was titrated to achieve LDL and HDL goals unless an adverse effect occurred. Direct medical costs were determined for each treatment to determine cost-effectiveness. RESULTS: For both the 130 mg/dL and 100 mg/dL LDL goal analyses (and HDL e40 mg/dL), lovastatin/extended-release niacin had higher success rates and lower estimated direct-medical costs than simvastatin. Simvastatin had the highest success rate in achieving LDL level <160 mg/dL and HDL e40 mg/dL; however, its estimated direct-medical cost was approximately twice that of lovastatin/extended-release niacin (665 US dollars versus 333 US dollars). CONCLUSION: For the LDL goals <130 mg/dL and <100 mg/dL (and HDL e40 mg/dL) required of the majority of U.S. residents, lovastatin/extended-release niacin was both more successful and less costly than simvastatin.     

Effect of Atorvastatin versus Simvastatin on Lipid Profile and Plasma Fibrinogen in Patients with Hypercholesterolaemia: A Pilot, Randomised, Double-Blind, Dose-Titrating Study

OBJECTIVE: To investigate the effect of atorvastatin vs simvastatin on lipid profile and plasma fibrinogen in patients with hypercholesterolaemia. PATIENTS: 30 outpatients (25 men), with a median age of 51 years were studied. Eight patients had established coronary artery disease (CAD) and four had diabetes mellitus at baseline. 11 patients presented a Frederickson's IIb phenotype and 19 a IIa phenotype at baseline. STUDY DESIGN: After a 6-week placebo period, patients were randomly assigned to simvastatin (10 mg/day, n = 15) or atorvastatin (10 mg/day, n = 15). Lipid profile, apolipoproteins B and A-I and plasma fibrinogen were measured for a 16-week period, at 4-week intervals. Thereafter, the dose of each drug was doubled only in patients with low density lipoprotein cholesterol (LDL-C) levels above 130 mg/dl for a further 16-week period. RESULTS: Ten of 15 patients on atorvastatin 10mg (66%) and four of 15 on simvastatin 10mg (27%) achieved the LDL-C <130 mg/dl goal. Apolipoprotein B was reduced by both drugs (-33%, p < 0.001 for atorvastatin and -18%, p < 0.05 for simvastatin), but plasma fibrinogen and triglyceride were reduced only by atorvastatin (-20%, p < 0.01; -36%, p < 0.001, respectively). During the second 16-week period seven of 11 patients receiving the simvastatin 20mg dose (64%) achieved the LDL-C <130 mg/dl goal. The comparison of atorvastatin 10mg with simvastatin 20mg showed that the drugs appear to be equipotent in terms of LDL-C lowering. CONCLUSIONS: Atorvastatin in equipotent doses to simvastatin appeared to be more effective than the latter in reducing triglyceride and plasma fibrinogen in patients with hypercholesterolaemia, mainly in those with Frederickson's phenotype Iib.     

Effectiveness of simvastatin therapy in raising HDL-C in patients with type 2 diabetes and low HDL-C

SUMMARY

Objective: To evaluate the efficacy of high and moderate doses of simvastatin (80 and 40?mg), for raising high density lipoprotein-cholesterol (HDL-C), improving HDL sub-fractions, and affecting other parameters, including high sensitivity C-reactive protein (hs-CRP), in patients with type 2 diabetes mellitus (DM) and low HDL-C.

Research design and methods: This double-blind, placebo-controlled, randomized, 3-period, complete block, 6-week crossover study examined the efficacy of simvastatin in adult men and women (N = 151) with stable type 2 DM (HbA_1C < 9%), low density lipoprotein-cholesterol (LDL-C) > 100?mg/dL (2.6?mmol/L), HDL-C < 40?mg/dL (< 1?mmol/L), and fasting triglyceride level > 150 (> 1.7?mmol/L) and < 700?mg/dL (< 7.9?mmol/L). This study included adult men (71%) and women (29%) of various races (89% white, 6% black, 1% Asian, 3% other) enrolled from 29 practice-based sites in the United States.

Main outcome measures: Percentage change in HDL-C from baseline at the end of each 6-week treatment interval.

Results: Both simvastatin 80 and 40?mg significantly increased total HDL-C from baseline (mean increases of 8% ± 1 [SE] and 5% ± 1, respectively; p < 0.001) compared with placebo, and significantly reduced plasma concentrations of LDL-C (?p < 0.001), triglycerides (?p < 0.001), apolipoprotein B (?p < 0.001), and hs-CRP (?p ≤ 0.012). Compared with simvastatin 40?mg, the 80?mg dose provided additional efficacy. Simvastatin 80?mg also significantly (?p < 0.001) increased HDL₂ from baseline (14% ± 3[SE]) and placebo phases (10 ± 3). An exploratory analysis showed 87% (simvastatin 80?mg) and 82% (simvastatin 40?mg) of patients reached the NCEP ATP III treatment goals for LDL-C compared with 14% on placebo.

Conclusions: Both simvastatin 80 and 40?mg raise HDL-C and improve other measures associated with elevated coronary risk in patients with type 2 DM and low HDL-C.     

LDL-C goal attainment with the addition of ezetimibe to ongoing simvastatin treatment in coronary heart disease patients with hypercholesterolemia

OBJECTIVE: To evaluate the addition of ezetimibe or placebo to on-going simvastatin treatment on attaining the LDL-C treatment target of 2.60 mmol/L and 100 mg/dL and 相似文献   

Efficacy and Safety of Rosuvastatin and Fenofibric Acid Combination Therapy versus Simvastatin Monotherapy in Patients with Hypercholesterolemia and Hypertriglyceridemia

Objectives

To evaluate the efficacy and safety of fixed-dose combinations of rosuvastatin and fenofibric acid (rosuvastatin/fenofibric acid) compared with simvastatin in patients with high levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG).

Background

Combination therapy with a statin and a fibrate is one of the treatment options to manage multiple lipid abnormalities in patients with hypercholesterolemia and elevated TGs.

Methods

In this randomized, double-blind study, patients (n=474) with LDL-C ≥160 mg/dL and ≤240 mg/dL and TG ≥150 mg/dL and <400 mg/dL were treated for 8 weeks with simvastatin 40 mg, rosuvastatin/fenofibric acid 5 mg/135 mg, rosuvastatin/fenofibric acid 10 mg/135 mg, or rosuvastatin/fenofibric acid 20 mg/135 mg. Primary and secondary variables were mean percent changes in LDL-C comparing rosuvastatin/fenofibric acid 20 mg/135 mg with simvastatin 40 mg and rosuvastatin/fenofibric acid 10 mg/135 mg and rosuvastatin/fenofibric acid 5 mg/135 mg with simvastatin 40 mg, respectively. Additional efficacy variables included non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein (Apo) B, HDL-C, TG, and high-sensitivity C-reactive protein (hsCRP). Safety was evaluated based on data collected for adverse events (AEs), physical and electrocardiographic examinations, vital sign measurements, and clinical laboratory tests.

Results

Significantly greater reductions in LDL-C levels from baseline values were observed with the combination of rosuvastatin/fenofibric acid 20 mg/135 mg (?47.2%, p < 0.001), rosuvastatin/fenofibric acid 10 mg/135 mg (?46.0%, p < 0.001), and rosuvastatin/fenofibric acid 5 mg/135 mg (?38.9%, p = 0.007) than with simvastatin 40 mg (?32.8%). Significant (p ≤ 0.04 for all comparisons) improvements in non-HDL-C, ApoB, HDL-C, TG, and hsCRP levels were also observed with each of the rosuvastatin/fenofibric acid doses as compared with simvastatin 40 mg. Treatment-related AEs and discontinuations due to AEs were similar across groups. The incidence of serious AEs was 0% with simvastatin 40 mg, 3.4% with rosuvastatin/fenofibric acid 5 mg/135 mg, 0.8% with rosuvastatin/fenofibric acid 10 mg/135 mg, and 2.5% with rosuvastatin/fenofibric acid 20 mg/135 mg. No cases of rhabdomyolysis or drug-related myopathy were reported.

Conclusion

In patients with high LDL-C and TG levels, combination treatment with rosuvastatin/fenofibric acid was well tolerated, and each of the rosuvastatin/fenofibric acid doses produced greater reductions in LDL-C and improvements in other efficacy parameters, compared with simvastatin 40 mg.     

Reaching goal in hypercholesterolaemia: dual inhibition of cholesterol synthesis and absorption with simvastatin plus ezetimibe

ABSTRACT

Lowering serum cholesterol levels reduces the risk of coronary heart disease (CHD)-related events. Statins are commonly prescribed as first-line treatment but many patients at high-risk for CHD still fail to reach their cholesterol or low-density lipoprotein cholesterol (LDL-C) goals with statin monotherapy.

National and international guidelines for the prevention of CHD recommend the modification of lipid profiles and particularly LDL‐C [e.g. the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III; 2001) and Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice (2003) Guidelines]. Several recent clinical trials indicated an added benefit from aggressive lowering of LDL‐C levels. Based on these findings, the NCEP ATP III revised the LDL‐C target from < 100?mg/dL (2.6?mmol/L) to < 70?mg/dL (1.8?mmol/L) (optional target) for very high-risk patients and < 130?mg/dL (3.4?mmol/L) to < 100?mg/dL (2.6?mmol/L) for moderately high-risk patients.

For patients who fail to achieve their LDL‐C target, inhibiting the two main sources of cholesterol – synthesis and uptake – can produce more effective lipid lowering, allowing more patients to reach their LDL‐C goal. Ezetimibe is a highly-selective inhibitor of cholesterol absorption and simvastatin is an evidence-based inhibitor of cholesterol synthesis. The LDL‐C-lowering efficacy of targeting both major sources of cholesterol with ezetimibe plus simvastatin was demonstrated in several multicentre, double-blind, placebo-controlled trials in patients with hypercholesterolaemia. For patients who do not reach their cholesterol goal with a statin, adding ezetimibe 10?mg significantly reduces LDL‐C compared with statin monotherapy. Thus, this treatment option may help patients reach the new ‘stricter’ cholesterol goals.

This review, based on a Medline database search from January 2000 to August 2005, considers the LDL‐C-lowering efficacy of ezetimibe and discusses the role of this agent for patients who fail to achieve guideline cholesterol goals with statin monotherapy.     

Long-term (48-week) safety of ezetimibe 10 mg/day coadministered with simvastatin compared to simvastatin alone in patients with primary hypercholesterolemia*

ABSTRACT

Objective: This study evaluated the long-term safety and tolerability of ezetimibe/simvastatin coadministration therapy compared to simvastatin monotherapy in patients with primary hypercholesterolemia.

Research design and methods: After completing a 12-week randomized, double-blind, placebo-controlled, factorial, 10-armed study comparing ezetimibe 10?mg/simvastatin 10, 20, 40, or 80?mg; simvastatin 10, 20, 40, or 80?mg; ezetimibe 10?mg; or placebo, 768 patients entered a 48-week extension, with randomized, blinded, reassignment of the simvastatin 10?mg, ezetimibe, and placebo groups to one of the ezetimibe/simvastatin groups. Patients previously receiving ezetimibe/simvastatin combination therapy, or simvastatin 20, 40, and 80?mg monotherapy continued the same therapies in this 7-arm extension study. During the extension study, investigators assessed adverse events (AEs).

Main outcome measures and results: Ezetimibe/simvastatin (n?=?539) and simvastatin monotherapy (n?=?229) groups generally had a similar incidence of all clinical AEs (73 vs. 69%), treatment-related AEs (14 vs. 11%), clinical serious AEs (SAE) (5.2 vs. 2.6%), treatment-related SAEs (0.2 vs. 0%), discontinuations due to all clinical AEs (4.5 vs. 2.6%) and discontinuations due to treatment-related AEs (2.8 vs. 2.2%), respectively. The incidence of total laboratory-related AEs for the ezetimibe/simvastatin and simvastatin monotherapy groups was also similar (12.2 vs. 11.9%), as was treatment-related laboratory AEs (6.2 vs. 5.3%), laboratory SAEs (0 vs. 0%), treatment-related laboratory SAEs (0 vs. 0%), discontinuations due to laboratory AEs (3.0 vs. 0.9%) and discontinuations due to treatment-related laboratory AEs (3.0 vs. 0.4%), respectively. There were no cases of myopathy, rhabdomyolysis, or serious hepatotoxicity observed in any group during this extension study.

Conclusions: During this 48-week extension study, the coadministration of ezetimibe/simvastatin was generally as well tolerated as simvastatin monotherapy. The direct application of study observations to clinical practice is limited by patient selection criteria and dosage regime, which randomly applied relatively high doses rather than titration which often occurs in clinical practice.     

Effect of pravastatin-to-simvastatin conversion on low-density-lipoprotein cholesterol.

The effects of a pravastatin-to-simvastatin conversion program on low-density-lipoprotein (LDL) cholesterol levels were studied. Patients receiving pravastatin at a Veterans Affairs medical center were switched to simvastatin beginning in 1997. The dosage of simvastatin was based on the additional percent reduction in LDL cholesterol needed to achieve the goal specified by the National Cholesterol Education Program. The primary endpoint was the change in the percentage of patients meeting their LDL cholesterol goal at baseline and follow-up. Changes in lipid indices, the relative risk (RR) of coronary heart disease (CHD), and program costs were also evaluated. A total of 1032 patients completed the program. The mean +/- S.D. daily doses of pravastatin and simvastatin were 25.2 +/- 11.3 and 22.7 +/- 13.3 mg, respectively. Median baseline and follow-up LDL cholesterol concentrations were 116 and 99 mg/dL, respectively (p < 0.001). Overall, 44% of the patients met their LDL cholesterol goal while taking pravastatin, compared with 69% after conversion to simvastatin (p < 0.001). The predicted mean RR of a future CHD event (based on changes in serum lipids) was 0.87 (95% confidence interval, 0.83-0.91) four years after conversion. The total cost of the program was $40,644 in the first year, and there was a net saving thereafter. Therapeutic interchange between pravastatin and simvastatin increased the number of patients meeting their LDL cholesterol goal.     

A comparison of simvastatin and atorvastatin up to maximal recommended doses in a large multicenter randomized clinical trial

OBJECTIVE: At higher doses, simvastatin has been shown to produce significantly greater increases in high-density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I than atorvastatin. To extend and confirm these findings, a 36-week, randomized, double-blind, dose-titration study was performed in 826 hypercholesterolemic patients to compare the effects of simvastatin and atorvastatin on HDL cholesterol, apo A-I, and clinical and laboratory safety. PRIMARY HYPOTHESIS: Simvastatin, across a range of doses, will be more effective than atorvastatin at raising HDL cholesterol and apo A-I levels. METHODS: A total of 826 hypercholesterolemic patients were enrolled in this double-blind, randomized, parallel, 36-week, dose-escalation study. Patients randomized to simvastatin received 40 mg/day for the first 6 weeks, 80 mg/day for the next 6 weeks, and remained on 80 mg/day for the final 24 weeks. Patients randomized to atorvastatin received 20 mg/day for the first 6 weeks, 40 mg/day for the next 6 weeks, and 80 mg/day for the remaining 24 weeks. RESULTS: During the first 12 weeks of the study, simvastatin increased HDL cholesterol and apo A-I more than the comparative doses of atorvastatin, while producing slightly lower reductions in low-density lipoprotein (LDL) cholesterol and triglycerides. At the maximal dose comparison, simvastatin 80 mg and atorvastatin 80 mg, the HDL cholesterol and apo A-I differences favoring simvastatin were larger than at the lower doses. In addition, at the maximal dose comparison, the incidence of drug-related clinical adverse experiences was approximately two-fold higher with atorvastatin 80 mg than with simvastatin 80 mg (23 versus 12%, p < 0.001), due predominantly to a greater incidence of gastrointestinal symptoms with atorvastatin (10 versus 3%, p < 0.001). The incidence of clinically significant alanine aminotransferase elevations was also higher with atorvastatin 80 mg than with simvastatin 80 mg (3.8 versus 0.5%, p < 0.010), especially in women (6.0 versus 0.6%). CONCLUSIONS: At the doses compared in this study, simvastatin led to greater increases in HDL cholesterol and apo A-I levels than atorvastatin. At the maximum dose comparison, there were fewer drug-related gastrointestinal symptoms and clinically significant aminotransferase elevations with simvastatin.     

The effect of simvastatin on asymmetric dimethylarginine and flow-mediated vasodilation after optimizing the LDL level: a randomized, placebo-controlled study

Research of statin influence on asymmetric dimethylarginine (ADMA) and flow-mediated vasodilatation (FMD) reveals controversial results. The aim of this study was to investigate the effects of moderate (40mg) and high (80mg) simvastatin doses on the levels of ADMA, total homocysteine (tHcy) and %FMD in patients with newly diagnosed severe hypercholesterolemia, after optimizing the LDL level. The study included 650 patients with severe hypercholesterolemia (total cholesterol≥7.5mmol/l; LDL≥4.9mmol/l). The treatment groups were administered 80mg simvastatin over a period of one month. The results indicated a reduction in ADMA and tHcy levels and an increase in %FMD in the treatment groups, compared with the control groups (receiving placebo or 40mg simvastatin). There was a statistically significant correlation between the %FMD changes and the baseline levels of Apo-B, ADMA and tHcy, as well as between the %ADMA changes and %LDL, % apolipoprotein-B and %tHcy-changes in patients on 80mg Simvastatin. A statistical linear regression analysis (in the treatment group) indicated that the baseline ADMA level is the most important statistically significant predictor related to %FMD-changes. A linear regression analysis additionally documented that % apolipoprotein-B-changes is a predictor of %ADMA-changes. In conclusion, in cases with optimized LDL-target levels (patients on 80mg Simvastatin), the baseline level of ADMA appears to be a major modulator of %FMD-changes.     

Evaluation of a new formulation of fenofibric acid, ABT-335, co-administered with statins : study design and rationale of a phase III clinical programme

BACKGROUND and objective: Atherogenic lipid parameters in patients with mixed dyslipidaemia have been demonstrated to increase atherosclerotic coronary heart disease (CHD) risk. Clinical studies have shown that HMG-CoA reductase inhibitor (statin) and fibric acid derivative (fibrate) combination therapy is effective at improving multiple lipid abnormalities in different patient populations at increased risk of CHD. However, inconsistencies with respect to trial designs and safety issues have limited the clinical use of this combination therapy. A comprehensive, controlled clinical trial programme was thus designed to evaluate three separate statins in combination with ABT-335, a new formulation of fenofibric acid. METHODS: Three separate 22-week, phase III, double-blind, active-controlled trials will evaluate combination therapy with ABT-335 135 mg/day and either rosuvastatin (10 mg/day and 20 mg/day), atorvastatin (20 mg/day and 40 mg/day) or simvastatin (20 mg/day and 40 mg/day) in comparison to either ABT-335 or the corresponding statin monotherapy. An approximate total of 2400 patients with elevated triglycerides (TG) [> or =150 mg/dL], reduced high-density lipoprotein cholesterol (HDL-C) [<40 mg/dL for men and <50 mg/dL for women], and elevated low-density lipoprotein cholesterol (LDL-C) [> or =130 mg/dL] will be randomized to one of six intervention arms per trial (two combination therapy and four monotherapy groups). The pre-specified primary efficacy endpoint is a composite of the mean percent changes in HDL-C and TG (comparing each combination therapy with the corresponding statin monotherapy dose) and LDL-C (comparing each combination therapy with ABT-335 monotherapy). Secondary endpoints include mean percent changes in non-HDL-C, very LDL-C, total cholesterol, apolipoprotein B and high sensitivity C-reactive protein levels. At study end, patients may enroll in a 12-month open-label extension study that will evaluate the long-term efficacy and safety of combination therapy. CONCLUSION: This is the largest phase III randomized, controlled clinical programme to date evaluating the efficacy and safety of the combined use of a new formulation of fenofibric acid (ABT-335) with three commonly prescribed statins in patients with mixed dyslipidaemia.     

Lipid altering-efficacy of ezetimibe co-administered with simvastatin compared with rosuvastatin: a meta-analysis of pooled data from 14 clinical trials

ABSTRACT

Objective: Results of direct comparative studies between ezetimibe/simvastatin and rosuvastatin therapies have not been reported. Both of these treatment options offer significant reductions in LDL-C. To evaluate the lipid efficacy of each of these therapies relative to each other, a meta-analysis of data from 14 randomized, double-blind clinical trials that compared the effectiveness of two new options for cholesterol lowering was performed.

Data sources: PubMed, EMBASE and BIOSIS databases were searched up to March 14, 2004.

Methods of study selection: Efficacy results from clinical trials with the co-administration of ezetimibe 10?mg with simvastatin or with the ezetimibe/simvastatin combination product (ezetimibe/simvastatin 10/10?mg, 10/20?mg, 10/40?mg, and 10/80?mg) were compared with efficacy results from clinical trials of rosuvastatin 5?mg, 10?mg, 20?mg, and 40?mg in patients with primary hypercholesterolemia. Trials in healthy patients, heterozygous familial hypercholesterolemia or combined hyperlipidemia, and pharmacokinetic trials were excluded.

Data extraction and synthesis: This analysis used pooled data for LDL-C, HDL-C, non-HDL-C, triglycerides, total cholesterol, apolipoprotein (apo) A-I, and apo B for the two therapies at their lowest doses (ezetimibe/simvastatin 10/10?mg and rosuvastatin 5?mg) through their highest doses (ezetimibe/simvastatin 10/80?mg and rosuvastatin 40?mg), and estimated within-treatment percentage changes in these parameters. Percentage reductions from baseline in LDL-C for the pooled data were 46.2% and 41.8% for ezetimibe/simvastatin 10/10?mg and rosuvastatin 5?mg, respectively; 50.6% and 47.4% for ezetimibe/simvastatin 10/20?mg and rosuvastatin 10?mg, respectively; 55.9% and 52.1% for ezetimibe/simvastatin 10/40?mg and rosuvastatin 20?mg, respectively; and 59.7% and 58.5% for ezetimibe/simvastatin 10/80?mg and rosuvastatin 40?mg, respectively.

Conclusions: The results of this meta-analysis suggest greater LDL-C lowering with ezetimibe/simvastatin compared with rosuvastatin. These results need to be confirmed in a head-to-head comparison of both therapies.     

Effects of ketanserin on lipids, lipoproteins, and plasma atrial natriuretic factor in patients with essential hypertension

The effects of ketanserin, 40 mg/day (KE40) and 80 mg/day (KE80) on mean arterial pressure, lipids, lipoproteins, and circulating atrial natriuretic factor (ANF) were investigated in a 24-week controlled study in 29 patients suffering from mild to moderate hypertension. A significant decrease in mean arterial pressure (MAP) was observed after 18 weeks of therapy, accompanied by a 64% (P less than .05) and 80% (P less than .02) increase in circulating ANF levels with KE40 and KE80, respectively. There were no significant changes in mean total cholesterol, triglycerides, or cholesterol of the high density lipoproteins (HDL), low density lipoproteins (LDL), and very low density lipoproteins (VLDL) fractions. There was a significant increase in the mean apo B levels and consequently a slight but statistically significant decrease in the ratio of LDL C/B. It is concluded that both doses of KE are effective for monotherapy of mild to moderate essential hypertension. The drug sharply increases circulating ANF levels without significantly altering the plasma lipids. In contrast, by increasing the apolipoprotein B content of the LDL fraction, the beneficial cardiovascular effect of a lowered blood pressure may be partly blunted.