LDL‐C/HDL‐C ratio in subjects with cardiovascular disease and a low HDL‐C: results of the RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study

ABSTRACT

Background: The ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (LDL‐C/HDL‐C) is a reliable predictor of cardiovascular risk. Low HDL‐C levels in patients with coronary artery disease are associated with a high risk for cardiovascular events.

Objectives: This study compared the effects of rosuvastatin and atorvastatin on the LDL‐C/HDL‐C ratio in patients with cardiovascular disease and low HDL‐C.

Methods: Patients aged 40–80 years with established cardiovascular disease and HDL‐C < 1.0?mmol/L (< 40?mg/dL) entered a 6‐week dietary run-in period, before randomisation to open-label treatment with rosuvastatin 10?mg (n = 230) or atorvastatin 20?mg (n = 231) for 6 weeks. Doses were increased after 6 weeks to rosuvastatin 20?mg or atorvastatin 40?mg, and after 12 weeks to rosuvastatin 40?mg or atorvastatin 80?mg. Serum lipid parameters were measured at baseline and 6, 12 and 18 weeks.

Results: After 6 weeks of treatment, mean percentage change from baseline in LDL‐C/HDL‐C ratio was –47.0% in the rosuvastatin group and –41.9% in the atorvastatin group (?p < 0.05 for between-group comparison). After 12 and 18 weeks of treatment, change from baseline was –53.0% and –57.3%, respectively, for rosuvastatin, compared with –47.9% and –49.6%, respectively, for atorvastatin (?p < 0.01 and p < 0.001, respectively, for between-group comparison). Rosuvastatin also reduced LDL‐C, total cholesterol and non-HDL‐C significantly more than atorvastatin at all three time points, and significantly improved total cholesterol/HDL‐C and apolipoprotein B/A‐I ratios.

Conclusions: Rosuvastatin 10, 20 and 40?mg is significantly more effective than atorvastatin 20, 40 and 80?mg, respectively, in improving the LDL‐C/HDL‐C ratio in patients with cardiovascular disease and low HDL‐C. Further studies are required to clarify the benefits of rosuvastatin for reduction of cardiovascular risk.     

Effect of rosuvastatin versus atorvastatin treatment on paraoxonase-1 activity in men with established cardiovascular disease and a low HDL-cholesterol

ABSTRACT

Objective: Paraoxonase-1 (PON-1) is a high-density lipoprotein (HDL) associated enzyme involved in the protective mechanisms of HDL. Our aim was to compare the effect of treatment with rosuvastatin and atorvastatin on serum PON-1 activity.

Methods: We performed a prespecified prospective study in 68 patients, part of a larger, multicentre randomized study – RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport). Patients aged 40–80 years, all men, with established cardiovascular disease and high-density lipoprotein cholesterol (HDL?C) < 1.0?mmol/L (< 40?mg/dL) entered a 6-week dietary run-in period before receiving treatment with rosuvastatin 10?mg or atorvastatin 20?mg daily for 6 weeks. Doses were increased after 6 weeks to rosuvastatin 20?mg or atorvastatin 40?mg and after 12 weeks to rosuvastatin 40?mg or atorvastatin 80?mg daily. Serum PON-1 activity and lipid profile were determined at baseline, 6 and 18 weeks.

Results: After 18 weeks, the rosuvastatin arm showed a significant increase of PON-1 activity (6.39?U/L, p = 0.02) whereas this was not observed in the atorvastatin arm (1.84?U/L, p = 0.77). The difference between groups did not reach significance (?p = 0.11). Both rosuvastatin and atorvastatin resulted in significant (?p = 0.0001) and similar increases in HDL?C after 6 weeks [0.06?mmol/L (2.32?mg/dL) vs. 0.05?mmol/L (1.93?mg/dL)] and after 18 weeks [0.10?mmol/L (3.87?mg/dL) vs. 0.10?mmol/L (3.87?mg/dL)].

Conclusions: Rosuvastatin treatment resulted in a significant increment of serum PON-1 activity with increasing dose while this was not observed with atorvastatin.     

Lipid-modifying effects of rosuvastatin in postmenopausal women with hypercholesterolemia who are receiving hormone replacement therapy

OBJECTIVE: To evaluate the efficacy and safety of rosuvastatin in postmenopausal women with hypercholesterolemia who are receiving hormone replacement therapy (HRT) in a randomized, double-blind, placebo-controlled trial. METHODS: After a 6-week dietary lead-in period, 135 postmenopausal women who had been taking a stable HRT regimen for at least 3 months were randomized to receive rosuvastatin 5 mg, 10 mg or placebo for 12 weeks. Fasting levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) were assessed at weeks 0, 2, 6, 10, and 12; apolipoprotein (Apo) B and Apo A-I were measured at weeks 0 and 12. RESULTS: Rosuvastatin 5 mg and 10 mg significantly reduced LDL-C by 38% (SE = 2.1) and 49% (SE = 2.1), respectively, compared with placebo (1% [SE = 2.1]; p < 0.001). TC, TG, Apo B, and all lipid ratios examined (LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C, and Apo B/Apo A-I) were also reduced significantly by both rosuvastatin doses (p < 0.001). HDL-C levels increased significantly in the rosuvastatin groups (11% and 8% for 5 mg and 10 mg, respectively, vs. -0.5% for placebo; p < 0.001), as did Apo A-I levels (p < 0.05). The combination of rosuvastatin plus HRT was well tolerated with no apparent differences among treatments in the numbers or types of adverse events reported. CONCLUSIONS: Rosuvastatin 5 mg or 10 mg once daily is a well-tolerated and highly efficacious lipid-lowering therapy in postmenopausal women receiving HRT.     

Rosuvastatin: a highly efficacious statin for the treatment of dyslipidaemia

Rosuvastatin is a synthetic enantiomer that is hepatoselective, relatively hydrophilic and has minimal metabolism via the cytochrome P450 3A4 system (similar to pravastatin). Rosuvastatin, like atorvastatin, has a plasma half-life of about 20 h and is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The majority of HMG-CoA reductase inhibitory activity in plasma is associated with the parent rosuvastatin compound. In a Phase II study, rosuvastatin across a dose range of 1 - 80 mg lowered low-density lipoprotein cholesterol (LDL-C) by 34 - 65%. Phase III trials have demonstrated greater reductions in LDL-C for rosuvastatin compared to atorvastatin as well as greater increases in high-density lipoprotein cholesterol (HDL-C). The drug appears to be well tolerated at all doses up to 80 mg/day. A starting dose of 10 mg will reduce LDL-C by approximately 50%, which should adequately treat most patients to within the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) goals.     

Rosuvastatin: a highly efficacious statin for the treatment of dyslipidaemia

Rosuvastatin is a synthetic enantiomer that is hepatoselective, relatively hydrophilic and has minimal metabolism via the cytochrome P450 3A4 system (similar to pravastatin). Rosuvastatin, like atorvastatin, has a plasma half-life of about 20 h and is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The majority of HMG-CoA reductase inhibitory activity in plasma is associated with the parent rosuvastatin compound. In a Phase II study, rosuvastatin across a dose range of 1 - 80 mg lowered low-density lipoprotein cholesterol (LDL-C) by 34 - 65%. Phase III trials have demonstrated greater reductions in LDL-C for rosuvastatin compared to atorvastatin as well as greater increases in high-density lipoprotein cholesterol (HDL-C). The drug appears to be well tolerated at all doses up to 80 mg/day. A starting dose of 10 mg will reduce LDL-C by approximately 50%, which should adequately treat most patients to within the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) goals.     

Rosuvastatin

Abstract

Rosuvastatin (Crestor®), an HMG-CoA reductase inhibitor (statin), has a favorable pharmacologic profile, including its selective uptake by hepatic cells, hydrophilic nature, and lack of metabolism by cytochrome P450 (CYP) 3A4 isoenzyme. This last property means that the potential for CYP3A4-mediated drug interactions and, as a consequence, adverse events is low in those requiring concomitant therapy with a statin and agents metabolized by CYP3A4. In a broad spectrum of adult patients with dyslipidemias, oral rosuvastatin 5–40mg once daily effectively and rapidly improved lipid profiles in several large, randomized, mainly double-blind, multicenter trials of up to 52 weeks’ duration. After 12 weeks’ treatment, rosuvastatin was significantly (all p < 0.05) more effective at milligram equivalent dosages than atorvastatin, pravastatin, and simvastatin in improving the overall lipid profiles of patients with hypercholesterolemia (intent-to-treat analyses). Moreover, overall a significantly (all p < 0.001) higher proportion of patients achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III low-density lipoprotein-cholesterol (LDL-C) goals with rosuvastatin 10 mg/day than with therapeutic starting dosages of these other statins after 12 weeks’ treatment in pooled analyses. Rosuvastatin treatment for up to 52 weeks was generally well tolerated in patients with dyslipidemias in clinical trials. The most commonly reported treatment-related adverse events were myalgia, constipation, asthenia, abdominal pain, and nausea; these were mostly transient and mild. The incidence of proteinuria or microscopic hematuria with rosuvastatin 10 or 20 mg/day was <1% versus <1.5% with rosuvastatin 40 mg/day; these events were mostly transient and not associated with acute or progressive deterioration in renal function at recommended dosages. Importantly, very few patients experienced elevations in serum creatine phosphokinase (CPK) levels of over 10-fold the upper limit of normal (0.2–0.4% of patients) or treatment-related myopathy (≤0.1%) [i. e. muscle aches or weakness plus the same elevated serum CPK levels] at dosages of 5–40 mg/day. In conclusion, rosuvastatin treatment effectively and rapidly improves the lipid profile in patients with a broad spectrum of dyslipidemias. In those with hypercholesterolemia (including high-risk patients), rosuvastatin was more efficacious than and generally as well tolerated as atorvastatin, simvastatin, and pravastatin, with significantly more rosuvastatin recipients achieving their NCEP ATP III target LDL-C levels. Thus, rosuvastatin has emerged as a valuable choice for first-line treatment in the management of low- to high-risk patients requiring lipid-lowering drug therapy.

Pharmacodynamic Properties

Rosuvastatin is a single enantiomeric hydroxy acid that is administered as the calcium salt. The drug has a relatively low lipophilicity. Rosuvastatin has a high affinity for the active site of HMG-CoA reductase activity. In in vitro and in vivo studies, rosuvastatin typically inhibits HMG-CoA reductase and cholesterol synthesis to a significantly greater extent than other statins. Rosuvastatin is selectively taken up by hepatic cells in vitro and in vivo, with minimal uptake by nonhepatic cells. Rosuvastatin has a high affinity for the predominantly hepatic organic anion transport protein C. Rosuvastatin increases clearance of plasma low-density lipoprotein-cholesterol (LDL-C) by upregulation of hepatic LDL-C receptors and affects LDL production by decreasing hepatic production of very low-density lipoprotein. In healthy volunteers, rosuvastatin 10 mg/day reduced serum LDL-C (44.2%), total cholesterol (31.8%), triglycerides (22.7%), and apolipoprotein (Apo) B (35.3%). Rosuvastatin was equally effective in lowering serum LDL-C following morning or evening administration. Non-lipid-lowering effects, such as improvements in endothelial function, anti-inflammatory effects, vasculo-protective and cardio/cerebro-protective effects, and improvements in neural function have been reported in in vivo and in vitro studies.

Pharmacokinetic Properties

The Pharmacokinetic properties of rosuvastatin are dose-proportional, with little or no accumulation after repeated administration. Maximum rosuvastatin plasma concentrations of 19–25 μg/L are reached 3–5 hours after administration of a single oral dose of rosuvastatin 40mg in healthy volunteers. The absolute bioavailability of rosuvastatin is approximately 20%. Food decreases the rate of rosuvastatin absorption by 20%, but the extent of absorption remains unchanged. At steady state, the mean volume of distribution of rosuvastatin is approximately 134L. Rosuvastatin is reversibly bound to plasma proteins (88%). Rosuvastatin undergoes very limited metabolism (≈10% of radiolabelled drug recovered as metabolites from urine), with metabolism primarily occurring via cytochrome P450 (CYP) 2C9. N-desmethyl rosuvastatin is the major metabolite. Rosuvastatin undergoes predominantly biliary excretion, with 90% of a single oral dose of radioactive rosuvastatin recovered in the feces (92% as the parent compound). The plasma elimination half-life of rosuvastatin after a single oral dose of rosuvastatin 40mg is 18 24 hours. There were no clinically relevant changes in the pharmacokinetics of rosuvastatin with differences in patient age or gender, time of administration, or mild to moderate renal impairment. However, plasma concentrations of rosuvastatin were increased in patients with severe renal impairment. Rosuvastatin maximum plasma concentration and area under the plasma concentration-time curve values were increased in patients with mild to moderate hepatic impairment. Coadministration of rosuvastatin and ketoconazole, erythromycin, itraconazole (inhibitors of CYP3A4), fenofibrate, fluconazole (metabolized by CYP2C9 and CYP2C19), or digoxin had no clinically relevant effect on the pharmacokinetics of rosuvastatin. Coadministration of rosuvastatin and warfarin increased the International Normalized Ratio. Concomitant rosuvastatin plus cyclosporine or gemfibrozil resulted in a clinically relevant increase in systemic exposure to rosuvastatin. Administration of antacid 2 hours after rosuvastatin avoided clinically relevant decreases in plasma concentrations of rosuvastatin. Administration of contraceptives (ethinyl estradiol and norgestrel) and rosuvastatin increased the plasma concentrations of ethinyl estradiol and norgestrel by 26% and 34%.

Therapeutic Efficacy

Treatment with oral rosuvastatin 5–40mg once daily effectively and rapidly improved lipid profiles across a broad spectrum of patients with dyslipidemias in several large, randomized, mainly double-blind, multicenter trials of up to 52 weeks’ duration. In well-designed trials of 6–12 weeks’ duration in patients with hypercholesterolemia, rosuvastatin (5 and 10 mg/day) recipients achieved significantly (all p < 0.05) greater improvements in plasma LDL-C and total cholesterol levels than those receiving atorvastatin 10 mg/day, pravastatin 20 mg/day or simvastatin 20 mg/day, according to primary endpoint intent-to-treat analyses. All other aspects of the lipid profile improved to the same or a greater extent with rosuvastatin treatment than with these other statins, including increases in plasma high-density lipoprotein-cholesterol (HDL-C) levels and reductions in plasma Apo B, triglycerides, and non-HDL-C levels. As assessed in individual trials and pooled analyses, these improvements were in turn reflected in significantly greater improvements in lipid ratios of atherogenic to non-atherogenic lipid components (e. g. LDL-C: HDL-C, non-HDL-C: HDL-C, Apo B: Apo A1 ratios) with rosuvastatin treatment relative to other statins. Notably, rosuvastatin treatment proved effective, irrespective of the patient’s age, gender, postmenopausal status, and/or the presence of type 2 diabetes mellitus with or without metabolic syndrome, hypertension, atherosclerosis, and/or obesity. Pooled analyses indicated that overall a significantly (all p < 0.001) higher proportion of patients achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL-C goals with rosuvastatin 10 mg/day than with therapeutic starting dosages of other statins after 12 weeks’ treatment, with 80% of rosuvastatin 10 mg/day recipients achieving their goals. Rosuvastatin 10 mg/day was significantly (all p < 0.05) more effective than simvastatin 20 mg/day or pravastatin 20 mg/day based on individual NCEP ATP III goals: LDL-C target <100 mg/dL 63%, 22%, and 5% of patients achieved target, respectively; LDL-C target <130 mg/ dL 89%, 74%, and 40%; and LDL-C target <160 mg/dL 99%, 90%, and 88%. Relative to atorvastatin 10 mg/day recipients, significantly more rosuvastatin 10 mg/day recipients achieved their target of <100 mg/dL (60% vs 19% in the atorvastatin group; p < 0.05), although response rates were not statistically different in those with targets of <130 mg/dL (88% vs 80%) or <160 mg/dL (96% vs 91%). Results of the STELLAR (Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin) trial confirmed data from these pooled analyses. In the 16-week MERCURY I (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY) trial, patients who switched from previous statin treatment to rosuvastatin 10 mg/day achieved significantly (all p < 0.0001) greater reductions in plasma LDL-C than those who continued to receive atorvastatin 10 mg/day (46.2% vs 38.5% reduction), simvastatin 20 mg/day (45.6% vs 37.4%) or pravastatin 40 mg/day (46.6% vs 32.4%). Improvements in lipid parameters that were observed after switching to rosuvastatin were generally reflected in significantly (all p ≤ 0.0001) greater reductions in lipid ratios for LDL-C: HDL-C, non-HDL-C: HDL-C, and Apo B: Apo A1. Furthermore, significantly more patients who switched to rosuvastatin 10 mg/day at 8 weeks achieved NCEP ATP III LDL-C targets than those who remained on existing treatment. In difficult-to-treat patient populations, such as those with type 2 diabetes with mixed dyslipidemia, combining rosuvastatin with fenofibrate enhanced reductions in plasma triglyceride levels versus rosuvastatin monotherapy. However, combining rosuvastatin 40 mg/day with niacin extended-release (ER) 1 g/day had no additional benefit in terms of reduction in atherogenic lipid parameters to those achieved with the equivalent dosage of rosuvastatin monotherapy in patients with Fredrickson type IIb or IV hyperlipidemia, although mean plasma HDL-C levels increased by a significantly greater extent with rosuvastatin 10 mg/day plus niacin ER 2 g/ day than with rosuvastatin 40 mg/day monotherapy (11% vs 24%; p < 0.001).

Tolerability

Rosuvastatin was generally well tolerated in clinical trials of up to 1 year’s duration, with tolerability data based on pooled analyses and extension phases of these trials. Overall, in clinical trials the most commonly reported adverse events possibly or probably related to rosuvastatin treatment were myalgia, constipation, asthenia, abdominal pain, and nausea (incidence not reported). Most adverse events were of mild intensity and transient, with 3.7% of 10 275 rosuvastatin recipients discontinuing treatment because of a drug-related adverse event. No rosuvastatin-related deaths occurred during participation in clinical trials. A few rosuvastatin recipients have developed proteinuria (<1% of patients receiving rosuvastatin 10 or 20 mg/day and <1.5% of 40 mg/day recipients) and microscopic hematuria, with these effects generally being mild, mostly transient, possibly tubular in origin, and not associated with acute or progressive deterioration in renal function. There was usually no change or a decrease in mean serum creatinine levels from baseline with rosuvastatin 10–40 mg/day treatment for up to 96 weeks. Notably, in controlled clinical trials with rosuvastatin 5–40 mg/day, 0.2–0.4% of patients experienced elevations in serum creatine phosphokinase (CPK) levels of over 10-fold the upper limit of normal, whereas ≤0.1% of recipients experienced treatment-related myopathy (i. e. muscle aches or weakness plus elevated serum CPK levels of over 10-fold the upper limit of normal); these incidences were similar to those reported with other statins. In clinical trials, rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria occurred with rosuvastatin treatment at the higher-than-recommended 80mg dose. Overall, rosuvastatin 10–40 mg/day had a similar tolerability profile to that of atorvastatin 10–80 mg/day, simvastatin 10–80 mg/day, or pravastatin 10–40 mg/day in controlled clinical trials (nature and incidence of adverse events not reported), with 2.9%, 3.2%, 2.5%, and 2.5% of recipients, respectively, discontinuing treatment because of a treatment-related adverse event. As with rosuvastatin 10 or 20 mg/day, less than 1% of patients experienced a positive dipstick test for proteinuria at the final visit with atorvastatin 10–80 mg/day, simvastatin 10–80 mg/day, and pravastatin 10–40 mg/day, with a numerically higher incidence (<1.5%) in those receiving rosuvastatin 40 mg/day. In addition, rare cases (0.2% of patients) of clinically relevant elevations in serum ALT levels have occurred with rosuvastatin ≤80 mg/day, atorvastatin ≤80 mg/day, simvastatin ≤80 mg/ day, or pravastatin ≤40 mg/day. Rosuvastatin (40 mg/day) was as well tolerated as niacin ER (2 g/day) monotherapy in patients with mixed dyslipidemia, with numerically fewer rosuvastatin (n = 46) than niacin ER recipients (n = 72) experiencing treatment-related adverse events (28.3% vs 59.7%). The most common treatment-related adverse events in the rosuvastatin and niacin ER monotherapy groups were flushing (0% vs 43.1%), pruritus (0% vs 13.9%), rash (0% vs 6.9%), paresthesia (0% vs 2.8%), and myalgia (6.5% vs 1.4%). Limited data also indicate that rosuvastatin (5 or 10 mg/day) plus fenofibrate (201 mg/day) combination therapy was as well tolerated as treatment with the same dosages of the individual agents in a 24-week study.

Dosage and Administration

Rosuvastatin is indicated for the treatment of patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson type IIa and IIb) as an adjunct to diet. The recommended dosage is 5–40mg once daily. Rosuvastatin 40 mg/day should only be administered to patients unable to achieve LDL-C goals with 20 mg/day. The drug may be taken without regard to food, with the dosage individualized based on the patient’s response, LDL-C goal, presence of other comorbid conditions, and/or whether the individual is receiving concomitantly administered drugs. Rosuvastatin is also indicated in patients with elevated triglyceride levels (Fredrickson type IV) as an adjunct to diet (recommended dosages not reported in US prescribing information), and in those with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments such as LDL apheresis. Rosuvastatin should be prescribed with caution in patients with predisposing factors for myopathy. Liver function tests should be performed before treatment commences and at key timepoints throughout the treatment. Dosage reduction should be considered for those receiving rosuvastatin 40 mg/day with persistent unexplained proteinuria. Rosuvastatin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases, and in pregnant women and breastfeeding mothers.     

The DISCOVERY PENTA study: a DIrect Statin COmparison of LDL-C Value--an Evaluation of Rosuvastatin therapY compared with atorvastatin

BACKGROUND: International guidelines emphasize the need to achieve recommended low-density lipoprotein cholesterol (LDL-C) levels in order to reduce morbidity and mortality associated with coronary heart disease (CHD). However, many patients with hypercholesterolemia fail to achieve LDL-C goals on treatment. OBJECTIVE: The primary objective was to compare the efficacy of rosuvastatin and atorvastatin for enabling patients to achieve National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL-C goals. Secondary objectives were European LDL-C goal achievement, changes in the lipid profile, and safety. RESEARCH DESIGN AND METHODS: This 12-week, multicenter, multinational, randomized, open-label trial compared the efficacy and safety of rosuvastatin 10 mg with atorvastatin 10 mg in statin-na?ve and switched patients with primary hypercholesterolemia from Brazil, Colombia, Mexico, Portugal, and Venezuela. RESULTS: A total of 1124 patients with similar baseline characteristics were randomized to the two treatment groups. After 12 weeks of treatment, a significantly greater percentage of patients receiving rosuvastatin 10 mg compared with atorvastatin 10 mg achieved NCEP ATP III LDL-C goals (71.2% vs 61.4%, p < 0.001), 1998 European LDL-C goals (73.5% vs 59.2%, p < 0.001) and 2003 European LDL-C goals (58.9% vs 44.6%, p < 0.001). Rosuvastatin treatment was associated with significant reductions in LDL-C and total cholesterol (TC) and, in statin-na?ve patients, a significant increase in high-density lipoprotein cholesterol (HDL-C) compared with atorvastatin treatment. Both treatments were well tolerated with a similar incidence of adverse events. Clinically significant elevations in creatinine, creatine kinase or hepatic transaminases were low and similar between treatment groups. CONCLUSIONS: Rosuvastatin 10 mg is significantly more effective at achieving NCEP ATP III and European LDL-C goals, lowering LDL-C and TC in both na?ve and switched patients and increasing HDL-C in na?ve patients than atorvastatin 10mg, with a similar safety and tolerability profile. This study also provides evidence regarding the comparative effects of rosuvastatin versus atorvastatin in Latin American and Portuguese populations.     

Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin in achieving lipid goals: results from the STELLAR trial

In the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial, the efficacy of rosuvastatin calcium (Crestor) was compared with that of atorvastatin (Lipitor), simvastatin (Zocor), and pravastatin (Pravachol) for lowering plasma low-density lipoprotein cholesterol (LDL-C) after 6 weeks of treatment. In this multicenter, parallel-group, open-label trial, adults with hypercholesterolemia were randomized to treatments with rosuvastatin 10, 20, 40, or 80 mg, atorvastatin 10, 20, 40, or 80 mg, simvastatin 10, 20, 40, or 80 mg, or pravastatin 10, 20, or 40 mg. Efficacy and safety results from this trial have been previously published. The additional analyses included in this report show that 53% (83/156) to 80% (125/157) of patients in the rosuvastatin 10- to 40-mg groups achieved LDL-C levels < 100 mg/dl (< 2.6 mmol/l), compared with 18% (28/158) to 70% (115/165) of patients who received atorvastatin, 8% (13/165) to 53% (86/163) of patients who received simvastatin, and 1% (1/160) to 8% (13/161) of patients who received pravastatin. Other additional analyses showed that more patients in the rosuvastatin 10- to 40-mg groups than in the comparator groups who were at high risk of coronary heart disease according to National Cholesterol Education Program Adult Treatment Panel (ATP) III, Joint European Societies, or Canadian guidelines achieved the LDL-C goals of < 100 mg/dl (< 2.6 mmol/l) (55% to 77% compared with 0 to 64%), < 3.0 mmol/l (< 116 mg/dl) (76% to 94% compared with 6% to 81%), and < 2.5 mmol/l (< 97 mg/dl) (47% to 69% compared with 0 to 53%), respectively. Results favoring rosuvastatin versus the comparators were also reported for patients: (a) who had triglycerides > or = 200mg/dl (> or = 2.3 mmol/l), and achieved both ATP III LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) goals (80% to 84% versus 15% to 84%); (b) overall who achieved the Canadian LDL-C goals of < 2.5 (< 97 mg/dl) to < 5.0 mmol/l (< 193 mg/dl) (85% to 91% versus 44% to 86%); and (c) who achieved all 3 Canadian goals for LDL-C, triglycerides (< 3.0 mmol/l [< 266 mg/dl] to < 2.0 mmol/l [< 177 mg/dl]), and the total cholesterol/high-density lipoproteincholesterol ratio (< 4 to < 7) (70% to 83% versus 35% to 79%).     

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.     

Effects of Low-Dose Atorvastatin and Rosuvastatin on Plasma Lipid Profiles

BACKGROUND AND OBJECTIVE: Despite the favorable effects of reduction of low-density lipoprotein-cholesterol (LDL-C) levels in decreasing the risk of coronary heart disease, many patients treated with lipid-lowering HMG-CoA reductase inhibitors (statins) do not achieve goal LDL-C levels. This may be due to high doses of statins prescribed that could potentially induce adverse effects and compromise patient safety and compliance with considerable expense in the long-term. We compared the actions of rosuvastatin and atorvastatin, administered at the low dosages of 10 and 20 mg/day, respectively, in reducing plasma LDL-C levels and their effects on other components of the atherogenic lipid profile in patients with primary hypercholesterolemia. METHODS: In this randomized, parallel group, open-label clinical study, 106 patients with LDL-C >200 mg/dL were treated with rosuvastatin 10 mg/day (group A; n = 52), or atorvastatin 20 mg/day (group B; n = 54) for 48 weeks. RESULTS: At 48 weeks, rosuvastatin 10 mg/day was associated with a significantly greater reduction in plasma LDL-C levels compared with atorvastatin 20 mg/day (-44.32% vs -30%; p < 0.005). Compared with atorvastatin, rosuvastatin also produced a greater reduction in plasma total cholesterol, triglycerides, and non-high-density lipoprotein-cholesterol (non-HDL-C) levels (p < 0.005). Plasma HDL-C levels were not affected significantly, independent of the drug used. CONCLUSION: In high-risk patients with primary hypercholesterolemia, rosuvastatin 10 mg/day was more efficacious than atorvastatin 20 mg/day in reducing plasma LDL-C levels, enabling goal LDL-C levels to be achieved and improving other lipid parameters. Both treatments were well tolerated over 48 weeks.     

瑞舒伐他汀钙治疗原发性高胆固醇血症的有效性和安全性II期临床试验

目的:评价不同起始剂量的瑞舒伐他汀钙治疗原发性高胆固醇血症患者的有效性和安全性.方法:采用多中心、随机、双盲、双模拟、阳性药平行对照临床试验设计,经4周安慰剂导入和饮食控制期后筛选出符合入选条件的患者进入为期8周的不同起始剂量的药物(分别给予瑞舒伐他汀钙5或10 mg、或阿托伐他汀钙10 mg)治疗期.治疗至第4周末时,如患者的低密度脂蛋白胆固醇(LDL-C)≥3.12 mmol/L(120 mg/dl),则所服药物剂量加倍.结果:治疗8周后,各组LDL-C水平均较基线时明显下降(P＜0.05),且瑞舒伐他汀钙10 mg组与阿托伐他汀钙10 mg组间的差异有统计学意义(P＜0.05).以相差5个百分点为非劣效判断标准,发现瑞舒伐他汀钙5和10 mg两组降低LDL-C水平的疗效均不劣于阿托伐他汀钙10 mg组.结论:瑞舒伐他汀钙5和10 mg治疗在中国人群中的降脂疗效与阿托伐他汀10 mg相当,均具有良好的安全性和耐受性.     

Lipid-modifying effects of rosuvastatin in postmenopausal women with hypercholesterolemia who are receiving hormone replacement therapy*

SUMMARY

Objective: To evaluate the efficacy and safety of rosuvastatin in postmenopausal women with hypercholesterolemia who are receiving hormone replacement therapy (HRT) in a randomized, double-blind, placebo-controlled trial.

Methods: After a 6-week dietary lead-in period, 135 postmenopausal women who had been taking a stable HRT regimen for at least 3 months were randomized to receive rosuvastatin 5?mg, 10?mg or placebo for 12 weeks. Fasting levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) were assessed at weeks 0, 2, 6, 10, and 12; apolipoprotein (Apo) B and Apo A-I were measured at weeks 0 and 12.

Results: Rosuvastatin 5?mg and 10?mg significantly reduced LDL-C by 38% (SE = 2.1) and 49% (SE = 2.1), respectively, compared with placebo (1% [SE = 2.1]; p < 0.001). TC, TG, Apo B, and all lipid ratios examined (LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C, and Apo B/Apo A-I) were also reduced significantly by both rosuvastatin doses (?p < 0.001). HDL-C levels increased significantly in the rosuvastatin groups (11% and 8% for 5?mg and 10?mg, respectively, vs. –0.5% for placebo; p < 0.001), as did Apo A-I levels (?p < 0.05). The combination of rosuvastatin plus HRT was well tolerated with no apparent differences among treatments in the numbers or types of adverse events reported.

Conclusions: Rosuvastatin 5?mg or 10?mg once daily is a well-tolerated and highly efficacious lipid-lowering therapy in postmenopausal women receiving HRT.     

瑞舒伐他汀对急性冠状动脉综合征伴高脂血症患者血脂及炎性因子的影响

目的 观察瑞舒伐他汀治疗急性冠状动脉综合征(ACS)伴高脂血症的I临床疗效及安全性.方法 2010年9月至2011年1月就诊于北京安贞医院心内科的ACS伴高脂血症患者90例,完全随机分为辛伐他汀组(药物使用量:10 mg/d,n=42)和瑞舒伐他汀组(药物使用量:10 mg/d,n=48),疗程均为1周,观察治疗前后各项主要血脂指标变化率、达标率及血清肿瘤坏死因子仪(TNF-a)及C反应蛋白(CRP)变化.结果 在降低TC、LDL-C、脂蛋白(Lp)(a)及升高HDL-C方面,瑞舒伐他汀组优于辛伐他汀组[TC:瑞舒伐他汀组治疗后(4.80±0.36)mmol/L、治疗前(6.80±0.27)mmol/L、变化率-29%,辛伐他汀组分别为(5.50±0.19)mmoL/L、(6.90±0.21)mmol/L、-21%;LDL-C:瑞舒伐他汀组治疗后(2.00±0.26)mmol/L、治疗前(4.50±0.10)mmol/L、变化率-56%,辛伐他汀组(3.30±0.27)mmol/L、(4.00±0.21)mmol/L、-18%;Lp(a):瑞舒伐他汀组治疗后(72±15)mmol/L、治疗前(115±21)mmol/L、变化率一37%,辛伐他汀组(101±24)mmol/L、(108±21)mmoL/L、-6%;HDL-C:瑞舒伐他汀组治疗后(0.98±0.05)mmol/L、治疗前(0.72±0.04)mmol/L、变化率+36%,辛伐他汀组(0.90±0.02)mmol/L、(0.80±0.05)mmoL/L、+13%].2组对肝、肾功能的影响差异无统计学意义.舒伐他汀治疗组降低炎症标志物TNF-a和CRP水平强于辛伐他汀组[TNF-a:瑞舒伐他汀组治疗后(62+20)U/ml、治疗前(90±10)U/ml、变化率-31%,辛伐他汀组分别为(71±15)U/ml、(86±13)U/ml、-17%;CRP:瑞舒伐他汀组治疗后(2.7+1.6)mg/L、治疗前(4.8±1.8)mg/L、变化率-44%,辛伐他汀组(4.0±1.3)ms/L、(5.2±1.5)ms/L、-23%].2组患者治疗期间未出现明显的、难以耐受的不良反应.结论 瑞舒伐他汀(10 mg/d)可以更全面地调理ACS伴混合性高脂血症患者的血脂异常,尤其是在升高HDL-C、降低LDL-C方面,并具有良好的安全性.瑞舒伐他汀具有较强抗炎作用.

Abstract：

Objective To investigate the effects and the safety of rosuvastiatin in actute coronary syndrome (ACS)complicated with hyperlipidemia.Methods Ninety patients with hyperlipidernia were randomly assigned into simvastatin group (n=42) and rosuvastatin group(n=48).They were treated with simvasmtin and rosuvastatin respeetively 10 mg/d and 10 mg/d for 1 week.Lipid profile and physical laboratory investigations for adverse effects were also assessed.Serum levels of total cholesterol (TC),triglyceride (TG),low density lipoprotein cholesterol (LDL-C),high density lipoprotein cholesterol(HDL-C)and Lp(a)were measured at the end of 1 weeks of the trial period. Results Rosuvastatin treatment was more effective than simvastatin in reducing serunl levels of TC,LDL-C and Lp(a)and in raising HDL-C.The difference of liver and kidney function of 2 groups was not statistically significant.The abilities of atorvastatin treatment group in decreasing inflammatory markers in TNF-a and CRP levels were stronger than those in the simvastatin group.Conclusion Rosuvastatin has full-scale lipid-regulating effects,especially in reducing serum levels of TC,LDL-C and Lp(a) and in raising HDL-C.     

瑞舒伐他汀对急性心肌梗死患者血清炎症因子和脂联素水平的影响

目的比较瑞舒伐他汀与阿托伐他汀对急性心肌梗死（AMI）患者的血清胆固醇（TC）、低密度脂蛋白（LDL-C）、高敏c反应蛋白（hs-CRP）、可溶性白细胞分化抗原40配体（sCD40L）和脂联素（APN）水平的影响。方法选择54例AMI患者,随机分为瑞舒伐他汀组（瑞舒伐他汀10～20mg,qd,28例）和阿托伐他汀组（阿托伐他汀20-40mg,qa,26例）,分别检测治疗前及治疗4周后2组患者TC、LDL-C、hs—CRP、sCD40L和APN水平。结果瑞舒伐他汀组和阿托伐他汀组治疗后血清,TC、LDL-C、hs-CRP、sCD40L水平较治疗前明显降低,APN水平明显升高,差异有统计学意义（P〈0．05）。治疗4周后瑞舒伐他汀组血清hs-CRP、sCD40L水平与阿托伐他汀组相比明显降低,APN水平明显升高,差异有统计学意义（P〈0．05）。结论瑞舒伐他汀和阿托伐他汀都能降低TC、LDL-C、sCD40L、hs—CRP水平,升高APN水平,但瑞舒伐他汀治疗急性心肌梗死的效果明显优于阿托伐他汀。     

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

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.     

The Cost Effectiveness of Statin Therapies in Spain in 2010, after the Introduction of Generics and Reference Prices

Background

HMG-CoA reductase inhibitors (statins) are the first-line drugs for use in the reduction of low-density lipoprotein cholesterol (LDL-C) levels and prevention of coronary heart disease (CHD) in patients with hypercholesterolemia. Generic statins could change the cost effectiveness of statin therapies in Spain, and more population groups could be included in the recommendations for reduction of cholesterol levels based on cost effectiveness.

Objectives

The objectives of this study were: (i) to assess the cost effectiveness of available statins for the reduction of LDL-C levels in Spain in 2010, after the introduction of generics and reference prices; (ii) to assess the cost effectiveness of combination therapy using a statin plus cholestyramine or ezetimibe; and (iii) to estimate the mean cost per patient to achieve National Cholesterol Education Program (Adult Treatment Panel-III) therapeutic objectives.

Methods

The following treatments were evaluated: rosuvastatin 5–20mg/day; atorvastatin, simvastatin, and pravastatin 10–40mg/day; lovastatin and fluvastatin 20–80mg/day; and combination therapy with a statin plus either cholestyramine 12–24g/day or ezetimibe 10mg/day. The cost effectiveness was evaluated in terms of cost per percentage point reduction in LDL-C, comparing the annual treatment costs with the effectiveness in reducing LDL-C. Treatment costs included those for medications (2010 wholesale prices), control measures, and treatment of adverse drug effects. The effectiveness of statins was estimated by developing a meta-analysis of clinical trials published between 1993 and 2005 that met several inclusion criteria. Average and incremental cost-effectiveness ratios were calculated to assess the efficiency of individual statin and combination therapies in reducing LDL-C levels.

Results

The effectiveness in terms of percentage reduction in LDL-C ranged from 19% for pravastatin 10mg/day to 55% for atorvastatin 80mg/day. Annual treatment costs ranged from €189.7 for simvastatin 10mg/day to €759.3 for atorvastatin 80mg/day. The cost-effectiveness ratios, in terms of cost per percentage point reduction in LDL-C, were: €6 for simvastatin, €10–12 for rosuvastatin, €10 for lovastatin, €13–16 for atorvastatin, €13–14 for fluvastatin, and €14–20 for pravastatin. Rosuvastatin + ezetimibe, simvastatin + ezetimibe, and atorvastatin + ezetimibe were the most cost-effective combination therapies for reducing LDL-C levels. Rosuvastatin was the most cost-effective statin for achieving the LDL-C therapeutic goal in patients at high risk for CHD, with a mean cost per patient of €516. Simvastatin was the most cost-effective statin to achieve the LDL-C goal in patients with moderate or low CHD risk, with a cost per patient of €217 and €190, respectively.

Conclusion

Rosuvastatin should be the first-choice agent in patients with high CHD risk, while simvastatin should be the first choice in patients with moderate or low risk. The addition of ezetimibe to rosuvastatin, simvastatin, or atorvastatin should be the preferred combination therapies when greater LDL-C reductions are required. The cost effectiveness of all statin therapies has increased in Spain after the introduction of generic statins and reference prices.     

瑞舒伐他汀钙治疗原发性高胆固醇血症的有效性和安全性Ⅱ期临床试验

目的：评价不同起始剂量的瑞舒伐他汀钙治疗原发性高胆固醇血症患者的有效性和安全性。方法：采用多中心、随机、双盲、双模拟、阳性药平行对照临床试验设计,经4周安慰剂导入和饮食控制期后筛选出符合入选条件的患者进入为期8周的不同起始剂量的药物（分别给予瑞舒伐他汀钙5或10mg、或阿托伐他汀钙10mg）治疗期。治疗至第4周末时,如患者的低密度脂蛋白胆固醇（LDL—C）≥3．12mmol／L（120mg／d1）,则所服药物剂量加倍。结果：治疗8周后,各组LDL—C水平均较基线时明显下降（P〈0．05）,且瑞舒伐他汀钙10mg组与阿托伐他汀钙10mg组间的差异有统计学意义（P〈0．05）。以相差5个百分点为非劣效判断标准,发现瑞舒伐他汀钙5和10mg两组降低LDL—C水平的疗效均不劣于阿托伐他汀钙10mg组。结论：瑞舒伐他汀钙5和10mg治疗在中国人群中的降脂疗效与阿托伐他汀10mg相当,均具有良好的安全性和耐受性。     

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.     

Fenofibric Acid

? Fenofibric acid activates peroxisome proliferator-activated receptor α to modify fatty acid and lipid metabolism. Fenofibric acid is the first member of the fibric acid derivatives (fibrates) class approved for use as combination therapy with HMG-CoA reductase inhibitors (statins). ? In three randomized, double-blind, multicenter, phase III trials in adult patients with mixed dyslipidemia, up to 12 weeks’ treatment with once-daily fenofibric acid 135 mg plus a low- or moderate-dose statin (atorvastatin 20 or 40 mg, rosuvastatin 10 or 20 mg, or simvastatin 20 or 40 mg) improved high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels to a significantly greater extent than statin monotherapy, and improved low-density lipoprotein cholesterol (LDL-C) levels to a significantly greater extent than fenofibric acid monotherapy. ? In a 52-week, open-label, multicenter, extension study, HDL-C, TG, and LDL-C levels continued to improve, or were maintained, during combination therapy with once-daily fenofibric acid 135 mg plus a moderate-dose statin (atorvastatin 40 mg, rosuvastatin 20 mg, or simvastatin 40 mg). ? Once-daily fenofibric acid 135 mg plus a statin was generally as well tolerated as monotherapy with fenofibric acid 135 mg/day or the corresponding statin dosage in the three phase III trials in patients with mixed dyslipidemia. The incidence of adverse events was similar between the combination therapy group and both monotherapy groups. ? In the extension trial, once-daily fenofibric acid 135 mg plus a moderate-dose statin (atorvastatin 40 mg, rosuvastatin 20 mg, or simvastatin 40 mg) for up to 52 weeks was generally well tolerated.     

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.