Efficacy and Safety of Fenofibric Acid Co-Administered with Low- or Moderate-Dose Statin in Patients with Mixed Dyslipidemia and Type 2 Diabetes Mellitus

Background

Monotherapy with lipid-modifying medication is frequently insufficient to normalize lipid abnormalities in patients with mixed dyslipidemia and type 2 diabetes mellitus.

Objective

To evaluate the efficacy and safety of fenofibric acid + statin combination therapy in this population.

Study Design

A pooled, subgroup analysis of three randomized, controlled, double-blind, 12-week trials.

Setting

Multiple clinical research facilities in the US and Canada.

Patients

Patients with mixed dyslipidemia and type 2 diabetes (n= 586).

Intervention

Fenofibric acid (Trilipix®) 135 mg monotherapy; low-, moderate-, or high-dose statin monotherapy (rosuvastatin [Crestor®] 10, 20, or 40 mg; simvastatin [Zocor®] 20, 40, or 80 mg; or atorvastatin [Lipitor®] 20, 40, or 80 mg); or fenofibric acid + low- or moderate-dose statin.

Main Outcome Measure

Mean percentage changes in lipid parameters, percentages of patients achieving optimal serum lipid/apolipoprotein levels, and incidence of adverse events.

Results

Fenofibric acid + low-dose statin resulted in significantly (p<0.001) greater mean percentage changes in high-density lipoprotein cholesterol (HDL-C) [16.8%] and triglycerides (?43.9%) than low-dose statin monotherapy (4.7% and ?18.1%, respectively) and significantly (p<0.001) greater reductions in lowdensity lipoprotein cholesterol (LDL-C) [?34.0%] than fenofibric acid monotherapy (?5.3%). Similarly, fenofibric acid + moderate-dose statin resulted in significantly (p≤0.011) greater mean percentage changes in HDL-C (16.3%) and triglycerides (?43.4%) than moderate-dose statin monotherapy (8.7% and ?24.2%, respectively) and significantly (p<0.001) greater reductions in LDL-C (?32.6%) than fenofibric acid monotherapy (?5.3%). Compared with low- or moderate-dose statin, fenofibric acid + low- or moderate-dose statin resulted in over 5-fold higher percentages of patients achieving optimal levels of LDL-C, non-HDL-C, apolipoprotein B, HDL-C, and triglycerides simultaneously. Incidence of adverse events was generally similar among treatments.

Conclusion

Fenofibric acid + statin combination therapy in patients with mixed dyslipidemia and type 2 diabetes was well tolerated and resulted in more comprehensive improvement in the lipid/apolipoprotein profile than either monotherapy.     

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.     

One-Year Efficacy and Safety of Rosuvastatin + Fenofibric Acid Combination Therapy in Patients with Mixed Dyslipidemia

Background

Statins are the standard-of-care therapy for reducing low-density lipoprotein cholesterol (LDL-C) levels; however, combination with other lipid-modifying agents may be necessary to normalize lipid profiles in patients with mixed dyslipidemia who, in addition to high LDL-C, also have high triglycerides (TG) and low levels of high-density lipoprotein cholesterol (HDL-C).

Objective

This study aimed to evaluate the 1-year efficacy and safety of rosuvastatin in combination with fenofibric acid in a subgroup of patients treated for 12 weeks with rosuvastatin 10 mg+ fenofibric acid 135 mg and subsequently treated for up to 52 weeks with rosuvastatin 20 mg+ fenofibric acid 135 mg.

Methods

The efficacy and safety of combination therapy with rosuvastatin + fenofibric acid were demonstrated in a 12-week controlled study (NCT00300482) of patients with mixed dyslipidemia who were randomized to rosuvastatin 10, 20, or 40 mg, fenofibric acid 135 mg, or rosuvastatin 10 or 20 mg+ fenofibric acid 135 mg. All patients who completed the controlled study were eligible to enroll in a subsequent 52-week open-label extension study (NCT00300430) and received rosuvastatin 20 mg+ fenofibric acid 135 mg. The present post hoc analysis evaluated patients who were treated with rosuvastatin 10 mg+ fenofibric acid 135 mg in the controlled study and received rosuvastatin 20 mg+ fenofibric acid 135 mg in the open-label extension study. The study was carried out at investigative sites in the US (including Puerto Rico) and Canada. Patients included in the study were men and women ≥18 years of age with mixed dyslipidemia, defined as TG ≥150 mg/dL, LDL-C ≥130 mg/dL, and HDL-C <40/50 mg/dL for men/women (at screening in the controlled trial). Efficacy variables included mean percentage changes in LDL-C, HDL-C, non-HDL-C, and apolipoprotein B (ApoB), and median percentage changes in TG and high-sensitivity C-reactive protein (hsCRP) from baseline (i.e. start of the open-label extension after 12 weeks of treatment with rosuvastatin 10 mg+ fenofibric acid 135 mg) to incremental time points up to 52 weeks in the extension study, and the proportion of patients achieving individual and combined goals for LDL-C and non-HDL-C. Adverse events (AEs) and clinical laboratory values were also assessed.

Results

Of the 261 patients initially randomized to rosuvastatin 10 mg+ fenofibric acid 135 mg, 220 completed the controlled study and 187 continued treatment with rosuvastatin 20 mg+ fenofibric acid 135 mg in the extension study. Increasing the rosuvastatin dose from 10 mg to 20 mg in combination with fenofibric acid 135 mg for up to 52 weeks resulted in significant (p≤ 0.005 for all comparisons) mean percentage changes from baseline in LDL-C (?9.5%), non-HDL-C (?6.0%), ApoB (?8.5%), and HDL-C (3.6%), while median TG levels remained largely unchanged (0.8%, p = 0.055) at the week 52 visit. Greater percentages of patients achieved their risk-stratified lipid goals at week 52 compared with baseline for LDL-C (89% vs 84%), non-HDL-C (50% vs 25%), and both LDL-C and non-HDL-C (50% vs 19%). Combination therapy was generally well tolerated. The incidence of muscle-, hepatic-, and renal-related AEs and laboratory values were within the expected range.

Conclusion

This study demonstrates that 1-year therapy with rosuvastatin + fenofibric acid is well tolerated and that increasing the rosuvastatin dose from 10 mg to 20 mg in the combination results in additional beneficial effects on key lipid parameters in patients with mixed dyslipidemia.

Clinical Trial Registration

Clinicaltrials.gov identifiers NCT00300482 and NCT00300430.     

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.     

The role of a new formulation of fenofibric acid in the treatment of mixed dyslipidemia in type 2 diabetes

Diabetes, due to its multifactorial effects, increases the risk of developing cardiovascular disease. Dyslipidemia is an important modifiable risk factor. Mixed dyslipidemia (low high-density lipoprotein cholesterol [HDL-C], elevated triglycerides and a high percentage of small, dense lowdensity lipoprotein cholesterol [LDL-C]) is a common lipid disorder in diabetics and is considered especially atherogenic. Research suggests that in patients with dyslipidemia, combination therapy with fibrates and statins may be more effective than statin monotherapy alone. The choline salt of fenofibric acid (choline fibrate) is indicated for the treatment of mixed dyslipidemia, either as a single treatment or in combination with statin therapy. It does not require first-pass metabolism, but dissociates in the gastrointestinal tract into the pharmacologically active fenofibric acid. This new formulation of fenofibric acid in combination with a low or moderate dose of statin has been shown to be effective in increasing HDL-C and lowering triglycerides beyond that provided by statin monotherapy alone. The ACCORD trial failed to show a mortality or morbidity benefit after combination therapy, although the data suggested that combination therapy may benefit patients with mixed dyslipidemia.     

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.     

Efficacy and safety of coadministration of ezetimibe and statins in elderly patients with primary hypercholesterolaemia

OBJECTIVE: To compare the efficacy and safety of statin (HMG-CoA reductase inhibitor) monotherapy versus ezetimibe 10mg plus statin in older and younger adults with primary hypercholesterolaemia. PATIENTS AND METHODS: Four multicentre, randomised, double-blind, placebo-controlled, balanced parallel-group trials were pooled for analysis. After washout and placebo run-in period, men and women >/=18 years of age (n = 1861) with primary hypercholesterolaemia (plasma low-density lipoprotein-cholesterol [LDL-C] level from >/=3.76 to /=65 years; age <75 versus >/=75 years. RESULTS: Across age groupings, coadministration of ezetimibe and statin produced significant incremental reductions in LDL-C compared with statin monotherapy. The beneficial effects of ezetimibe plus statin on LDL-C, triglycerides and high-density lipoprotein-cholesterol (HDL-C) were overall independent of age groupings. Ezetimibe plus statin therapy was generally well tolerated, with similar incidence of adverse events, serious adverse events and changes in liver function and muscle enzymes in the given age groups compared with statin therapy alone. CONCLUSION: The beneficial effects of ezetimibe coadministered with statins on LDL-C, triglycerides and HDL-C were similar between older and younger hypercholesterolaemic patients, with a favourable safety profile across all patient age groups.     

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.     

Combination of a sterol absorption inhibitor and cardiovascular agents for the treatment of dyslipidemia

Although statins are effective in reducing cardiovascular risk, combination therapy may be required to meet recommended target LDL-C levels. However, the utility of current combination therapies with niacin or bile acid sequestrants is limited by side effects and compliance. Ezetimibe, as a selective cholesterol absorption inhibitor, represent a new class of pharmaceutical agents. The combination of ezetimibe with statins has shown a 16-21% increase in the percentage of patients achieving their ATP III LDL-C goal. Randomized, double-blind studies have shown that coadministration of ezetimibe with simvastatin is well tolerated, causing dose-dependent reduction in LDL-C and total cholesterol levels, with no apparent effect on high-density lipoprotein cholesterol or triglycerides. Even in diabetes mellitus type 2 patients; the addition of ezetimibe 10 mg to simvastatin 20 mg is more efficacious than doubling the dose of simvastatin in lowering lipid parameters. Similarly the coadministration of ezetimibe and rosuvastatin, has shown a mean incremental reduction in LDL-C of -16%, compared with rosuvastatin alone, while there was no apparent effect on HDL-C or triglycerides. Ezetimibe and fenofibrate co-administration has shown also improvement in the lipid/lipoprotein profile. The combination therapy with ezetimibe and statin or fibrate may be an effective therapeutic option for patients with dyslipidemia.     

Comparison of efficacy,safety, and cost-effectiveness of various statins in dyslipidemic diabetic patients

Background and Aim:

To determine efficacy safety and the cost effectiveness, of the four most commonly prescribed statins (rosuvastatin, atorvastatin, pravastatin, and simvastatin) in the treatment of dyslipidemia among diabetic patients.

Materials and Methods:

This is a cohort, observational, population-based study conducted at diabetic clinics of the Hamad Medical Hospital and Primary Health Care Centers (PHCC) over a period from January 2007 to September 2012. The study included 1,542 consecutive diabetes patients above 18 years of age diagnosed with dyslipidemia and prescribed any of the indicated statins. Laboratory investigations were taken from the Electronic Medical Records Database (EMR-viewer). The sociodemographic, height, weight, and physical activities were collected from Patient''s Medical Records. Information about statin was extracted from the pharmacy drug database. The effective reductions in total cholesterol using rosuvastatin with atorvastatin, simvastatin, and pravastatin in achieving cholesterol goals and improving plasma lipids in dyslipidemic diabetic patients were measured. Serum lipid levels measured a 1 week before the treatment and at the end 2^nd year.

Results:

Rosuvastatin (10 mg) was the most effective in reducing low-density lipoprotein cholesterol (LDL-C; 28.59%), followed by simvastatin 20 mg (16.7%), atorvastatin 20 mg (15.9%), and pravastatin 20 mg (11.59.3%). All statins were safe with respect to muscular and hepatic functions. Atorvastatin was the safest statin as it resulted in the least number of patients with microalbuminuria (10.92%) as compared to other statins. Treatment with rosuvastatin 10 mg was more effective in allowing patients to reach European and Adult Treatment Plan (ATP) III LDL-C goals as compared to other statins (P < 0.0001) and produced greater reductions in LDL-C, total cholesterol, and non-HDL-C, produced similar or greater reductions in triglycerides (TGs) and increased in HDL-C.

Conclusion:

Rosuvastatin 10 mg was the most effective statin in reducing serum lipids and total cholesterol in dyslipidemic diabetic patients.KEY WORDS: Atorvastatin, cost effective, dyslipidemic diabetic patients, efficacy, pravastatin, rosuvastatin, safety of statin use in dyslipidemic diabetic patients, safety, simvastatin     

基于层次分析法合理选择他汀类药物

目的基于最高的性价比选择他汀类药物。方法在调脂强度达标的范围内,基于层次分析法构建评价指标体系,确定减低LDL-C强度和价格为评价指标,设计问卷调查表确定个体化的评价指标权重,使用matlab软件进行矩阵计算,根据结果选择最适合患者长期治疗的性价比最高的他汀类药物。结果根据患者调脂目标及经济能力合理选择他汀,如更关注药物的调脂强度,则依次选择阿托伐他汀40mg,瑞舒伐他汀10mg,阿托伐他汀20mg,辛伐他汀20mg,阿托伐他汀10mg,辛伐他汀40mg,氟伐他汀80mg,普伐他汀80mg及普伐他汀40mg。如更加关注价格,依次选择辛伐他汀20mg,阿托伐他汀10mg,氟伐他汀80mg,辛伐他汀40mg,瑞舒伐他汀10mg,阿托伐他汀20mg,普伐他汀40mg,阿托伐他汀40mg及普伐他汀80mg。如药物的调脂强度和价格同等重要,则依次选择辛伐他汀20mg,阿托伐他汀10mg,氟伐他汀80mg,辛伐他汀40mg,瑞舒伐他汀10mg,阿托伐他汀20mg,阿托伐他汀40mg,普伐他汀40mg及普伐他汀80mg。结论在调脂强度达标的范围内,可以通过层次分析法获得最适合患者的性价比最高的他汀类药物。     

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

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. METHODS: Patients aged 40-80 years with established cardiovascular disease and HDL-C < 1.0 mmol/L (< 40 mg/dL) entered as 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 rosucastatin, 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/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.     

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.     

ABT-335, the choline salt of fenofibric acid, does not have a clinically significant pharmacokinetic interaction with rosuvastatin in humans

ABT-335 is the choline salt of fenofibric acid under clinical development as a combination therapy with rosuvastatin for the management of dyslipidemia. ABT-335 and rosuvastatin have different mechanisms of actions and exert complementary pharmacodynamic effects on lipids. The current study assessed the pharmacokinetic interaction between the 2 drugs following a multiple-dose, open-label, 3-period, randomized, crossover design. Eighteen healthy men and women received 40 mg rosuvastatin alone, 135 mg ABT-335 alone, and the 2 drugs in combination once daily for 10 days. Blood samples were collected prior to dosing on multiple days and up to 120 hours after day 10 dosing for the measurements of fenofibric acid and rosuvastatin plasma concentrations. Coadministering 40 mg rosuvastatin had no significant effect on the steady-state Cmax, Cmin, or AUC24 of fenofibric acid (P > .05). Coadministering ABT-335 had no significant effect on the steady-state Cmin or AUC24 of rosuvastatin (P > .05) but increased Cmax by 20% (90% confidence interval: 12%-28%). All 3 regimens were generally well tolerated with no clinically significant changes in clinical laboratory values, vital signs, or electrocardiograms during the study. Results from this study demonstrate no clinically significant pharmacokinetic interaction between ABT-335 at the full clinical dose and rosuvastatin at the highest approved dose.     

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.     

Atorvastatin Plus Pravastatin for the Treatment of Heterozygous Familial Hypercholesterolaemia -A Pilot Study

Summary

The most common side-effect of statins, mainly during dose titration, is liver toxicity. In these cases, sufficient control of low density lipoprotein cholesterol (LDL-C) in patients with heterozygous familial hypercholesterolaemia (HFH) becomes problematical. In patients with intolerance to resins as well, especially in the presence of coronary artery disease (CAD), it is practically impossible to reach the LDL-C treatment goal. This study included seven HFH patients with CAD, who presented with alanine amino transferase levels greater than three times the upper normal limit during dose titration of atorvastatin or simvastatin of from 20?mg/day to 40?mg/day. They could not tolerate concomitant cholestyramine administration, and presented with LDL-C levels significantly higher than the treatment goal (100mg/dl; 2.6?mmol/l). In these patients, a combination of two statins with different pharmacokinetics (20?mg/day of atorvastatin plus 40?mg/day of pravastatin) was administered for a mean period of one year. Efficacy was compared with that of monotherapy with each drug alone and with that of 40?mg of torvastatin in 13 patients, who could also not tolerate resin co-administration, and that of 40mg/day of atorvastatin plus 12g of cholestyramine in 30 patients, with similar pretreatment LDL-C levels. No increase in serum transaminases and no symptom or sign of myopathy was recorded during the administration of the combination of the two statins for a mean period of 12 months. The atorvastatin plus pravastatin regimen was more effective than both monotherapies and equally effective with the 40?mg of atorvastatin and the 40?mg of atorvastatin plus 12?g of cholestyramine regimens in reducing LDL-C (59% vs. 57% and 61%, respectively) and triglyceride levels (31% vs. 32% and 28%, respectively), while it also had a better effect on high density lipoprotein cholesterol (13% vs. 7% and 8%). The data suggest that the atorvastatin-pravastatin combination has a highly beneficial effect on all lipid parameters, without causing hepatotoxicity, in HFH patients with CAD who are sensitive to higher doses of statins in monotherapy. These results require confirmation in larger studies.     

Fenofibrate

Fenofibrate is a fibric acid derivative with lipid-modifying effects that are mediated by the activation of peroxisome proliferator-activated receptor-α. Fenofibrate also has a number of nonlipid, pleiotropic effects (e.g. reducing levels of fibrinogen, C-reactive protein, and various pro-inflammatory markers, and improving flow-mediated dilatation) that may contribute to its clinical efficacy, particularly in terms of improving microvascular outcomes. The beneficial effects of fenofibrate on the lipid profile have been shown in a number of randomized controlled trials. In primary dyslipidemia, fenofibrate monotherapy consistently decreased triglyceride (TG) levels to a significantly greater extent than placebo; significantly greater increases in high-density lipoprotein cholesterol (HDL-C) levels and significantly greater reductions in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were also seen in some trials. Monotherapy with fenofibrate or gemfibrozil had generally similar effects on TG and HDL-C levels, although in one trial, TC and LDL-C levels were reduced to a significantly greater extent with fenofibrate than with gemfibrozil. Fenofibrate monotherapy tended to improve TG and HDL-C levels to a significantly greater extent than statin monotherapy in primary dyslipidemia, whereas statin monotherapy decreased LDL-C and TC levels to a significantly greater extent than fenofibrate monotherapy. Fenofibrate also had a beneficial effect on atherogenic dyslipidemia in patients with the metabolic syndrome or type 2 diabetes mellitus, reducing TG levels, tending to increase HDL-C levels, and promoting a shift to larger low-density lipoprotein particles. In terms of cardiovascular outcomes, fenofibrate did not reduce the risk of coronary heart disease (CHD) events to a greater extent than placebo in patients with type 2 diabetes in the FIELD trial. However, the risk of some nonfatal macrovascular events (e.g. nonfatal myocardial infarction, revascularization) and certain microvascular outcomes (e.g. amputation, first laser therapy for diabetic retinopathy, progression of albuminuria) was reduced to a significantly greater extent with fenofibrate than with placebo. Subgroup analysis revealed a significant reduction in the cardiovascular disease (CVD) event rate among fenofibrate recipients in the subgroup of patients with marked hypertriglyceridemia or marked dyslipidemia at baseline. In the ACCORD Lipid trial, there were no significant differences between patients with type 2 diabetes and a high risk of CVD events who received fenofibrate plus simvastatin and those who received placebo plus simvastatin for any of the primary or secondary cardiovascular outcomes. However, fenofibrate plus simvastatin was of benefit in patients who had markedly high TG levels and markedly low HDL-C levels at baseline. In addition, fenofibrate plus simvastatin slowed the progression of diabetic retinopathy. Fenofibrate is generally well tolerated. Common adverse events included increases in transaminase levels that were usually transient, minor, and asymptomatic, and gastrointestinal signs and symptoms. In conclusion, monotherapy with fenofibrate remains a useful option in patients with dyslipidemia, particularly in atherogenic dyslipidemia characterized by high TG and low HDL-C levels.     

The efficacy of statin monotherapy uptitration versus switching to ezetimibe/simvastatin: results of the EASEGO study

ABSTRACT

Objective: To assess the incremental low-density lipoprotein-cholesterol (LDL-C) lowering efficacy of doubling the statin dose or switching to the ezetimibe/simvastatin 10/20?mg combination tablet (EZE/SIMVA) in patients on simvastatin 20?mg or atorvastatin 10?mg not at LDL-C target < 2.5?mmol/L.

Study design and methods: Patients with documented coronary heart disease (CHD) and/or type 2 diabetes (DM2) with LDL-C ≥ 2.5 and < 5.0?mmol/L despite treatment with atorvastatin 10?mg or simvastatin 20?mg were randomized to (1) double statin dose or (2) switch to ezetimibe/simvastatin 10/20, according to a PROBE study design. LDL-C, lipoprotein subfractions and safety data were assessed during the study.

Results: 119 of 178 (67%) patients in the EZE/SIMVA group and 49 of 189 (26%) in the doubling statin group reached target LDL-C < 2.5?mmol/L. The odds ratio of success for EZE/SIMVA versus doubling statin treatment in reaching the LDL-C target of < 2.5?mmol/L was 5.7 (95% CI: 3.7–9.0, p < 0.0001). A reduction in total cholesterol (TC), total/high density lipoprotein (HDL) cholesterol ratio and apolipoprotein B was observed in both groups, but this reduction was significantly more pronounced in the EZE/SIMVA group as compared with the doubling statin dose group. Treatment was well tolerated and no difference was observed between the two groups with regard to adverse effects.

Conclusions: In CHD/DM2 patients treated with simvastatin or atorvastatin with LDL-C persistently ≥ 2.5?mmol/L, switching to the EZE/SIMVA was more effective in attaining the LDL-C target of < 2.5?mmol/L than doubling the statin dose.