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.     

Perspectives on low-density lipoprotein cholesterol goal achievement

ABSTRACT

Background: Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk of coronary heart disease (CHD). European and US guidelines now recommend lower LDL-C levels, particularly in high-risk patients. Although LDL-C treatment goals to reduce the risk of CHD are clear, many patients do not reach their LDL-C goals.

Objectives: Examine consensus guideline targets for LDL-C lowering in patients at high or very high cardiovascular risk; examine cholesterol goal achievement in clinical practice; evaluate the effectiveness of ezetimibe/statin and other adjunctive lipid-lowering treatments in achieving LDL-C goals; and consider ongoing controversies and the randomized controlled trials that may help to resolve or better illuminate them.

Methods: An English-language PubMed search was conducted to identify prospective randomized controlled trials, open-label studies, and retrospective and observational studies from 2001 (same year that the executive summary of the National Cholesterol Education Program's Adult Treatment Panel III was published) to present for an analysis of the effects of adjunctive therapies on LDL-C lowering and goal attainment in patients at elevated cardiovascular risk.

Results: Elevated LDL-C is the primary target of lipid-lowering therapy; aggressive lowering is of great benefit to those at high risk. Statins are recommended first-line lipid-lowering agents, with a long, well-regarded history of efficacy and safety. Not all patients, however, can achieve recommended LDL-C goals simply using starting doses of statins. For such patients, more intensive therapy utilizing high-dose statins or combination therapy, including statins combined with other lipid-lowering agents, such as ezetimibe, bile acid resins (BARs), or niacin, is warranted. Potential limitations of the present review include possible publication bias and the focus on pharmacotherapy rather than lifestyle modification and the important objective of multiple risk-factor modification to reduce absolute global cardiovascular risk.

Conclusions: With a well-established link between elevated LDL-C and cardiovascular risk, aggressive LDL-C lowering becomes particularly important. Patients needing intensive LDL-C lowering to achieve goals will often require adjunctive treatments, including ezetimibe, BARs, or niacin along with statins. Given both their high mg: mg potency in lowering LDL-C and favorable tolerability and patient acceptance/adherence profile, ezetimibe/statin combination regimens arguably provide the greatest likelihood for patients to reach new, lower LDL-C targets; however, efficacy and safety data of any adjunctive treatment, along with drug costs and patient adherence to treatment (partly related to complexity of the regimen) all need to be considered when determining the optimal regimen to achieve LDL-C goals in individual patients according to their baseline absolute cardiovascular risk, LDL-C level, and consensus LDL-C targets.     

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.     

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.     

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.     

Statins: can the new generation make an impression?

Although large-scale statin trials have demonstrated significant reductions in cardiovascular risk, there are many patients who have a cardiovascular event despite receiving statin therapy. There is increasing evidence that larger reductions in low-density lipoprotein cholesterol (LDL-C) are associated with greater improvements in cardiovascular morbidity and mortality, which highlights the need for more efficacious statins. This article will review the lipid-altering effects of two new statins, rosuvastatin and pitavastatin. Rosuvastatin represents an advance in the pharmacological and clinical properties of other available agents. The large LDL-C reductions observed with rosuvastatin, even at the start dose of 10 mg and in patients switched from other statins to rosuvastatin 10 mg, should help to improve goal attainment, while reducing the need for dose titration. The ability of rosuvastatin to improve other elements of the lipid profile, such as high-density lipoprotein cholesterol (HDL-C), triglycerides and non-HDL-C, may be of utility in patients with diabetes and the metabolic syndrome. Increases in HDL-C, along with the greater efficacy of rosuvastatin for reducing LDL-C and non-HDL-C, may obviate the need for combination therapy. Results of a number of outcome studies with rosuvastatin are expected over the next 5 years, which will contribute to the evidence base for statin therapy and cardiovascular disease prevention.     

Population pharmacodynamic analysis of LDL-cholesterol lowering effects by statins and co-medications based on electronic medical records

Aims

HMG-CoA reductase inhibitors are available for use in low density lipoprotein-cholesterol (LDL-C) lowering therapy. The purposes of this study were to develop a population pharmacodynamic (PPD) model to describe the time course for the LDL-C lowering effects of statins and assess the efficacy of combination therapy based on electronic medical records.

Methods

Patient backgrounds, laboratory tests and prescribed drugs were collected retrospectively from electronic medical records. Patients who received atorvastatin, pitavastatin or rosuvastatin were enrolled. A physiological indirect response model was used to describe the changes observed in LDL-C concentrations. The PPD analysis was performed using nonmem 7.2.0 with the first order conditional estimation method with interaction (FOCE-INTER).

Results

An indirect response I_max model, based on the 2863 LDL-C concentrations of 378 patients, successfully and quantitatively described the time course for the LDL-C lowering effects of three statins. The combination of ezetimibe, a cholesterol absorption inhibitor, decreased the LDL synthesis rate (K_in) by 10.9%. A simulation indicated that the combined treatment of ezetimibe with rosuvastatin (2.5 mg day⁻¹) led to superior clinical responses than those with high doses of rosuvastatin (5.0 mg day⁻¹) monotherapy, even in patients with higher baseline LDL-C concentrations prior to the treatment.

Conclusions

A newly constructed PPD model supported previous evidence for the beneficial effects of ezetimibe combined with rosuvastatin. In addition, the established framework is expected to be applicable to other drugs without pharmacokinetic data in clinical practice.     

Pharmacodynamic interaction between ezetimibe and rosuvastatin

BACKGROUND: Ezetimibe is a lipid-lowering drug indicated for the treatment of hypercholesterolemia as co-administration with HMG-CoA reductase inhibitors (statins) or as monotherapy. The primary objectives of this study were to evaluate the pharmacodynamic effects and safety of the co-administration of ezetimibe and the new statin rosuvastatin. A secondary objective was to examine the potential for a pharmacokinetic interaction between ezetimibe and rosuvastatin. METHODS: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study in healthy hypercholesterolemic subjects (untreated low-density lipoprotein cholesterol [LDL-C] > or = 130 mg/dL [3.37 mmol/L]). After the outpatient screening and NCEP Step I diet stabilization periods, 40 subjects were randomized to one of the 4 following treatments: rosuvastatin 10 mg plus ezetimibe 10 mg (n = 12); rosuvastatin 10 mg plus placebo (matching ezetimibe 10 mg) (n = 12); ezetimibe 10 mg plus placebo (matching ezetimibe 10 mg) (n = 8); or placebo (2 tablets, matching ezetimibe 10 mg) (n = 8). All study treatments were administered once daily in the morning for 14 days as part of a 16-day inpatient confinement period. Fasting serum lipids were assessed pre-dose on days 1 (baseline), 7, and 14 by direct quantitative assay methods. Safety was evaluated by monitoring laboratory tests and recording adverse events. Blood samples were collected for ezetimibe and rosuvastatin pharmacokinetic evaluation prior to the first and last dose and at frequent intervals after the last dose (day 14) of study treatment. Plasma ezetimibe, total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and rosuvastatin concentrations were determined by validated liquid chromatography with tandem mass spectrometric detection (LC-MS/MS) assay methods. RESULTS: All active treatments caused statistically significant (p < or = 0.02) decreases in LDL-C concentration versus placebo from baseline to day 14. The co-administration of ezetimibe and rosuvastatin caused a significantly (p < 0.01) greater reduction in LDL-C and total cholesterol than either drug alone. In this 2-week inpatient study with restricted physical activity there was no apparent effect of any treatment on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The co-administration of ezetimibe and rosuvastatin caused a significantly (p < 0.01) greater percentage reduction in mean LDL-C (-61.4%) than rosuvastatin alone (-44.9%), with a mean incremental reduction of -16.4% (95%CI -26.3 to -6.53). Reported side effects were generally mild, nonspecific, and similar among treatment groups. There were no significant increases or changes in clinical laboratory tests, particularly those assessing muscle and liver function. There was no significant pharmacokinetic drug interaction between ezetimibe and rosuvastatin. CONCLUSIONS: Co-administration of ezetimibe 10 mg with rosuvastatin 10 mg daily caused a significant incremental reduction in LDL-C compared with rosuvastatin alone. Moreover, co-administering ezetimibe and rosuvastatin was well tolerated in patients with hypercholesterolemia.     

Pharmacodynamic interaction between ezetimibe and rosuvastatin

SUMMARY

Background: Ezetimibe is a lipid-lowering drug indicated for the treatment of hypercholesterolemia as co-administration with HMG-CoA reductase inhibitors (statins) or as monotherapy. The primary objectives of this study were to evaluate the pharmacodynamic effects and safety of the co-administration of ezetimibe and the new statin rosuvastatin. A secondary objective was to examine the potential for a pharmacokinetic interaction between ezetimibe and rosuvastatin.

Methods: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study in healthy hypercholesterolemic subjects (untreated low-density lipoprotein cholesterol [LDL-C] ≥ 130?mg/dL [3.37?mmol/L]). After the outpatient screening and NCEP Step I diet stabilization periods, 40 subjects were randomized to one of the 4 following treatments: rosuvastatin 10?mg plus ezetimibe 10?mg (n = 12); rosuvastatin 10?mg plus placebo (matching ezetimibe 10?mg) (n = 12); ezetimibe 10?mg plus placebo (matching ezetimibe 10?mg) (n = 8); or placebo (2 tablets, matching ezetimibe 10?mg) (n = 8). All study treatments were administered once daily in the morning for 14 days as part of a 16-day inpatient confinement period. Fasting serum lipids were assessed pre-dose on days 1 (baseline), 7, and 14 by direct quantitative assay methods. Safety was evaluated by monitoring laboratory tests and recording adverse events. Blood samples were collected for ezetimibe and rosuvastatin pharmacokinetic evaluation prior to the first and last dose and at frequent intervals after the last dose (day 14) of study treatment. Plasma ezetimibe, total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and rosuvastatin concentrations were determined by validated liquid chromatography with tandem mass spectrometric detection (LC–MS/MS) assay methods.

Results: All active treatments caused statistically significant (?p ≤ 0.02) decreases in LDL-C concentration versus placebo from baseline to day 14. The co-administration of ezetimibe and rosuvastatin caused a significantly (?p < 0.01) greater reduction in LDL-C and total cholesterol than either drug alone. In this 2-week inpatient study with restricted physical activity there was no apparent effect of any treatment on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The co-administration of ezetimibe and rosuvastatin caused a significantly (?p < 0.01) greater percentage reduction in mean LDL-C (–61.4%) than rosuvastatin alone (–44.9%), with a mean incremental reduction of –16.4% (95%CI –26.3 to –6.53). Reported side effects were generally mild, nonspecific, and similar among treatment groups. There were no significant increases or changes in clinical laboratory tests, particularly those assessing muscle and liver function. There was no significant pharmacokinetic drug interaction between ezetimibe and rosuvastatin.

Conclusions: Co-administration of ezetimibe 10?mg with rosuvastatin 10?mg daily caused a significant incremental reduction in LDL-C compared with rosuvastatin alone. Moreover, co-administering ezetimibe and rosuvastatin was well tolerated in patients with hypercholesterolemia.     

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

Lowering serum cholesterol levels reduces the risk of coronary heart disease (CHD)-related events. Statins are commonly prescribed as first-line treatment but many patients at high-risk for CHD still fail to reach their cholesterol or low-density lipoprotein cholesterol (LDL-C) goals with statin monotherapy. National and international guidelines for the prevention of CHD recommend the modification of lipid profiles and particularly LDL-C [e.g. the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III; 2001) and Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice (2003) Guidelines]. Several recent clinical trials indicated an added benefit from aggressive lowering of LDL-C levels. Based on these findings, the NCEP ATP III revised the LDL-C target from < 100 mg/dL (2.6 mmol/L) to < 70 mg/dL (1.8 mmol/L) (optional target) for very high-risk patients and < 130 mg/dL (3.4 mmol/L) to < 100 mg/dL (2.6 mmol/L) for moderately high-risk patients. For patients who fail to achieve their LDL-C target, inhibiting the two main sources of cholesterol - synthesis and uptake - can produce more effective lipid lowering, allowing more patients to reach their LDL-C goal. Ezetimibe is a highly-selective inhibitor of cholesterol absorption and simvastatin is an evidence-based inhibitor of cholesterol synthesis. The LDL-C-lowering efficacy of targeting both major sources of cholesterol with ezetimibe plus simvastatin was demonstrated in several multicentre, double-blind, placebo-controlled trials in patients with hypercholesterolaemia. For patients who do not reach their cholesterol goal with a statin, adding ezetimibe 10 mg significantly reduces LDL-C compared with statin monotherapy. Thus, this treatment option may help patients reach the new 'stricter' cholesterol goals. This review, based on a Medline database search from January 2000 to August 2005, considers the LDL-C-lowering efficacy of ezetimibe and discusses the role of this agent for patients who fail to achieve guideline cholesterol goals with statin monotherapy.     

New cholesterol guidelines,new treatment challenges

Coronary heart disease (CHD) is the largest single killer of Americans. Epidemiologic trials have indicted low-density lipoprotein cholesterol (LDL) as directly correlating with CHD events, and clinical trials confirmed that lipid-lowering therapy decreases the risk of CHD events. The literature also indicates that only about 18% of these patients are treated to their goal LDL levels. New guidelines from the National Cholesterol Education Program extend the LDL-lowering recommendations, add a new non-high-density lipoprotein cholesterol (non-HDL) goal for patients with hypertriglyceridemia, and increase the number of drug-eligible patients from about 15 to 36 million. Most of those who are eligible for lipid-altering drug therapy have the highest CHD risk and require the most aggressive treatment to achieve goals. This presents a challenge to clinicians: how best to achieve LDL and non-HDL goals. Statins are the most effective agents for lowering LDL and one of the most effective for lowering non-HDL. This efficacy and the ability to reduce CHD risk were well documented in a number of randomized clinical trials. When statin monotherapy fails to achieve goals, a bile acid resin, niacin, or both may be added to lower LDL further, or a fibrate, niacin, or fish oils may be added to lower non-HDL further. Drugs are under development that may enhance our ability to reach LDL and non-HDL goals. Included are a group of so-called super statins, rosuvastatin and pitavastatin; agents that interfere with cholesterol or bile acid transport in the gut, such as ezetimibe; and dual peroxisome proliferator-activated receptor agonists that have both fibrate and thiazolidinedione-like effects.     

Predictors of uncontrolled hyperlipidaemia in high-risk ambulatory patients in primary care

ABSTRACT

Objective: To determine (a) the proportion of patients at high risk of cardiovascular events who achieve low-density lipoprotein cholesterol (LDL-C) goals as recommended by the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) guidelines, and (b) the predictors of poor LDL-C control.

Methods: Two open-label, prospective, non-randomised, observational studies (study 1 with n?=?19 194 patients, predominantly with coronary artery disease (CHD); study 2 with n?=?19 484 patients, predominantly with diabetes mellitus (DM)). Patients received, usually after statin pretreatment, ezetimibe 10?mg plus simvastatin as fixed-dose combinations over 3?months. Bivariate and multivariate regression analysis was performed to identify factors associated with poor LDL-C control.

Results: At study end, 38?%?(up from 4.7?%?at baseline) of CHD and 35?%?(up from 3.3?%?at baseline) of diabetic patients achieved the target LDL value?<?100?mg/dl (2.6?mmol/l) after treatment with a fixed-dose ezetimibe–simvastatin combination. In both studies, concomitant atherosclerotic disease was associated with good control. Conversely, factors associated with poor control were, among others, high baseline LDL-C values, pretreatment with certain statins, and (in the DM study) high HbA_1c, and high body mass index.

Conclusion: Under real world, general practice conditions, a substantial proportion of high-risk patients with CHD and/or DM met LDL-C target levels on dual cholesterol inhibition with ezetimibe/simvastatin. A limited number of easily recognisable factors allow physicians to identify high risk patients whose LDL-C is likely to be difficult to control. Early identification of this patient group may have profound clinical benefits in general practice by enabling specific early interventions such as counselling on physical activity, dietary support and/or follow up visits to the GP.     

Effects of ezetimibe,simvastatin, atorvastatin,and ezetimibe–statin therapies on non-cholesterol sterols in patients with primary hypercholesterolemia

ABSTRACT

Background: Levels of cholesterol are regulated by its synthesis, absorption, and elimination. Plasma levels of phytosterols (e.g., sitosterol, campesterol) and ratios of these sterols to total cholesterol (TC) are reported to correlate with efficiency of intestinal cholesterol absorption, whereas levels of certain cholesterol precursor sterols (e.g., desmosterol, lathosterol) and their ratios to TC correlate with cholesterol biosynthesis. However, there is a paucity of published data concerning the effects of combined treatment using HMG-CoA reductase inhibitors (statins) and a cholesterol absorption inhibitor (ezetimibe) on these parameters.

Objectives: To characterize the effects of ezetimibe co-administered with statins, compared with each treatment alone, on cholesterol precursor sterols and plasma phytosterol levels.

Methods: A post-hoc analysis was performed to determine the effects of treatment with ezetimibe 10?mg, simvastatin (10–80?mg), and atorvastatin (10–80?mg), alone or in combination, on these non-cholesterol sterols using plasma samples from two randomized controlled trials involving patients with primary hypercholesterolemia (low-density lipoprotein [LDL-C]?=?145–250?mg/dL; triglycerides ≤350?mg/dL; N?=?975) but without a recent (≤6-month) history of coronary heart disease (CHD) or either uncontrolled or newly diagnosed diabetes mellitus.

Results: Ezetimibe monotherapy significantly reduced plasma sitosterol and campesterol concentrations from baseline compared with placebo (both p?<?0.001), whereas statins significantly lowered desmosterol and lathosterol levels (p?<?0.001 vs. placebo). Co-administration of ezetimibe and statins significantly decreased plasma levels of all of these sterols (p?<?0.001).

Conclusions: The observed effects of co-administration of ezetimibe and statins on non-cholesterol sterols are consistent with net inhibition of sterol absorption (driven by ezetimibe) in conjunction with net inhibition of cholesterol synthesis (driven by statins). The potential influence of treatment-induced changes in phytosterols on cardiovascular risk warrants further investigation in long-term, prospective, randomized controlled trials. This post-hoc study was by nature exploratory, and, because data from such analyses are not customarily adjusted for multiple comparisons, some associations may have emerged as statistically significant by chance. Future prospective randomized controlled studies may help to confirm our findings and address other research issues, such as the generalizability of our findings to patients with CHD or diabetes mellitus and possible dose:response relationships between escalating statin (or ezetimibe–statin) doses and circulating non-cholesterol levels.     

Evolocumab: A Review in Hyperlipidemia

Evolocumab (Repatha^®) is a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered subcutaneously at a dosage of 140 mg every 2 weeks or 420 mg once monthly. Across 12-week phase III trials in patients with primary hypercholesterolemia or mixed dyslipidemia, evolocumab was more effective than placebo (treatment difference ?54.8 to ?76.3 %) and/or ezetimibe (treatment difference ?36.9 to ?47.2 %) at reducing low-density lipoprotein cholesterol (LDL-C) levels, including when added to statin therapy, when administered to statin-intolerant patients, when administered as monotherapy, and in patients with heterozygous familial hypercholesterolemia who were receiving statins with or without other lipid-lowering drugs. Evolocumab also significantly lowered LDL-C levels (treatment difference of ≈30 % vs. placebo) in patients with homozygous familial hypercholesterolemia when added to statins with or without ezetimibe in a 12-week phase III trial. The efficacy of evolocumab was maintained in the longer term, and it was well tolerated. In conclusion, subcutaneous evolocumab is a valuable new treatment for use in primary hypercholesterolemia or mixed dyslipidemia and homozygous familial hypercholesterolemia, particularly in patients unable to reach LDL-C goals despite treatment with statins with or without other lipid-lowering therapies and in patients who do not tolerate or are not able to receive statins.     

Lipid-lowering treatment in coronary artery disease: how low should cholesterol go?

The randomised clinical trial data, which supports preventing coronary heart disease (CHD) events by lowering low density lipoprotein cholesterol (LDL-C) levels, is substantial, consistent and highly significant. HMG-CoA reductase inhibitors (statins), which are the preferred medications for lowering LDL-C levels, are well tolerated, with greater efficacy than other lipid-altering medications. In 1993, the National Cholesterol Education Program (NCEP) guidelines recommended LDL-C target levels to be achieved with therapy in high-risk individuals. In particular, the LDL-C goal of therapy in patients with CHD was < or = 100 mg/dl (2.6 mmol/L), with no specific guidance as to the lower limit or whether additional clinical benefit could be expected. Because little clinical trial data existed at that time to offer support, and because some epidemiological data raised concern about the potential detriments associated with very low total cholesterol and LDL-C levels, the NCEP Adult Treatment Panel remained appropriately vague on the 'how low should you go' question. In the last few years, several additional clinical trials have provided sufficient efficacy and safety data to re-examine that question. Analyses of on-treatment LDL-C levels and subsequent CHD events from three landmark trials with HMG-CoA reductase inhibitors suggest that progressively lower LDL-C levels are associated with lower CHD events in a curvilinear fashion. The Post Coronary Artery Bypass Graft (Post-CABG) trial and Atorvastatin Versus Revascularisation Trial (AVERT) examined a more intensive versus less intensive drug regimen for LDL-C reduction, and concluded that the more aggressively treated patients had better angiographic and end-point outcomes. Most importantly, there did not appear to be any change in noncardiovascular end-points associated with lower LDL-C levels. In several ongoing clinical trials, patients with CHD have been randomised to receive HMG-CoA reductase inhibitors with targets for LDL-C levels of 100 mg/dl versus 75 mg/dl (1.94 mmol/L). These trials have sufficient patient numbers and power to definitely determine if reducing LDL-C levels to approximately 75 mg/dl can provide an acceptable benefit-to-risk-ratio.     

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.     

Clinical implications of the IMPROVE-IT trial in the light of current and future lipid-lowering treatment options

Introduction: A residual risk of morbidity and mortality from cardiovascular (CV) disease remains despite statin therapy. This situation has generated an interest in finding novel approaches of combining statins with other lipid-lowering agents, or finding new lipid and non-lipid targets, such as triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, cholesterol ester transfer protein (CETP), lipoprotein (a), fibrinogen or C-reactive protein. Areas covered: The recent results from the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated an incremental clinical benefit when ezetimibe, a non-statin agent, was added to simvastatin therapy. Expert opinion: The results from IMPROVE-IT revalidated the concept that low-density lipoprotein cholesterol (LDL-C) levels are a clinically relevant treatment goal. This trial also suggested that further decrease of LDL-C levels (53 vs. 70 mg/dl; 1.4 vs. 1.8 mmol/l) was more beneficial in lowering CV events. This “even lower is even better” evidence for LDL-C levels may influence future guidelines and the use of new drugs. Furthermore, these findings make ezetimibe a more realistic option to treat patients with statin intolerance or those who cannot achieve LDL-C targets with statin monotherapy.     

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%).     

Rosuvastatin

The HMG-CoA reductase inhibitor (statin) rosuvastatin (Crestor) is widely available for use in the management of dyslipidemia, and was recently approved in the US to slow the progression of atherosclerosis as part of a strategy to lower low-density lipoprotein-cholesterol (LDL-C) and total cholesterol (TC) to target levels. Rosuvastatin has greater lipid-lowering efficacy than any of the other currently available statins, and significantly more patients receiving rosuvastatin than other statins achieve LDL-C goals. Rosuvastatin delayed the progression of carotid atherosclerosis in patients with subclinical carotid atherosclerosis, moderately elevated cholesterol levels, and a low risk of cardiovascular disease in a primary prevention trial (METEOR). The results of METEOR suggest a possible role for the earlier use of rosuvastatin in primary prevention, although more data are needed from trials examining the effects of the drug on cardiovascular endpoints. Significant regression of atherosclerosis was seen with rosuvastatin 40 mg/day in patients with established coronary heart disease (CHD) in the ASTEROID trial, supporting the use of intensive lipid lowering in secondary prevention patients (although it should be noted that it has not yet been established that atherosclerotic regression translates into improved cardiovascular outcomes). Rosuvastatin is generally well tolerated, with a similar tolerability profile to that of other currently available statins. Thus, rosuvastatin is an important lipid-lowering treatment option that has been shown to cause regression of atherosclerosis in secondary prevention patients, and has a potential future role in delaying atherosclerosis in primary prevention patients.     

The use of ezetimibe in achieving low density lipoprotein lowering goals in clinical practice: position statement of a United Kingdom consensus panel

ABSTRACT

There is no doubt that lowering serum cholesterol levels reduces the risk of major coronary events. This evidence has led treatment guidelines to set progressively lower targets for low density lipoprotein cholesterol (LDL-C). However, despite widespread use of statins, substantial numbers of patients do not achieve the LDL-C goals. Using higher doses of statins in an attempt to achieve these targets may increase the risk of serious adverse effects. Furthermore, the use of combination therapy with agents such as bile acid sequestrants, niacin and fibrates has been limited by increased potential for side effects, drug interactions and poor compliance.

Ezetimibe, a selective cholesterol transport inhibitor, reduces the intestinal uptake of cholesterol without affecting absorption of triglycerides or fatsoluble vitamins. In clinical studies, ezetimibe 10?mg, in combination with statins or as monotherapy, was well tolerated and reduced LDL-C by 34–53% and 17–18%, respectively.

The available evidence for ezetimibe is reviewed. The role of ezetimibe in increasing the proportion of patients attaining LDL-C treatment goals is discussed.