Treating to target patients with primary hyperlipidaemia:comparison of the effects of ATOrvastatin and ROSuvastatin (the ATOROS study)

ABSTRACT

Objectives: In a 24-week, open-label, randomized, parallel-group study, we compared the efficacy and metabolic effects, beyond low density lipoprotein cholesterol (LDL-C)-lowering, of atorvastatin (ATV) and rosuvastatin (RSV) in cardiovascular diseasefree subjects with primary hyperlipidaemia, treated to an LDL-C target (130 mg/dL).

Methods: After a 6‐week dietary lead-in period, patients were randomized to RSV 10?mg/day (?n = 60) or ATV 20?mg/day (?n = 60). After 6 weeks on treatment the dose of the statin was increased (to RSV 20?mg/day or ATV 40?mg/day) if the treatment goal was not achieved. A control group of healthy volunteers (?n = 60) was also included for the validation of baseline serum and urinary laboratory parameters. The primary outcome was the percentage of patients reaching the LDL‐C goal; secondary outcomes were changes in lipid and non-lipid metabolic parameters.

Results: A total of 45 patients (75.0%) in the RSV-treated group and 43 (71.7%) in the ATV-treated group achieved the treatment target at the initial dose. Both regimens were generally well tolerated and there were no withdrawals due to treatment-related serious adverse events. Similar significant reductions in total cholesterol, LDL‐C, apolipoprotein (apo) B, triglycerides, apoB/apoA1 ratio, fibrinogen and high-sensitivity C‐reactive protein levels were seen. RSV had a significant high density lipoprotein cholesterol (HDL‐C)-raising effect and showed a trend towards increasing apoA1 levels. Glycaemic control and renal function parameters were not influenced by statin therapy. ATV, but not RSV, showed a significant hypouricaemic effect.

Conclusions: RSV and ATV were equally efficacious in achieving LDL‐C treatment goals in patients with primary hyperlipidaemia at the initial dose and following dose titration. RSV seems to have a significantly higher HDL‐C-raising effect, while ATV lowers serum uric acid 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.     

Treating to target patients with primary hyperlipidaemia: comparison of the effects of ATOrvastatin and ROSuvastatin (the ATOROS study)

OBJECTIVES: In a 24-week, open-label, randomized, parallel-group study, we compared the efficacy and metabolic effects, beyond low density lipoprotein cholesterol (LDL-C)-lowering, of atorvastatin (ATV) and rosuvastatin (RSV) in cardiovascular disease-free subjects with primary hyperlipidaemia, treated to an LDL-C target (130 mg/dL). METHODS: After a 6-week dietary lead-in period, patients were randomized to RSV 10 mg/day (n = 60) or ATV 20 mg/day (n = 60). After 6 weeks on treatment the dose of the statin was increased (to RSV 20 mg/day or ATV 40 mg/day) if the treatment goal was not achieved. A control group of healthy volunteers (n = 60) was also included for the validation of baseline serum and urinary laboratory parameters. The primary outcome was the percentage of patients reaching the LDL-C goal; secondary outcomes were changes in lipid and non-lipid metabolic parameters. RESULTS: A total of 45 patients (75.0%) in the RSV-treated group and 43 (71.7%) in the ATV-treated group achieved the treatment target at the initial dose. Both regimens were generally well tolerated and there were no withdrawals due to treatment-related serious adverse events. Similar significant reductions in total cholesterol, LDL-C, apolipoprotein (apo) B, triglycerides, apoB/apoA1 ratio, fibrinogen and high-sensitivity C-reactive protein levels were seen. RSV had a significant high density lipoprotein cholesterol (HDL-C)-raising effect and showed a trend towards increasing apoA1 levels. Glycaemic control and renal function parameters were not influenced by statin therapy. ATV, but not RSV, showed a significant hypouricaemic effect. CONCLUSIONS: RSV and ATV were equally efficacious in achieving LDL-C treatment goals in patients with primary hyperlipidaemia at the initial dose and following dose titration. RSV seems to have a significantly higher HDL-C-raising effect, while ATV lowers serum uric acid levels.     

A multicentre,open study to assess the effect of individualizing starting doses of atorvastatin according to baseline LDL-C levels on achieving cholesterol targets: the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST-2) study

ABSTRACT

Objectives: ACTFAST-2 was designed to match the starting dose of a statin to the baseline low density lipoprotein-cholesterol (LDL-C) value, to allow high-risk European subjects to achieve LDL-C targets within 12 weeks with the initial dose or one up-titration.

Research design and methods: This was a 12-week, prospective, open-label trial that enrolled 610 high-risk subjects from 8 European countries. Subjects with LDL-C > 2.6?mmol/L (> 100?mg/dL),but ≤ 5.7?mmol/L (≤ 220?mg/dL) were assigned a starting dose of atorvastatin (10, 20, 40, 80?mg/day) according to LDL-C level and status of statin use at baseline (either statin-free or statin-treated), with a single up-titration at 6 weeks if needed.

Results: At 12 weeks, 68.0% of subjects overall, including 73.5% of statin-free and 60.5% of statin-treated subjects, achieved LDL-C target (< 2.6?mmol/L (< 100?mg/dL). The total cholesterol/high density lipoprotein-cholesterol (TC/HDL-C) ratio target was achieved by 75.2% of subjects overall, including 78.1% of statin-free and 71.2% of statin-treated subjects. In the statin-free group, LDL-C decreased by a mean of 42%. In the statin-treated group, atorvastatin led to an additional 31% reduction in LDL-C over the statin used at baseline. Mean decreases in TC/HDL-C ratio were 30% and 20% in the statin-free and statin-treated groups, respectively. The incidence of AST/ALT greater than 3 times of upper limit of normal range in all patients was 0.8% and no rhabdomyolysis was reported.

Conclusion: This study confirms that use of a flexible starting dose of atorvastatin allows the large majority of high-risk subjects to achieve their LDL-C target safely within 12 weeks with an initial dose or just a single up-titration.     

Efficacy and safety of ezetimibe co-administered with atorvastatin in untreated patients with primary hypercholesterolaemia and coronary heart disease

ABSTRACT

Objective: Combination of ezetimibe (EZE) with a statin represents an attractive strategy for cholesterol-lowering treatment, as it inhibits the two main sources of cholesterol: absorption from the intestine (inhibited by EZE) and endogenous biosynthesis (inhibited by statins).

Research design and methods: This multicentre, double-blind, placebo-controlled study randomised a total of 148 men and women with primary hypercholesterol­aemia and coronary heart disease (CHD) to receive treatment for 6 weeks with either EZE 10?mg + atorvastatin 10?mg (EZE + ATV; n = 72) or placebo/atorvastatin 10?mg (ATV; n = 76). The primary efficacy variable was the mean percentage change in low-density lipoprotein cholesterol (LDL?C) from baseline to study endpoint.

Results: At 6 weeks, EZE + ATV provided a significantly greater adjusted mean change from baseline in LDL?C compared with ATV monotherapy (–50.5% vs. –36.5%; p < 0.0001), equating to an additional 14.1% reduction (95% CI –17.90, –10.19) in LDL?C. A significantly higher proportion of patients on EZE + ATV achieved the new Joint British Societies (JBS 2) recommended LDL?C goal of < 2?mmol/L (62% vs. 12% with ATV alone; p < 0.0001) and the JBS 2 minimum treatment standard of < 3?mmol/L (93% vs. 79% with ATV alone). Patients receiving EZE + ATV were 12 times more likely to reach LDL?C targets (odds ratio 12.1; 95% CI 5.8, 25.1; p < 0.0001) compared with patients receiving ATV monotherapy. Clinical chemistry profiles and the incidence of adverse events were similar in both groups.

Conclusions: Adding EZE to ATV monotherapy represents an attractive and well-tolerated treatment option to bring patients at high risk of CHD to the aggressive LDL?C goals recommended by recent treatment guidelines.     

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

ABSTRACT

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

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

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

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

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

Effects of ezetimibe added to on-going statin therapy on the lipid profile of hypercholesterolemic patients with diabetes mellitus or metabolic syndrome

SUMMARY

Objective: To conduct a post-hoc assessment of the lipid-modifying effects of adding the cholesterol absorption inhibitor, ezetimibe, to on-going statin therapy in patients with diabetes mellitus (DM) or metabolic syndrome (MetS).

Research design and methods: This was a post-hoc analysis of data from a randomized, double-blind, placebo-controlled trial designed to evaluate the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy and safety of adding ezetimibe 10?mg/day versus placebo to ongoing, open-label statin treatment for 8 weeks in hypercholesterolemic patients. Qualifying LDL-C levels and target LDL-C goals were based on National Cholesterol Education Program risk categories. The DM subgroup were patients who entered the study with a prior diagnosis of DM. Patients were classified as having MetS if they met 3 or more of the following criteria at baseline: triglycerides (TG) ≥ 150?mg/dL (1.69 mmol/L); high-density lipoprotein cholesterol (HDL-C) < 40?mg/dL (1.04 mmol/L) for men or < 50?mg/dL (1.29 mmol/L) for women; fasting serum glucose (FSG) ≥ 110?mg/dL (≥ 6.1 mmol/L); a diagnosis of hypertension or taking hypertension medication or blood pressure ≥ 130/ ≥ 85 mmHg; waist circumference > 88?cm (women) or > 102?cm (men). DM patients were excluded from the MetS subgroup analysis.

Main outcome measures: The objectives were to assess the effects of treatment on plasma concentrations of LDL-C and other lipid variables, and on the percentage of patients achieving LDL-C target levels at the end of the study.

Results: Of 769 patients enrolled in the original study, there were 191 (24.8%) with DM and 195 (25.4%) with MetS. Regardless of subgroup, ezetimibe + statin was significantly more effective than statin alone at lowering plasma levels of LDL-C, non-HDL-C, total cholesterol, apolipoprotein B, and triglycerides (between-group p < 0.001 for all). For all lipid parameters, the relative treatment effects were generally consistent regardless of DM or MetS status. Significantly more ezetimibe than placebo patients in all subgroups achieved prespecified LDL-C goals (?p < 0.001 for all), and although more patients in the DM and MetS groups, respectively, achieved the goal compared with their non-DM and non-MetS counterparts [83.6% (DM) versus 67.2 (non-DM) and 71.8% (MetS) versus 65.6% (non-MetS)], these differences were not significant after adjusting for differences in baseline LDL-C levels. Ezetimibe was well-tolerated and had a favorable safety profile in all subgroups.

Conclusions: The co-administration of ezetimibe with statins, a therapeutic regimen that inhibits both the absorption and synthesis of cholesterol, offers a well-tolerated and efficacious treatment to lower LDL-C in patients with DM and MetS.     

Protective effect of ursodeoxycholic acid,resveratrol, and N-acetylcysteine on nonalcoholic fatty liver disease in rats

Context: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Resveratrol (RSV) and N-acetylcysteine (NAC) are safe representatives of natural and synthetic antioxidants, respectively.

Objective: The objective of this study was to evaluate protective effects of RSV and NAC, compared with ursodeoxycholic acid (UDCA), on experimental NAFLD.

Materials and methods: NAFLD was induced by feeding rats a methionine choline-deficient diet (MCDD) for four cycles, each of 4?d of MCDD feeding and 3?d of fasting. Animals were divided into normal control, steatosis control, and five treatment groups, receiving UDCA (25?mg/kg/d), RSV (10?mg/kg/d), NAC (20?mg/kg/d), UDCA?+?RSV, and UDCA?+?NAC orally for 28?d. Liver integrity markers (liver index and serum transaminases), serum tumor necrosis factor-α (TNF-α), glucose, albumin, renal functions (urea, creatinine), lipid profile (total cholesterol; TC, triglycerides, high density lipoproteins, low density lipoproteins; LDL-C, very low density lipoproteins, leptin), and oxidative stress markers (hepatic malondialdehyde; MDA, glutathione; GSH, glutathione-S-transferase; GST) were measured using automatic analyzer, colorimetric kits, and ELISA kits, supported by a liver histopathological study.

Results: RSV and NAC administration significantly improved liver index (RSV only), alanine transaminase (52, 52%), TNF-α (70, 70%), glucose (69, 80%), albumin (122, 114%), MDA (55, 63%), GSH (160, 152%), GST (84, 84%), TC (86, 86%), LDL-C (83, 81%), and leptin (59, 70%) levels compared with steatosis control values. A combination of RSV or NAC with UDCA seems to ameliorate their effects.

Discussion and conclusion: RSV and NAC are effective on NAFLD through antioxidant, anti-inflammatory, and lipid-lowering potentials, where as RSV seems better than UDCA or NAC.     

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.     

Statin plus ezetimibe treatment in clinical practice: the SI-SPECT (Slovenia (SI) Statin Plus Ezetimibe in Cholesterol Treatment) monitoring of clinical practice study

ABSTRACT

Background: Poor results from lipid-lowering therapy are mainly due to inadequate dosing and increased adverse effects with high-dose statin monotherapy or drug combinations.

Objectives: The SI-SPECT (Slovenia (SI) Statin Plus Ezetimibe in Cholesterol Treatment) study evaluated the effectiveness of either ezetimibe (EZE) 10?mg as monotherapy or co-administered with on-going statin treatment (S?+?EZE) in clinical practice.

Design and methods: A total of 1053 dyslipidaemic patients (52% men, age 60.3 years, 42.9% with CHD, 32.0% with diabetes mellitus and 69.6% with hypertension) were enrolled. The majority (n?=?986; 93.6%) were treated with EZE as ‘add-on’ to their already prescribed statin, the rest only received EZE (n?=?67).

Main outcome measures: Baseline lipid levels were compared with those obtained 16 weeks after initiating treatment.

Results: Total (TC) and low density lipoprotein cholesterol (LDL-C), as well as triglycerides (TG) decreased significantly with S?+?EZE (by 25.3%, 31.4% and 28.9%, respectively; p?<?0.0001 for all comparisons), while monotherapy with EZE resulted in a decrease of 20.8% for TC (?p?<?0.0001), 28.0% for LDL-C (?p?<?0.0001) and 28.8% for TG (?p?=?0.016). At the end of the study 43.9% of patients achieved target TC (<?5.0?mmol/L for primary prevention and <?4.5?mmol/L for secondary prevention), 50.5% target LDL-C (<?3.0?mmol/L for primary prevention and <?2.5?mmol/L for secondary prevention) and 61.6% target TG (<?2.0?mmol/L). The overall incidence of adverse effects during the treatment period, and probably related to EZE use, was low (n?=?6, 0.6% of patients).

Conclusions: (1) S?+?EZE combination therapy was effective and safe irrespective of the statin used, (2) the S?+?EZE combination resulted in significantly more patients reaching their recommended target lipid levels and (3) the lipid-lowering efficacy of EZE in monotherapy as well as of the S?+?EZE combination was related to initial lipid values. The much greater decrease of TG than expected could be, at least in part, due to better control/compliance regarding diet and drug treatment during the study and adherence to the need for an overnight fast before sampling.     

Effects of ezetimibe on the pharmacodynamics and pharmacokinetics of lovastatin

SUMMARY

Background: Ezetimibe is a cholesterol absorption inhibitor which decreases low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. This study investigated the potential for pharmacodynamic and/or pharmacokinetic interactions between ezetimibe and lovastatin.

Methods: In a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study, 48 healthy men with hypercholesterolemia (screening LDL-C ≥ 130?mg/dL) who were stabilized and maintained on a National Cholesterol Education Program (NCEP) Step I diet were randomized to one of the following six oral treatments once daily for 14?days: lovastatin 20?mg; lovastatin 20?mg plus ezetimibe 5, 10, or 20?mg; lovastatin 40?mg plus ezetimibe 10?mg; or placebo.

Results: Reported adverse events were generally mild, nonspecific, and similar among treatments. There were no significant changes in safety laboratory test results, including those for enzymes indicative of muscle or liver injury. Co-administration of ezetimibe and lovastatin did not increase the plasma concentrations of lovastatin or β-hydroxylovastatin. In this parallel comparison study there was an apparent decrease in lovastatin exposure, however, the reduction in lovastatin or β-hydroxylovastatin concentrations was not related to the ezetimibe dose and is not considered to be clinically important. Ezetimibe 5, 10, or 20?mg combined with lovastatin 20?mg caused a significantly (?p < 0.01) greater reduction in LDL-C than lovastatin 20?mg alone, with no apparent effect on HDL-C or triglycerides. LDL-C was reduced by 51.0% with ezetimibe 10?mg plus lovastatin 20?mg, 56.0% with ezetimibe 10?mg plus lovastatin 40?mg, 33.2% with lovastatin alone, and 17.3% with placebo.

Conclusions: The co-administration of ezetimibe and lovastatin was well tolerated and resulted in a significantly greater percentage reduction in serum LDL-C concentrations than with lovastatin alone, with an average incremental reduction of 16–18%. Ezetimibe 10?mg appears to be the optimal dose when co-administered with lovastatin 20?mg once daily. Further incremental reductions in LDL-C from the co-administration of ezetimibe and lovastatin are expected only when the dose of lovastatin is increased. The co-administration of ezetimibe and lovastatin has the potential to produce clinically significant reductions in LDL-C compared to either drug alone, with favorable safety and tolerability.     

Effects of statin treatment in men and women with stable coronary heart disease: a subgroup analysis of the GREACE Study

ABSTRACT

Background: Reducing low-density lipoprotein cholesterol (LDL-C) levels to National Cholesterol Expert Panel (NCEP) goal is recommended. However, sex-specific effects may influence benefit.

Methods and results: In this post hoc analysis of the GREek Atorvastatin and Coronary heart disease (CHD) Evaluation [GREACE] study we investigated the extent in vascular event reduction by statin treatment according to sex. From a total of 1600 patients with stable CHD, 624/176 and 632/168 were men/women on atorvastatin or on usual care, respectively. During 3-year follow-up, comparison of atorvastatin treatment with usual care demonstrated a relative risk reduction (RRR) of the primary end point (all vascular events) of 54?%?in women (hazard ratio [HR] 0.46, 95?%?confidence interval [CI] 0.24–0.87, p?=?0.003) and of 50?%?in men (HR 0.50, 95?%?CI 0.32–0.70, p?<?0.001). The fall in LDL-C levels played the key role in end point reduction in both sexes. However, in men there was an additional benefit related to the atorvastatin-induced increase in high density lipoprotein cholesterol (HDL-C) and estimated glomerular filtration rate (eGFR), while in women end points were related to a substantial triglycerides (TG) reduction.

Conclusions: Treatment with atorvastatin to the NCEP LDL-C goal compared with “usual care” significantly reduced CHD morbidity and mortality in both men and women. Both men and women benefited from statin treatment possibly with different mechanisms making a contribution over and above LDL-C reduction.     

Dual cholesterol inhibition with ezetimibe/simvastatin in pre-treated hypercholesterolaemic patients with coronary heart disease or diabetes mellitus: prospective observational cohort studies in clinical practice

ABSTRACT

Objective: Patients with primary hypercholesterolaemia and concomitant coronary heart disease (CHD) and/or diabetes mellitus (DM), who are at particularly high risk of cardiovascular events such as stroke or myocardial infarction, benefit from aggressive lipid lowering strategies. The present studies investigated the incremental efficacy and safety of dual cholesterol inhibition with ezetimibe/simvastatin in such high-risk patients pre-treated with statins but not reaching the 100?mg/dL (2.6?mmol/L) low density cholesterol (LDL?C) cholesterol threshold in the primary care setting.

Methods: Two open-label, prospective, non-random­ised, observational studies (study 1 with n = 19?194 patients, predominantly with CHD; study 2 with n = 19?484 patients, predominantly with DM). Patients received – almost all after statin pre-treatment – ezetimibe 10?mg plus simvastatin 10?mg (study 1: 15%, study 2: 16%), 20?mg (in 68% each), 40?mg (12%/10%) or 80?mg (1%/1%) as fixed dose combinations over 3 months (dosage at investigator's discretion).

Results: Mean LDL-C was reduced by 28%/27% (study 1/ study 2) compared with baseline values (on statin monotherapy). Mean total cholesterol was decreased by 22% in each study, mean triglycerides by 16/17%, and mean high density cholesterol (HDL?C) was increased by 9/10%. Adverse events were reported in 0.3% and 0.2% of patients, respectively.

Conclusion: Dual cholesterol inhibition with ezetimibe/simvastatin was effective and well tolerated under real practice conditions in high-risk patients with CHD and/or DM.     

Systematic literature review and meta-analysis of dual therapy with fenofibrate or fenofibric acid and a statin versus a double or equivalent dose of statin monotherapy

Objective:

To assess the efficacy of fenofibrate and statin dual therapy versus a double or equivalent dose of statin monotherapy.

Methods:

A systematic literature search and meta-analysis was performed for publications before 1 January 2014 in MEDLINE, Embase, and BIOSIS Previews, among others.

Results:

The difference in percentage change from baseline was in favor of dual therapy versus a double dose of statin monotherapy for triglycerides (difference ?20%; standard error [SE] 2.6%) and HDL-C (8.7%; SE 1.2%), but not for LDL-C (8.4%; SE 1.5%), non-HDL-C (2.8%; SE 1.1%), total cholesterol (4.5%; SE 1.0%) and apolipoprotein B (2.6%; SE 1.1%). For high intensity statins, the difference in percentage change from baseline was in favor of dual therapy versus equivalent statin monotherapy for triglycerides (?17%; SE 2.6%) and for HDL-C (8.7%; SE 1.9%). The difference in percentage change from baseline for LDL-C was 6% (SE 1.7%), implying a greater reduction in LDL-C with statin monotherapy. For moderate intensity statins, the difference in percentage change from baseline was in favor of dual therapy versus equivalent statin monotherapy for triglycerides (?24.2%; SE 1.2%) and HDL-C (8.2%; SE 0.9%). LDL-C decreased 2.2% (SE 1.4%) more with dual therapy.

Conclusions and implications of key findings:

When aiming to change HDL-C or triglycerides, dual therapy is to be preferred to doubling the statin dose; conversely, doubling the statin dose is to be preferred when aiming to reduce LDL-C. If the aim is both to change HDL-C or triglycerides and to reduce LDL-C, the importance of the three outcomes may need to be weighed depending on the intensity of the statin. Combining high intensity statin therapy with fenofibrate improves the effect on HDL-C and triglycerides, but lowers the effect on LDL-C. Combining a moderate intensity statin with fenofibrate improves the effect on HDL-C and triglycerides without reducing the effect on LDL-C. There is a need for long-term randomized clinical trials to compare dual therapy versus doubling the statin dose to assess the importance of improvement in HDL-C and triglycerides versus improvement in LDL-C in terms of cardiovascular outcomes. Further, the addition of ezetimibe to statin/fenofibrate therapy may be of interest.     

Efficacy and safety of losartan 100 mg or losartan 100 mg plus hydrochlorothiazide 25 mg in the treatment of patients with essential arterial hypertension and CV risk factors: obser-vational,prospective study in primary care

ABSTRACT

Background: Patients with high cardiovascular risk are prevalent in ambulatory care. To achieve adequate blood pressure control, such patients require higher drug doses and/or combination therapy. We aimed to assess the efficacy and safety of losartan 100?mg as monotherapy or in fixed-dose combination with hydrochlorothiazide 25?mg.

Design and methods: Multicentre, prospective, open observational study over 13 weeks in patients with essential hypertension, whose blood pressure was not adequately controlled despite pretreatment. Main outcome parameters were the systolic (SBP) and diastolic (DBP) blood pressure reduction, the rate of normalized patients at study end compared to baseline, and the number and type of adverse events (AEs).

Results: Of the 7702 documented patients, 53.1% (N?=?4088) were men, with a mean age of 63.5?±?10.7 years. Comorbidities were frequent (diabetes mellitus in 57.4% [N?=?4418], coronary heart disease in 30.3% [N?=?2330], left ventricular hypertrophy in 28.2% [N?=?2172], heart failure in 14.0% [N?=?1079], and peripheral arterial disease in 9.0% [N?=?690]). Patients received losartan 100?mg in 45.7% (N?=?3521), losartan/HCTZ in 53.8% (N?=?4143); additional antihypertensive drugs were given in 45.5% (N?=?3505). Physicians reported somewhat lower target values than those stipulated by the guidelines (irrespective of age, gender, and concomitant diseases except for diabetes). Mean SBP/DBP decreased from a baseline value of 158/93?mmHg by 24/12?mmHg at study end. The BP lowering effect was similar in subgroups by treatment or comorbidity, respectively, however target attainment rates were substantially higher in non-diabetic patients. Metabolic and renal parameters (fasting glucose, HbA_1c, serum creatinine and albumin in urine) showed trends for improvement. Tolerability was very good, as only 0.43% (N?=?33) experienced an AE (in 0.31% [N?=?24] serious AEs), and 0.08% (N?=?6) discontinued therapy due to reasons related to study drug.

Conclusion: In high-risk patients, treatment with losartan 100?mg or losartan/HCTZ 100/25?mg was effective and well tolerated, irrespective of comorbidity. These findings from a real-life setting are in line with those from randomized controlled trials.     

Effects of rotigotine on daytime symptoms in patients with primary restless legs syndrome: a randomized,placebo-controlled study

Objective:

This 12 week double-blind, placebo-controlled study (ClinicalTrials.gov: NCT01569464) was conducted to evaluate the effects of rotigotine transdermal patch on daytime symptoms in patients with idiopathic restless legs syndrome (RLS).

Methods:

Adult patients with moderate-to-severe RLS were randomized to rotigotine (optimal dose: 1–3?mg/24?h) or placebo. A modified four-assessment version (4:00?pm, 6:00?pm, 8:00?pm, and 10:00?pm) of the Multiple Suggested Immobilization Test (m-SIT) was performed at baseline and end of 4 week maintenance (EoM). Primary study outcomes were change from baseline to EoM in International Restless Legs Syndrome Rating Scale (IRLS) and in average of means for the m-SIT Discomfort Scale (m-SIT-DS) (combined average of mean values from each of the individual assessments). Secondary outcomes included average of means of Periodic Limb Movement during Wakefulness Index (PLMWI; PLM/hour) for the combination of m-SIT.

Results:

A total of 150 patients were randomized and 137 (rotigotine: 92/101 [91.1%]; placebo: 45/49 [91.8%]) completed maintenance. All 150 randomized patients were assessed for efficacy. At EoM, mean change in IRLS was ?14.9?±?9.3 with rotigotine vs. ?12.7?±?7.6 with placebo (ANCOVA, LS mean treatment difference [95% CI]: ?0.27 [?2.96, 2.42]; p?=?0.8451). Changes in average of means of m-SIT-DS values of each individual SIT were comparable with rotigotine (?2.68?±?2.31) vs. placebo (?2.62?±?2.61) (ANCOVA, LS mean treatment difference [95% CI]: 0.07 [?0.61, 0.75]; p?=?0.8336) and comparable reductions in PLMWI were observed in both treatment groups (8.34 [?8.50, 25.17]; p?=?0.3290). Rotigotine was generally well tolerated. Application site reactions (rotigotine: 20 patients [19.8%]; placebo: 4 [8.2%]) and nausea (16 [15.8%]; 3 [6.1%]) were the most common AEs.

Conclusions:

Rotigotine was beneficial in improving overall RLS symptom severity (assessed by IRLS) and RLS symptom severity at various times of the day (m-SIT-DS); however, superiority to placebo was not established.     

Efficacy and safety of simvastatin in Asian and non-Asian coronary heart disease patients: a comparison of the GOALLS and STATT studies

SUMMARY

Background: Asians are thought to be more responsive to the lipid-lowering effects of statins than non-Asians although there are no head-to-head trials that examine this perception.

Objective: To compare the results of the GOALLS and STATT studies that used similar titrate-to-goal protocols with 20?mg up to 80?mg simvastatin in Asian and non-Asian coronary heart disease (CHD) patients.

Methods: GOALLS (N = 198; included non-Asians and Asians) and STATT (N = 133; included Asians only) were both multi-center, open-label 14-week studies in CHD patients with serum low density lipoprotein cholesterol (LDL-C) levels 115?mg/dL–180?mg/dL and triglycerides (TG) levels ≤ 400?mg/dL. Simvastatin was titrated from 20?mg/day up to 80?mg/day in order to achieve the National Cholesterol Education Program (NCEP) LDL-C target ≤ 100?mg/dL. The primary efficacy variable was the percentage of patients attaining the NCEP LDL-C target at Week 14. Secondary endpoints included proportion of patients achieving the European Society of Cardiology/European Atherosclerosis Society/European Society of Hypertension (European) LDL-C target ≤ 115?mg/dL at Week 14 and percentage change in lipid parameters. Safety and tolerability were assessed by monitoring adverse experiences and safety laboratory tests. Fifteen Asian patients were part of the GOALLS cohort and their data were compared separately with results of non-Asians from GOALLS and Asians from the STATT study.

Results: After 14?weeks of simvastatin treatment, 87.1% of GOALLS non-Asians, 85.7% of GOALLS Asians, and 78.2% of STATT patients attained the NCEP LDL-C target. At Week 14, 94.4%, 92.9%, and 91.7% of the GOALLS non-Asians, GOALLS Asians, and STATT patients achieved the European LDL-C target, respectively. The average treatment doses to attain NCEP and European targets were comparable among groups. The percentage reductions in lipid parameters from baseline to week 14 were similar among groups except, changes in high density lipoprotein cholesterol and apolipoprotein A-I favored Asian subjects. There was also a greater reduction in TG in the STATT study, but this was not consistent with TG reductions experienced by Asians in the GOALLS study. In both studies, simvastatin was generally well tolerated by all patients across the dosage range of 20?mg–80?mg. No cases of rhabdomyolysis or myopathy were reported in either study.

Conclusions: A great majority of CHD patients is able to achieve LDL-C treatment goals (up to 90%) on simvastatin regardless of racial background. Simvastatin treatment at doses of 20?mg–80?mg is well-tolerated in Asian and non-Asian CHD patients. This side-by-side comparison provides evidence that Asian and non-Asian CHD populations respond similarly to comparable doses of simvastatin.     

Effects of statins on all-cause mortality at different low-density-lipoprotein cholesterol levels in Asian patients with type 2 diabetes

Objective: To investigate the effects of statins on all-cause mortality risk at different low-density lipoprotein cholesterol (LDL-C) levels, and to compare the mortality risk between statin users and non-users with identical LDL-C levels in a type 2 diabetes cohort.

Methods: In total, 10,582 outpatients aged ≥18 years with type 2 diabetes mellitus (T2DM) between 2009 and 2012 were enrolled in this retrospective cohort study in central Taiwan. All-cause mortality events were followed up until the end of 2014. According to the medical records during the follow-up period, the patients were classified into statin (+) and statin (?) groups. Patients were categorized into different LDL-C segments based on their mean LDL-C levels during the 2.8-year follow-up.

Results: Non-cardiovascular mortality accounted for more than half the deaths. Overall, statin therapy significantly reduced the all-cause mortality risk in both univariable and multivariable models (hazard ratios?=?0.39 and 0.38, respectively). Sub-group analyses showed that the lowest mortality risk occurred in the 80–89?mg/dL segment in the statin (?) group and in the 90–99?mg/dL segment in the statin (+) group. Statin therapy significantly reduced the mortality risk at all LDL-C levels except for low LDL-C (<60?mg/dL).

Conclusions: In addition to reducing LDL-C levels, statin therapy reduced all-cause mortality risk in Taiwanese patients with T2DM. Statins further reduced the mortality risk at most LDL levels. However, at low LDL-C levels, the positive effects of statins may have been nullified.     

Eletriptan for the acute treatment of migraine: results of bridging a Japanese study to Western clinical trials

SUMMARY

Objective: To compare the efficacy, safety and tolerability of eletriptan (20,40 and 80?mg) to placebo when given to Japanese and Western patients for the acute treatment of migraine.

Methods: A double-blind, randomized, parallel-group trial with the aforementioned therapeutic objectives was conducted in Japan (N?=?321). By bridging analysis, data from this study were compared to two migraine trials previously conducted in the US (N?=?1190) and Europe (N?=?563).

Results: The 2-h post-dose headache response rates (i.e., the primary efficacy endpoint) of Japanese migraineursto eletriptan 20, 40 and 80?mg were 64, 67 and 76%, respectively; European and American migraineurs showed similar trends and, in these studies, eletriptan was significantly superior to placebo (p <0.05). Japanese patients did demonstrate a higher placebo response than Westerners, possibly due to differences in previous triptan exposure or expectation. Adverse events were generally mild to moderate, were comparable in all three studies, and showed a modest dose-response effect.

Conclusion:The efficacy and tolerability of eletriptan for the acute treatment of migraine is comparable in Japan, Europe and the US.