Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients

OBJECTIVE: To assess the lipid-altering efficacy and safety of ezetimibe/simvastatin single tablet product compared with rosuvastatin at the approved usual starting, next highest, and maximum doses. RESEARCH DESIGN AND METHODS: Double-blind, multicenter, 6-week, parallel-group study in hypercholesterolemic patients (n = 2959). Patients were randomized based on stratification by low-density lipoprotein cholesterol (LDL-C) levels to ezetimibe/simvastatin or rosuvastatin, respectively, at the usual starting (10/20 or 10 mg/day), the next highest (10/40 or 20 mg/day), and maximum doses (10/80 or 40 mg/day). RESULTS: At all doses and across doses, ezetimibe/simvastatin reduced LDL-C levels significantly more (52-61%) than rosuvastatin (46-57%; p < or = 0.001). Significantly greater percentages of all patients (p < 0.001) and high risk patients (p < or = 0.005) attained LDL-C levels < 70 mg/dL (1.8 mmol/L) following ezetimibe/simvastatin treatment compared with rosuvastatin at the prespecified doses and across doses. Ezetimibe/simvastatin also produced significantly greater reductions in total cholesterol (p < 0.001), non-high-density lipoprotein cholesterol (p < 0.001), lipid ratios (p < or = 0.003), and apolipoprotein B (p < 0.05). Reductions in triglycerides were significantly greater with ezetimibe/simvastatin than rosuvastatin at the usual starting (p = 0.004) and next highest (p = 0.006) doses, and across all doses (p < 0.001). Increases in high-density lipoprotein cholesterol, and decreases in high sensitivity C reactive protein (hsCRP) were similar between treatment groups. Safety profiles were comparable for both treatments; however, the percent of patients with proteinuria was significantly higher following rosuvastatin treatment than ezetimibe/simvastatin, respectively at 10 mg versus 10/20 mg/day (p = 0.004) and 40 mg versus 10/80 mg/day (p < 0.001). CONCLUSION: Ezetimibe/simvastatin was more effective than rosuvastatin in LDL-C lowering, and provided greater or comparable improvements in other lipid measures and hsCRP at the approved usual starting, next highest, and maximum doses in hypercholesterolemic patients. Although the doses compared in this study were not equivalent on a milligram basis, the results provide clinically relevant information regarding the use of these drugs for initial therapy and for subsequent use at higher doses when appropriate. Both treatments were generally well-tolerated; however, this study was not powered nor of sufficient duration to assess the prevalence of rare clinical adverse effects. Overall, ezetimibe/simvastatin offers an effective and tolerable treatment option for lipid management. An assessment of its full clinical benefit awaits evaluation in longer-term clinical studies

Combination therapy in dyslipidemia : where are we now?

Lowering low-density lipoprotein cholesterol (LDL-C) reduces the risk of cardiovascular disease: each 1.0mmol/L (38.7mg/dL) reduction in LDL-C reduces the incidence of major coronary events, coronary revascularizations, and ischemic stroke by approximately 20%. Statins are a well-established treatment option for dyslipidemia, with LDL-C reduction in the range of 27-55%.Several lipid goal-driven guidelines recommend reducing LDL-C to <2.59mmol/L (100mg/dL) or <1.81mmol/L (70mg/dL) in very high-risk patients. Many patients treated with statins do not reach these goals, and remain at risk of future cardiovascular events. The 2013 American College of Cardiology/American Heart Association guidelines move away from advocating LDL-C treatment targets with focus placed on identifying patients most likely to benefit from high-intensity or moderate-intensity statin therapy.While increasing the statin dose can prove efficacious in some patients, this approach typically offers limited additional LDL-C lowering, and is associated with increased incidence of adverse side effects. Indeed, this has led to the investigation of statins in combination with other lipid-modifying agents for the treatment of dyslipidemia.This review of the evidence for statin use in combination with fibrates, niacin, bile acid sequestrants, and the cholesterol absorption inhibitor, ezetimibe, in dyslipidemic patients at increased risk of cardiovascular disease, explores the impact of such combination therapies on lipids, attainment of lipid targets, inflammatory markers, and on cardiovascular outcomes and pathology. Additionally, new and emerging dyslipidemia treatments are summarized

Effect on Fasting Serum Glucose Levels of Adding Ezetimibe to Statins in Patients With Nondiabetic Hypercholesterolemia

Statin therapy is associated with a slightly increased risk of developing diabetes mellitus and insulin resistance in patients without diabetes. Ezetimibe combined with statins may be considered for high-risk patients who do not achieve optimal low-density lipoprotein cholesterol lowering on statin monotherapy or who are statin intolerant. Changes in fasting serum glucose (FSG) levels during ezetimibe, ezetimibe/statin, and statin treatments were assessed using data pooled from clinical trials in hypercholesterolemic and heterozygous familial hypercholesterolemic patients, who were or were not receiving statin therapy. Study types included first-line trials in statin-naive/wash-out patients and second-line add-on and uptitration studies in patients on stable statin therapy. Similar analyses of FSG changes were performed separately for each study type in patients who were nondiabetic at baseline. Across all study types and treatments, mean FSG increases from baseline were small (0.5 to 3.7\ua0mg/dl with ezetimibe/statin; 0.2 to 4.6\ua0mg/dl with statins) and decreased over time; between-treatment differences (0.3 to 1.4\ua0mg/dl) were nonsignificant for all comparisons. Proportions of patients with elevated FSG 65126\ua0mg/dl during therapy were low and similar for all treatments in the overall cohort (1.2% to 4.3%). Elevations were highest (3.3% to 25.7%) among patients with baseline factors characteristic of metabolic syndrome and prediabetes, including higher FSG, body mass index, and triglyceride levels, and numerically lower baseline high-density lipoprotein cholesterol; however, these factors were not related to FSG increases. Changes in low-density lipoprotein cholesterol, body mass index, high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B were not significantly correlated with FSG increases. In conclusion, statin therapy was associated with small FSG increases, and the addition of ezetimibe did not further increase FSG levels beyond those of statins when given to patients who are statin naive or those on statin therapy

Comparing remnant lipoprotein cholesterol measurement methods to evaluate efficacy of ezetimibe/statin vs statin therapy

Background: Elevated remnant lipoprotein cholesterol (RLP-C) levels increase cardiovascular disease risk. However, RLP-C measurement methods are not standardized, leading to variations across studies. Objective: To evaluate the effect of ezetimibe (Eze) + statins vs statin monotherapy on RLP-C using immunoseparation (IM), vertical auto profile (VAP) ultracentrifugation, and calculated RLP-C measurement methods. Methods: This post hoc analysis evaluated data pooled from 3 first-line (all-statin [simvastatin 10/20/40/80 mg] vs Eze + statin [Eze 10 mg + simvastatin]) and 2 second-line (statin [atorvastatin uptitrated to 40/80 mg] vs statin + Eze [atorvastatin 20/40 mg + Eze 10 mg]) studies. Similarity of RLP-C methods was evaluated using Pearson correlation coefficients and Bland-Altman plots. RLP-C changes and percent changes from baseline were measured by all 3 methods in first-line and VAP and calculated methods in second-line studies. Results: Correlations between methods were generally moderate to strong for RLP-C levels, changes, and percent changes across treatment groups (r = 0.29\u20130.79) but with little evidence of agreement by Bland-Altman plots. Baseline RLP-C levels for Eze + statin vs all-statin groups were lower by IM (14.0 vs 14.0) compared with VAP (36.9 vs 35.9) and calculated (32.8 vs 33.3) methods. RLP-C changes (mg/dL) and percent changes from baseline were significantly greater (P &lt; .01) with Eze + statins vs statins by VAP, calculated, and IM methods (between-treatment differences: 125.0 and 1212.0, 122.0 and 125.4, and 121.5 and 1212.1, respectively) in first-line, and VAP and calculated methods (between-treatment differences: 125.0 and 1219.9 and 122.0 and 127.3) in second-line studies. Conclusion: Although the 3 methods showed little agreement, each supported Eze + statins for achieving greater RLP-C reductions vs statin monotherapy; variability of results reinforces urgent need to standardize RLP-C measurements