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Design and rationale of the GAUSS-2 study trial: a double-blind, ezetimibe-controlled phase 3 study of the efficacy and tolerability of evolocumab (AMG 145) in subjects with hypercholesterolemia who are intolerant of statin therapy.
Cho, L, Rocco, M, Colquhoun, D, Sullivan, D, Rosenson, RS, Dent, R, Xue, A, Scott, R, Wasserman, SM, Stroes, E
Clinical cardiology. 2014;(3):131-9
Abstract
Statins effectively lower low-density lipoprotein cholesterol (LDL-C), reducing cardiovascular morbidity and mortality. Most patients tolerate statins well, but approximately 10% to 20% experience side effects (primarily muscle-related) contributing to diminished compliance or discontinuation of statin therapy and subsequent increase in cardiovascular risk. Statin-intolerant patients require more effective therapies for lowering LDL-C. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a compelling target for LDL-C-lowering therapy. Evolocumab (AMG 145) is a fully human monoclonal antibody that binds PCSK9, inhibiting its interaction with the LDL receptor to preserve LDL-receptor recycling and reduce LDL-C. Phase 2 studies have demonstrated the safety, tolerability, and preliminary efficacy of subcutaneous evolocumab in diverse populations, including statin-intolerant patients. This article describes the rationale and design of the Goal Achievement After Utilizing an anti-PCSK9 Antibody in Statin-Intolerant Subjects 2 (GAUSS-2) trial, a randomized, double-blind, ezetimibe-controlled, multicenter phase 3 study to evaluate the effects of 12 weeks of evolocumab 140 mg every 2 weeks or 420 mg every month in statin-intolerant patients with hypercholesterolemia. Eligible subjects were unable to tolerate effective doses of ≥2 statins because of myalgia, myopathy, myositis, or rhabdomyolysis that resolved with statin discontinuation. The primary objective of the study is to assess the effects of evolocumab on percentage change from baseline in LDL-C. Secondary objectives include evaluation of safety and tolerability, comparison of the effects of evolocumab vs ezetimibe on absolute change from baseline in LDL-C, and percentage changes from baseline in other lipids. Recruitment of approximately 300 subjects was completed in August 2013.
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Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial.
Roth, EM, Taskinen, MR, Ginsberg, HN, Kastelein, JJ, Colhoun, HM, Robinson, JG, Merlet, L, Pordy, R, Baccara-Dinet, MT
International journal of cardiology. 2014;(1):55-61
Abstract
BACKGROUND Efficacy and safety of alirocumab were compared with ezetimibe in hypercholesterolemic patients at moderate cardiovascular risk not receiving statins or other lipid-lowering therapy. METHODS In a Phase 3, randomized, double-blind, double-dummy study (NCT01644474), patients (low-density lipoprotein cholesterol [LDL-C] 100-190 mg/dL, 10-year risk of fatal cardiovascular events ≥ 1%-<5% [systemic coronary risk estimation]) were randomized to ezetimibe 10mg/day (n=51) or alirocumab 75 mg subcutaneously (via 1-mL autoinjector) every 2 weeks (Q2W) (n=52), with dose up-titrated to 150 mg Q2W (also 1 mL) at week 12 if week 8 LDL-C was ≥ 70 mg/dL. Primary endpoint was mean LDL-C % change from baseline to 24 weeks, analyzed using all available data (intent-to-treat approach, ITT). Analyses using on-treatment LDL-C values were also conducted. RESULTS Mean (SD) baseline LDL-C levels were 141.1 (27.1) mg/dL (alirocumab) and 138.3 (24.5) mg/dL (ezetimibe). The 24-week treatment period was completed by 85% of alirocumab and 86% of ezetimibe patients. Least squares mean (SE) LDL-C reductions were 47 (3)% with alirocumab versus 16 (3)% with ezetimibe (ITT; p<0.0001) and 54 (2)% versus 17 (2)% (on-treatment; p<0.0001). At week 12, before up-titration, alirocumab 75 mg Q2W reduced LDL-C by 53 (2)% (on-treatment). Injection site reactions were infrequent (<2% and <4% of alirocumab and ezetimibe patients, respectively). CONCLUSIONS Alirocumab demonstrated significantly greater LDL-C lowering versus ezetimibe after 24 weeks with the lower 75 mg Q2W dose sufficient to provide ≥ 50% LDL-C reduction in the majority of the patients. Adverse events were comparable between groups.
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Clinical usefulness of additional treatment with ezetimibe in patients with coronary artery disease on statin therapy. - From the viewpoint of cholesterol metabolism.-.
Okada, K, Kimura, K, Iwahashi, N, Endo, T, Himeno, H, Fukui, K, Kobayashi, S, Shimizu, M, Iwasawa, Y, Morita, Y, et al
Circulation journal : official journal of the Japanese Circulation Society. 2011;(10):2496-504
Abstract
BACKGROUND Ezetimibe-plus-statin therapy has been reported to provide greater reduction in low-density lipoprotein cholesterol (LDL-C) level than statin monotherapy. The aim of the present study was to evaluate the relationship between LDL-C lowering effect and baseline cholesterol absorption and synthesis markers in patients with coronary artery disease (CAD). METHODS AND RESULTS A total of 171 patients with CAD whose LDL-C level was ≥ 100 mg/dl after treatment with atorvastatin (10mg/day) or rosuvastatin (2.5 mg/day) for 4 weeks were assigned to additionally receive ezetimibe (10mg/day) plus a statin or a double dose of statin for 12 weeks. The decreases in LDL-C (-30.0 ± 15.6 mg/dl vs. -19.2 ± 14.2 mg/dl) and the ratio of campesterol, an absorption marker, to total cholesterol levels (-1.35 ± 0.90 µg/mg vs. 0.33 ± 0.74 µg/mg) were greater in the ezetimibe-plus-statin group (P<0.05, respectively). The decrease in LDL-C level in the ezetimibe-plus-statin group was greatest in patients with baseline levels of higher absorption and lower synthesis markers and smallest in patients with baseline levels of lower absorption and higher synthesis markers (-34.3 ± 15.6 mg/dl vs. -21.5 ± 16.7 mg/dl, P<0.05). The decrease in LDL-C did not differ, irrespective of baseline levels of cholesterol absorption and synthesis markers, in the double-dose statin group, and was similar to that in patients with lower absorption and higher synthesis markers in the ezetimibe-plus-statin group. CONCLUSIONS Ezetimibe-plus-statin therapy may be useful for lowering LDL-C level, irrespective of baseline levels of cholesterol absorption and synthesis markers.
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Influence of ezetimibe monotherapy on ischemia-modified albumin levels in hypercholesterolemic patients.
Kotani, K, Caccavello, R, Sakane, N, Miyamoto, M, Gugliucci, A
Pharmacological reports : PR. 2011;(5):1248-51
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Ischemia-modified albumin (IMA) is considered to be a novel biochemical marker for ischemic and atherosclerotic conditions. This study aimed to investigate the influence of ezetimibe monotherapy on circulating IMA levels in hypercholesterolemic patients. A total of 31 patients (mean age 65.7 years) received 10 mg of ezetimibe daily during a 12-week treatment period. The levels of low-density lipoprotein cholesterol and IMA were significantly reduced after ezetimibe treatment. The adjusted regression analyses revealed that the changes in the IMA levels were not significantly correlated with those of the other atherosclerotic risk markers, such as body mass index, blood pressure, glucose and lipid panels. The significant reduction of the IMA levels following ezetimibe treatment, which was independent of the reduction of low-density lipoprotein cholesterol levels, suggests that ezetimibe may improve the oxidative stress burden in hypercholesterolemic patients.
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Efficacy of ezetimibe as monotherapy or combination therapy in hypercholesterolemic patients with and without diabetes.
Kishimoto, M, Sugiyama, T, Osame, K, Takarabe, D, Okamoto, M, Noda, M
The journal of medical investigation : JMI. 2011;(1-2):86-94
Abstract
Ezetimibe selectively inhibits dietary and biliary cholesterol absorption and reduces serum cholesterol levels when administered alone (monotherapy) and along with common lipid-regulating agents (combination therapy). To evaluate the effect of ezetimibe therapy on the lipid profile, glucose metabolism, and levels of cholesterol absorption and synthesis markers, we administered 10 mg ezetimibe to 50 hypercholesterolemic patients with or without diabetes. The serum levels of low-density lipoprotein cholesterol and total cholesterol were significantly reduced at 4 and 12 weeks of ezetimibe therapy in diabetic patients of both the monotherapy and combination-therapy groups and in nondiabetic patients of the combination-therapy group. The serum levels of the cholesterol absorption markers were significantly reduced, while those of the cholesterol synthesis markers were significantly increased at 12 weeks of ezetimibe therapy. No significant differences were noted in the values of the parameters of glucose metabolism in all patients. We also investigated the clinical characteristics of patients who exhibited a good response to ezetimibe (ezetimibe responders); however, multivariate regression analysis did not reveal a correlation between ezetimibe efficacy and patient characteristics such as gender, age, BMI, diabetic condition, method of ezetimibe administration, and the initial absolute values of cholesterol absorption/synthesis markers levels. In conclusion, ezetimibe therapy significantly improved the lipid profile without disturbing glucose metabolism. We were unable to identify the specific characteristics of ezetimibe responders among our subjects. However, we may interpret this result as suggesting that ezetimibe can be used in any population to lower low-density lipoprotein cholesterol levels.
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Lipid-lowering effects of ezetimibe for hypercholesterolemic patients with and without type 2 diabetes mellitus.
Okada, K, Yagyu, H, Kotani, K, Miyamoto, M, Osuga, J, Nagasaka, S, Ishibashi, S
Endocrine journal. 2010;(10):903-8
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To date, there are very few clinical reports that have compared the effects of ezetimibe on lipid parameters between hypercholesterolemic patients with and without type 2 diabetes mellitus (T2DM). In this study, we recruited patients for hypercholesterolemic groups with T2DM (n = 42; men/women = 24/18; HbA1c = 6.7 ± 5.4%) and without T2DM (n = 21; men/women = 7/14; HbA1c = 5.3 ± 0.4%). Patients were prescribed ezetimibe at a dose of 10 mg/daily for the course of the 12-week study. At baseline and after 12 weeks of treatment, several lipid parameters, including serum low-density-lipoprotein cholesterol (LDL-C), non-high-density-lipoprotein cholesterol (non-HDL-C), high-sensitivity C-reactive protein (hs-CRP), and cholesterol synthesis/absorption-related markers, were measured. Compared with those at the baseline, the levels of LDL-C, non-HDL-C, campesterol, and sitosterol were significantly reduced after 12 weeks of ezetimibe treatment in both groups. After adjusting for confounding factors, such as age, gender, smoking, and BMI, the levels of LDL-C and non-HDL-C displayed significantly greater reductions in the patients with T2DM (-25.1 ± 13.6% in LDL-C, -20.5 ± 11.2% in non-HDL-C) than those without T2DM (-20.5 ± 7.8% in LDL-C, P < 0.05; -17.4 ± 7.6% in non-HDL-C, P < 0.05). The reduction of the level of cholestanol was significantly and positively correlated with those of LDL-C and non-HDL-C in the patients with T2DM. Taken together, these findings indicate that ezetimibe could reduce the levels of atherogenic lipoproteins to a greater extent in hypercholesterolemic patients with T2DM than in those without T2DM.
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Indices of cholesterol metabolism and relative responsiveness to ezetimibe and simvastatin.
Lakoski, SG, Xu, F, Vega, GL, Grundy, SM, Chandalia, M, Lam, C, Lowe, RS, Stepanavage, ME, Musliner, TA, Cohen, JC, et al
The Journal of clinical endocrinology and metabolism. 2010;(2):800-9
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CONTEXT The level and duration of exposure to circulating low-density lipoprotein-cholesterol (LDL-C) are major contributors to coronary atherosclerosis. Therefore, optimal prevention will require long-term LDL-C reduction, making it important to select the most effective agent for each individual. OBJECTIVE We tested the hypothesis that individuals with high fractional absorption of cholesterol respond better to the cholesterol absorption inhibitor ezetimibe than to simvastatin, whereas low absorbers, who have elevated rates of cholesterol synthesis, respond better to simvastatin. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled, crossover trial was performed in 215 African- and European-American men. INTERVENTION Participants were randomized to placebo, ezetimibe (10 mg/d), simvastatin (10 mg/d), and both drugs for 6 wk each. MAIN OUTCOME Plasma levels of LDL-C, surrogate markers for cholesterol absorption (campesterol) and synthesis (lathosterol), and proprotein convertase subtilisin-like kexin type 9 were measured at baseline and after treatment. RESULTS LDL-C levels were reduced by 19% (ezetimibe), 25% (simvastatin), and 41% (ezetimibe+simvastatin) from a baseline of 146 +/- 20 mg/dl; results were similar between ethnic groups. Reduction in LDL-C correlated poorly with baseline levels of noncholesterol sterols and proprotein convertase subtilisin-like kexin type 9. Although individual responses varied widely, change in LDL-C on ezetimibe correlated with response to simvastatin (r = 0.46, P < 0.001). Combination therapy lowered LDL-C by 15% or greater in more than 95% of participants. CONCLUSIONS Baseline cholesterol absorption and synthesis did not predict responsiveness to LDL-lowering drugs. Responsiveness to simvastatin and ezetimibe were highly correlated, suggesting that factors downstream of the primary sites of action of these drugs are a major determinant of response.
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Effects of ezetimibe on remnant-like particle cholesterol, lipoprotein (a), and oxidized low-density lipoprotein in patients with dyslipidemia.
Nozue, T, Michishita, I, Mizuguchi, I
Journal of atherosclerosis and thrombosis. 2010;(1):37-44
Abstract
AIM: Ezetimibe is a novel cholesterol absorption inhibitor that reduces the level of low-density lipoprotein (LDL)-cholesterol (C). The effects of ezetimibe on remnant-like particle (RLP)-C, lipoprotein (a) [Lp(a)], and oxidized LDL (Ox-LDL) levels have not been examined. METHODS Fifty patients with dyslipidemia were treated with 10 mg/day of ezetimibe. At baseline and 12 weeks after treatment with ezetimibe, we measured the levels of RLP-C, Lp(a), Ox-LDL, and high-sensitivity C-reactive protein (hs-CRP). RESULTS The mean levels of total cholesterol (TC), LDL-C, triglycerides (TG), and apolipoprotein (apo) B, respectively, showed a significant decrease from 229+/-39 to 191+/-37 mg/dL (-16%, p<0.0001), from 151+/-34 to 118+/-33 mg/dL (-22%, p<0.0001), from 162+/-82 to 135+/-55 mg/dL (-7%, p<0.01), and from 116+/-22 to 94+/-21 mg/dL (-18%, p<0.0001) after 12 weeks of treat-ment with ezetimibe. The mean level of RLP-C and median level of hs-CRP also decreased signifi-cantly from 6.8+/-4.0 to 4.8+/-2.5 mg/dL (-21%, p<0.0001) and from 0.6 to 0.4 mg/L (-33%, p<0.05). The median level of Lp(a) decreased significantly from 14 to 10 mg/dL (-29%, p<0.05) in patients treated with ezetimibe monotherapy. CONCLUSIONS Ezetimibe was effective for reducing the levels of TC, LDL-C, TG, and RLP-C. Ezeti-mibe could be a potential therapeutic option for decreasing the Lp(a) level.
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Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial.
Fleg, JL, Mete, M, Howard, BV, Umans, JG, Roman, MJ, Ratner, RE, Silverman, A, Galloway, JM, Henderson, JA, Weir, MR, et al
Journal of the American College of Cardiology. 2008;(25):2198-205
Abstract
OBJECTIVES This secondary analysis from the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial examines the effects of lowering low-density lipoprotein cholesterol (LDL-C) with statins alone versus statins plus ezetimibe on common carotid artery intima-media thickness (CIMT) in patients with type 2 diabetes and no prior cardiovascular event. BACKGROUND It is unknown whether the addition of ezetimibe to statin therapy affects subclinical atherosclerosis. METHODS Within an aggressive group (target LDL-C 40 years of age receiving statins plus ezetimibe versus statins alone. The CIMT changes in both aggressive subgroups were compared with changes in the standard subgroups (target LDL-C RESULTS Mean (95% confidence intervals) LDL-C was reduced by 31 (23 to 37) mg/dl and 32 (27 to 38) mg/dl in the aggressive group receiving statins plus ezetimibe and statins alone, respectively, compared with changes of 1 (-3 to 6) mg/dl in the standard group (p < 0.0001) versus both aggressive subgroups. Within the aggressive group, mean CIMT at 36 months regressed from baseline similarly in the ezetimibe (-0.025 [-0.05 to 0.003] mm) and nonezetimibe subgroups (-0.012 [-0.03 to 0.008] mm) but progressed in the standard treatment arm (0.039 [0.02 to 0.06] mm), intergroup p < 0.0001. CONCLUSIONS Reducing LDL-C to aggressive targets resulted in similar regression of CIMT in patients who attained equivalent LDL-C reductions from a statin alone or statin plus ezetimibe. Common carotid artery IMT increased in those achieving standard targets. (Stop Atherosclerosis in Native Diabetics Study [SANDS]; NCT00047424).