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Synthesis and LDL-C Lowering Efficacy of Ezetimibe Add-on Therapy†
286 160 Association of Statin Potency with Markers of Cholesterol Absorption/Synthesis and LDL-C Lowering Efficacy of Ezetimibe Add-on Therapy†
Journal of Clinical Lipidology, Vol 6, No 3, June 2012 produced greater reductions in absorption markers and smaller increases in synthesis markers than seen with medium and low potency statins. Despite these differences, ezetimibe add-on therapy appears to be equally effective in lowering LDL-C across all statin potency groups.
Ernst J. Schaefer, MD, Nuntakorn Thongtang, MD, Jianxin Lin, MS, Robert S. Lowe, PhD, Joanne E. Tomassini, PhD, Arvind K. Shah, PhD, Andrew M. Tershakovec, MD, MPH, (Boston, MA) Synopsis: Statins inhibit cholesterol synthesis but may also up-regulate cholesterol absorption. Studies evaluating markers of cholesterol metabolism suggest that cholesterol-lowering treatment efficacy may be the greatest with maximal inhibition of synthesis and limited compensatory increases in absorption. Ezetimibe is a selective cholesterol absorption inhibitor that also increases markers of cholesterol synthesis. Co-administration of ezetimibe with statins produces complementary effects and significantly greater reductions in LDL-C lowering than either drug alone. Purpose: To test the hypothesis that ezetimibe added to ongoing statin therapy would be most effective in lowering low-density lipoprotein cholesterol (LDL-C) in subjects on high-potency statins and that these effects would be related to alterations in markers of cholesterol absorption (bsitosterol, b-sitosterol/cholesterol) and synthesis (lathosterol, lathosterol/cholesterol). Methods: Post hoc analysis of the EASE study. Hypercholesterolemic subjects with LDL-C levels greater than NCEP ATP III recommended targets while on statin therapy were allocated to additional treatment with ezetimibe 10 mg/day or placebo for 6 weeks. A subset of subjects receiving ezetimibe (n 5 874) had baseline and on-treatment lathosterol and b-sitosterol measured in addition to standard lipids. Analysis of these data compared changes from baseline and versus placebo by ANOVA for low (n 5 133), medium (n 5 582); and high (n 5 159) statin potency subgroups on the basis of statin brand and dose. Results: Subjects on high potency statins had significantly lower baseline lathosterol levels (1.93 vs. 2.58 vs. 3.17 mmol/L; P , .001) and greater baseline b-sitosterol values (6.21 vs. 4.58 vs. 4.51 mmol/L, P ,.001) than those receiving medium and low-potency statins. Ezetimibe add-on treatment in the high potency group resulted in significantly greater reductions from baseline in LDL-C than mediumand low-potency groups (229.1% vs. 225.0% vs. 222.7%; P , .001) when evaluating unadjusted data. These effects and group differences were significantly (P , .05) related to greater reductions in beta-sitosterol, and smaller increases in lathosterol. However LDL-C reduction differences were no longer significant after controlling for placebo effects (P 5 .91), due mainly to modest LDL-C lowering by placebo in the high potency statin group. Conclusions: Patients on high-potency statins had the lowest levels of cholesterol synthesis markers and the highest levels of cholesterol absorption markers at baseline. Ezetimibe treatment in the high statin potency group
161 AMG 145, a Fully Human Monoclonal Antibody Against PCSK9, Reduces LDL-C in Healthy Volunteers and Patients on Stable Doses of Statins† Adam J. Shaywitz, MD, Clapton Dias, Brian Smith, Bing Gao, John Gibbs, Maurice Emery, Caroline Crispino, Ren Xu, Dina Stolman, Alexander Colbert, Marc Retter, Blaire Cooke, Stephen Uy, Karen Smirnakis, Scott M. Wasserman, Mark Matson, Evan Stein, (Thousand Oaks, CA) Synopsis: Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates surface expression of the lowdensity lipoprotein (LDL) receptor (LDL-R), increasing circulating LDL cholesterol (LDL-C). Statin therapy increases serum PCSK9 levels. AMG 145 is a fully human monoclonal antibody that binds PCSK9, preventing its interaction with LDL-R. Purpose: In 2 phase 1 studies, AMG 145 was evaluated for safety, tolerability, and effects on LDL-C and other lipids in healthy adults (phase 1a) and hypercholesterolemic adults on stable doses of statin therapy (phase 1b). Methods: Phase 1a subjects were randomized 3:1 (7 cohorts) to receive one subcutaneous (SC) or intravenous dose of AMG 145 or placebo. Phase 1b subjects, who were on stable doses of statins, were randomized 3:1 or 2:1 (7 cohorts) to receive multiple doses of SC AMG 145 or placebo; doses ranged from once weekly (6 doses) to once every 4 weeks (2 doses). Greater-dose cohorts were initiated sequentially once the tolerability of the lower dose was established. The phase 1b study also included a cohort of patients receiving highest approved doses of atorvastatin or
Journal of Clinical Lipidology, Vol 6, No 3, June 2012 produced greater reductions in absorption markers and smaller increases in synthesis markers than seen with medium and low potency statins. Despite these differences, ezetimibe add-on therapy appears to be equally effective in lowering LDL-C across all statin potency groups.
Ernst J. Schaefer, MD, Nuntakorn Thongtang, MD, Jianxin Lin, MS, Robert S. Lowe, PhD, Joanne E. Tomassini, PhD, Arvind K. Shah, PhD, Andrew M. Tershakovec, MD, MPH, (Boston, MA) Synopsis: Statins inhibit cholesterol synthesis but may also up-regulate cholesterol absorption. Studies evaluating markers of cholesterol metabolism suggest that cholesterol-lowering treatment efficacy may be the greatest with maximal inhibition of synthesis and limited compensatory increases in absorption. Ezetimibe is a selective cholesterol absorption inhibitor that also increases markers of cholesterol synthesis. Co-administration of ezetimibe with statins produces complementary effects and significantly greater reductions in LDL-C lowering than either drug alone. Purpose: To test the hypothesis that ezetimibe added to ongoing statin therapy would be most effective in lowering low-density lipoprotein cholesterol (LDL-C) in subjects on high-potency statins and that these effects would be related to alterations in markers of cholesterol absorption (bsitosterol, b-sitosterol/cholesterol) and synthesis (lathosterol, lathosterol/cholesterol). Methods: Post hoc analysis of the EASE study. Hypercholesterolemic subjects with LDL-C levels greater than NCEP ATP III recommended targets while on statin therapy were allocated to additional treatment with ezetimibe 10 mg/day or placebo for 6 weeks. A subset of subjects receiving ezetimibe (n 5 874) had baseline and on-treatment lathosterol and b-sitosterol measured in addition to standard lipids. Analysis of these data compared changes from baseline and versus placebo by ANOVA for low (n 5 133), medium (n 5 582); and high (n 5 159) statin potency subgroups on the basis of statin brand and dose. Results: Subjects on high potency statins had significantly lower baseline lathosterol levels (1.93 vs. 2.58 vs. 3.17 mmol/L; P , .001) and greater baseline b-sitosterol values (6.21 vs. 4.58 vs. 4.51 mmol/L, P ,.001) than those receiving medium and low-potency statins. Ezetimibe add-on treatment in the high potency group resulted in significantly greater reductions from baseline in LDL-C than mediumand low-potency groups (229.1% vs. 225.0% vs. 222.7%; P , .001) when evaluating unadjusted data. These effects and group differences were significantly (P , .05) related to greater reductions in beta-sitosterol, and smaller increases in lathosterol. However LDL-C reduction differences were no longer significant after controlling for placebo effects (P 5 .91), due mainly to modest LDL-C lowering by placebo in the high potency statin group. Conclusions: Patients on high-potency statins had the lowest levels of cholesterol synthesis markers and the highest levels of cholesterol absorption markers at baseline. Ezetimibe treatment in the high statin potency group
161 AMG 145, a Fully Human Monoclonal Antibody Against PCSK9, Reduces LDL-C in Healthy Volunteers and Patients on Stable Doses of Statins† Adam J. Shaywitz, MD, Clapton Dias, Brian Smith, Bing Gao, John Gibbs, Maurice Emery, Caroline Crispino, Ren Xu, Dina Stolman, Alexander Colbert, Marc Retter, Blaire Cooke, Stephen Uy, Karen Smirnakis, Scott M. Wasserman, Mark Matson, Evan Stein, (Thousand Oaks, CA) Synopsis: Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates surface expression of the lowdensity lipoprotein (LDL) receptor (LDL-R), increasing circulating LDL cholesterol (LDL-C). Statin therapy increases serum PCSK9 levels. AMG 145 is a fully human monoclonal antibody that binds PCSK9, preventing its interaction with LDL-R. Purpose: In 2 phase 1 studies, AMG 145 was evaluated for safety, tolerability, and effects on LDL-C and other lipids in healthy adults (phase 1a) and hypercholesterolemic adults on stable doses of statin therapy (phase 1b). Methods: Phase 1a subjects were randomized 3:1 (7 cohorts) to receive one subcutaneous (SC) or intravenous dose of AMG 145 or placebo. Phase 1b subjects, who were on stable doses of statins, were randomized 3:1 or 2:1 (7 cohorts) to receive multiple doses of SC AMG 145 or placebo; doses ranged from once weekly (6 doses) to once every 4 weeks (2 doses). Greater-dose cohorts were initiated sequentially once the tolerability of the lower dose was established. The phase 1b study also included a cohort of patients receiving highest approved doses of atorvastatin or