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Hypercholesterolemia: HELP
Articles by Erik S. G. Stroes
Based on 23 articles published since 2010
(Why 23 articles?)
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Between 2010 and 2020, Erik Stroes wrote the following 23 articles about Hypercholesterolemia.
 
+ Citations + Abstracts
1 Review Lipoprotein(a): the revenant. 2017

Gencer, Baris / Kronenberg, Florian / Stroes, Erik S / Mach, François. ·Cardiology Division, Geneva University Hospitals, Switzerland. · Department of Medical Genetics, Division of Genetic Epidemiology, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Austria. · Academic Medical Center, Amsterdam, AZ 1100, The Netherlands. ·Eur Heart J · Pubmed #28329241.

ABSTRACT: In the mid-1990s, the days of lipoprotein(a) [Lp(a)] were numbered and many people would not have placed a bet on this lipid particle making it to the next century. However, genetic studies brought Lp(a) back to the front-stage after a Mendelian randomization approach used for the first time provided strong support for a causal role of high Lp(a) concentrations in cardiovascular disease and later also for aortic valve stenosis. This encouraged the use of therapeutic interventions to lower Lp(a) as well numerous drug developments, although these approaches mainly targeted LDL cholesterol, while the Lp(a)-lowering effect was only a 'side-effect'. Several drug developments did show a potent Lp(a)-lowering effect but did not make it to endpoint studies, mainly for safety reasons. Currently, three therapeutic approaches are either already in place or look highly promising: (i) lipid apheresis (specific or unspecific for Lp(a)) markedly decreases Lp(a) concentrations as well as cardiovascular endpoints; (ii) PCSK9 inhibitors which, besides lowering LDL cholesterol also decrease Lp(a) by roughly 30%; and (iii) antisense therapy targeting apolipoprotein(a) which has shown to specifically lower Lp(a) concentrations by up to 90% in phase 1 and 2 trials without influencing other lipids. Until the results of phase 3 outcome studies are available for antisense therapy, we will have to exercise patience, but with optimism since never before have we had the tools we have now to prove Koch's extrapolated postulate that lowering high Lp(a) concentrations might be protective against cardiovascular disease.

2 Clinical Trial Consistent LDL-C response with evolocumab among patient subgroups in PROFICIO: A pooled analysis of 3146 patients from phase 3 studies. 2018

Stroes, Erik / Robinson, Jennifer G / Raal, Frederick J / Dufour, Robert / Sullivan, David / Kassahun, Helina / Ma, Yuhui / Wasserman, Scott M / Koren, Michael J. ·Department of Vascular Medicine, Academic Medical Center of Amsterdam, Amsterdam, Netherlands. · Departments of Epidemiology and Medicine, University of Iowa, Iowa City, Iowa. · Department of Medicine, University of the Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa. · Institut de recherches cliniques de Montréal, Université de Montréal, Montreal, Canada. · Department of Clinical Biochemistry, Prince Alfred Hospital, Camperdown, Australia. · Amgen Inc., Thousand Oaks, California. · Jacksonville Center for Clinical Research, Jacksonville, Florida. ·Clin Cardiol · Pubmed #30120772.

ABSTRACT: BACKGROUND: Evolocumab significantly lowers low-density lipoprotein cholesterol (LDL-C) when dosed 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) subcutaneously. HYPOTHESIS: LDL-C changes are comparable among different patient subgroups in a pooled analysis of data from phase 3 trials. METHODS: A total of 3146 patients received ≥1 dose of evolocumab or control in four 12-week phase 3 studies. Percent change from baseline in LDL-C for evolocumab 140 mg Q2W or 420 mg QM vs control was reported as the average of week 10 and 12 values. Quantitative and qualitative interactions between treatment group and subgroup by dose regimen were tested. RESULTS: In the pooled analysis, treatment differences vs placebo or ezetimibe were similar for both 140 mg Q2W and 420 mg QM doses across ages (<65 years, ≥65 years); gender; race (Asian, black, white, other); ethnicity (Hispanic, non-Hispanic); region (Europe, North America, Asia Pacific); glucose tolerance status (type 2 diabetes mellitus, metabolic syndrome, neither); National Cholesterol Education Program risk categories (high, moderately high, moderate, low); and European Society of Cardiology/European Atherosclerosis Society risk categories (very high, high, moderate, or low). Certain low-magnitude variations in LDL-C lowering among subgroups led to significant quantitative interaction P values that, when tested by qualitative interaction, were not significant. The incidences of adverse events were similar across groups treated with each evolocumab dosing regimen or control. CONCLUSIONS: Consistent reductions in LDL-C were observed in the evolocumab group regardless of demographic and disease characteristics.

3 Clinical Trial Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study. 2016

Stroes, Erik / Guyton, John R / Lepor, Norman / Civeira, Fernando / Gaudet, Daniel / Watts, Gerald F / Baccara-Dinet, Marie T / Lecorps, Guillaume / Manvelian, Garen / Farnier, Michel / Anonymous730881. ·Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands e.s.stroes@amc.uva.nl. · Duke University Medical Center, Durham, NC. · Westside Medical Associates of Los Angeles Cedars-Sinai Heart Institute, Beverly Hills, CA. · Lipid Unit, Hospital Universitario Miguel Servet, IIS Aragon, Zaragoza, Spain. · ECOGENE-21 Clinical and Translational Research Center and Department of Medicine, Université de Montréal, Chicoutimi, Quebec, Canada. · Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. · Sanofi, Clinical Development, R&D, Montpellier, France. · Sanofi, Chilly-Mazarin, France. · Regeneron Pharmaceuticals Inc, Tarrytown, NY. · Lipid Clinic, Point Médical, Dijon, France. ·J Am Heart Assoc · Pubmed #27625344.

ABSTRACT: BACKGROUND: The PCSK9 antibody alirocumab (75 mg every 2 weeks; Q2W) as monotherapy reduced low-density lipoprotein-cholesterol (LDL-C) levels by 47%. Because the option of a monthly dosing regimen is convenient, ODYSSEY CHOICE II evaluated alirocumab 150 mg Q4W in patients with inadequately controlled hypercholesterolemia and not on statin (majority with statin-associated muscle symptoms), receiving treatment with fenofibrate, ezetimibe, or diet alone. METHODS AND RESULTS: Patients were randomly assigned to placebo, alirocumab 150 mg Q4W or 75 mg Q2W (calibrator arm), with dose adjustment to 150 mg Q2W at week (W) 12 if W8 predefined LDL-C target levels were not met. The primary efficacy endpoint was LDL-C percentage change from baseline to W24. Mean baseline LDL-C levels were 163.9 mg/dL (alirocumab 150 mg Q4W, n=59), 154.5 mg/dL (alirocumab 75 mg Q2W, n=116), and 158.5 mg/dL (placebo, n=58). In the alirocumab 150 mg Q4W and 75 mg Q2W groups (49.1% and 36.0% of patients received dose adjustment, respectively), least-squares mean LDL-C changes from baseline to W24 were -51.7% and -53.5%, respectively (placebo [+4.7%]; both groups P<0.0001 versus placebo). In total, 63.9% and 70.3% of alirocumab-treated patients achieved their LDL-C targets at W24. Treatment-emergent adverse events occurred in 77.6% (alirocumab 150 mg Q4W), 73.0% (alirocumab 75 mg Q2W), and 63.8% (placebo) of patients, with injection-site reactions among the most common treatment-emergent adverse events. CONCLUSIONS: Alirocumab 150 mg Q4W can be considered in patients not on statin with inadequately controlled hypercholesterolemia as a convenient option for lowering LDL-C. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02023879.

4 Clinical Trial Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia and LDL-C of 160 mg/dl or Higher. 2016

Ginsberg, Henry N / Rader, Daniel J / Raal, Frederick J / Guyton, John R / Baccara-Dinet, Marie T / Lorenzato, Christelle / Pordy, Robert / Stroes, Erik. ·Columbia University College of Physicians and Surgeons, Irving Institute for Clinical and Translational Research, Columbia University, 622 West 168th Street, New York, NY, 10032, USA. hng1@cumc.columbia.edu. · Departments of Medicine and Genetics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA. · Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa. · Duke University Medical Center, Durham, NC, USA. · Sanofi, Montpellier, France. · Sanofi, Paris, France. · Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. ·Cardiovasc Drugs Ther · Pubmed #27618825.

ABSTRACT: PURPOSE: Even with statins and other lipid-lowering therapy (LLT), many patients with heterozygous familial hypercholesterolemia (heFH) continue to have elevated low-density lipoprotein cholesterol (LDL-C) levels. ODYSSEY HIGH FH (NCT01617655) assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 monoclonal antibody, versus placebo in patients with heFH and LDL-C ≥ 160 mg/dl despite maximally tolerated statin ± other LLT. METHODS: Patients were randomized to subcutaneous alirocumab 150 mg or placebo every 2 weeks (Q2W) for 78 weeks. The primary endpoint was percent change in LDL-C from baseline to week 24. RESULTS: Mean baseline LDL-C levels were 196.3 mg/dl in the alirocumab (n = 71) and 201.0 mg/dl in the placebo groups (n = 35). Significant mean (standard error [SE]) reductions in LDL-C from baseline to week 24 were observed with alirocumab (-45.7 [3.5] %) versus placebo (-6.6 [4.9] %), a difference of -39.1 (6.0) % (P < 0.0001). Absolute mean (SE) LDL-C levels were reduced from baseline by 90.8 (6.7) mg/dl with alirocumab at week 24, with reductions maintained to week 78. Treatment-emergent adverse events were generally comparable between groups. Injection-site reactions were more frequent in the alirocumab group (8.3 %) versus placebo (5.7 %); most were mild in severity and did not result in study medication discontinuation. CONCLUSIONS: In patients with heFH and very high LDL-C baseline levels despite maximally tolerated statin ± other LLT, alirocumab 150 mg Q2W demonstrated significant reductions in LDL-C levels with 41 % of patients achieving predefined LDL-C goals. Alirocumab was generally well tolerated.

5 Clinical Trial Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin-Intolerant Patients: Design of the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3) Trial. 2016

Nissen, Steven E / Dent-Acosta, Ricardo E / Rosenson, Robert S / Stroes, Erik / Sattar, Naveed / Preiss, David / Mancini, G B John / Ballantyne, Christie M / Catapano, Alberico / Gouni-Berthold, Ioanna / Stein, Evan A / Xue, Allen / Wasserman, Scott M / Scott, Rob / Thompson, Paul D / Anonymous4710860. ·Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio. · Department of Clinical Development, and Biostatistics, Amgen Inc., Thousand Oaks, California. · The Cardiometabolic Disorders Unit, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands. · Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom. · Clinical Trial Service Unit and Epidemiological Services Unit, University of Oxford, Oxford, United Kingdom. · Department of Medicine, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Medicine, Baylor College of Medicine and Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, Texas. · Department of Pharmacological Sciences, University of Milan, and IRCCS Multimedica, Milan, Italy. · Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany. · Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio. · Department of Cardiology, Hartford Hospital, Hartford, Connecticut. ·Clin Cardiol · Pubmed #26946077.

ABSTRACT: Statins are the accepted standard for lowering low-density lipoprotein cholesterol (LDL-C). However, 5% to 10% of statin-treated patients report intolerance, mostly due to muscle-related adverse effects. Challenges exist to objective identification of statin-intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL-C reduction. We report the design of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3), a phase 3, multicenter, randomized, double-blind, ezetimibe-controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin-controlled, double-blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL-C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins (one of which was atorvastatin ≤10 mg/d) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin. This trial has 2 co-primary endpoints: mean percent change from baseline in LDL-C at weeks 22 and 24 and percent change from baseline in LDL-C at week 24. Key secondary efficacy endpoints include change from baseline in LDL-C, percent of patients attaining LDL-C <70 mg/dL (1.81 mmol/L), and percent change from baseline in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B. Recruitment of 511 patients was completed on November 28, 2014.

6 Clinical Trial Clinical Profile of Statin Intolerance in the Phase 3 GAUSS-2 Study. 2016

Cho, Leslie / Rocco, Michael / Colquhoun, David / Sullivan, David / Rosenson, Robert S / Dent, Ricardo / Xue, Allen / Scott, Rob / Wasserman, Scott M / Stroes, Erik. ·Preventive Cardiology and Rehabilitation, Cleveland Clinic, 9500 Euclid Ave. Desk JB1, Cleveland, OH, USA. chol@ccf.org. · Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Ave. Desk JB1, Cleveland, OH, USA. · Wesley Medical Centre, 40 Chasely Street, Auchenflower, Brisbane, 4066, QLD, Australia. · Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Building 65 Missenden Road, Camperdown, NSW, Australia. · Cardiometabolic Disorders, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, Box 1030, New York, NY, 10029, USA. · Amgen (Europe) GmbH, Dammstrasse 23, 6300, Zug, Switzerland. · Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA. · Department of Vascular Medicine, F4.211, Academic Medical Center, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands. ·Cardiovasc Drugs Ther · Pubmed #26936841.

ABSTRACT: PURPOSE: Recent evidence suggests that statin intolerance may be more common than reported in randomized trials. However, the statin-intolerant population is not well characterized. The goal of this report is to characterize the population enrolled in the phase 3 Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant Subjects Study (GAUSS-2; NCT 01763905). METHODS: GAUSS-2 compared evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) to ezetimibe in hypercholesterolemic patients who discontinued statin therapy due to statin-associated muscle symptoms (SAMS). GAUSS-2 was a 12-week, double-blind, placebo-controlled, randomized study that enrolled patients with elevated LDL-C who were either not on a statin or able to tolerate only a low-dose due to SAMS. Patients had received ≥2 statins and were unable to tolerate any statin dose or increase in dose above a specified weekly dose due to SAMS. RESULTS: Three hundred seven patients (mean [SD] age, 62 [10] years; 54 % males) were randomized 2:1 (evolocumab:ezetimibe). Mean (SD) LDL-C was 4.99 (1.51) mmol/L. Patients had used ≥2 (100 %), ≥3 (55 %), or ≥4 (21 %) statins. Coronary artery disease was present in 29 % of patients. Statin-intolerant symptoms were myalgia in 80 % of patients, weakness in 39 %, and more serious complications in 20 %. In 98 % of patients, SAMS interfered with normal daily activity; in 52 %, symptoms precluded moderate exertion. CONCLUSION: Evaluation of the GAUSS-2 trial population of statin-intolerant patients demonstrates that most patients were high risk with severely elevated LDL-C and many had statin-associated muscle symptoms that interfered with their quality of life.

7 Clinical Trial Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans. 2015

Mooij, Hans L / Bernelot Moens, Sophie J / Gordts, Philip L S M / Stanford, Kristin I / Foley, Erin M / van den Boogert, Marjolein A W / Witjes, Julia J / Hassing, H Carlijne / Tanck, Michael W / van de Sande, Michiel A J / Levels, J Han / Kastelein, John J P / Stroes, Erik S G / Dallinga-Thie, Geesje M / Esko, Jeff D / Nieuwdorp, Max. ·Department of Vascular Medicine. · Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA. · Department of Clinical Epidemiology, Biostatistics and Bioinformatics. · Department of Orthopedics, Leiden University Medical Center, Leiden, the Netherlands. · Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. · Department of Vascular Medicine Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. ·J Lipid Res · Pubmed #25568062.

ABSTRACT: Elevated nonfasting TG-rich lipoprotein levels are a risk factor for CVD. To further evaluate the relevance of LDL-receptor (LDLr) pathway and heparan sulfate proteoglycans (HSPGs) in TG homeostasis, we analyzed fasting and postprandial TG levels in mice bearing combined heterozygous mutations in both Exostosin (Ext) 1 and Ldlr, in subjects with hereditary multiple exostosis (HME) due to a heterozygous loss-of-function mutation in EXT1 or EXT2 (N = 13), and in patients with heterozygous mutations in LDLR [familial hypercholesterolemia (FH)] and SNPs in major HSPG-related genes (n = 22). Mice bearing a homozygous mutation in hepatic Ext1 exhibited elevated plasma TGs similar to mice lacking other key enzymes involved in HSPG assembly. Compound heterozygous mice lacking Ldlr and Ext1 showed synergy on plasma TG accumulation and postprandial clearance. In human subjects, a trend was observed in HME patients toward reduced postprandial TG clearance with a concomitant reduction in chylomicron clearance [area under the curve (AUC)-retinyl ester (RE) HME, 844 ± 127 vs. controls, 646 ± 119 nM/h, P = 0.09]. Moreover, in FH subjects with a high HSPG gene score, retinyl palmitate excursions were higher (AUC-RE, 2,377 ± 293 vs. 1,565 ± 181 nM/h, P < 0.05). Incremental AUC-apoB48 was similar between the groups. In conclusion, the data are supportive for a minor yet additive role of HSPG in human postprandial TG clearance, and further studies are warranted.

8 Clinical Trial Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. 2014

Stroes, Erik / Colquhoun, David / Sullivan, David / Civeira, Fernando / Rosenson, Robert S / Watts, Gerald F / Bruckert, Eric / Cho, Leslie / Dent, Ricardo / Knusel, Beat / Xue, Allen / Scott, Rob / Wasserman, Scott M / Rocco, Michael / Anonymous960790. ·Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. Electronic address: e.s.stroes@amc.uva.nl. · Wesley Medical Centre, Auchenflower, Australia. · Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, Australia. · Hospital Universitario Miguel Servet, Zaragoza, Spain. · Cardiometabolic Disorders Department, Icahn School of Medicine at Mount Sinai, New York, New York. · Lipid Disorders Clinic, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. · Hopital Pitie-Salpetriere, Paris, France. · Preventive Cardiology and Rehabilitation, Cleveland Clinic, Cleveland, Ohio. · Amgen, Thousand Oaks, California. · Cardiovascular Medicine Department, Cleveland Clinic, Cleveland, Ohio. ·J Am Coll Cardiol · Pubmed #24694531.

ABSTRACT: OBJECTIVES: This study sought to evaluate the efficacy and safety of subcutaneous evolocumab compared with oral ezetimibe in hypercholesterolemic patients who are unable to tolerate effective statin doses. BACKGROUND: Statin intolerance, which is predominantly due to muscle-related side effects, is reported in up to 10% to 20% of patients. Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), demonstrated marked reductions in plasma low-density lipoprotein cholesterol (LDL-C) in a phase 2 study in statin-intolerant patients. METHODS: The GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects) trial was a 12-week, double-blind study of randomized patients (2:2:1:1) to evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg. Co-primary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12, and at week 12. RESULTS: Three hundred seven patients (age 62 ± 10 years; LDL-C 193 ± 59 mg/dl) were randomized. Evolocumab reduced LDL-C from baseline by 53% to 56%, corresponding to treatment differences versus ezetimibe of 37% to 39% (p <0.001). Muscle adverse events occurred in 12% of evolocumab-treated patients and 23% of ezetimibe-treated patients. Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups. CONCLUSIONS: Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the largely unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant. (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2; NCT01763905).

9 Clinical Trial 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. 2014

Cho, Leslie / Rocco, Michael / Colquhoun, David / Sullivan, David / Rosenson, Robert S / Dent, Ricardo / Xue, Allen / Scott, Rob / Wasserman, Scott M / Stroes, Erik. ·Department of Preventive Cardiology and Rehabilitation, Cleveland Clinic, Cleveland, Ohio. ·Clin Cardiol · Pubmed #24477778.

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.

10 Clinical Trial Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. 2010

Akdim, Fatima / Stroes, Erik S G / Sijbrands, Eric J G / Tribble, Diane L / Trip, Mieke D / Jukema, J Wouter / Flaim, Joann D / Su, John / Yu, Rosie / Baker, Brenda F / Wedel, Mark K / Kastelein, John J P. ·Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. ·J Am Coll Cardiol · Pubmed #20378080.

ABSTRACT: OBJECTIVES: The aim of this study was to evaluate the efficacy and safety of mipomersen in hypercholesterolemic subjects taking stable statin therapy. BACKGROUND: Mipomersen is an apolipoprotein (apo) B synthesis inhibitor that has demonstrated significant reductions in apo B and low-density lipoprotein (LDL) cholesterol in Phase 1 clinical trials in healthy volunteers. METHODS: A randomized, placebo-controlled, dose-escalation Phase 2 study was designed to evaluate the effects of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Seventy-four subjects were enrolled sequentially into 1 of 6 dose cohorts at a 4:1 (active/placebo) ratio. Subjects received 7 doses of 30 to 400 mg over 5 weeks in the first 5 cohorts and 15 doses of 200 mg over 13 weeks in the sixth cohort. Pre-specified end points included percentage change from baseline in apo B and LDL cholesterol. Safety was assessed with laboratory test results and by the incidence and severity of adverse events. RESULTS: The apo B and LDL cholesterol were reduced by 19% to 54% and 21% to 52%, respectively, at doses of 100 mg/week mipomersen and higher in the 5-week treatment cohorts. Efficacy seemed to increase upon treatment for 13 weeks at a dose of 200 mg/week. Injection site reactions (mild to moderate erythema [90%]) and hepatic transaminase increases (17%) were the most common adverse events, leading to discontinuation in 2 subjects and 1 subject, respectively. In the 13-week treatment cohort, 5 of 10 subjects (50%) had elevations >or=3x the upper limit of normal, 4 of which persisted on 2 consecutive occasions. CONCLUSIONS: Mipomersen might hold promise for treatment of patients not reaching target LDL cholesterol levels on stable statin therapy. Further studies are needed to address the mechanisms and clinical relevance of transaminase changes after mipomersen administration. (Dose-Escalating Safety Study in Subjects on Stable Statin Therapy; NCT00231569).

11 Article Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. 2020

Ballantyne, Christie M / Laufs, Ulrich / Ray, Kausik K / Leiter, Lawrence A / Bays, Harold E / Goldberg, Anne C / Stroes, Erik Sg / MacDougall, Diane / Zhao, Xin / Catapano, Alberico L. ·Department of Medicine, Baylor College of Medicine, USA. · Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Germany. · Imperial Centre for Cardiovascular Disease Prevention, Imperial College London, UK. · Division of Endocrinology and Metabolism, St Michael's Hospital, Canada. · Louisville Metabolic and Atherosclerosis Research Center, USA. · Washington University School of Medicine, USA. · Department of Vascular Medicine, Academic Medical Centre, The Netherlands. · Esperion Therapeutics, Inc., USA. · Department of Pharmacological and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Italy. ·Eur J Prev Cardiol · Pubmed #31357887.

ABSTRACT: AIMS: The aim of this study was to evaluate the low-density lipoprotein cholesterol lowering efficacy and safety of a bempedoic acid 180 mg and ezetimibe 10 mg fixed-dose combination in patients with hypercholesterolemia and a high risk of cardiovascular disease receiving maximally tolerated statin therapy. METHODS: This phase 3, double-blind clinical trial enrolled adult patients at high risk of cardiovascular disease due to atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors. Patients were randomly assigned (2:2:2:1) to treatment with the fixed-dose combination, bempedoic acid 180 mg, ezetimibe 10 mg or placebo added to stable background statin therapy for 12 weeks. The primary efficacy endpoint was the percentage change from baseline to week 12 in low-density lipoprotein cholesterol. RESULTS: Among the 301 patients included in the primary analysis, the mean baseline low-density lipoprotein cholesterol level was 3.87 mmol/L (149.8 mg/dL). At week 12, the fixed-dose combination lowered low-density lipoprotein cholesterol (-36.2%) significantly more than placebo (1.8% (placebo-corrected difference -38.0%); CONCLUSION: The bempedoic acid and ezetimibe fixed-dose combination significantly lowered low-density lipoprotein cholesterol versus placebo or other oral monotherapies and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03337308.

12 Article Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance. 2019

Laufs, Ulrich / Banach, Maciej / Mancini, G B John / Gaudet, Daniel / Bloedon, LeAnne T / Sterling, Lulu Ren / Kelly, Stephanie / Stroes, Erik S G. ·1 Klinik und Poliklinik für Kardiologie Universitätsklinikum Leipzig Leipzig Germany. · 2 Department of Hypertension Medical University of Lodz Poland. · 3 Division of Cardiology University of British Columbia Vancouver British Columbia Canada. · 4 Lipidology Unit, Community Genomic Medicine Centre and ECOGENE-21 Department of Medicine Université de Montréal Saguenay Quebec Canada. · 5 Esperion Therapeutics, Inc. Ann Arbor MI. · 6 Department of Vascular Medicine Academic Medical Center of Amsterdam Netherlands. ·J Am Heart Assoc · Pubmed #30922146.

ABSTRACT: Background Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction. Bempedoic acid, a prodrug that is activated by a hepatic enzyme not present in skeletal muscle, inhibits ATP -citrate lyase, an enzyme upstream of β-hydroxy β-methylglutaryl-coenzyme A reductase in the cholesterol biosynthesis pathway. Methods and Results The phase 3, double-blind, placebo-controlled CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Serenity study randomized 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the lowest available dose) 2:1 to bempedoic acid 180 mg or placebo once daily for 24 weeks. The primary end point was mean percent change from baseline to week 12 in low-density lipoprotein cholesterol. The mean age was 65.2 years, mean baseline low-density lipoprotein cholesterol was 157.6 mg/dL, and 93% of patients reported a history of statin-associated muscle symptoms. Bempedoic acid treatment significantly reduced low-density lipoprotein cholesterol from baseline to week 12 (placebo-corrected difference, -21.4% [95% CI, -25.1% to -17.7%]; P<0.001). Significant reductions with bempedoic acid versus placebo were also observed in non-high-density lipoprotein cholesterol (-17.9%), total cholesterol (-14.8%), apolipoprotein B (-15.0%), and high-sensitivity C-reactive protein (-24.3%; P<0.001 for all comparisons). Bempedoic acid was safe and well tolerated. The most common muscle-related adverse event, myalgia, occurred in 4.7% and 7.2% of patients who received bempedoic acid or placebo, respectively. Conclusions Bempedoic acid offers a safe and effective oral therapeutic option for lipid lowering in patients who cannot tolerate statins. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02988115.

13 Article Achieved LDL cholesterol levels in patients with heterozygous familial hypercholesterolemia: A model that explores the efficacy of conventional and novel lipid-lowering therapy. 2018

Hartgers, Merel L / Besseling, Joost / Stroes, Erik S / Wittekoek, Janneke / Rutten, Joost H W / de Graaf, Jacqueline / Visseren, Frank L J / Imholz, Ben P M / Roeters van Lennep, Jeanine E / Huijgen, Roeland / Kastelein, John J P / Hovingh, G Kees. ·Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. · Landelijk Expertisecentrum Familiaire Hypercholesterolemie (LEEFH), Amsterdam, The Netherlands. · Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. · Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Internal Medicine, Elisabeth-TweeSteden Ziekenhuis, Tilburg, The Netherlands. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: g.k.hovingh@amc.uva.nl. ·J Clin Lipidol · Pubmed #29934068.

ABSTRACT: BACKGROUND: A large proportion of patients with heterozygous familial hypercholesterolemia (heFH) do not reach low-density lipoprotein cholesterol (LDL-c) levels advocated by international guidelines (<70 mg/dL or <100 mg/dL). OBJECTIVE: We set out to model which proportion of patients reach targets using conventional and novel therapies. METHODS: We performed a cross-sectional analysis in a large cohort of genetically identified heFH patients and calculated the proportion reaching treatment targets in four scenarios: (1) after 50% LDL-c reduction (representing maximal dose statin); (2) after 70% LDL-c reduction (maximal dose statin + ezetimibe); (3) additional 40% LDL-c reduction representing cholesteryl ester transfer protein inhibitor (CETPi); and (4) 60% LDL-c reduction (proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK9i]), on top of scenario 2. We applied 100% adherence rates and literature-based adherence rates from 62% to 80%. RESULTS: We included 1,059 heFH patients with and 9,420 heFH patients without coronary heart disease (CHD). With maximal dose statin, 8.3% and 48.1% of patients with and without CHD would reach their recommended LDL-c targets, respectively. This increases to 54.3% and 93.2% when ezetimibe is added. Addition of CETPi increases these numbers to 95.7% and 99.7%, whereas adding PCSK9i would result in 99.8% and 100% goal attainment. Using literature-based adherence rates, these numbers decrease to 3.8% and 27.3% for maximal dose statin, 5.8% and 38.9% combined with ezetimibe, 31.4% and 81.2% when adding CETPi, and 40.3% and 87.1% for addition of PCSK9i. CONCLUSIONS: Less than 10% with and 50% of heFH patients without CHD would reach treatment targets with maximal dose statin, but this substantially increases on addition of ezetimibe, CETPi, or PCSK9i. However, considering recently published adherence data, this might be lower in real life, especially in heFH patients with CHD.

14 Article Interplay between hypercholesterolaemia and inflammation in atherosclerosis: Translating experimental targets into clinical practice. 2018

Tuñón, José / Bäck, Magnus / Badimón, Lina / Bochaton-Piallat, Marie-Luce / Cariou, Bertrand / Daemen, Mat J / Egido, Jesus / Evans, Paul C / Francis, Sheila E / Ketelhuth, Daniel Fj / Lutgens, Esther / Matter, Christian M / Monaco, Claudia / Steffens, Sabine / Stroes, Erik / Vindis, Cécile / Weber, Christian / Hoefer, Imo E / Anonymous6390946. ·1 Fundación Jiménez Díaz, Autónoma University and CiberCV, Madrid, Spain. · 2 Karolinska University Hospital, Stockholm, Sweden. · 3 Karolinska Institutet, Stockholm, Sweden. · 4 Cardiovascular Sciences Institute (ICCC) and CiberCV, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. · 5 University of Geneva, Switzerland. · 6 L'Institut du Thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, France. · 7 Academic Medical Centre, Amsterdam, The Netherlands. · 8 Fundación Jiménez Díaz, Autónoma University and CIBERDEM, Madrid, Spain. · 9 University of Sheffield, UK. · 10 University of Amsterdam, The Netherlands. · 11 Institute for Cardiovascular Prevention, LMU Munich and German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Germany. · 12 University Heart Centre, University Hospital Zurich and Centre for Molecular Cardiology, University of Zurich, Switzerland. · 13 Kennedy Institute, NDORMS, University of Oxford, UK. · 14 INSERM UMR-1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France. · 15 Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands. · 16 University Medical Centre Utrecht, Netherlands. ·Eur J Prev Cardiol · Pubmed #29759006.

ABSTRACT: Dyslipidaemia and inflammation are closely interconnected in their contribution to atherosclerosis. In fact, low-density lipoprotein (LDL)-lowering drugs have anti-inflammatory effects. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) has shown that interleukin (IL)-1β blockade reduces the incidence of cardiovascular events in patients with previous myocardial infarction and C-reactive protein levels >2 mg/L. These data confirm the connection between lipids and inflammation, as lipids activate the Nod-like receptor protein 3 inflammasome that leads to IL-1β activation. LDL-lowering drugs are the foundation of cardiovascular prevention. Now, the CANTOS trial demonstrates that combining them with IL-1β blockade further decreases the incidence of cardiovascular events. However, both therapies are not at the same level, given the large evidence showing that LDL-lowering drugs reduce cardiovascular risk as opposed to only one randomized trial of IL-1β blockade. In addition, IL-1β blockade has only been studied in patients with C-reactive protein >2 mg/L, while the benefit of LDL-lowering is not restricted to these patients. Also, lipid-lowering drugs are not harmful even at very low ranges of LDL, while anti-inflammatory therapies may confer a higher risk of developing fatal infections and sepsis. In the future, more clinical trials are needed to explore whether targeting other inflammatory molecules, both related and unrelated to the IL-1β pathway, reduces the cardiovascular risk. In this regard, the ongoing trials with methotrexate and colchicine may clarify whether the cardiovascular benefit of IL-1β blockade extends to other anti-inflammatory mechanisms. A positive result would represent a major change in the future treatment of atherosclerosis.

15 Article PCSK9 inhibitors in clinical practice: Delivering on the promise? 2018

Stoekenbroek, Robert M / Hartgers, Merel L / Rutte, Roger / de Wijer, Douwe D / Stroes, Erik S G / Hovingh, G Kees. ·Department of Vascular Medicine, Academic Medical Center, 1100DD Amsterdam, The Netherlands. · Department of Vascular Medicine, Academic Medical Center, 1100DD Amsterdam, The Netherlands. Electronic address: g.k.hovingh@amc.uva.nl. ·Atherosclerosis · Pubmed #29254691.

ABSTRACT: BACKGROUND AND AIMS: In clinical trials, protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors robustly lowered LDL-cholesterol (LDL-c) and had a favorable tolerability and safety profile. Based on these findings, PCSK9 inhibitors are incorporated in updates of clinical treatment guidelines. However, trial results do not necessarily predict the effectiveness under real-world conditions. The aim of the current study is to determine the efficacy and tolerability of PCSK9 inhibitors in routine outpatient care. METHODS: The cohort comprised all patients who were prescribed evolocumab or alirocumab at the outpatient clinic of a large university hospital in the Netherlands. Eligible patients required additional lipid-lowering despite maximally tolerated statin therapy and ezetimibe, or were statin intolerant. Data were systematically collected during routine outpatient visits. RESULTS: The study included 238 patients of whom 67.2% had familial hypercholesterolemia (FH) and 42.9% were statin intolerant. The mean LDL-c reduction was 55.0% from a baseline of 4.4 mmol/L. LDL-c goals were attained by 62.3% of patients. Side effects were reported by 15.5% of patients and 2.5% discontinued treatment. No meaningful differences in efficacy or tolerability were observed between patients with FH or statin intolerance, or across treatment regimens. CONCLUSIONS: The observed lipid reductions and side effects profile of PCSK9 inhibitors in a routine care setting were comparable to observations in clinical trials.

16 Article Very low LDL-cholesterol concentrations achieved: which target is next? 2017

Hovingh, G Kees / Boekholdt, S Matthijs / Stroes, Erik S. ·Department of Vascular Medicine, Academic Medical Center, 1100DD Amsterdam, Netherlands. Electronic address: g.k.hovingh@amc.uva.nl. · Department of Cardiology, Academic Medical Center, 1100DD Amsterdam, Netherlands. · Department of Vascular Medicine, Academic Medical Center, 1100DD Amsterdam, Netherlands. ·Lancet · Pubmed #28859941.

ABSTRACT: -- No abstract --

17 Article Identification and Management of Statin-Associated Symptoms in Clinical Practice: Extension of a Clinician Survey to 12 Further Countries. 2017

Rosenson, Robert S / Gandra, Shravanthi R / McKendrick, Jan / Dent, Ricardo / Wieffer, Heather / Cheng, Lung-I / Catapano, Alberico L / Oh, Paul / Kees Hovingh, G / Stroes, Erik S. ·Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, MC1 Level, New York, NY, 10029, USA. robert.rosenson@mssm.edu. · Amgen Inc., Thousand Oaks, CA, USA. · PRMA Consulting, Fleet, Hampshire, UK. · University of Milano and IRCCS Multimedica, Milan, Italy. · Toronto Rehabilitation Institute, Toronto, ON, Canada. · Academic Medical Center, Amsterdam, the Netherlands. ·Cardiovasc Drugs Ther · Pubmed #28466399.

ABSTRACT: PURPOSE: Statins are the first-choice pharmacological treatment for patients with hypercholesterolemia and at risk for cardiovascular disease; however, a minority of patients experience statin-associated symptoms (SAS) and are considered to have reduced statin tolerance. The objective of this study was to establish how patients with SAS are identified and managed in clinical practice in Austria, Belgium, Colombia, Croatia, the Czech Republic, Denmark, Portugal, Switzerland, Russia, Saudi Arabia, Turkey, and the United Arab Emirates. METHODS: A cross-sectional survey was conducted (2015-2016) among clinicians (n = 60 per country; Croatia: n = 30) who are specialized/experienced in the treatment of hypercholesterolemia. Participants were asked about their experience of patients presenting with potential SAS and how such patients were identified and treated. RESULTS: Muscle-related symptoms were the most common presentation of potential SAS (average: 51%; range across countries [RAC] 17-74%); other signs/symptoms included persistent elevation in transaminases. To establish whether symptoms are due to statins, clinicians required rechallenge after discontinuation of statin treatment (average: 77%; RAC 40-90%); other requirements included trying at least one alternative statin. Clinicians reported that half of high-risk patients with confirmed SAS receive a lower-dose statin (average: 53%; RAC 43-72%), and that most receive another non-statin lipid-lowering therapy with or without a concomitant statin (average: 65%; RAC 52-83%). CONCLUSIONS: The specialists and GPs surveyed use stringent criteria to establish causality between statin use and signs or symptoms, and persevere with statin treatment where possible.

18 Article Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. 2016

Nissen, Steven E / Stroes, Erik / Dent-Acosta, Ricardo E / Rosenson, Robert S / Lehman, Sam J / Sattar, Naveed / Preiss, David / Bruckert, Eric / Ceška, Richard / Lepor, Norman / Ballantyne, Christie M / Gouni-Berthold, Ioanna / Elliott, Mary / Brennan, Danielle M / Wasserman, Scott M / Somaratne, Ransi / Scott, Rob / Stein, Evan A / Anonymous12560863. ·Cleveland Clinic, Cleveland, Ohio. · University of Amsterdam Faculty of Medicine, Amsterdam, the Netherlands. · Amgen Inc, Thousand Oaks, California. · School of Medicine at Mount Sinai, New York, New York. · Flinders University, Bedford Park, SA, Australia. · University of Glasgow, Glasgow, United Kingdom. · Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom8Epidemiological Services Unit, University of Oxford, Oxford, United Kingdom. · University Hospital of Paris 6, Paris, France. · Charles University in Prague, Prague, Czech Republic11General University Hospital in Prague, Prague, Czech Republic. · David Geffen School of Medicine at the University of California, Los Angeles. · Baylor College of Medicine, Houston, Texas. · Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany. · Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio. ·JAMA · Pubmed #27039291.

ABSTRACT: IMPORTANCE: Muscle-related statin intolerance is reported by 5% to 20% of patients. OBJECTIVE: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. DESIGN, SETTING, AND PARTICIPANTS: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. INTERVENTIONS: Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). MAIN OUTCOME AND MEASURES: Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. RESULTS: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7% (95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5% (95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8 mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). CONCLUSIONS AND RELEVANCE: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01984424.

19 Article Identification and management of patients with statin-associated symptoms in clinical practice: A clinician survey. 2016

Hovingh, G Kees / Gandra, Shravanthi R / McKendrick, Jan / Dent, Ricardo / Wieffer, Heather / Catapano, Alberico L / Oh, Paul / Rosenson, Robert S / Stroes, Erik S. ·Academic Medical Center, Department of Vascular Medicine, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands. Electronic address: g.k.hovingh@amc.uva.nl. · Amgen Inc., One Amgen Center Dr., MS 28-3-A, Thousand Oaks, CA 91320, USA. · PRMA Consulting Ltd, Cygnus House, 1 Waterfront Business Park, Fleet, Hampshire GU51 3QT, UK. · Department of Pharmacological and Biomolecular Sciences, University of Milan and IRCCS Multimedica, Via Balzaretti 9, Milan 20133, Italy. · Toronto Rehabilitation Institute, 347 Rumsey Road, Toronto, Ontario M4G 1R7, Canada. · Mount Sinai Heart, Mount Sinai Icahn School of Medicine, 1425 Madison Ave, MC1 Level, New York 10029, USA. · Academic Medical Center, Department of Vascular Medicine, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands. ·Atherosclerosis · Pubmed #26717273.

ABSTRACT: BACKGROUND AND AIMS: Discontinuation of statin therapy by patients with hypercholesterolemia because of the onset of side-effects (statin-associated symptoms [SAS]) increases the risk of cardiovascular morbidity and mortality. We aimed to understand how patients with SAS, particularly those with statin-associated muscle symptoms (SAMS), are identified and managed in the outpatient setting. METHODS: A web-based survey involving 60 clinicians in each of 12 countries and 90 clinicians in the US was conducted. Clinicians answered questions about the diagnostic criteria, estimated incidence of SAS, and choice of treatment for patients with SAS. RESULTS: Overall, 810 clinicians (78% cardiologists) completed the survey. An average of 72% of patients with potential SAS were reported to present with muscle-related symptoms (range across countries [RAC] 50-87%) that could be SAMS. Clinicians took a range of steps to confirm SAMS in these patients, including discontinuation of statin (average 59%; RAC 48-67%); re-challenge with ≥ 2 statins (average 74%; RAC 60-85%); modification of statin regimen (average 76%; RAC 65-85%); or a combination of these steps. Overall, 6% of patients with hypercholesterolemia were estimated to eventually have SAS (RAC 2-12%). In patients with SAS, on average 52% continued to receive a low-dose statin, usually with other lipid-lowering therapies (LLT). Of the remaining 49%, 38% received alternative LLT only; 11% did not receive any LLT. CONCLUSION: There is some consistency and stringency in clinical practice for identifying patients with SAS; however, a structured work-up for identification, followed by a defined therapeutic algorithm, may improve their management.

20 Article Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. 2015

Robinson, Jennifer G / Farnier, Michel / Krempf, Michel / Bergeron, Jean / Luc, Gérald / Averna, Maurizio / Stroes, Erik S / Langslet, Gisle / Raal, Frederick J / El Shahawy, Mahfouz / Koren, Michael J / Lepor, Norman E / Lorenzato, Christelle / Pordy, Robert / Chaudhari, Umesh / Kastelein, John J P / Anonymous5700823. ·From the University of Iowa, Iowa City (J.G.R.) · Point Médical, Dijon (M.F.), Centre Hospitalier Universitaire de Nantes-Hôpital Nord Laennec, Saint-Herblain (M.K.), University Hospital of Lille, Lille (G. Luc), and Sanofi, Chilly-Mazarin (C.L.) - all in France · Clinique des Maladies Lipidiques de Québec, Quebec, QC, Canada (J.B.) · Università di Palermo-Policlinico P. Giaccone, Palermo, Italy (M.A.) · the Department of Vascular Medicine, Academic Medical Center, Amsterdam (E.S.S., J.J.P.K.) · Lipid Clinic, Oslo University Hospital, Oslo (G. Langslet) · University of the Witwatersrand, Johannesburg (F.J.R.) · Cardiovascular Center of Sarasota, Sarasota (M.E.S.), and Jacksonville Center for Clinical Research, Jacksonville (M.J.K.) - both in Florida · Westside Medical Associates of Los Angeles, Beverly Hills, CA (N.E.L.) · Regeneron Pharmaceuticals, Tarrytown, NY (R.P.) · and Sanofi, Bridgewater, NJ (U.C.). ·N Engl J Med · Pubmed #25773378.

ABSTRACT: BACKGROUND: Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy. METHODS: We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24. RESULTS: At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02). CONCLUSIONS: Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831.).

21 Article Liver histology during Mipomersen therapy for severe hypercholesterolemia. 2014

Hashemi, Nikroo / Odze, Robert D / McGowan, Mary P / Santos, Raul D / Stroes, Erik S G / Cohen, David E. ·Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Genzyme Corporation, Cambridge, MA, USA; Department of Medicine, Division of Cardiology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. · Heart institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil. · Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. · Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: dcohen@partners.org. ·J Clin Lipidol · Pubmed #25499943.

ABSTRACT: BACKGROUND: Mipomersen is an antisense oligonucleotide that inhibits apolipoprotein B synthesis and lowers plasma low-density lipoprotein cholesterol even in the absence of low-density lipoprotein receptor function, presumably from inhibition of hepatic production of triglyceride-rich very low-density lipoprotein particles. By virtue of this mechanism, mipomersen therapy commonly results in the development of hepatic steatosis. Because this is frequently accompanied by alanine aminotransferase elevations, concern has arisen that mipomersen could promote the development of steatohepatitis, which could in turn lead to fibrosis and cirrhosis over time. OBJECTIVE: The objective of this study was to assess the liver biopsy findings in patients treated with mipomersen. METHODS: We describe 7 patients who underwent liver biopsy during the mipomersen clinical development programs. Liver biopsies were reviewed by a single, blinded pathologist. RESULTS: The histopathological features were characterized by simple steatosis, without significant inflammation or fibrosis. CONCLUSION: These findings suggest that hepatic steatosis resulting from mipomersen is distinct from nonalcoholic steatohepatitis.

22 Article Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. 2012

Visser, Maartje E / Wagener, Gilbert / Baker, Brenda F / Geary, Richard S / Donovan, Joanne M / Beuers, Ulrich H W / Nederveen, Aart J / Verheij, Joanne / Trip, Mieke D / Basart, Dick C G / Kastelein, John J P / Stroes, Erik S G. ·Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. ·Eur Heart J · Pubmed #22507979.

ABSTRACT: AIMS: A randomized, double-blind, placebo-controlled study was conducted to investigate the safety and efficacy of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, in patients who are statin intolerant and at high risk for cardiovascular disease (CVD). METHODS AND RESULTS: Thirty-three subjects, not receiving statin therapy because of statin intolerance, received a weekly subcutaneous dose of 200 mg mipomersen or placebo (2:1 randomization) for 26 weeks. The primary endpoint was per cent change in LDL cholesterol (LDL-c) from the baseline to Week 28. The other efficacy endpoints were per cent change in apoB and lipoprotein a [Lp(a)]. Safety was determined using the incidence of treatment-emergent adverse events (AEs) and clinical laboratory evaluations. After 26 weeks of mipomersen administration, LDL-c was reduced by 47 ± 18% (P < 0.001 vs. placebo). apoB and Lp(a) were also significantly reduced by 46 and 27%, respectively (P < 0.001 vs. placebo). Four mipomersen (19%) and two placebo subjects (17%) discontinued dosing prematurely due to AEs. Persistent liver transaminase increases ≥ 3× the upper limit of normal were observed in seven (33%) subjects assigned to mipomersen. In selected subjects, liver fat content was assessed, during and after treatment, using magnetic resonance spectroscopy. Liver fat content in these patients ranged from 0.8 to 47.3%. Liver needle biopsy was performed in two of these subjects, confirming hepatic steatosis with minimal inflammation or fibrosis. CONCLUSION: The present data suggest that mipomersen is a potential therapeutic option in statin-intolerant patients at high risk for CVD. The long-term follow-up of liver safety is required. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00707746.

23 Article Dalcetrapib: turning the tide for CETP inhibition? 2011

Stroes, Erik S G / van Wijk, Diederik F. ·Department of Vascular Medicine, Academisch Medisch Centrum, Meibergdreef, 1105 AZ Amsterdam, Netherlands. e.s.stroes@amc.uva.nl ·Lancet · Pubmed #21908039.

ABSTRACT: -- No abstract --