DOCSLIB.ORG

Review of LDL-C Lowering with Focus on New and Emerging Agents

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Review of LDL-C Lowering with Focus on New and Emerging Agents Review of LDL-C Lowering with Focus on New and Emerging Agents Eliot A. Brinton, MD, FAHA, FNLA, FACE Disclosure Note: This CME activity includes discussion about medications not approved by the US Food and Drug Administration and uses of medications outside of their approved labeling. CONTINUING MEDICAL EDUCATION LEARNING OBJECTIVES Dr. Brinton serves on the advisory board METHOD OF PARTICIPATION • Identify the benefits and limitations of for Esperion, Amarin, 89bio, AstraZen- PHYSICIANS: To receive CME credit, statin therapy as a treatment option for eca, Kowa and Novartis, and on the please read the journal article and, on lowering LDL-C. speakers’ bureau for Amarin and Esper- completion, go to www.pceconsortium. • Intensify treatment in appropriate pa- ion. He is a grant recipient for Kowa. Dr. org/hyper to complete the online post-test tients or refer for intensification. Backes, editorial support, discloses that and receive your certificate of completion. • Describe the safety and efficacy of he serves on the speakers' bureau for PHYSICIAN ASSISTANTS AND NURSE ezetimibe, bempedoic acid, PCSK9 in- Kowa Pharmaceuticals. Dr. Scott, edito- PRACTITIONERS: AANP, ANCC, and hibitors, LDL apheresis. rial support, discloses that he has no real AAPA accept certificates of participation • Describe the safety and efficacy of or apparent conflicts of interest to report. of educational activities certified for AMA medications in late-stage development PRA Category 1 Credit™ from organiza- or under review by the FDA for LDL-C SPONSORSHIP tions accredited by ACCME. reduction. This activity is sponsored by Primary Care Education Consortium, in collabo- SUPPORT TARGET AUDIENCE ration with the Primary Care Metabolic This article is supported by an educa- Family physicians and clinicians who Group. tional grant from Novartis Pharmaceutical wish to gain increased knowledge and Corporation. greater competency regarding primary ACCREDITATION care management of hyperlipidemia. The Primary Care Education Consortium FACULTY is accredited by the ACCME to pro- DISCLOSURES vide continuing medical education for Eliot Brinton MD, FAHA, FNLA, FACE, Past President, American Board of Clini- As a continuing medical education pro- physicians. cal Lipidology, President, Utah Lipid Cen- vider accredited by the ACCME, PCEC ter, Salt Lake City, UT. requires any individual in a position to CREDIT DESIGNATION influence educational content to disclose AMA PRA Category 1 – Primary Care Ed- ACKNOWLEDGMENT any financial interest or other personal ucation Consortium designates this en- relationship with any commercial interest. during material for a maximum of 1.0 AMA Editorial support was provided by Jim Mechanisms are in place to identify and PRA Category 1 credit(s)™. Physicians Backes, PharmD, and Gregory Scott, resolve any potential conflict of interest should claim only the credit commensu- PharmD, RPh of PCEC. prior to the start of the activity. In addi- rate with the extent of their participation in tion, any discussion of off-label, experi- the activity. CME is available September mental, or investigational use of drugs or 1, 2020 to August 31, 2021. devices will be disclosed by the faculty. INTRODUCTION ASCVD risk.4-8 Further, extensive mechanistic data strongly There is growing consensus that the “LDL Hypothesis” has support a causal role for LDL in atherogenesis.9 Causation is been proven. First, essentially every well-conducted cardio- further supported by several Mendelian randomization stud- vascular outcomes trial (CVOT) with low-density lipopro- ies of a wide variety of genetic conditions, which have consis- tein cholesterol (LDL-C)-lowering has also shown reduction tently reported decreased or increased ASCVD risk related to in atherosclerotic cardiovascular disease (ASCVD). This is genetically decreased or increased LDL-C, respectively. true not only for the many CVOTs with statins, but also for This first section of this review will discuss familial hyper- at least 5 other classes of medications as well as 3 non-phar- cholesterolemia (FH), the most important disease of elevated macological treatments.1-3 Meta-analyses of these trials show LDL-C levels, in the context of other causes of LDL-C eleva- a log-linear relationship between on-treatment LDL-C and tions. Next, it will discuss risk assessment and stratification, Supplement to The Journal of Family Practice | Vol 69, No 7 | SEPTEMBER 2020 S69 REVIEW OF LDL-C LOWERING relevant to decision-making for LDL-C lowering treatment. major ASCVD events (acute coronary syndrome within the Next, LDL-C lowering medications will be covered, begin- past 12 months, heart attack, ischemic stroke, or symptomatic ning with statins, which are by far the best-established agents peripheral arterial disease) or one such event plus ≥2 high- and which are universally used as first-line treatment for risk conditions (age ≥65 years, HeFH, history of coronary LDL-C lowering and ASCVD prevention. Finally, existing and revascularization [outside of a major ASCVD event], diabetes emerging statin adjuncts will be discussed, regarding their mellitus [DM], chronic kidney disease, hypertension, smok- use in management of patients who cannot achieve appro- ing, congestive heart failure, or LDL-C ≥100 mg/dL despite priate LDL-C control with a statin alone. maximally-tolerated statin therapy). These patients warrant maximally-tolerated statin therapy followed by ezetimibe FAMILIAL HYPERCHOLESTEROLEMIA and then a PCSK9i mAb for LDL-C ≥70 mg/dL. FH may be the single most common monogenic disease,10 Patients with a prior event who do not meet these crite- with the prevalence of heterozygous FH (HeFH) estimated ria are termed “not very high-risk ASCVD” and are divided by to be ~1/200 patients in the general population,11 and homo- age ≤75 or >75 years. In the former group, treatment is similar zygous FH (HoFH) being rare, at roughly 1/300,000.12 HeFH to that for very high-risk but PCSK9i are not indicated. For the typically presents with untreated LDL-C levels ≥190 mg/ former group, high- or moderate-intensity statins are war- dL, Achilles tendon xanthomas (after ~40 years old), and a ranted, whereas for patients age >75 years, statin continuation positive family history of LDL-C >190 mg/dL and premature may be considered, but initiation of statin therapy is not said ASCVD. In contrast, patients with HoFH typically present to be warranted. That said, a CVOT with ezetimibe in patients with LDL-C levels >500 mg/dL and widespread xanthomas age >75 years (EWTOPIA, see below) was first reported at the or even a CV event in childhood.13 time of the presentation of the 2018 Multi-Society guidelines. The 2018 American College of Cardiology (ACC)/Ameri- The results of EWTOPIA showed convincing ASCVD benefit can Heart Association (AHA)/National Lipid Association with ezetimibe monotherapy, which should, therefore, be (NLA) Multi-Society Guideline on the Management of Blood considered in these patients. Cholesterol recommends that patients age 20 to 75 years The 2018 guidelines also state that, for patients without without ASCVD but with an LDL-C ≥190 mg/dL should be a prior ASCVD event, those with DM and age 40-75 years treated with maximally tolerated statin therapy to achieve should receive at least moderate-intensity statin therapy an LDL-C reduction >50%. Further, statin adjuncts are to be regardless of calculated ASCVD risk. High-intensity statins considered for secondary prevention if LDL-C remains above are warranted in patients with DM in the setting of multiple a treatment threshold of 70 mg/dL for very high-risk and 100 additional risk factors, independent of age. Treatment of mg/dL for high-risk patients.14 The addition of ezetimibe is patients age 40-75 years without prior ASCVD, DM, or FH the first of statin-adjunct. In patients failing to achieve an may be guided by the estimated 10-year ASCVD risk score. LDL-C decrease of 50%, or with LDL-C remaining above For risk <5%, lifestyle is sufficient. For risk 5% to 20%, mod- 100 mg/dL, with both a statin and ezetimibe, use of a pro- erate-intensity statins are usually recommended, depend- protein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) ing on the presence and number of ASCVD “risk enhancers” may then be considered.15 For HoFH, early identification [eg, family history of premature ASCVD, South Asian ances- and referral to a lipid specialist is needed. Treatment is more try, metabolic syndrome, Lp(a) or triglycerides, renal insuf- aggressive than for HeFH in that more than 1 statin adjunct is ficiency and/or inflammatory conditions/markers]. For a always required, and usually also LDL-apheresis (also used 10-year ASCVD risk ≥20%, statins are always warranted, with for more severe HeFH) and sometimes lomitapide (indicated a goal to reduce LDL-C by ≥50%.14 only for HoFH) as well. BEYOND STATINS RISK STRATIFICATION AND PATIENT SELECTION A key question for clinicians is: What is the overarching strat- FOR STATINS AND STATIN ADJUNCTS egy for LDL-C lowering? In contrast to treatment of hyperten- Risk stratification is crucial, first, to identify which patients sion or type 2 DM, where overtreatment is always a practical warrant consideration of statin therapy, then to determine concern, there is good evidence for additional benefit and no the appropriate level of statin intensity, and finally, to direct harm from treatment to very low LDL-C levels. Patient cost any needed use of statin adjuncts. and inconvenience, and side effects of LDL-lowering medi- For patients with
Load more

Recommended publications
  • Download This PDF File
    Journal of Cardiology and Therapy Online Submissions: http: //www.ghrnet.org/index./jct/ Journal of Cardiol Ther 2021 January; 8(1): 967-970 DOI: 10.17554/j.issn.2309-6861.2021.08.183 ISSN 2309-6861(print), ISSN 2312-122X(online) REVIEW The Role of Non-statin Therapy to Improve Cardiovascular Outcomes Abdulhalim Jamal Kinsara1, FRCP, FACC,FESC; Domenico Galzerano2, FESC; Olga Vriz2, MD 1 Ministry of National Guard-Health Affairs, King Saud Bin Ab- disease risk, while other therapy are showing less evidence. The dulaziz University for Health Sciences, COM-WR, King Abdullah current review highlights the evidence related to non-statins in the International Medical Research Center, Jeddah, Saudi Arabia; reduction of CV outcomes. 2 King Faisal Specialist Hospital and Research Centre and Alfaisal University. Key words: Ezetimibe; Proprotein convertase subtilisin kexin type 9 Inhibitor; Lomitapide; Mipomersen; Inclisiran; Bempedoic acid; Conflict-of-interest statement: The author(s) declare(s) that there Nexletol & Nexlizet; Bile acid sequestrants; Fibrates; Nicotinic acid; is no conflict of interest regarding the publication of this paper. Plasmapheresis Open-Access: This article is an open-access article which was © 2021 The Author(s). Published by ACT Publishing Group Ltd. All selected by an in-house editor and fully peer-reviewed by external rights reserved. reviewers. It is distributed in accordance with the Creative Com- mons Attribution Non Commercial (CC BY-NC 4.0) license, which Kinsara AJ, Galzerano D, Vriz O. The Role of Non-statin Therapy permits others to distribute, remix, adapt, build upon this work non- to Improve Cardiovascular Outcomes. Journal of Cardiology and commercially, and license their derivative works on different terms, Therapy 2021; 8(1): 967-970 Available from: URL: http://www.
    [Show full text]
  • Intervention to Improve LDL Receptor Function Emerging Therapies
    Intervention to improve LDL receptor function Emerging Therapies Marina Cuchel, MD, PhD Perelman School of Medicine University of Pennsylvania Most Lipid Lowering Drugs Affect LDL-C Levels By Up-Regulating the LDLR B100 apoB MTP VLDL TG TG statins ezetimibe bile acid sequestrants IDL PCSK9 -inhibitors LDL TG Cuchel NLA 2017 Do we really need more LDL-C lowering drugs? • LDL-C still not a goal with existing LLTs in a significant portion of subjects • Drug intolerance (statins) • Cost of new treatments • Other reasons Cuchel NLA 2017 Outline • PCSK9 – beyond monoclonal antibodies • ETC-1002 – inhibiting upstream HMGCoAR • Replacing LDLR - Gene therapy • ANGPTL3 inhibitors and other drug affecting LDL production Cuchel NLA 2017 PCSK9 enhances LDLR degradation Cuchel NLA 2017 Use of PCSK9i is complementary to that of statins PCSK9i evolucumab alirocumab [other monoclonal ABs] statins HMG-CoA ↑LDLR ↑PCSK9 ↓LDL-C ↓Cholesterol Cuchel NLA 2017 PCSK9 inhibition is very effective in lowering LDL-C Sabatine MS et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1615664 Cuchel NLA 2017 PCSK9 – beyond monoclonal Antibodies • Monoclonal PCSK9i are expensive • Require high doses • Are injectable • ?May lose responsiveness over time? Cuchel NLA 2017 Targeting PCSK9 with novel strategies • Vaccines • siRNA • Small molecules Cuchel NLA 2017 Targeting PCSK9 with novel strategies Vaccines antibodies response SREBP-2 pathway ↑ HMGCoA Red ↑ LDL-R Target protein ↑Epitope PCSK9 identification Conjugation with Administration Antibodies foreign peptide production Clinicaltrials.gov NCT02508896 Cuchel NLA 2017 Vaccine against PCSK9 lowers LDL-C in primates Crossey E. Vaccine, 2015 , 33, 5747–5755 Cuchel NLA 2017 Targeting PCSK9 with novel strategies siRNA SREBP-2 pathway ↑ HMGCoA Red ↑ LDL-R ↓PCSK9 Gene silencing Clinicaltrials.gov NCT02597127, NCT02314442 Cuchel NLA 2017 The RNAi inhibitor of PCSK9 - inclisiran - lowers PCSK9 and LDL-C levels in humans Ray KK et al.
    [Show full text]
  • Bempedoic Acid and Inclisiran for Patients with Heterozygous Familial Hypercholesterolemia and for Secondary Prevention of ASCVD: Effectiveness and Value
    Bempedoic Acid and Inclisiran for Patients with Heterozygous Familial Hypercholesterolemia and for Secondary Prevention of ASCVD: Effectiveness and Value Draft Evidence Report November 12, 2020 Prepared for ©Institute for Clinical and Economic Review, 2020 ICER Staff and Consultants Modeling Team Grace A. Lin, MD, MAS Dhruv S. Kazi, MD, MSc, MS Associate Professor of Medicine and Health Policy Associate Director, Smith Center for Outcomes University of California, San Francisco Research in Cardiology Director, Cardiac Critical Care Unit Jane Jih, MD, MPH Beth Israel Deaconess Medical Center Assistant Professor, Division of General Internal Associate Professor, Harvard Medical School Medicine University of California, San Francisco Foluso Agboola, MBBS, MPH Director, Evidence Synthesis Dr. Kazi was responsible for the development of the ICER cost-effectiveness model, interpretation of results, and drafting of the economic sections of this report; the Rick Chapman, PhD, MS resulting ICER reports do not necessarily represent the Director of Health Economics views of Beth Israel Deaconess Medical Center or ICER Harvard Medical School. Steven D. Pearson, MD, MSc President ICER DATE OF PUBLICATION: November 12, 2020 How to cite this document: Lin GA, Kazi DS, Jih J, Agboola F, Chapman R, Pearson SD. Inclisiran and Bempedoic Acid for Patients with Heterozygous Familial Hypercholesterolemia and for Secondary Prevention of ASCVD: Effectiveness and Value; Draft Evidence Report. Institute for Clinical and Economic Review, November 12, 2020. https://icer-review.org/material/high-cholesterol-update- draft-evidence-report/ Grace Lin served as the lead author for the report and wrote the background, other benefits, and contextual considerations sections of the report, with Jane Jih serving as a co-author.
    [Show full text]
  • Assessment Report
    15 October 2020 EMA/696912/2020 Committee for Medicinal Products for Human Use (CHMP) Assessment report Leqvio International non-proprietary name: inclisiran Procedure No. EMEA/H/C/005333/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us An agency of the European Union Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 © European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged. Administrative information Name of the medicinal product: Leqvio applicant: Novartis Europharm Limited Vista Building Elm Park Merrion Road Dublin 4 IRELAND Active substance: INCLISIRAN International Non-proprietary Name/Common inclisiran Name: Pharmaco-therapeutic group lipid modifying agents, plain, other lipid (ATC Code): modifying agents (C10AX) treatment for primary hypercholesterolaemia Therapeutic indication(s): or mixed dyslipidaemia Pharmaceutical form(s): Solution for injection Strength(s): 284 mg Route(s) of administration: Subcutaneous use Packaging: pre-filled syringe (glass) Package size(s): 1 pre-filled syringe Assessment report EMA/696912/2020 Page 2/143 Table of contents 1. Background information on the procedure ............................................ 12 1.1. Submission of the dossier ...................................................................................
    [Show full text]
  • The Effectiveness and Value of Bempedoic Acid and Inclisiran for Heterozygous Familial Hypercholesterolemia and Secondary Prevention of ASCVD
    PERSPECTIVES ON VALUE 961 The effectiveness and value of bempedoic acid and inclisiran for heterozygous familial hypercholesterolemia and secondary prevention of ASCVD A summary from the Institute for Clinical and Economic Review’s Midwest Comparative Effectiveness Public Advisory Council Foluso Agboola, MBBS, MPH; Grace A Lin, MD, MAS; Dhruv S Kazi, MD, MSc, MS; Avery McKenna; and Steven D Pearson, MD, MSc Atherosclerotic cardiovascular dis- necessary, a proprotein convertase ease (ASCVD) encompasses a set of subtilisin/kexin type 9 (PCSK9) inhib- Author affiliations 9 chronic conditions that includes coro- itor is recommended. Foluso Agboola, MBBS, MPH; Avery nary artery disease, peripheral artery A new option for lowering choles- McKenna; and Steven D Pearson, MD, disease, cerebrovascular disease, and terol is bempedoic acid (combined MSc, Institute for Clinical and Economic aortic atherosclerotic disease. In the with ezetimibe [Nexlizet] or with- Review, Boston, MA. Grace A Lin, MD, United States, ASCVD affects approxi- out ezetimibe [Nexletol], Esperion MAS, Division of General Internal mately 1 in 10 people; represents a high Therapeutics, Inc.), which was Medicine and Philip R. Lee Institute risk for future major adverse cardio- approved by the US Food and Drug for Health Policy Studies, University of California, San Francisco. Dhruv S Kazi, vascular events (MACE), such as heart Administration (FDA) in February MD, MSc, MS, Smith Center for Outcomes attacks and strokes; and is the leading 2020. Bempedoic acid is an inhibitor of Research in Cardiology, Beth Israel 1,2 cause of death. adenosine triphosphate (ATP) citrate Deaconess Medical Center and Harvard Heterozygous familial hypercholes- lyase that lowers LDL-C by reduc- Medical School, Boston, MA.
    [Show full text]
  • Inclisiran 284Mg Solution for Injection in Pre-Filled Syringe (Leqvio®)
    1 www.scottishmedicines.org.uk SMC2358 inclisiran 284mg solution for injection in pre-filled syringe (Leqvio®) Novartis Pharmaceuticals UK Limited 09 July 2021 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHSScotland. The advice is summarised as follows ADVICE: following a full submission inclisiran (Leqvio®) is accepted for use restricted use within NHSScotland. Indication under review: for adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet: • in combination with a statin or statin with other lipid lowering therapies in patients who are unable to reach LDL-C goals with the maximum tolerated dose of a statin, or • alone or in combination with other lipid lowering therapies in patients who are statin intolerant, or for whom a statin is contraindicated. SMC restriction: for specialist use only in patients at high cardiovascular risk as follows: • patients with heterozygous familial hypercholesterolaemia (HeFH) and LDL-C ≥5.0mmol/L, for primary prevention of cardiovascular events or, • patients with HeFH and LDL-C≥3.5mmol/L, for secondary prevention of cardiovascular events or, • patients with high risk due to previous cardiovascular events and LDL-C≥4.0mmol/L or, • patients with recurrent/polyvascular disease and LDL-C≥3.5mmol/L. In three phase III studies, both the percentage reduction in LDL-C to day 510 and the time- adjusted percentage in LDL-C from day 90 to day 540 were significantly larger with inclisiran compared with placebo.
    [Show full text]
  • December 11, 2020 Maggie O'grady Program Manager Institute For
    December 11, 2020 Maggie O’Grady Program Manager Institute for Clinical and Economic Review 2 Liberty Square, 9th Floor Boston, MA 02109 Submitted Electronically: [email protected]; [email protected] Dear Ms. O’Grady, Thank you for the opportunity to provide feedback to ICER on its draft evidence report for assessing the comparative clinical effectiveness and value of inclisiran (Novartis) and bempedoic acid (Nexletol™, Esperion Therapeutics, Inc.) for treatment of high cholesterol in the setting of heterozygous familial hypercholesterolemia (HeFH) and for secondary prevention of atherosclerotic cardiovascular disease (ASCVD). We appreciate your willingness to review comments and recommendations from the National Forum’s Value & Access Steering Committee and partners working on these issues. The Value & Access (V&A) Steering Committee and partners operate under the consensus goal to enhance health and well-being by supporting people’s access to evidence-based care that is appropriate for them by: • Identifying evidence-based strategies for determining appropriateness of care • Supporting the implementation of evidence-based care that aligns incentives for patients, providers, payers, other stakeholders The (V&A) Steering Committee and partners jointly offer the following feedback for ICER’s consideration in the development of the draft evidence report. Positives The Steering Committee and partners appreciate ICER’s inclusion in the draft evidence report of our recommendations on the draft scoping document : • That ICER’s value framework includes both quantitative and qualitative comparisons across treatments to ensure that the full range of benefits and harms (e.g., health disparities and access to care issues) are evaluated. We encourage ICER to continue increasing patient advocacy groups’ involvement in the process through direct outreach to groups with expertise in areas of focus, opportunities for meetings with ICER and its experts, and enhanced explanation of ICER’s processes.
    [Show full text]
  • The Current Landscape of Nucleic Acid Therapeutics
    REVIEW ARTICLE https://doi.org/10.1038/s41565-021-00898-0 The current landscape of nucleic acid therapeutics Jayesh A. Kulkarni 1,2,3,7, Dominik Witzigmann 2,3,4,7, Sarah B. Thomson 1, Sam Chen5, Blair R. Leavitt 1, Pieter R. Cullis 2,4 and Roy van der Meel 6 ✉ The increasing number of approved nucleic acid therapeutics demonstrates the potential to treat diseases by targeting their genetic blueprints in vivo. Conventional treatments generally induce therapeutic effects that are transient because they target proteins rather than underlying causes. In contrast, nucleic acid therapeutics can achieve long-lasting or even curative effects via gene inhibition, addition, replacement or editing. Their clinical translation, however, depends on delivery technologies that improve stability, facilitate internalization and increase target affinity. Here, we review four platform technologies that have enabled the clinical translation of nucleic acid therapeutics: antisense oligonucleotides, ligand-modified small interfering RNA conjugates, lipid nanoparticles and adeno-associated virus vectors. For each platform, we discuss the current state-of-the-art clinical approaches, explain the rationale behind its development, highlight technological aspects that facilitated clinical trans- lation and provide an example of a clinically relevant genetic drug. In addition, we discuss how these technologies enable the development of cutting-edge genetic drugs, such as tissue-specific nucleic acid bioconjugates, messenger RNA and gene-editing therapeutics. early half a century ago, Friedmann and Roblin concep- include Strimvelis—patient-derived CD34+ cells transduced with a tualized that inherited genetic disorders resulting in dys- γ-retroviral vector to express DNA encoding the human adenosine functional gene products could be treated by introducing deaminase (ADA) enzyme, treating severe combined immunode- N 1 5 a functional gene copy .
    [Show full text]
  • Inclisiran: a New Promising Agent in the Management of Hypercholesterolemia
    diseases Review Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia Constantine E. Kosmas 1,*, Alba Muñoz Estrella 2, Andreas Sourlas 3, Delia Silverio 4, Elizabeth Hilario 4, Peter D. Montan 4 and Eliscer Guzman 5 1 Department of Medicine, Division of Cardiology, Mount Sinai Hospital, New York, NY 11357, USA 2 Department of Medicine, Mount Sinai St. Luke’s-West Hospital, New York, NY 10025, USA; [email protected] 3 School of Medicine, University of Crete, 71003 Heraklion, Greece; [email protected] 4 Cardiology Clinic, Cardiology Unlimited, PC, New York, NY 10033, USA; [email protected] (D.S.); [email protected] (E.H.); [email protected] (P.D.M.) 5 Department of Medicine, Division of Cardiology, Montefiore Medical Center, Bronx, NY 10467, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-646-734-7969 Academic Editor: Ahmed Bakillah Received: 29 June 2018; Accepted: 11 July 2018; Published: 13 July 2018 Abstract: The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9), a serine protease which binds to the low-density lipoprotein (LDL) receptors and targets the receptors for lysosomal degradation, offered an additional route through which plasma LDL-cholesterol (LDL-C) levels can be controlled. Initially, the therapeutic approaches to reduce circulating levels of PCSK9 were focused on the use of monoclonal antibodies. To that effect, evolocumab and alirocumab, two human monoclonal antibodies directed against PCSK9, given on a background of statin therapy, have been shown to markedly decrease LDL-C levels and significantly reduce cardiovascular risk. The small interfering RNA (siRNA) molecules have been used recently to target the hepatic production of PCSK9.
    [Show full text]
  • Riktige Legemidler Til Rett Pris Områdegjennomgang Av Legemidler Under Folketrygden
    Rapport 2021/01 | For Helse- og omsorgsdepartementet og Finansdepartementet Riktige legemidler til rett pris Områdegjennomgang av legemidler under folketrygden Dag Morten Dalen, Mari Brekke Holden, Øyvind Lian, Ingeborg Rasmussen og Andreas Skulstad Riktige legemidler til rett pris. Dokumentdetaljer Tittel Riktige legemidler til rett pris. Områdegjennomgang av legemidler under folketrygden Rapportnummer 2021/01 ISBN 978-82-8126-504-2 Forfattere Dag Morten Dalen, Mari Brekke Holden, Øyvind Lian, Ingeborg Rasmussen og Andreas Skulstad Prosjektleder Ingeborg Rasmussen Kvalitetssikrer Steinar Strøm og Finn Holm Oppdragsgiver Finansdepartementet og Helse og omsorgsdepartementet Dato for overlevering 7. januar 2021 Tilgjengelighet Offentlig. Oppdragsgiver fastsetter dato for offentliggjøring Nøkkelord Legemiddeløkonomi, samfunnsøkonomi, regulering og konkurranseøko- nomi Om Vista Analyse Vista Analyse AS er et samfunnsfaglig analyseselskap med hovedvekt på økonomisk utredning, evaluering, rådgivning og forskning. Vi utfører oppdrag med høy faglig kvalitet, uavhengighet og integritet. Våre sentrale temaområder er klima, energi, samferdsel, næringsutvikling, byutvikling og velferd. Vista Analyse er vinner av Evalueringsprisen 2018. Våre medarbeidere har meget høy akademisk kompetanse og bred erfaring innenfor konsulentvirksomhet. Ved be- hov benytter vi et velutviklet nettverk med selskaper og ressurspersoner nasjonalt og internasjonalt. Selskapet er i sin helhet eiet av medarbeiderne. Om EY EY er en ledende global aktør innen revisjon, skatt og avgift, transaksjoner og rådgivning. Gjennom kontinuerlig fokus på kvalitet bygger vi tillit i kapitalmarkedene og i økonomier over hele verden. Gjennom å utvikle gode ledere som forplikter seg til å levere det vi lover bidrar vi til å bygge et bedre arbeidsliv for våre ansatte, kunder og lokalsamfunn. Vårt nettverk omfatter mer enn 280 000 ansatte i 150 land.
    [Show full text]
  • Download Info Sheet
    Why may I need to take medications that lower my blood lipids? The short answer is that even after changing your diet and sticking to an exercise program, you may still have cholesterol or triglyceride (kinds of ® lipids or “fats” in your blood) levels that are too high for your health. This can put you at risk for having heart problems in the future. Taking certain medication(s) in addition to leading a healthy lifestyle can decrease your low-density lipoprotein (LDL) cholesterol level, your triglyceride level, or both. High levels of cholesterol, especially LDL-cholesterol, can cause health problems such as heart attack and stroke. Medicines that lower LDL-cholesterol The most common medications that are used to lower LDL-cholesterol levels are medicines from the STATIN family. These are the medications ending in “statin” such as atorvastatin or rosuvastatin. Statins work by blocking cholesterol from being made in the liver. Statins are very effective but sometimes people don’t tolerate them or need additional medications to get to the ideal LDL-cholesterol level recommended by their doctor. If you are on a statin and or are unable to take a statin, there are other ways to lower your LDL-cholesterol. Drugs often work in different ways to lower cholesterol and triglycerides. However, You can learn more about statins generally, they either reduce absorption, decrease production, or increase disposal of at – just cholesterol and triglycerides to help you achieve healthy levels of both. That, in part, LearnYourLipids.com is why your doctor may recommend combinations of drugs to help you stay healthy.
    [Show full text]
  • Lipidology Trials - What’S New and What’S in the Pipeline?
    Lipidology Trials - What’s New and What’s in the Pipeline? Professor Basil S. Lewis, MD, FRCP, FACC, FESC Past Chairman, WG on Cardiovascular Pharmacotherapy European Society of Cardiology SUPPORTED BY AN EDUCATIONAL GRANT FROM AMGEN and NOVARTIS Declaration of Conflict Of Interest I have the following potential conflict(s) of interest to report Type of affiliation / financial interest Name of commercial company Receipt of grants/research support: AstraZeneca, Bayer Healthcare, MSD, Resverlogix, KOWA, Pfizer Receipt of honoraria or consultation fees: Bayer Healthcare, MSD, Pfizer, Novo Nordisk Participation in a company sponsored Pfizer, Novo Nordisk speaker’s bureau: Challenges in Lipidology Trials • What is the pathophysiology? • What are the targets? • LDL? HDL? TG? LP(a)? • Relation between lipidology, atherosclerosis and CV events? • Time discrepancies? • What are the end-points? • Surrogate endpoints? Plasma lipids? Plaque volume? Extent of disease? • Can these guide in early/late phases of drug development? • Outcome events – This is what matters! • What is the comparator? • Keeping pace with a rapidly evolving field Targets • Targeting LDL • PCSK9 Inhibitors (FOURIER, SPIRE, ODYSSEY) • RNA interference (RNAi) to reduce PCSK9 (ORION) • Decreasing LDL synthesis - Bempedoic acid • Targeting HDL • CETP inhibitors • Epigenetics - BET on MACE program • Apo-A1 infusion – AEGIS program • Targeting triglycerides • REDUCE-IT • PROMINENT • New - Targeting ANGPTL3 (inh of lipoprotein lipase) IMPROVE-IT - Proves again the LDL Hypothesis IMPROVE-IT
    [Show full text]