DOCSLIB.ORG

Raising High-Density Lipoprotein Levels: out with the New, in with the Old?

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Raising High-Density Lipoprotein Levels: out with the New, in with the Old? James V. Felicetta, MD Editor-in-Chief Raising High-Density Lipoprotein Levels: Out with the New, In with the Old? ecent years have witnessed a HDL levels might not be all they were And the lipid benefits of niacin don’t tremendous interest in phar- cracked up to be. But a closer examina- stop there. It turns out that niacin is Rmacologic strategies to increase tion of the situation reveals a few rays also fairly potent at lowering both LDL high-density lipoprotein (HDL) choles- of hope. For instance, data on several and triglyceride levels, either alone or terol levels. The hope has been that the other candidate CETP inhibitors under in combination with other medications well known antiatherosclerotic benefits development by rival drug companies (such as statins). Additionally, it’s the associated with lowering low-density seem, thus far, to show comparable only agent other than estrogens that lipoprotein (LDL) cholesterol levels elevations in HDL levels without any has been shown to lower lipoprotein(a) could be enhanced significantly by associated effects on blood pressure. levels. High lipoprotein(a) levels may medications designed to elevate levels These data, though preliminary, suggest be an independent risk factor for of HDL. that the blood pressure problem might coronary artery disease in certain This past fall, however, advocates be specific to torcetrapib.5 patients. of this strategy suffered a major set- Furthermore, in our quest for the Given these substantial benefits, back when Pfizer (New York, NY) latest pharmaceutical blockbuster, we why aren’t we using niacin much more pulled its promising candidate drug, may have neglected a tried and true widely? The answer, of course, is that torcetrapib, from further develop- remedy that, since the 1950s, has been the drug has acquired a reputation for ment. This action was prompted by known to produce quite reliable and being difficult, a situation that isn’t results from the Investigation of Lipid robust HDL elevations. I am speak- helped by the reluctance of major drug Level Management to Understand ing, of course, of niacin, or nicotinic companies to speak on its behalf. But its Impact in Atherosclerotic Events acid. Niacin has long suffered from its is niacin really that problematic? I (ILLUMINATE) trial, which showed “lowly” status as a generic medication, would submit that the answer is no— an increased number of deaths in the with very limited appeal to the pharma- if both the patient and the provider group of patients randomly assigned ceutical industry as a source of revenue show a modest amount of patience to receive a combination of torcetrapib and profit. But despite the lack of pro- and persistence. and atorvastatin compared with those motion, it’s a highly effective medication The main concern with niacin is assigned to atorvastatin alone.1,2 with a good safety profile when pre- the adverse effect of flushing, which Data on torcetrapib from several scribed by a knowledgeable provider. occurs almost universally—though studies also has shown a consistent, Let’s review what niacin can do for the number of flushing episodes may though modest, increase in blood pres- lipids. First and foremost, its ability be fewer with a newer, proprietary, sure with this drug.3 Even slight blood to cause robust elevations in HDL extended-release formulation, Niaspan pressure elevations can translate— levels—up to 40%—renders it in a (Kos Pharmaceuticals, Cranbury, across large patient populations—into class by itself in terms of efficacy. By NJ).6 Flushing usually abates after significant associated increases in car- contrast, statins typically raise HDL lev- several days in all but the most fairly diovascular morbidity and mortality.4 els in the range of 5% to 10%. Fibrates complexioned individuals. Although Could it be that torcetrapib’s potential (including fenofibrate and gemfibro- flushing does no serious or lasting effects on HDL levels, which occur zil) may do a little better, sometimes damage to the body, it’s amazing how through inhibition of the enzyme in the range of 10% to 15%. It’s true dismayed patients and providers can cholesteryl ester transfer protein that thiazolidinediones (also known as become over this phenomenon. It may (CETP), were “swamped out” by this glitazones) may raise HDL levels by as help to provide patients with some compound’s unfortunate proclivity to much as 20%, but their use is strictly tips for managing flushing (such as increase blood pressure? The connec- confined to patients with diabetes. avoiding ingestion of alcohol or hot tion does not seem implausible. Diabetic patients certainly are at high drinks around the time they take the Given this disappointment, a pes- risk for atherosclerotic events, but they drug)—and to suggest to them that simist hardly could be blamed for represent a relatively modest fraction of this nuisance can be a reminder that concluding that strategies for raising all patients with low HDL levels. the medication is hard at work increas- MARCH 2007 • FEDERAL PRACTITIONER • 15 EDITORIAL ing their good cholesterol and lowering this outcome if one sticks to the crystal- adverse effects—before administering their bad cholesterol. line or extended-release formulations. pharmacologic therapy to patients. Another persistent hindrance to the It is disappointing to have lost widespread use of niacin is the idea the promise of torcetrapib from the REFERENCES 1. In interests of patient safety, Pfizer stops all torcetra- that it shouldn’t be used in diabetic therapeutic armamentarium. But the pib clinical trials; company has notified FDA and is patients due to a detrimental effect silver lining in this dark cloud is in in the process of notifying all clinical investigators and other regulatory authorities [press release]. New on blood glucose control. Two large the opportunity to rediscover an old York, NY: Pfizer Inc; December 2, 2006. studies, the Arterial Disease Multiple friend—niacin. Niacin has been highly 2. Pfizer stops all torcetrapib clinical trials in interest of patient safety [FDA statement]. Rockville, MD: U.S. Intervention Trial (ADMIT) on crys- effective at improving lipids for half a Food and Drug Administration; December 3, 2006. talline niacin and the Assessment of century and undoubtedly will remain 3. O’Riordan M. Larger-than-anticipated increases in systolic blood pressure with torcetrapib. New York, Diabetes Control and Evaluation of the an important lipid lowering medication NY: Medscape; November 3, 2006. Available at: Efficacy of Niaspan Trial (ADVENT), 50 years from now. ● www.medscape.com/viewarticle/518571. Accessed February 13, 2007. showed that the effects on blood glu- 4. Lewington S, Clarke R, Qizilbash N, Peto R, Collins cose levels are generally very small and Author disclosures R, and the Prospective Studies Collaboration. Age- specific relevance of usual blood pressure to vascu- easily managed with a minor tweaking Dr. Felicetta reports no actual or potential lar mortality: A meta-analysis of individual data for of the antiglycemic regimen.7,8 Indeed, conflicts of interest with regard to this one million adults in 61 prospective studies. Lancet. 2002;360:1903–1913. diabetic patients are high risk individu- editorial. 5. Cortez MF, Zimm A. Pfizer’s cholesterol setback als who typically have subpar levels of may help Roche, Merck. New York, NY: Bloomberg; November 13, 2006. Available at: www.bloomberg. HDL and, therefore, are strong candi- Disclaimer com/apps/news?pid=newsarchive&sid=aIXFovccQ dates for niacin therapy. The opinions expressed herein are those of HBM. Accessed February 16, 2007. 6. Niaspan [prescribing information]. Cranbury, NJ: The other adverse effects of niacin the author and do not necessarily reflect Kos Pharmaceuticals Inc; 2005. are relatively infrequent. Mild gastroin- those of Federal Practitioner, Quadrant 7. Elam MB, Hunninghake, DB, Davis KB, et al, for the ADMIT Investigators. Effect of niacin on lipid and testinal distress is seen occasionally, and HealthCom Inc., the U.S. government, lipoprotein levels and glycemic control in patients an acute episode of gout can sometimes or any of its agencies. This article may with diabetes and peripheral arterial disease. JAMA. 2000;284:1263–1270. be precipitated by niacin therapy. The discuss unlabeled or investigational use 8. Grundy SM, Vega GL, McGovern ME, et al, for disastrous complication of fulminant of certain drugs. Please review complete the Diabetes Multicenter Research Group. Efficacy, safety, and tolerability of once-daily niacin for the hepatic necrosis essentially is seen only prescribing information for specific drugs treatment of dyslipidemia associated with type 2 with the long-acting, timed-release or drug combinations—including indica- diabetes. Arch Intern Med. 2002;162:1568–1576. preparations. There is little need to fear tions, contraindications, warnings, and 16 • FEDERAL PRACTITIONER • MARCH 2007.
Load more

Recommended publications
  • Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: the Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol
    Diabetes Volume 65, July 2016 1767 Changting Xiao,1 Satya Dash,1 Cecilia Morgantini,1 Robert A. Hegele,2 and Gary F. Lewis1 Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol Diabetes 2016;65:1767–1778 | DOI: 10.2337/db16-0046 Notwithstanding the effectiveness of lowering LDL cho- has been the primary goal of dyslipidemia management, lesterol, residual CVD risk remains in high-risk popula- with statins as the treatment of choice for CVD prevention. tions, including patients with diabetes, likely contributed Large-scale, randomized, clinical trials of LDL-lowering PERSPECTIVES IN DIABETES to by non-LDL lipid abnormalities. In this Perspectives therapies have demonstrated significant reduction in CVD in Diabetes article, we emphasize that changing demo- events over a wide range of baseline LDL-C levels (2,3). graphics and lifestyles over the past few decades have However, even with LDL-C levels lowered substantially or “ resulted in an epidemic of the atherogenic dyslipidemia at treatment goals with statin therapy, CVD risks are not ” complex, the main features of which include hypertrigly- eliminated and there remains significant “residual risk.” In- ceridemia, low HDL cholesterol levels, qualitative changes tensifying statin therapy may provide additional benefits in LDL particles, accumulation of remnant lipoproteins, (4,5); this approach, however, has limited potential, owing and postprandial hyperlipidemia. We brieflyreviewthe to tolerability, side effects, and finite efficacy. Further LDL-C underlying pathophysiology of this form of dyslipidemia, lowering may also be achieved with the use of nonstatin in particular its association with insulin resistance, obe- sity, and type 2 diabetes, and the marked atherogenicity agents, such as cholesterol absorption inhibitors and PCSK9 of this condition.
    [Show full text]
  • I Regulations
    23.2.2007 EN Official Journal of the European Union L 56/1 I (Acts adopted under the EC Treaty/Euratom Treaty whose publication is obligatory) REGULATIONS COUNCIL REGULATION (EC) No 129/2007 of 12 February 2007 providing for duty-free treatment for specified pharmaceutical active ingredients bearing an ‘international non-proprietary name’ (INN) from the World Health Organisation and specified products used for the manufacture of finished pharmaceuticals and amending Annex I to Regulation (EEC) No 2658/87 THE COUNCIL OF THE EUROPEAN UNION, (4) In the course of three such reviews it was concluded that a certain number of additional INNs and intermediates used for production and manufacture of finished pharmaceu- ticals should be granted duty-free treatment, that certain of Having regard to the Treaty establishing the European Commu- these intermediates should be transferred to the list of INNs, nity, and in particular Article 133 thereof, and that the list of specified prefixes and suffixes for salts, esters or hydrates of INNs should be expanded. Having regard to the proposal from the Commission, (5) Council Regulation (EEC) No 2658/87 of 23 July 1987 on the tariff and statistical nomenclature and on the Common Customs Tariff (1) established the Combined Nomenclature Whereas: (CN) and set out the conventional duty rates of the Common Customs Tariff. (1) In the course of the Uruguay Round negotiations, the Community and a number of countries agreed that duty- (6) Regulation (EEC) No 2658/87 should therefore be amended free treatment should be granted to pharmaceutical accordingly, products falling within the Harmonised System (HS) Chapter 30 and HS headings 2936, 2937, 2939 and 2941 as well as to designated pharmaceutical active HAS ADOPTED THIS REGULATION: ingredients bearing an ‘international non-proprietary name’ (INN) from the World Health Organisation, specified salts, esters or hydrates of such INNs, and designated inter- Article 1 mediates used for the production and manufacture of finished products.
    [Show full text]
  • Articles Article: Non-Statin Treatments for Managing LDL Cholesterol and Their Outcomes Download
    Clinical Therapeutics/Volume 37, Number 12, 2015 Review Article Non-statin Treatments for Managing LDL Cholesterol and Their Outcomes Traci Turner, MD; and Evan A. Stein, MD, PhD Metabolic & Atherosclerosis Research Center, Cincinnati, Ohio ABSTRACT agents are being developed as orphan indications ex- Purpose: Over the past 3 decades reducing LDL-C pressly for patients with homozygous familial hyper- has proven to be the most reliable and easily achiev- cholesterolemia, including peroxisome proliferator able modifiable risk factor to decrease the rate of activated receptor-δ agonists, angiopoietin-like protein 3 cardiovascular morbidity and mortality. Statins are inhibitors, and gene therapy. effective, but problems with their side effects, adher- Implications: Monoclonal antibodies that inhibit ence, or LDL-C efficacy in some patient groups PCSK9 were shown to be very effective reducers of remain. Most currently available alternative lipid- LDL-C and well tolerated despite subcutaneous ad- modifying therapies have limited efficacy or tolerabil- ministration, and no significant safety issues have yet ity, and additional effective pharmacologic modalities emerged during large Phase II and III trials. They have to reduce LDL-C are needed. the potential to substantially impact further the risk of Methods: Recent literature on new and evolving cardiovascular disease. A number of additional new, LDL-C–lowering modalities in preclinical and clinical but less effective, oral LDL-C–lowering agents are development was reviewed. also in various stages of development, including Findings: Several new therapies targeting LDL-C are some which are targeted only to patients with homo- in development. Inhibition of proprotein convertase sub- zygous familial hypercholesterolemia. (Clin Ther.
    [Show full text]
  • 2 12/ 35 74Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 22 March 2012 (22.03.2012) 2 12/ 35 74 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/16 (2006.01) A61K 9/51 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 9/14 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/EP201 1/065959 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 14 September 201 1 (14.09.201 1) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (25) Filing Language: English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (26) Publication Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/382,653 14 September 2010 (14.09.2010) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, NANOLOGICA AB [SE/SE]; P.O Box 8182, S-104 20 ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Stockholm (SE).
    [Show full text]
  • High-Density Lipoproteins in the Prevention of Cardiovascular Disease: Changing the Paradigm
    State of the Art STATE ART nature publishing group High-Density Lipoproteins in the Prevention of Cardiovascular Disease: Changing the Paradigm S Tuteja1 and DJ Rader1 High-density-lipoprotein cholesterol (HDL-C) has been identified in population studies as an independent inverse predictor of cardiovascular events. Although the causal nature of this association has been questioned, HDL and its major protein, apolipoprotein (apo)A1, have been shown to prevent and reverse atherosclerosis in animal models. In addition, HDL and apoA1 have several putatively atheroprotective functions, such as the ability to promote efflux of cholesterol from macrophages in the artery wall, inhibit vascular inflammation, and enhance endothelial function. Therefore, HDL-C and apoA1 have been investigated as therapeutic targets for coronary heart disease. However, recent clinical trials with drugs that raise HDL-C, such as niacin and inhibitors of cholesteryl ester transfer protein, have been disappointing. Here, we review the current state of the science regarding HDL as a therapeutic target. Advances in the treatment of hypercholesterolemia, primarily increase HDL-C will prevent the occurrence of CHD.10 Te with statins, are responsible for the decline in mortality due to Veterans Afairs HDL Intervention Trial was one of the frst pro- coronary heart disease (CHD); however, CHD is still the cause spective studies to demonstrate that a therapy that increased lev- of death for one in six Americans.1 Low-density-lipoprotein els of HDL-C, gemfbrozil, reduced major
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • Systems Biology of Inborn Errors of Metabolism
    Systems biology of inborn errors of metabolism Swagatika Sahoo FacultyFaculty of of Faculty Faculty of of Life Life and and Environmental Environmental Sciences Sciences UniversityUniversity of of Iceland Iceland 20132013 SYSTEMS BIOLOGY OF INBORN ERRORS OF METABOLISM Swagatika Sahoo Dissertation submitted in partial fulllment of Philosophiae Doctor degree in Biology Advisor Professor Ines Thiele Thesis Committee Professor Ólafur S. Andrésson Professor Ines Thiele Professor Jón J. Jónsson Opponents Professor Hermann-Georg Holzhütter Professor Barbara Bakker Life and Environmental Sciences School of Engineering and Natural Sciences University of Iceland Reykjavik, September 2013 Systems biology of inborn errors of metabolism Systems biology : inborn errors of metabolism Dissertation submitted in a partial fulfillment of a Ph.D. degree in Biology Copyright © 2013 Swagatika Sahoo All rights reserved Life and Environmental Sciences School of Engineering and Natural Sciences University of Iceland Sturlugata 8 101, Reykjavik, Reykjavik Iceland Telephone: 525 4000 Bibliographic information: Swagatika Sahoo, 2013, Systems biology of inborn errors of metabolism, Ph.D. the- sis, Faculty of Life and Environmental Sciences, University of Iceland. ISBN 978-9935-9164-5-7 Printing: Háskólaprent, Fálkagata 2, 107 Reykjavik Reykjavik, Iceland, September 2013 Abstract Inborn errors of metabolism (IEMs) are the hereditary metabolic disorders often leading to life threatening conditions when left un-treated. IEMs not only demand better diagnostic methods and efficient therapeutic regimen, but also, a high level understanding of the precise biochemical pathology involved. Constraint-based metabolic network reconstruction and modeling is the core systems biology meth- ods to analyze the complex interactions between cellular components that maintain cellular homeostasis. Simultaneously, the global human metabolic networks, Re- con 1 and Recon 2, are landmarks in this regard.
    [Show full text]
  • Old and New in Lipid Lowering Therapy: Focus on The
    FARMACIA, 2014, Vol. 62, 5 811 OLD AND NEW IN LIPID LOWERING THERAPY: FOCUS ON THE EMERGING DRUGS DANIELA BARTOȘ, CAMELIA DIACONU, ELISABETA BĂDILĂ*, ANA MARIA DARABAN University of Medicine and Pharmacy Carol Davila, Internal Medicine Clinic, Clinical Emergency Hospital of Bucharest, România * corresponding author: [email protected] Abstract The link between cholesterol and atherosclerosis has been long known. Studies on HDL (high density lipoprotein) cholesterol showed that it has two important roles: one in the transport of cholesterol and another directly on vascular endothelium, with a protective action and potential anti-atherogenic effects. Statins are the most common lipid- lowering drugs. Other drugs used in the treatment dyslipidemia are bile acid sequestrants, nicotinic acid, ezetimibe, probucol, neomycin, and fibrates. Because the response to treatment is not always satisfactory, new classes of drugs with different mechanisms of action have been developed in the latest years. Rezumat Legătura dintre colesterol şi ateroscleroză este de mult timp cunoscută. Studiile efectuate asupra HDL-colesterolului (high density lipoprotein) au arătat două roluri importante: unul asupra transportului de colesterol şi altul direct asupra endoteliului vascular, având o acţiune protectoare şi cu efecte potenţial anti-aterogene. Statinele sunt cele mai cunoscute medicamente hipolipemiante. Alte categorii de medicamente folosite în tratamentul dislipidemiilor sunt: sechestranţii de acizi biliari, acidul nicotinic, ezetimib, probucol, neomicina, fibraţii. Deoarece răspunsul la tratament nu este totdeauna satisfăcător, în ultimii ani au fost introduse în terapie noi clase de medicamente hipolipemiante, cu mecanisme de acţiune diferite faţă de cele cunoscute până acum. Keywords: dislipidemia, new lipid lowering drugs. Introduction In 1910, the German researchers have drawn attention to the link between cholesterol and atherosclerosis.
    [Show full text]
  • Studies on Cholesterol and Bile Acid Metabolism in Relation to Plasma Lipoproteins in Humans
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Publications from Karolinska Institutet From DEPARTMENT OF MEDICINE Karolinska Institutet, Stockholm, Sweden STUDIES ON CHOLESTEROL AND BILE ACID METABOLISM IN RELATION TO PLASMA LIPOPROTEINS IN HUMANS Beatrice G Sjöberg Stockholm 2016 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by Printed by E-Print AB 2016 © Beatrice Sjöberg, 2016 ISBN 978-91-7676-299-8 Studies on cholesterol and bile acid metabolism in relation to plasma lipoproteins THESIS FOR DOCTORAL DEGREE (Ph.D.) By Beatrice G Sjöberg Principal Supervisor: Opponent: Professor Mats Rudling Adjunct Professor Eva Hurt-Camejo Karolinska Institutet Karolinska Institutet Department of Medicine, Huddinge Department of Laboratory Medicine Co-supervisor(s): Examination Board: Professor Bo Angelin Professor Ewa Ehrenborg Karolinska Institutet Karolinska Institutet Department of Medicine, Huddinge Department of Medicine, Solna Professor Gunnar Norstedt Karolinska Institutet Department of Women’s and Children’s Health Docent Ingrid Wernstedt Asterholm Göteborgs Universitet Department of Physiology To My Family ABSTRACT The metabolism of cholesterol and bile acids is tightly controlled but only partially characterized. The liver is responsible for most of the clearance and catabolism of plasma cholesterol, and the hepatocyte expression of LDL receptors is central in this process. The major pathways for net excretion of cholesterol from the body are through biliary excretion as free cholesterol or after conversion to bile acids. Through activation of the nuclear receptor FXR and the G protein-coupled receptor TGR5, bile acids regulate not only their own homeostasis but also lipid, glucose and energy metabolism.
    [Show full text]
  • Utility of Biomarkers and Imaging in the Development of Drugs for the Treatment of Coronary Atherosclerosis
    UCSF UC San Francisco Previously Published Works Title Utility of biomarkers and imaging in the development of drugs for the treatment of coronary atherosclerosis. Permalink https://escholarship.org/uc/item/7xj3w6n9 Journal The Canadian journal of cardiology, 28(6) ISSN 0828-282X Author Waters, David D Publication Date 2012-11-01 DOI 10.1016/j.cjca.2012.03.003 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Canadian Journal of Cardiology 28 (2012) 687–692 Review Utility of Biomarkers and Imaging in the Development of Drugs for the Treatment of Coronary Atherosclerosis David D. Waters, MD Division of Cardiology, San Francisco General Hospital, and the Department of Medicine, University of California, San Francisco, California, USA ABSTRACT RÉSUMÉ Biomarkers and imaging trials have often been used as guideposts in Les biomarqueurs et les essais en imagerie ont souvent été utilisés the development of drugs for atherosclerosis. This article explores the comme référence dans le développement de médicaments pour role of biomarkers and imaging trials in the development of 4 drugs: traiter l’athérosclérose. Cet article explore le rôle des biomarqueurs et rimonabant, torcetrapib, ezetimibe, and niacin. Rimonabant, a selec- des essais en imagerie dans le développement de 4 médicaments : le tive cannabinoid-1 receptor, causes weight loss and exerts favourable rimonabant, le torcétrapibe, l’ézétimibe et la niacine. Le rimonabant, effects on lipid biomarkers. An intracoronary ultrasound study showed un récepteur cannabinoïde 1, cause une perte de poids et exerce des no effect for the primary but significant benefit for the secondary end effets favorables sur les biomarqueurs lipidiques.
    [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]
  • Fenofibrate Toxicity and Impact on Clinical Biomarkers in Patients with Dyslipidaemia
    Fenofibrate toxicity and impact on clinical biomarkers in patients with dyslipidaemia Ivo Sama Fombon Department of Applied Sciences University of the West of England, Bristol May 2020 A thesis submitted in partial fulfilment of the requirements of the University of the West of England, Bristol for the degree of Professional Doctorate in Biomedical Sciences Fombon, I.S. (2020) Copyright Disclaimer This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without appropriate acknowledgement. i Fombon, I.S. (2020) ACKNOWLEDGEMENTS This thesis and the entire project could not have been achieved without the support of my supervisors, colleagues, family and friends. I would like to thank them immensely for their support. Firstly, I would like to thank my director of studies, Prof Myra Conway, for her guidance, support and encouragement. I am extremely grateful for her valuable time, expertise and advice on the design and conduct of the studies described in this thesis. I have learnt an incredible amount from her teachings, patience and hard work. I would like to thank Dr David James for making it possible for this project to be carried out at the laboratories of the Southwest Pathology Services, Taunton. Thank you too, Prof. Tim Reynolds for accepting to take part in this project and for helping to obtain the ethics approval for this project. Prof Tim Reynolds and Dr David James also recruited the participants for this project. To the staff of Southwest Pathology Services, Taunton, and Queen’s Hospital, Burton-on-Trent, I say thank you for helping with the collection and storage of patient samples.
    [Show full text]