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      The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation

      review-article
      1 , , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 10 , 45 , 46 , 47 , 1 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69
      Cardiovascular Diabetology
      BioMed Central
      Residual cardiovascular risk, Visceral obesity, Diabetes, Atherogenic dyslipidemia, Triglycerides, Remnant cholesterol, Selective peroxisome proliferator-activated receptor alpha modulator, SPPARMalpha, Pemafibrate (K-877), Inflammation, PROMINENT

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          Abstract

          In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.

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          The online version of this article (10.1186/s12933-019-0864-7) contains supplementary material, which is available to authorized users.

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          Most cited references97

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          2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol

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            Acetyl-CoA and the Regulation of Metabolism: Mechanisms and Consequences

            Acetyl-CoA represents a key node in metabolism due to its intersection with many metabolic pathways and transformations. Emerging evidence reveals that cells monitor the levels of acetyl-CoA as a key indicator of their metabolic state, through distinctive protein acetylation modifications dependent on this metabolite. We offer the following conceptual model for understanding the role of this sentinel metabolite in metabolic regulation. High nucleocytosolic acetyl-CoA amounts are a signature of a “growth” or “fed” state and promote its utilization for lipid synthesis and histone acetylation. In contrast, under “survival” or “fasted” states, acetyl-CoA is preferentially directed into the mitochondria to promote mitochondrial-dependent activities such as the synthesis of ATP and ketone bodies. Fluctuations in acetyl-CoA within these subcellular compartments enable the substrate-level regulation of acetylation modifications, but also necessitates the function of sirtuin deacetylases to catalyze removal of spontaneous modifications that might be unintended. Thus, understanding the sources, fates, and consequences of acetyl-CoA as a carrier of two-carbon units has started to reveal its underappreciated but profound influence on the regulation of numerous life processes.
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              Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial.

              Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. Our aim was to assess whether long-term lipid-lowering therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50-75 years with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4895) or matching placebo (n=4900). At each clinic visit, information concerning laser treatment for diabetic retinopathy-a prespecified tertiary endpoint of the main study-was gathered. Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a substudy of 1012 patients, standardised retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481. Laser treatment was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease, but the need for such treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 [3.4%] patients on fenofibrate vs 238 [4.9%] on placebo; hazard ratio [HR] 0.69, 95% CI 0.56-0.84; p=0.0002; absolute risk reduction 1.5% [0.7-2.3]). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 [9.6%] patients on fenofibrate vs 57 [12.3%] on placebo; p=0.19) or in the subset of patients without pre-existing retinopathy (43 [11.4%] vs 43 [11.7%]; p=0.87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three [3.1%] patients vs 14 [14.6%]; p=0.004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0.66, 95% CI 0.47-0.94; p=0.022). Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.
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                Author and article information

                Contributors
                +41 61 560 24 24 , jean-Charles.fruchart@r3i.org , jeancharles.fruchart@yahoo.fr
                rauldsf@gmail.com
                caguilarsalinas@yahoo.com
                MAIKAWA@BWH.HARVARD.EDU
                k.alrasadi@gmail.com
                pierre.amarenco@aphp.fr
                pbarter@ozemail.com.au
                richard.ceska@lf1.cuni.cz
                alberto.corsini@unimi.it
                Jean-Pierre.Despres@criucpq.ulaval.ca
                patrick.duriez@univ-lille.fr
                Robert.Eckel@ucdenver.edu
                marat_ezhov@mail.ru
                michelfarnier@nerim.net
                hng1@cumc.columbia.edu
                michel.hermans@uclouvain.be
                ishibash@jichi.ac.jp
                fredrik.karpe@ocdem.ox.ac.uk
                kodama@lsbm.org
                koenig@dhm.mhn.de
                michel.krempf@univ-nantes.fr
                limsoo@snu.ac.kr
                Alberto.lorenzatti@gmail.com
                rmcpherson@ottawaheart.ca
                jesus.millan.nunezcortes@madrid.org
                Boerge.Nordestgaard@regionh.dk
                ogawah@ncvc.go.jp
                chris.j.packard@gmail.com
                JPLUTZKY@BWH.HARVARD.EDU
                ciponten@gmail.com
                apradhan@bwh.harvard.edu
                k.ray@imperial.ac.uk
                zreiner@kbc-zagreb.hr
                pridker@bwh.harvard.edu
                smsadikot@gmail.com
                hshimano@md.tsukuba.ac.jp
                rapst@mahidol.ac.th
                janestock@blueyonder.co.uk
                tachensu@gmail.com
                asus99@mail.ru
                asus99@mail.ru
                marja-riitta.taskinen@helsinki.fi
                altenen@yahoo.com
                laletok@gmail.com
                btomlinson@cuhk.edu.hk
                Anne.Tybjaerg.Hansen@regionh.dk
                paul.valensi@noos.fr
                michal.vrablik@vfn.cz
                walter.wahli@ntu.edu.sg
                gerald.watts@uwa.edu.au
                shizu@imed2.med.osaka-u.ac.jp
                kyokote@faculty.chiba-u.jp
                alberto.zambon@unipd.it
                PLIBBY@BWH.HARVARD.EDU
                Journal
                Cardiovasc Diabetol
                Cardiovasc Diabetol
                Cardiovascular Diabetology
                BioMed Central (London )
                1475-2840
                4 June 2019
                4 June 2019
                2019
                : 18
                : 71
                Affiliations
                [1 ]R3i Foundation, Picassoplatz 8, 4010 Basel, Switzerland
                [2 ]ISNI 0000 0001 2297 2036, GRID grid.411074.7, Hospital Israelita Albert Einstein, and Lipid Clinic, , Heart Institute (InCor) University of Sao Paulo Medical School Hospital, ; Sao Paulo, Brazil
                [3 ]ISNI 0000 0001 0698 4037, GRID grid.416850.e, Unidad de Investigacion de Enfermedades Metabolicas, Department of Endocrinolgy and Metabolism, , Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, ; Mexico City, Mexico
                [4 ]ISNI 0000 0001 2203 4701, GRID grid.419886.a, Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, ; Monterrey, Mexico
                [5 ]Center for Interdisciplinary Cardiovascular Sciences and Center for Excellence in Vascular Biology, Division of Cardiovascular Medicine and Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
                [6 ]ISNI 0000 0004 0442 8821, GRID grid.412855.f, Department of Clinical Biochemistry, , Sultan Qaboos University Hospital, ; Muscat, Oman
                [7 ]ISNI 0000 0001 2308 1657, GRID grid.462844.8, Department of Neurology and Stroke Center, , Paris-Diderot-Sorbonne University, ; Paris, France
                [8 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, Lipid Research Group, School of Medical Sciences, , University of New South Wales, ; Sydney, NSW Australia
                [9 ]ISNI 0000 0004 1937 116X, GRID grid.4491.8, IIIrd Dept Int. Med, Center for Preventive Cardiology, 3rd Internal Medicine Clinic, , University General Hospital and Charles University, ; Prague, Czech Republic
                [10 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Department of Pharmacological and Biomolecular Sciences, , Università Degli Studi di Milano, ; Milan, Italy
                [11 ]ISNI 0000 0004 1936 8390, GRID grid.23856.3a, Centre de recherche sur les soins et les services de première ligne-Université Laval du CIUSSS de la Capitale-Nationale, Department of Kinesiology, Faculty of Medicine, , Université Laval, ; Québec, QC Canada
                [12 ]ISNI 0000 0001 2242 6780, GRID grid.503422.2, INSERM, CHU Lille, U1171-Degenerative & Vascular Cognitive Disorders, University of Lille, Faculty of Pharmacy, , University of Lille, UDSL, ; Lille, France
                [13 ]ISNI 0000 0001 0703 675X, GRID grid.430503.1, Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, , University of Colorado School of Medicine, ; Anschutz Medical Campus, Aurora, CO USA
                [14 ]ISNI 0000 0000 9216 2496, GRID grid.415738.c, Laboratory of Lipid Disorders, , National Cardiology Research Center, ; Moscow, Russian Federation
                [15 ]GRID grid.31151.37, Lipid Clinic, Point Médical and Department of Cardiology, , CHU Dijon-Bourgogne, ; Dijon, France
                [16 ]ISNI 0000000419368729, GRID grid.21729.3f, Columbia University Vagelos College of Physicians and Surgeons, ; New York, USA
                [17 ]ISNI 0000 0001 2294 713X, GRID grid.7942.8, Division of Endocrinology and Nutrition, Cliniques Universitaires St-Luc and Institut de Recherche Expérimentale et Clinique (IREC), , Université Catholique de Louvain, ; Brussels, Belgium
                [18 ]ISNI 0000000123090000, GRID grid.410804.9, Division of Endocrinology and Metabolism, Department of Internal Medicine, , Jichi Medical University, ; Shimotsuke, Japan
                [19 ]ISNI 0000 0004 0488 9484, GRID grid.415719.f, OCDEM, University of Oxford and the NIHR Oxford Biomedical Research Centre, OUH Foundation Trust, Churchill Hospital, ; Oxford, UK
                [20 ]ISNI 0000 0001 2151 536X, GRID grid.26999.3d, Laboratory for System Biology and Medicine Research Center for Advanced Science and Technology, , The University of Tokyo, ; Tokyo, Japan
                [21 ]ISNI 0000000123222966, GRID grid.6936.a, Deutsches Herzzentrum München, Technische Universitat München, Germany; DZHK (German Centre for Cardiovascular Research), ; Partner Site Munich Heart Alliance, Munich, Germany
                [22 ]ISNI 0000 0004 1936 9748, GRID grid.6582.9, Institute of Epidemiology and Medical Biometry, , University of Ulm, ; Ulm, Germany
                [23 ]Mass Spectrometry Core facility of West Human Nutrition Research Center (CRNHO), Hotel Dieu Hospital, Nantes, France
                [24 ]GRID grid.460203.3, Inra, UMR 1280, Physiologie des Adaptations Nutritionnelles, ; Nantes, France
                [25 ]Department of Endocrinology, Metabolic diseases and Nutrition, G and R Laennec Hospital, Nantes, France
                [26 ]Department of Internal Medicine, Seoul National University Bundang Hospital and Seoul National University College of Medicine, Seongnam, Republic of Korea
                [27 ]DAMIC Medical Institute/Rusculleda Foundation for Research, Córdoba, Argentina
                [28 ]Cardiology Department, Córdoba Hospital, Córdoba, Argentina
                [29 ]ISNI 0000 0001 2182 2255, GRID grid.28046.38, Ruddy Canadian Cardiovascular Genetics Centre, , University of Ottawa Heart Institute, ; Ottawa, Canada
                [30 ]ISNI 0000 0001 0277 7938, GRID grid.410526.4, Internal Medicine, Lipids Unit, , Gregorio Marañón University Hospital, ; Madrid, Spain
                [31 ]ISNI 0000 0001 2157 7667, GRID grid.4795.f, Department of Medicine, School of Medicine, , Universidad Complutense de Madrid, ; Madrid, Spain
                [32 ]Instituto de Investigaciones Sanitarias Gregorio Marañón, Madrid, Spain
                [33 ]ISNI 0000 0004 0646 7373, GRID grid.4973.9, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, , Copenhagen University Hospital, ; Herlev, Denmark
                [34 ]ISNI 0000 0004 0646 7373, GRID grid.4973.9, The Copenhagen General Population Study, Herlev and Gentofte Hospital, , Copenhagen University Hospital, ; Herlev, Denmark
                [35 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Faculty of Health and Medical Sciences, , University of Copenhagen, ; Copenhagen, Denmark
                [36 ]ISNI 0000 0004 0378 8307, GRID grid.410796.d, National Cerebral and Cardiovascular Center, ; Suita, Osaka Japan
                [37 ]ISNI 0000 0001 2193 314X, GRID grid.8756.c, Institute of Cardiovascular and Medical Sciences, , University of Glasgow, ; Glasgow, UK
                [38 ]Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
                [39 ]Unidad de Prevención Cardiometabólica Cardiocob. Servicio de Cardiología Hospital el Pino Santiago de Chile, Sociedad Inter Americana de Cardiología SIAC Chairman Cardiovascular Prevention Comite, Santiago de Chile, Chile
                [40 ]ISNI 0000 0001 2183 6745, GRID grid.239424.a, Division of Cardiovascular Medicine, , VA Boston Medical Center, ; Boston, MA USA
                [41 ]Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
                [42 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, , Imperial College London, ; London, UK
                [43 ]ISNI 0000 0001 0657 4636, GRID grid.4808.4, Department of Internal Medicine, University Hospital Centre Zagreb, School of Medicine, , Zagreb University, ; Kispaticeva 12, Zagreb, Croatia
                [44 ]Division of Cardiovascular Medicine and Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
                [45 ]ISNI 0000 0004 1766 8488, GRID grid.414939.2, Department of Endocrinology/Diabetology, , Jaslok Hospital and Research Centre, ; Mumbai, India
                [46 ]ISNI 0000 0001 2369 4728, GRID grid.20515.33, Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, , University of Tsukuba, ; Ibaraki, 305-8575 Japan
                [47 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Department of Medicine, Ramathibodi Hospital, , Mahidol University, ; Bangkok, Thailand
                [48 ]ISNI 0000 0004 0546 0241, GRID grid.19188.39, Departments of Internal Medicine and Environmental and Occupational Medicine, National Taiwan University; Institute of Occupational Medicine and Industrial Hygiene, , National Taiwan University College of Public Health, ; Taipei, Taiwan
                [49 ]Faculty of Clinical Pharmacology and Therapeutics, Academy for Postgraduate Continuous Medical Education, Moscow, Russian Federation
                [50 ]ISNI 0000 0001 2242 6780, GRID grid.503422.2, Faculté de Pharmacie de Lille, ; Lille, France
                [51 ]ISNI 0000 0000 9950 5666, GRID grid.15485.3d, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, , University of Helsinki and Clinical Research Institute, HUCH Ltd., ; Helsinki, Finland
                [52 ]ISNI 0000 0004 1937 0546, GRID grid.12136.37, Sackler Faculty of Medicine, , Tel Aviv University, ; 6997801 Tel Aviv, Israel
                [53 ]ISNI 0000 0001 2107 2845, GRID grid.413795.d, Cardiac Rehabilitation Institute, , Sheba Medical Center, ; 5265601 Tel Hashomer, Israel
                [54 ]ISNI 0000 0001 2342 7339, GRID grid.14442.37, Department of Cardiology, Faculty of Medicine, , Hacettepe University, ; Ankara, Turkey
                [55 ]Department of Medicine & Theraputics, The Chinese University of Hong Kong, Hong Kong, Hong Kong
                [56 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Department of Clinical Biochemistry, Rigshospitalet; Copenhagen University Hospital, Faculty of Health and Medical Sciences, , University of Copenhagen, ; Copenhagen, Denmark
                [57 ]ISNI 0000 0004 0646 7402, GRID grid.411646.0, The Copenhagen General Population Study, Herlev and Gentofte Hospital, ; Herlev, Denmark
                [58 ]ISNI 0000 0000 8897 490X, GRID grid.414153.6, Department of Endocrinology, Diabetology and Nutrition, , Jean-Verdier Hospital (AP-HP), ; Paris 13 University, Sorbonne Paris Cité, CRNH-IdF, CINFO, 93140 Bondy, France
                [59 ]ISNI 0000 0000 9100 9940, GRID grid.411798.2, 3rd Department of Medicine, , 1st Faculty of Medicine of Charles University and General University Hospital in Prague, ; Prague, Czech Republic
                [60 ]ISNI 0000 0001 2224 0361, GRID grid.59025.3b, Lee Kong Chian School of Medicine, , Nanyang Technological University Singapore, ; Clinical Sciences Building, 11 Mandalay Road, Singapore, 308232 Singapore
                [61 ]ISNI 0000 0001 2165 4204, GRID grid.9851.5, Center for Integrative Genomics, , Université de Lausanne, ; Le Génopode, CH-1015 Lausanne, Switzerland
                [62 ]GRID grid.420267.5, Institut National de La Recherche Agronomique (INRA), UMR1331 ToxAlim, ; Toulouse, France
                [63 ]ISNI 0000 0004 1936 7910, GRID grid.1012.2, Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, School of Medicine, , University of Western Australia, ; Perth, Australia
                [64 ]Rinku General Medical Center, Izumisano, Osaka Japan
                [65 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Department of Community Medicine, , Osaka University Graduate School of Medicine, ; Suita, Osaka Japan
                [66 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Department of Cardiovascular Medicine, , Osaka University Graduate School of Medicine, ; Suita, Osaka Japan
                [67 ]ISNI 0000 0004 0370 1101, GRID grid.136304.3, Department of Endocrinology, Hematology and Gerontology, Clinical Cell Biology and Medicine, , Chiba University Graduate School of Medicine, ; Chiba, Japan
                [68 ]ISNI 0000 0004 1757 3470, GRID grid.5608.b, Department of Medicine-DIMED, , University of Padua, ; Padua, Italy
                [69 ]Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
                Article
                864
                10.1186/s12933-019-0864-7
                6549355
                31164165
                2c733578-3c2c-4e98-a4d1-d0086e13a78f
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 24 April 2019
                : 29 April 2019
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                © The Author(s) 2019

                Endocrinology & Diabetes
                residual cardiovascular risk,visceral obesity,diabetes,atherogenic dyslipidemia,triglycerides,remnant cholesterol,selective peroxisome proliferator-activated receptor alpha modulator,spparmalpha,pemafibrate (k-877),inflammation,prominent

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