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.

3rd Department of Medicine 1st Faculty of Medicine of Charles University and General University Hospital Prague Prague Czech Republic

3rd Dept Int Med Center for Preventive Cardiology 3rd Internal Medicine Clinic University General Hospital and Charles University Prague Czech Republic

Cardiac Rehabilitation Institute Sheba Medical Center 5265601 Tel Hashomer Israel

Cardiology Department Córdoba Hospital Córdoba Argentina

Cardiovascular Medicine Brigham and Women's Hospital Harvard Medical School Boston MA USA

Center for Integrative Genomics Université de Lausanne Le Génopode CH 1015 Lausanne Switzerland

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

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

Columbia University Vagelos College of Physicians and Surgeons New York USA

DAMIC Medical Institute Rusculleda Foundation for Research Córdoba Argentina

Department of Cardiology Faculty of Medicine Hacettepe University Ankara Turkey

Department of Cardiovascular Medicine Osaka University Graduate School of Medicine Suita Osaka Japan

Department of Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital Herlev Denmark

Department of Clinical Biochemistry Rigshospitalet; Copenhagen University Hospital Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Department of Clinical Biochemistry Sultan Qaboos University Hospital Muscat Oman

Department of Community Medicine Osaka University Graduate School of Medicine Suita Osaka Japan

Department of Endocrinology Diabetology and Nutrition Jean Verdier Hospital Paris 13 University Sorbonne Paris Cité CRNH IdF CINFO 93140 Bondy France

Department of Endocrinology Diabetology Jaslok Hospital and Research Centre Mumbai India

Department of Endocrinology Hematology and Gerontology Clinical Cell Biology and Medicine Chiba University Graduate School of Medicine Chiba Japan

Department of Endocrinology Metabolic diseases and Nutrition G and R Laennec Hospital Nantes France

Department of Internal Medicine Faculty of Medicine University of Tsukuba Ibaraki 305 8575 Japan

Department of Internal Medicine Seoul National University Bundang Hospital and Seoul National University College of Medicine Seongnam Republic of Korea

Department of Internal Medicine University Hospital Centre Zagreb School of Medicine Zagreb University Kispaticeva 12 Zagreb Croatia

Department of Medicine and Theraputics The Chinese University of Hong Kong Hong Kong Hong Kong

Department of Medicine DIMED University of Padua Padua Italy

Department of Medicine Ramathibodi Hospital Mahidol University Bangkok Thailand

Department of Medicine School of Medicine Universidad Complutense de Madrid Madrid Spain

Department of Neurology and Stroke Center Paris Diderot Sorbonne University Paris France

Department of Pharmacological and Biomolecular Sciences Università Degli Studi di Milano Milan Italy

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

Deutsches Herzzentrum München Technische Universitat München Germany; DZHK Partner Site Munich Heart Alliance Munich Germany

Division of Cardiovascular Medicine and Center for Cardiovascular Disease Prevention Brigham and Women's Hospital Harvard Medical School Boston MA USA

Division of Cardiovascular Medicine Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston MA USA

Division of Cardiovascular Medicine VA Boston Medical Center Boston MA USA

Division of Endocrinology and Metabolism Department of Internal Medicine Jichi Medical University Shimotsuke Japan

Division of Endocrinology and Nutrition Cliniques Universitaires St Luc and Institut de Recherche Expérimentale et Clinique Université Catholique de Louvain Brussels Belgium

Division of Endocrinology Metabolism and Diabetes Department of Medicine University of Colorado School of Medicine Anschutz Medical Campus Aurora CO USA

Division of Preventive Medicine Brigham and Women's Hospital Harvard Medical School Boston MA USA

Faculté de Pharmacie de Lille Lille France

Faculty of Clinical Pharmacology and Therapeutics Academy for Postgraduate Continuous Medical Education Moscow Russian Federation

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Hospital Israelita Albert Einstein and Lipid Clinic Heart Institute University of Sao Paulo Medical School Hospital Sao Paulo Brazil

Imperial Centre for Cardiovascular Disease Prevention Department of Primary Care and Public Health Imperial College London London UK

Inra UMR 1280 Physiologie des Adaptations Nutritionnelles Nantes France

INSERM CHU Lille U1171 Degenerative and Vascular Cognitive Disorders University of Lille Faculty of Pharmacy University of Lille UDSL Lille France

Institut National de La Recherche Agronomique UMR1331 ToxAlim Toulouse France

Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow UK

Institute of Epidemiology and Medical Biometry University of Ulm Ulm Germany

Instituto de Investigaciones Sanitarias Gregorio Marañón Madrid Spain

Internal Medicine Lipids Unit Gregorio Marañón University Hospital Madrid Spain

Laboratory for System Biology and Medicine Research Center for Advanced Science and Technology The University of Tokyo Tokyo Japan

Laboratory of Lipid Disorders National Cardiology Research Center Moscow Russian Federation

Lee Kong Chian School of Medicine Nanyang Technological University Singapore Clinical Sciences Building 11 Mandalay Road Singapore 308232 Singapore

Lipid Clinic Point Médical and Department of Cardiology CHU Dijon Bourgogne Dijon France

Lipid Disorders Clinic Department of Cardiology Royal Perth Hospital School of Medicine University of Western Australia Perth Australia

Lipid Research Group School of Medical Sciences University of New South Wales Sydney NSW Australia

Mass Spectrometry Core facility of West Human Nutrition Research Center Hotel Dieu Hospital Nantes France

National Cerebral and Cardiovascular Center Suita Osaka Japan

OCDEM University of Oxford and the NIHR Oxford Biomedical Research Centre OUH Foundation Trust Churchill Hospital Oxford UK

R3i Foundation Picassoplatz 8 4010 Basel Switzerland

Research Program for Clinical and Molecular Metabolism Faculty of Medicine University of Helsinki and Clinical Research Institute HUCH Ltd Helsinki Finland

Rinku General Medical Center Izumisano Osaka Japan

Ruddy Canadian Cardiovascular Genetics Centre University of Ottawa Heart Institute Ottawa Canada

Sackler Faculty of Medicine Tel Aviv University 6997801 Tel Aviv Israel

Tecnologico de Monterrey Escuela de Medicina y Ciencias de la Salud Monterrey Mexico

The Copenhagen General Population Study Herlev and Gentofte Hospital Copenhagen University Hospital Herlev Denmark

The Copenhagen General Population Study Herlev and Gentofte Hospital Herlev Denmark

Unidad de Investigacion de Enfermedades Metabolicas Department of Endocrinolgy and Metabolism Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Mexico City Mexico

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

Zobrazit více v PubMed

Joseph P, Leong D, McKee M, Anand SS, Schwalm JD, Teo K, et al. Reducing the global burden of cardiovascular disease. Part 1: the epidemiology and risk factors. Circ Res. 2017;121:677–694. doi: 10.1161/CIRCRESAHA.117.308903. PubMed DOI

World Health Organization. Fact sheet. Obesity and overweight. http://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 21 Jan 2019.

NCD Countdown 2030 collaborators NCD Countdown 2030: worldwide trends in non-communicable disease mortality and progress towards Sustainable Development Goal target 3.4. Lancet. 2018;392:1072–1088. doi: 10.1016/S0140-6736(18)31992-5. PubMed DOI

Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84. doi: 10.1002/hep.28431. PubMed DOI

Olubamwo OO, Virtanen JK, Voutilainen A, Kauhanen J, Pihlajamäki J, Tuomainen TP. Association of fatty liver index with the risk of incident cardiovascular disease and acute myocardial infarction. Eur J Gastroenterol Hepatol. 2018;30:1047–1054. doi: 10.1097/MEG.0000000000001183. PubMed DOI

Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR) Eur Heart J. 2016;37:2315–2381. doi: 10.1093/eurheartj/ehw106. PubMed DOI PMC

Davidson MH. Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions. Expert Opin Drug Saf. 2006;5:145–156. doi: 10.1517/14740338.5.1.145. PubMed DOI

Mychaleckyj JC, Craven T, Nayak U, Buse J, Crouse JR, Elam M, et al. Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants. Diabetes Care. 2012;35:1008–1014. doi: 10.2337/dc11-1811. PubMed DOI PMC

Davis TM, Ting R, Best JD, Donoghoe MW, Drury PL, Sullivan DR, et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia. 2011;54:280–290. doi: 10.1007/s00125-010-1951-1. PubMed DOI

Hedrington MS, Davis SN. Peroxisome proliferator-activated receptor alpha-mediated drug toxicity in the liver. Expert Opin Drug Metab Toxicol. 2018;14:671–677. doi: 10.1080/17425255.2018.1483337. PubMed DOI

Fruchart JC, Sacks F, Hermans MP, Assmann G, Brown WV, Ceska R, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102(Suppl 10):1K–34K. doi: 10.1016/j.amjcard.2008.10.002. PubMed DOI

Jernberg T, Hasvold P, Henriksson M, Hjelm H, Thuresson M, Janzon M. Cardiovascular risk in post-myocardial infarction patients: nationwide real-world data demonstrate the importance of a long-term perspective. Eur Heart J. 2015;36:1163–1170. doi: 10.1093/eurheartj/ehu505. PubMed DOI

Sacks FM, Hermans MP, Fioretto P, Valensi P, Davis T, Horton E, et al. Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global case–control study in 13 countries. Circulation. 2014;129:999–1008. doi: 10.1161/CIRCULATIONAHA.113.002529. PubMed DOI

Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38:2459–2572. doi: 10.1093/eurheartj/ehx144. PubMed DOI PMC

Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–1722. doi: 10.1056/NEJMoa1615664. PubMed DOI

Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–2107. doi: 10.1056/NEJMoa1801174. PubMed DOI

Bonaca MP, Nault P, Giugliano RP, Keech AC, Pineda AL, Kanevsky E, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER Trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk) Circulation. 2018;137:338–350. doi: 10.1161/CIRCULATIONAHA.117.032235. PubMed DOI

Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5:941–950. doi: 10.1016/S2213-8587(17)30313-3. PubMed DOI

Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–1131. doi: 10.1056/NEJMoa1707914. PubMed DOI

Anand SS, Bosch J, Eikelboom JW, Connolly SJ, Diaz R, Widimsky P, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2018;391:219–229. doi: 10.1016/S0140-6736(17)32409-1. PubMed DOI

Patel KV, Pandey A, de Lemos JA. Conceptual framework for addressing residual atherosclerotic cardiovascular disease risk in the era of precision medicine. Circulation. 2018;137:2551–2553. doi: 10.1161/CIRCULATIONAHA.118.035289. PubMed DOI

Piché ME, Poirier P, Lemieux I, Després JP. Overview of epidemiology and contribution of obesity and body fat distribution to cardiovascular disease: an update. Prog Cardiovasc Dis. 2018;61:103–113. doi: 10.1016/j.pcad.2018.06.004. PubMed DOI

Lauridsen BK, Stender S, Kristensen TS, Kofoed KF, Køber L, Nordestgaard BG, et al. Liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease: mendelian randomization and meta-analysis of 279 013 individuals. Eur Heart J. 2018;39:385–393. doi: 10.1093/eurheartj/ehx662. PubMed DOI

Santos RD, Valenti L, Romeo S. Does nonalcoholic fatty liver disease cause cardiovascular disease? Current knowledge and gaps. Atherosclerosis. 2019;282:110–120. doi: 10.1016/j.atherosclerosis.2019.01.029. PubMed DOI

Taskinen M-R, Boren J. Why is apolipoprotein CIII emerging as a novel therapeutic target to reduce the burden of cardiovascular disease? Curr Atheroscler Rep. 2016;18:59. doi: 10.1007/s11883-016-0614-1. PubMed DOI PMC

Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Borén J, Catapano AL, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J. 2011;32:1345–1361. doi: 10.1093/eurheartj/ehr112. PubMed DOI PMC

Ponte-Negretti CI, Isea-Perez JE, Lorenzatti AJ, Lopez-Jaramillo P, Wyss-Q FS, Pintó X, et al. Atherogenic dyslipidemia in Latin America: prevalence, causes and treatment: expert’s position paper made by The Latin American Academy for the Study of Lipids (ALALIP) Endorsed by the Inter-American Society of Cardiology (IASC), the South American Society of Cardiology (SSC), the Pan-American College of Endothelium (PACE), and the International Atherosclerosis Society (IAS) Int J Cardiol. 2017;243:516–522. doi: 10.1016/j.ijcard.2017.05.059. PubMed DOI

Fan W, Philip S, Granowitz C, Toth PP, Wong ND. Hypertriglyceridemia in statin-treated US adults: the National Health and Nutrition Examination Survey. J Clin Lipidol. 2018 doi: 10.1016/j.jacl.2018.11.008. PubMed DOI

Reiner Ž, De Bacquer D, Kotseva K, Prugger C, De Backer G, Wood D, et al. Treatment potential for dyslipidaemia management in patients with coronary heart disease across Europe: findings from the EUROASPIRE III survey. Atherosclerosis. 2013;231:300–307. doi: 10.1016/j.atherosclerosis.2013.09.020. PubMed DOI

Tóth PP, Potter D, Ming EE. Prevalence of lipid abnormalities in the United States: the National Health and Nutrition Examination Survey 2003–2006. J Clin Lipidol. 2012;6:325–330. doi: 10.1016/j.jacl.2012.05.002. PubMed DOI

Halcox JP, Banegas JR, Roy C, Dallongeville J, De Backer G, Guallar E, et al. Prevalence and treatment of atherogenic dyslipidemia in the primary prevention of cardiovascular disease in Europe: EURIKA, a cross-sectional observational study. BMC Cardiovasc Disord. 2017;17:160. doi: 10.1186/s12872-017-0591-5. PubMed DOI PMC

Nussbaumerová B, Rosolová H, Mayer O, Filipovský J, Cífková R, Bruthans J. Residual cardiovascular risk in patients with stable coronary heart disease over the last 16 years (Czech part of the EUROASPIRE I–IV surveys) Cor et Vasa. 2014;56:e98–e104. doi: 10.1016/j.crvasa.2014.02.002. DOI

Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;31:811–822. PubMed

The Emerging Risk Factors Collaboration Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302:1993–2000. doi: 10.1001/jama.2009.1619. PubMed DOI PMC

Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012;380:572–580. doi: 10.1016/S0140-6736(12)60312-2. PubMed DOI PMC

Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–2122. doi: 10.1056/NEJMoa0706628. PubMed DOI

AIM-HIGH Investigators Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–2267. doi: 10.1056/NEJMoa1107579. PubMed DOI

Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–2099. doi: 10.1056/NEJMoa1206797. PubMed DOI

HPS2-THRIVE Collaborative Group HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013;34:1279–1291. doi: 10.1093/eurheartj/eht055. PubMed DOI PMC

Lincoff AM, Nicholls SJ, Riesmeyer JS, Barter PJ, Brewer HB, Fox KAA, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017;376:1933–1942. doi: 10.1056/NEJMoa1609581. PubMed DOI

Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123:2292–2333. doi: 10.1161/CIR.0b013e3182160726. PubMed DOI

Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J. 2015;36:774–776. doi: 10.1093/eurheartj/ehu500. PubMed DOI PMC

Nordestgaard BG, Langsted A, Mora S, Kolovou G, Baum H, Bruckert E, et al. Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut-points-a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur Heart J. 2016;37:1944–1958. doi: 10.1093/eurheartj/ehw152. PubMed DOI PMC

Austin MA, McKnight B, Edwards KL, Bradley CM, McNeely MJ, Psaty BM, et al. Cardiovascular disease mortality in familial forms of hypertriglyceridemia: a 20-year prospective study. Circulation. 2000;101:2777–2782. doi: 10.1161/01.CIR.101.24.2777. PubMed DOI

Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299–308. doi: 10.1001/jama.298.3.299. PubMed DOI

Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA. 2007;298:309–316. doi: 10.1001/jama.298.3.309. PubMed DOI

Miller M, Cannon CP, Murphy SA, Qin J, Ray KK, Braunwald E, PROVE IT-TIMI 22 Investigators Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008;51:724–730. doi: 10.1016/j.jacc.2007.10.038. PubMed DOI

Faergeman O, Holme I, Fayyad R, Bhatia S, Grundy SM, Kastelein JJ, et al. Plasma triglycerides and cardiovascular events in the treating to new targets and incremental decrease in end-points through aggressive lipid lowering trials of statins in patients with coronary artery disease. Am J Cardiol. 2009;104:459–463. doi: 10.1016/j.amjcard.2009.04.008. PubMed DOI

Kastelein JJ, van der Steeg WA, Holme I, Gaffney M, Cater NB, Barter P, et al. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation. 2008;117:3002–3009. doi: 10.1161/CIRCULATIONAHA.107.713438. PubMed DOI

Schwartz GG, Abt M, Bao W, DeMicco D, Kallend D, Miller M, et al. Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins. J Am Coll Cardiol. 2015;65:2267–2275. doi: 10.1016/j.jacc.2015.03.544. PubMed DOI

Puri R, Nissen SE, Shao M, Elshazly MB, Kataoka Y, Kapadia SR, et al. Non-HDL cholesterol and triglycerides: implications for coronary atheroma progression and clinical events. Arterioscler Thromb Vasc Biol. 2016;36:2220–2228. doi: 10.1161/ATVBAHA.116.307601. PubMed DOI

Klempfner R, Erez A, Sagit BZ, Goldenberg I, Fisman E, Kopel E, et al. Elevated triglyceride level is independently associated with increased all-cause mortality in patients with established coronary heart disease: twenty-two-year follow-up of the bezafibrate infarction prevention study and registry. Circ Cardiovasc Qual Outcomes. 2016;9:100–108. doi: 10.1161/CIRCOUTCOMES.115.002104. PubMed DOI

ACCORD Study Group. Ginsberg HN, Elam MB, Lovato LC, Crouse JR, 3rd, Leiter LA, Linz P, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Eng J Med. 2010;362:1563–1574. doi: 10.1056/NEJMoa1001282. PubMed DOI PMC

Nichols GA, Philip S, Reynolds K, Granowitz CB, Fazio S. Increased residual cardiovascular risk in patients with diabetes and high versus normal triglycerides despite statin-controlled LDL cholesterol. Diabetes Obes Metab. 2019;21:366–371. doi: 10.1111/dom.13537. PubMed DOI PMC

Toth PP, Granowitz C, Hull M, Liassou D, Anderson A, Philip S. High triglycerides are associated with increased cardiovascular events, medical costs, and resource use: a real-world administrative claims analysis of statin-treated patients with high residual cardiovascular risk. J Am Heart Assoc. 2018;7:e008740. doi: 10.1161/JAHA.118.008740. PubMed DOI PMC

Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet. 2014;384:626–635. doi: 10.1016/S0140-6736(14)61177-6. PubMed DOI

Adiels M, Taskinen MR, Packard C, Caslake MJ, Soro-Paavonen A, Westerbacka J, et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia. 2006;49:755–765. doi: 10.1007/s00125-005-0125-z. PubMed DOI

Ziouzenkova O, Perrey S, Asatryan L, Hwang J, MacNaul KL, Moller DE, et al. Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: evidence for an antiinflammatory role for lipoprotein lipase. Proc Natl Acad Sci USA. 2003;100:2730–2735. doi: 10.1073/pnas.0538015100. PubMed DOI PMC

Augustus A, Yagyu H, Haemmerle G, Bensadoun A, Vikramadithyan RK, Park SY, et al. Cardiac-specific knock-out of lipoprotein lipase alters plasma lipoprotein triglyceride metabolism and cardiac gene expression. J Biol Chem. 2004;279:25050–25057. doi: 10.1074/jbc.M401028200. PubMed DOI

Brown JD, Plutzky J. Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. Circulation. 2007;115:518–533. doi: 10.1161/CIRCULATIONAHA.104.475673. PubMed DOI

Tikka A, Jauhiainen M. The role of ANGPTL3 in controlling lipoprotein metabolism. Endocrine. 2016;52:187–193. doi: 10.1007/s12020-015-0838-9. PubMed DOI PMC

Kersten S. Angiopoietin-like 3 in lipoprotein metabolism. Nat Rev Endocrinol. 2017;13:731–739. doi: 10.1038/nrendo.2017.119. PubMed DOI

Borén J, Watts GF, Adiels M, Söderlund S, Chan DC, Hakkarainen A, et al. Kinetic and related determinants of plasma triglyceride concentration in abdominal obesity: multicenter tracer kinetic study. Arterioscler Thromb Vasc Biol. 2015;35:2218–2224. doi: 10.1161/ATVBAHA.115.305614. PubMed DOI

Nordestgaard BG, Wootton R, Lewis B. Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol. 1995;15:534–542. doi: 10.1161/01.ATV.15.4.534. PubMed DOI

Nordestgaard BG, Stender S, Kjeldsen K. Reduced atherogenesis in cholesterol-fed diabetic rabbits. Giant lipoproteins do not enter the arterial wall. Arteriosclerosis. 1988;8:421–428. doi: 10.1161/01.ATV.8.4.421. PubMed DOI

Vallejo-Vaz AJ, Fayyad R, Boekholdt SM, Hovingh GK, Kastelein JJ, Melamed S, et al. Triglyceride-rich lipoprotein cholesterol and risk of cardiovascular events among patients receiving statin therapy in the TNT Trial. Circulation. 2018;138:770–781. doi: 10.1161/CIRCULATIONAHA.117.032318. PubMed DOI

Varbo A, Benn M, Nordestgaard BG. Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment. Pharmacol Ther. 2014;141:358–367. doi: 10.1016/j.pharmthera.2013.11.008. PubMed DOI

Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013;61:427–436. doi: 10.1016/j.jacc.2012.08.1026. PubMed DOI

Varbo A, Freiberg JJ, Nordestgaard BG. Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90000 individuals from the general population. Clin Chem. 2015;61:533–543. doi: 10.1373/clinchem.2014.234146. PubMed DOI

Jepsen AM, Langsted A, Varbo A, Bang LE, Kamstrup PR, Nordestgaard BG. Increased remnant cholesterol explains part of residual risk of all-cause mortality in 5414 patients with ischemic heart disease. Clin Chem. 2016;62:593–604. doi: 10.1373/clinchem.2015.253757. PubMed DOI

Steinberg D, Carew TE, Fielding C, Fogelman AM, Mahley RW, Sniderman AD, et al. Lipoproteins and the pathogenesis of atherosclerosis. Circulation. 1989;80:719–723. doi: 10.1161/01.CIR.80.3.719. PubMed DOI

Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation. 1979;60:473–485. doi: 10.1161/01.CIR.60.3.473. PubMed DOI

Bernelot Moens SJ, Verweij SL, Schnitzler JG, Stiekema LCA, Bos M, Langsted A, et al. Remnant cholesterol elicits arterial wall inflammation and a multilevel cellular immune response in humans. Arterioscler Thromb Vasc Biol. 2017;37:969–975. doi: 10.1161/ATVBAHA.116.308834. PubMed DOI

Hansen SEJ, Madsen CM, Varbo A, Nordestgaard BG. Low-grade inflammation in the association between mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis: a study of more than 115000 individuals from the general population. Clin Chem. 2018 doi: 10.1373/clinchem.2018.294926. PubMed DOI

Pennacchio LA, Rubin EM. Apolipoprotein A5, a newly identified gene that affects plasma triglyceride levels in humans and mice. Arterioscler Thromb Vasc Biol. 2003;23:529–534. doi: 10.1161/01.ATV.0000054194.78240.45. PubMed DOI

Nilsson SK, Heeren J, Olivecrona G, Merkel M. Apolipoprotein A–V; a potent triglyceride reducer. Atherosclerosis. 2011;219:15–21. doi: 10.1016/j.atherosclerosis.2011.07.019. PubMed DOI

Khera AV, Won HH, Peloso GM, O’Dushlaine C, Liu D, Stitziel NO, Natarajan P, et al. Association of rare and common variation in the lipoprotein lipase gene with coronary artery disease. JAMA. 2017;317:937–946. doi: 10.1001/jama.2017.0972. PubMed DOI PMC

Nordestgaard BG, Abildgaard S, Wittrup HH, Steffensen R, Jensen G, Tybjaerg-Hansen A. Heterozygous lipoprotein lipase deficiency: frequency in the general population, effect on plasma lipid levels, and risk of ischemic heart disease. Circulation. 1997;96:1737–1744. doi: 10.1161/01.CIR.96.6.1737. PubMed DOI

Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32–41. doi: 10.1056/NEJMoa1308027. PubMed DOI

TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Crosby J, Peloso GM, Auer PL, Crosslin DR, Stitziel NO, Lange LA, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371:22–31. doi: 10.1056/NEJMoa1307095. PubMed DOI PMC

Dewey FE, Gusarova V, O’Dushlaine C, Gottesman O, Trejos J, Hunt C, et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med. 2016;374:1123–1133. doi: 10.1056/NEJMoa1510926. PubMed DOI PMC

Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Stitziel NO, Stirrups KE, Masca NG, Erdmann J, Ferrario PG, König IR, et al. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N Engl J Med. 2016;374:1134–1144. doi: 10.1056/NEJMoa1507652. PubMed DOI PMC

Stitziel NO, Khera AV, Wang X, Bierhals AJ, Vourakis AC, Sperry AE, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol. 2017;69:2054–2063. doi: 10.1016/j.jacc.2017.02.030. PubMed DOI PMC

Sacks FM, Alaupovic P, Moye LA, Cole TG, Sussex B, Stampfer MJ, et al. VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial. Circulation. 2000;102:1886–1892. doi: 10.1161/01.CIR.102.16.1886. PubMed DOI

Zheng C, Azcutia V, Aikawa E, Figueiredo JL, Croce K, Sonoki H, et al. Statins suppress apolipoprotein CIII-induced vascular endothelial cell activation and monocyte adhesion. Eur Heart J. 2013;34:615–624. doi: 10.1093/eurheartj/ehs271. PubMed DOI PMC

Juntti-Berggren L, Berggren PO. Apolipoprotein CIII is a new player in diabetes. Curr Opin Lipidol. 2017;28:27–31. PubMed

Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 doi: 10.1016/j.jacc.2018.11.003. PubMed DOI

Handelsman Y, Bloomgarden ZT, Grunberger G, Umpierrez G, Zimmerman RS, Bailey TS, et al. American association of clinical endocrinologists and american college of endocrinology—clinical practice guidelines for developing a diabetes mellitus comprehensive care plan—2015. Endocr Pract. 2015;21(Suppl 1):1–87. doi: 10.4158/EP15672.GLSUPPL. PubMed DOI PMC

Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, et al. ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR) Eur Heart J. 2016;37:2999–3058. doi: 10.1093/eurheartj/ehw272. PubMed DOI

Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med. 2010;363:692–694. doi: 10.1056/NEJMc1006407. PubMed DOI

Elam MB, Ginsberg HN, Lovato LC, Corson M, Largay J, Leiter LA, et al. Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes. JAMA Cardiol. 2017;2:370–380. doi: 10.1001/jamacardio.2016.4828. PubMed DOI PMC

Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090–1098. doi: 10.1016/S0140-6736(07)60527-3. PubMed DOI

Aung T, Halsey J, Kromhout D, Gerstein HC, Marchioli R, Tavazzi L, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials Involving 77 917 individuals. JAMA Cardiol. 2018;3:225–234. doi: 10.1001/jamacardio.2017.5205. PubMed DOI PMC

Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2018;380:11–22. doi: 10.1056/NEJMoa1812792. PubMed DOI

Fruchart JC. Peroxisome proliferator-activated receptor-alpha (PPARalpha): at the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis. 2009;205:1–8. doi: 10.1016/j.atherosclerosis.2009.03.008. PubMed DOI

Brocker CN, Patel DP, Velenosi TJ, Kim D, Yan T, Yue J, et al. Extrahepatic PPARα modulates fatty acid oxidation and attenuates fasting-induced hepatosteatosis in mice. J Lipid Res. 2018;59:2140–2152. doi: 10.1194/jlr.M088419. PubMed DOI PMC

Gronemeyer H, Laudet V. Transcription factors 3: nuclear receptors. Protein Profile. 1995;2:1173–1308. PubMed

Tugwood JD, Issemann I, Anderson RG, Bundell KR, McPheat WL, Green S. The mouse peroxisome proliferator activated receptor recognizes a response element in the 50-flanking sequence of the rat acyl CoA oxidase gene. EMBO J. 1992;11:433–439. doi: 10.1002/j.1460-2075.1992.tb05072.x. PubMed DOI PMC

Marx N, Duez H, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ Res. 2004;94:1168–1178. doi: 10.1161/01.RES.0000127122.22685.0A. PubMed DOI

Delerive P, De Bosscher K, Besnard S, Vanden Berghe W, Peters JM, Gonzalez FJ, et al. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem. 1999;274:32048–32054. doi: 10.1074/jbc.274.45.32048. PubMed DOI

Pineda Torra I, Jamshidi Y, Flavell DM, Fruchart JC, Staels B. Characterization of the human PPARalpha promoter: identification of a functional nuclear receptor response element. Mol Endocrinol. 2002;16:1013–1028. PubMed

Bougarne N, Weyers B, Desmet SJ, Deckers J, Ray DW, Staels B, et al. Molecular actions of PPARα in lipid metabolism and inflammation. Endocr Rev. 2018;39:760–802. doi: 10.1210/er.2018-00064. PubMed DOI

Marx N, Sukhova GK, Collins T, Libby P, Plutzky J. PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation. 1999;99:3125–3131. doi: 10.1161/01.CIR.99.24.3125. PubMed DOI PMC

Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature. 1996;384:39–43. doi: 10.1038/384039a0. PubMed DOI

Neve BP, Corseaux D, Chinetti G, Zawadzki C, Fruchart JC, Duriez P, et al. PPARalpha agonists inhibit tissue factor expression in human monocytes and macrophages. Circulation. 2001;103:207–212. doi: 10.1161/01.CIR.103.2.207. PubMed DOI

Marx N, Mackman N, Schoenbeck U, Yilmaz N, Hombach V, Libby P, et al. PPARα activators inhibit tissue factor expression and activity in human monocytes. Circulation. 2001;103:213–219. doi: 10.1161/01.CIR.103.2.213. PubMed DOI

Wahli W, Michalik L. PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol Metab. 2012;23:351–363. doi: 10.1016/j.tem.2012.05.001. PubMed DOI

Staels B, Maes M, Zambon A. Fibrates and future PPARalpha agonists in the treatment of cardiovascular disease. Nat Clin Pract Cardiovasc Med. 2008;5:542–553. doi: 10.1038/ncpcardio1278. PubMed DOI

Shi L, Tu BP. Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr Opin Cell Biol. 2015;33:125–131. doi: 10.1016/j.ceb.2015.02.003. PubMed DOI PMC

Angajala A, Lim S, Phillips JB, Kim JH, Yates C, You Z, et al. Diverse roles of mitochondria in immune responses: novel insights into immuno-metabolism. Front Immunol. 2018;9:1605. doi: 10.3389/fimmu.2018.01605. PubMed DOI PMC

Krishnan V, Heath H, Bryant HU. Mechanism of action of estrogens and selective estrogen receptor modulators. Vitam Horm. 2000;60:123–147. doi: 10.1016/S0083-6729(00)60018-3. PubMed DOI

Lewis JS, Jordan VC. Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance. Mutat Res. 2005;591:247–263. doi: 10.1016/j.mrfmmm.2005.02.028. PubMed DOI

Fruchart JC. Selective peroxisome proliferator-activated receptor α modulators (SPPARMα): the next generation of peroxisome proliferator-activated receptor α-agonists. Cardiovasc Diabetol. 2013;12:82. doi: 10.1186/1475-2840-12-82. PubMed DOI PMC

Nissen SE, Nicholls SJ, Wolski K, Howey DC, McErlean E, Wang MD, et al. Effects of a potent and selective PPAR-alpha agonist in patients with atherogenic dyslipidemia or hypercholesterolemia: two randomized controlled trials. JAMA. 2007;297:1362–1373. doi: 10.1001/jama.297.12.1362. PubMed DOI

Yamazaki Y, Abe K, Toma T, Nishikawa M, Ozawa H, Okuda A, et al. Design and synthesis of highly potent and selective human peroxisome proliferator-activated receptor alpha agonists. Bioorg Med Chem Lett. 2007;17:4689–4693. doi: 10.1016/j.bmcl.2007.05.066. PubMed DOI

Yamamoto Y, Takei K, Arulmozhiraja S, Sladek V, Matsuo N, Han SI, et al. Molecular association model of PPARα and its new specific and efficient ligand, pemafibrate: structural basis for SPPARMα. Biochem Biophys Res Commun. 2018;499:239–245. doi: 10.1016/j.bbrc.2018.03.135. PubMed DOI

Besseiche A, Riveline JP, Gautier JF, Bréant B, Blondeau B. Metabolic roles of PGC-1α and its implications for type 2 diabetes. Diabetes Metab. 2015;41:347–357. doi: 10.1016/j.diabet.2015.02.002. PubMed DOI

Fruchart JC. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia. Cardiovasc Diabetol. 2017;16:124. doi: 10.1186/s12933-017-0602-y. PubMed DOI PMC

Raza-Iqbal S, Tanaka T, Anai M, Matsumura Y, Ikeda K, Taguchi A, et al. Transcriptome analysis of K-877 (a novel Selective PPARα Modulator (SPPARMα))-regulated genes in primary human hepatocytes and the mouse liver. J Atheroscler Thromb. 2015;22:754–772. doi: 10.5551/jat.28720. PubMed DOI PMC

Kharitonenkov A, DiMarchi R. FGF21 Revolutions: recent advances illuminating FGF21 biology and medicinal properties. Trends Endocrinol Metab. 2015;26:608–617. doi: 10.1016/j.tem.2015.09.007. PubMed DOI

Schlein C, Talukdar S, Heine M, Fischer AW, Krott LM, Nilsson SK, et al. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues. Cell Metab. 2016;23:441–453. doi: 10.1016/j.cmet.2016.01.006. PubMed DOI

Ong KL, O’Connell R, Januszewski AS, Jenkins AJ, Xu A, Sullivan DR, et al. Baseline circulating FGF21 concentrations and increase after fenofibrate treatment predict more rapid glycemic progression in type 2 diabetes: results from the FIELD Study. Clin Chem. 2017;63:1261–1270. doi: 10.1373/clinchem.2016.270876. PubMed DOI

Takei K, Han SI, Murayama Y, Satoh A, Oikawa F, Ohno H, et al. Selective peroxisome proliferator-activated receptor-α modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-α pathway and improves lipid metabolism in mice. J Diabetes Investig. 2017;8:446–452. doi: 10.1111/jdi.12621. PubMed DOI PMC

Sairyo M, Kobayashi T, Masuda D, Kanno K, Zhu Y, Okada T, et al. A novel selective PPAR Modulator (SPPARM), K-877 (pemafibrate), attenuates postprandial hypertriglyceridemia in mice. J Atheroscler Thromb. 2018;25:142–152. doi: 10.5551/jat.39693. PubMed DOI PMC

Takei K, Nakagawa Y, Wang Y, Han SI, Satoh A, Sekiya M, et al. Effects of K-877, a novel selective PPARα modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockout mice. J Pharmacol Sci. 2017;133:214–222. doi: 10.1016/j.jphs.2017.02.003. PubMed DOI

Hennuyer N, Duplan I, Paquet C, Vanhoutte J, Woitrain E, Touche V, et al. The novel selective PPARα modulator (SPPARMα) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis. Atherosclerosis. 2016;249:200–208. doi: 10.1016/j.atherosclerosis.2016.03.003. PubMed DOI

Iwata H, Murakami K, Ricchiuto P, Singh S, Libby P, Aikawa E. The novel PPARα selective agonist K-877 suppresses pro-inflammatory pathways and experimental arterial lesion formation. Circ Res. 2014;115:e86–e93.

Araki M, Nakagawa Y, Oishi A, Han SI, Wang Y, Kumagai K, et al. The peroxisome proliferator-activated receptor α (PPARα) agonist pemafibrate protects against diet-induced obesity in mice. Int J Mol Sci. 2018;19:E2148. doi: 10.3390/ijms19072148. PubMed DOI PMC

Honda Y, Kessoku T, Ogawa Y, Tomeno W, Imajo K, Fujita K, et al. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep. 2017;7:42477. doi: 10.1038/srep42477. PubMed DOI PMC

Maki T, Maeda Y, Sonoda N, Makimura H, Kimura S, Maeno S, et al. Renoprotective effect of a novel selective PPARα modulator K-877 in db/db mice: a role of diacylglycerol-protein kinase C-NAD(P)H oxidase pathway. Metabolism. 2017;71:33–45. doi: 10.1016/j.metabol.2017.02.013. PubMed DOI

Varbo A, Freiberg JJ, Nordestgaard BG. Remnant cholesterol and myocardial infarction in normal weight, overweight, and obese individuals from the Copenhagen General Population Study. Clin Chem. 2018;64:219–230. doi: 10.1373/clinchem.2017.279463. PubMed DOI

Ishibashi S, Yamashita S, Arai H, Araki E, Yokote K, Suganami H, et al. Effects of K-877, a novel selective PPARα modulator (SPPARMα), in dyslipidaemic patients: a randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis. 2016;249:36–43. doi: 10.1016/j.atherosclerosis.2016.02.029. PubMed DOI

Arai H, Yamashita S, Yokote K, Araki E, Suganami H, Ishibashi S, K-877 Study Group Efficacy and safety of pemafibrate versus fenofibrate in patients with high triglyceride and low HDL cholesterol levels: a multicenter, placebo-controlled, double-blind, randomized trial. J Atheroscler Thromb. 2018;25:521–538. doi: 10.5551/jat.44412. PubMed DOI PMC

Ishibashi S, Arai H, Yokote K, Araki E, Suganami H, Yamashita S, K-877 Study Group Efficacy and safety of pemafibrate (K-877), a selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia: results from a 24-week, randomized, double blind, active-controlled, phase 3 trial. J Clin Lipidol. 2018;12:173–184. doi: 10.1016/j.jacl.2017.10.006. PubMed DOI

Arai H, Yamashita S, Yokote K, Araki E, Suganami H, Ishibashi S, K-877 Study Group Efficacy and safety of K-877, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), in combination with statin treatment: two randomised, double-blind, placebo-controlled clinical trials in patients with dyslipidaemia. Atherosclerosis. 2017;261:144–152. doi: 10.1016/j.atherosclerosis.2017.03.032. PubMed DOI

Araki E, Yamashita S, Arai H, Yokote K, Satoh J, Inoguchi T, et al. Effects of pemafibrate, a novel selective PPARα modulator, on lipid and glucose metabolism in patients with type 2 diabetes and hypertriglyceridemia: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2018;41:538–546. doi: 10.2337/dc17-1589. PubMed DOI

Kastelein JJP, Senko Y, Hounslow N. K-877, a selective PPAR alpha modulator (SPPARM alpha), improves dyslipidaemia in statin-treated patients with type 2 diabetes mellitus. Eur Heart J. 2015;36:1048.

Kastelein JJP, Senko Y, Hounslow N, Hovingh GK, Ginsberg HN. K-877, a selective PPAR alpha modulator (SPPARM alpha), ameliorates dyslipidaemia in patients with well-controlled LDL Cholesterol levels on statin therapy, without increases in serum creatinine. Eur Heart J. 2015;36:1048.

Yamashita S, Arai H, Yokote K, Araki E, Suganami H, Ishibashi S, K-877 Study Group Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia. J Clin Lipidol. 2018;12:1267–1279. doi: 10.1016/j.jacl.2018.06.010. PubMed DOI

Hounslow N, Mair S, Suganami H, Nakamura M. Pemafibrate has high bioavailability and is principally excreted via the liver. Atheroscler Suppl. 2018;32:155.

Yokote K, Yamashita S, Arai H, Araki E, Suganami H, Ishibashi S. Long-term efficacy and safety of pemafibrate, a novel selective peroxisome proliferator-activated receptor-α modulator (SPPARMα), in dyslipidemic patients with renal impairment. Int J Mol Sci. 2019;20:E706. doi: 10.3390/ijms20030706. PubMed DOI PMC

Yokote K, Yamashita S, Arai H, Araki E, Suganami H, Ishibashi S. A pooled analysis of pemafibrate Phase II/III clinical trials indicated significant improvement in glycemic and liver function-related parameters. Atheroscler Suppl. 2018;32:155. doi: 10.1016/j.atherosclerosissup.2018.04.471. DOI

Matsuba I, Matsuba R, Ishibashi S, Yamashita S, Arai H, Yokote K, et al. Effects of a novel selective peroxisome proliferator-activated receptor-α modulator, pemafibrate, on hepatic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance. J Diabetes Investig. 2018 doi: 10.1111/jdi.12845. PubMed DOI PMC

Pradhan AD, Paynter NP, Everett BM, Glynn RJ, Amarenco P, Elam M, et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J. 2018;206:80–93. doi: 10.1016/j.ahj.2018.09.011. PubMed DOI

PROMINENT-Eye Ancillary Study (Protocol AD). ClinicalTrials.gov Identifier NCT03345901. https://clinicaltrials.gov/ct2/show/NCT03345901. Accessed 7 Aug 2018.

Keech AC, Mitchell P, Summanen PA, O’Day J, Davis TM, Moffitt MS, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet. 2007;370:1687–1697. doi: 10.1016/S0140-6736(07)61607-9. PubMed DOI

ACCORD Study Group; ACCORD Eye Study Group. Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010;363:233–244. doi: 10.1056/NEJMoa1001288. PubMed DOI PMC

Doycheva I, Issa D, Watt KD, Lopez R, Rifai G, Alkhouri N. Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in young adults in the United States. J Clin Gastroenterol. 2018;52:339–346. doi: 10.1097/MCG.0000000000000925. PubMed DOI

Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66:1138–1153. doi: 10.1136/gutjnl-2017-313884. PubMed DOI

A study of pemafibrate in patients with nonalcoholic fatty liver disease (NAFLD). ClinicalTrials.gov Identifier. https://clinicaltrials.gov/ct2/show/NCT03350165. Accessed 21 Jan 2019.

Sasaki Y, Asahiyama M, Kamiya W, Sakai J, Kodama T, Tanaka T. Tofogliflozin and pemafibrate combination therapy prevents nonalcoholic steatohepatitis (NASH) development of novel metabolic syndrome-related NASH model mice. Diabetes. 2018;67:1. doi: 10.2337/db18-1153-p. PubMed DOI