New targets and mechanisms of action for lipid-lowering and anti-inflammatory therapies in atherosclerosis: where does the field stand?

References

• Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol. 2005 Oct 4;46(7):1225–1228. doi: 10.1016/j.jacc.2005.07.006
   PubMed Web of Science ®Google Scholar
• Ference BA, Ginsberg HN, Graham I, 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 Aug 21;38(32):2459–2472. doi: 10.1093/eurheartj/ehx144
   PubMed Web of Science ®Google Scholar
• Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010 Nov 13;376(9753):1670–1681. doi: 10.1016/S0140-6736(10)61350-5
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011 Dec 1;365(22):2078–2087. doi: 10.1056/NEJMoa1110874
   PubMed Web of Science ®Google Scholar
• Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006 Apr 5;295(13):1556–1565. doi: 10.1001/jama.295.13.jpc60002
   PubMed Web of Science ®Google Scholar
• Puri R, Libby P, Nissen SE, et al. Long-term effects of maximally intensive statin therapy on changes in coronary atheroma composition: insights from SATURN. Eur Heart J Cardiovasc Imaging. 2014 Apr;15(4):380–388. doi: 10.1093/ehjci/jet251
   PubMed Web of Science ®Google Scholar
• Grundy SM, Stone NJ, Bailey AL, 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. Circulation. 2019 Jun 18;139(25):e1082–e1143. doi: 10.1161/CIR.0000000000000625
   PubMed Web of Science ®Google Scholar
• Ray KK, Molemans B, Schoonen WM, et al. EU-Wide cross-sectional observational study of lipid-modifying therapy use in secondary and primary care: the DA VINCI study. Eur J Prev Cardiol. 2021 Sep 20;28(11):1279–1289. doi: 10.1093/eurjpc/zwaa047
   PubMed Web of Science ®Google Scholar
• Lin I, Sung J, Sanchez RJ, et al. Patterns of statin use in a real-world population of patients at high cardiovascular risk. J Manag Care Spec Pharm. 2016 Jun;22(6):685–698. doi: 10.18553/jmcp.2016.22.6.685
   PubMedGoogle Scholar
• De Vera MA, Bhole V, Burns LC, et al. Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review. Br J Clin Pharmacol. 2014 Oct;78(4):684–698. doi: 10.1111/bcp.12339
   PubMed Web of Science ®Google Scholar
• Khunti K, Danese MD, Kutikova L, et al. Association of a combined measure of adherence and treatment intensity with cardiovascular outcomes in patients with atherosclerosis or other cardiovascular risk factors treated with Statins and/or Ezetimibe. JAMA Netw Open. 2018 Dec 7;1(8):e185554. doi: 10.1001/jamanetworkopen.2018.5554
   PubMed Web of Science ®Google Scholar
• Tsujita K, Sugiyama S, Sumida H, et al. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial. J Am Coll Cardiol. 2015 Aug 04;66(5):495–507. doi: 10.1016/j.jacc.2015.05.065
   PubMed Web of Science ®Google Scholar
• Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015 Jun 18;372(25):2387–2397. doi: 10.1056/NEJMoa1410489
   PubMed Web of Science ®Google Scholar
• Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: The GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014 Jun 17;63(23):2541–2548. doi: 10.1016/j.jacc.2014.03.019
   PubMed Web of Science ®Google Scholar
• Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9(6):758–769. doi: 10.1016/j.jacl.2015.08.006
   PubMed Web of Science ®Google Scholar
• Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The gauss-3 randomized clinical trial. JAMA. 2016;315(15):1580–1590. doi: 10.1001/jama.2016.3608
   PubMed Web of Science ®Google Scholar
• Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL Cholesterol. N Engl J Med. 2012;366(12):1108–1118. doi: 10.1056/NEJMoa1105803
   PubMed Web of Science ®Google Scholar
• Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870–1882. doi: 10.1001/jama.2014.4030
   PubMed Web of Science ®Google Scholar
• Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014 May 8;370(19):1809–1819. doi: 10.1056/NEJMoa1316222
   PubMed Web of Science ®Google Scholar
• Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018 Nov 29;379(22):2097–2107. doi: 10.1056/NEJMoa1801174
   PubMed Web of Science ®Google Scholar
• Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017 Mar 17;376(18):1713–1722. doi: 10.1056/NEJMoa1615664
   PubMed Web of Science ®Google Scholar
• Raber L, Ueki Y, Otsuka T, et al. Effect of Alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: The PACMAN-AMI Randomized Clinical Trial. JAMA. 2022 Apr 3. doi: 10.1001/jama.2022.11836
   Web of Science ®Google Scholar
• Nicholls SJ, Kataoka Y, Nissen SE, et al. Effect of Evolocumab on coronary plaque phenotype and burden in statin-treated patients following myocardial infarction. JACC Cardiovasc Imaging. 2022 Mar 16. doi: 10.1016/j.jcmg.2022.03.002
   Google Scholar
• Nicholls SJ, Puri R, Anderson T, et al. Effect of Evolocumab on progression of coronary disease in statin-treated patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016 Dec 13;316(22):2373–2384. doi: 10.1001/jama.2016.16951
   PubMed Web of Science ®Google Scholar
• Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 Jan 1;41(1):111–188. doi: 10.1093/eurheartj/ehz455
   PubMed Web of Science ®Google Scholar
• Bilen O, Ballantyne CM. Bempedoic Acid (ETC-1002): an investigational inhibitor of ATP Citrate Lyase. Curr Atheroscler Rep. 2016 Oct;18(10):61. doi: 10.1007/s11883-016-0611-4
   PubMed Web of Science ®Google Scholar
• Ference BA, Ray KK, Catapano AL, et al. Mendelian randomization study of ACLY and cardiovascular disease. N Engl J Med. 2019 Mar 14;380(11):1033–1042. doi: 10.1056/NEJMoa1806747
   PubMed Web of Science ®Google Scholar
• Ballantyne CM, Davidson MH, Macdougall DE, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol. 2013 Sep 24;62(13):1154–1162. doi: 10.1016/j.jacc.2013.05.050
   PubMed Web of Science ®Google Scholar
• Gutierrez MJ, Rosenberg NL, Macdougall DE, et al. Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):676–683. doi: 10.1161/ATVBAHA.113.302677
   PubMed Web of Science ®Google Scholar
• Thompson PD, Rubino J, Janik MJ, et al. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance. J Clin Lipidol. 2015 May;9(3):295–304. doi: 10.1016/j.jacl.2015.03.003
   PubMed Web of Science ®Google Scholar
• Ballantyne CM, McKenney JM, MacDougall DE, et al. Effect of ETC-1002 on serum low-density lipoprotein cholesterol in hypercholesterolemic patients receiving statin therapy. Am J Cardiol. 2016 Jun 15;117(12):1928–1933. doi: 10.1016/j.amjcard.2016.03.043
   PubMed Web of Science ®Google Scholar
• Ballantyne CM, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study. Atherosclerosis. 2018 Oct;277:195–203. doi: 10.1016/j.atherosclerosis.2018.06.002
   PubMed Web of Science ®Google Scholar
• Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019 Mar 14;380(11):1022–1032. doi: 10.1056/NEJMoa1803917
   PubMed Web of Science ®Google Scholar
• Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: The CLEAR Wisdom Randomized Clinical Trial. JAMA. 2019 Nov 12;322(18):1780–1788. doi: 10.1001/jama.2019.16585
   PubMed Web of Science ®Google Scholar
• Laufs U, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc. 2019 Apr 2;8(7):e011662. doi: 10.1161/JAHA.118.011662
   PubMed Web of Science ®Google Scholar
• Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. 2020 Apr;27(6):593–603. doi: 10.1177/2047487319864671
   PubMed Web of Science ®Google Scholar
• Stroes ESG, Bays HE, Banach M, et al. Bempedoic acid lowers high-sensitivity C-reactive protein and low-density lipoprotein cholesterol: Analysis of pooled data from four phase 3 clinical trials. Atherosclerosis. 2023 May;373:1–9. doi: 10.1016/j.atherosclerosis.2023.03.020
   PubMed Web of Science ®Google Scholar
• Pinkosky SL, Filippov S, Srivastava RA, et al. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J Lipid Res. 2013 Jan;54(1):134–151. doi: 10.1194/jlr.M030528
   PubMed Web of Science ®Google Scholar
• Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023 Apr 13;388(15):1353–1364. doi: 10.1056/NEJMoa2215024
   PubMed Web of Science ®Google Scholar
• Nicholls S, Lincoff AM, Bays HE, et al. Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance. Am Heart J. 2021 May;235:104–112. doi: 10.1016/j.ahj.2020.10.060
   PubMed Web of Science ®Google Scholar
• Nissen SE, Menon V, Nicholls SJ, et al. Bempedoic acid for primary prevention of cardiovascular events in statin-intolerant patients. JAMA. 2023 Jul 11;330(2):131–140. doi: 10.1001/jama.2023.9696
   PubMed Web of Science ®Google Scholar
• Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017 Mar 17;376(16):1527–1539. doi: 10.1056/NEJMoa1701488
   PubMed Web of Science ®Google Scholar
• Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020 Apr 16;382(16):1520–1530. doi: 10.1056/NEJMoa1913805
   PubMed Web of Science ®Google Scholar
• Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017 Mar 17;376(15):1430–1440. doi: 10.1056/NEJMoa1615758
   PubMed Web of Science ®Google Scholar
• Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507–1519. doi: 10.1056/NEJMoa1912387
   PubMed Web of Science ®Google Scholar
• Ray KK, Kallend D, Leiter LA, et al. Effect of inclisiran on lipids in primary prevention: the ORION-11 trial. Eur Heart J. 2022 Dec 21;43(48):5047–5057. doi: 10.1093/eurheartj/ehac615
   PubMed Web of Science ®Google Scholar
• [cited 2022 Dec 31]. Available from: https://www.nature.com/articles/d41573-021-00195-4
   Google Scholar
• Raal F, Fourie N, Scott R, et al. Long-term efficacy and safety of lerodalcibep in heterozygous familial hypercholesterolaemia: the LIBerate-HeFH trial. Eur Heart J. 2023 Aug 28;44(40):4272–4280. doi: 10.1093/eurheartj/ehad596
   PubMed Web of Science ®Google Scholar
• Momtazi-Borojeni AA, Jaafari MR, Badiee A, et al. Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis. BMC Med. 2019 Dec 10;17(1):223. doi: 10.1186/s12916-019-1457-8
   PubMed Web of Science ®Google Scholar
• Lee RG, Mazzola AM, Braun MC, et al. Efficacy and safety of an investigational single-course CRISPR base-editing therapy targeting PCSK9 in nonhuman primate and mouse models. Circulation. 2022 Oct 31;147(3):242–253. doi: 10.1161/CIRCULATIONAHA.122.062132
   PubMed Web of Science ®Google Scholar
• Barter PJ, Chapman MJ, Hennekens CH, et al. Cholesteryl ester transfer protein. A novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23:160–167. doi: 10.1161/01.ATV.0000054658.91146.64
   PubMed Web of Science ®Google Scholar
• Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007 Nov 22;357(21):2109–2122. doi: 10.1056/NEJMoa0706628
   PubMed Web of Science ®Google Scholar
• Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012 Nov 29;367(22):2089–2099. doi: 10.1056/NEJMoa1206797
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Lincoff AM, Barter PJ, et al. Assessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: Rationale and design of the ACCELERATE trial. Am Heart J. 2015 Dec;170(6):1061–1069. doi: 10.1016/j.ahj.2015.09.007
   PubMed Web of Science ®Google Scholar
• Gotto AM Jr., Cannon CP, Li XS, et al. Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease. Am J Cardiol. 2014 Jan 1;113(1):76–83. doi: 10.1016/j.amjcard.2013.08.041
   PubMed Web of Science ®Google Scholar
• Ference BA, Kastelein JJP, Ginsberg HN, et al. Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk. JAMA. 2017 Sep 12;318(10):947–956. doi: 10.1001/jama.2017.11467
   PubMed Web of Science ®Google Scholar
• Hovingh GK, Kastelein JJ, van Deventer SJ, et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 2015 Aug 1;386(9992):452–460. doi: 10.1016/S0140-6736(15)60158-1
   PubMed Web of Science ®Google Scholar
• [cited 2022 Jun 26]. Available from: https://pace-cme.org/2021/11/29/dose-dependent-reduction-of-ldl-c-levels-by-cetp-inhibitor/
   Google Scholar
• Ballantyne CM, Ditmarsch M, Kastelein JJ, et al. Obicetrapib plus ezetimibe as an adjunct to high-intensity statin therapy: A randomized phase 2 trial. J Clin Lipidol. 2023 Jul;17(4):491–503. doi: 10.1016/j.jacl.2023.05.098
   PubMed Web of Science ®Google Scholar
• Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022 Oct 14;43(39):3925–3946. doi: 10.1093/eurheartj/ehac361
   PubMed Web of Science ®Google Scholar
• Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009 Jul 22;302(4):412–423. doi: 10.1001/jama.2009.1063
   PubMed Web of Science ®Google Scholar
• Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, et al. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009 Jun 10;301(22):2331–2339. doi: 10.1001/jama.2009.801
   PubMed Web of Science ®Google Scholar
• Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009 Dec 24;361(26):2518–2528. doi: 10.1056/NEJMoa0902604
   PubMed Web of Science ®Google Scholar
• Burgess S, Ference BA, Staley JR, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018 Jul 1;3(7):619–627. doi: 10.1001/jamacardio.2018.1470
   PubMed Web of Science ®Google Scholar
• Bittner VA, Szarek M, Aylward PE, et al. Effect of Alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol. 2020 Jan 21;75(2):133–144. doi: 10.1016/j.jacc.2019.10.057
   PubMed Web of Science ®Google Scholar
• O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation. 2019 Mar 19;139(12):1483–1492. doi: 10.1161/CIRCULATIONAHA.118.037184
   PubMed Web of Science ®Google Scholar
• Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med. 2020 Jan 16;382(3):244–255. doi: 10.1056/NEJMoa1905239
   PubMed Web of Science ®Google Scholar
• O’Donoghue ML, Rosenson RS, Gencer B, et al. Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. N Engl J Med. 2022 Nov 17;387(20):1855–1864. doi: 10.1056/NEJMoa2211023
   PubMed Web of Science ®Google Scholar
• Nissen SE, Wolski K, Balog C, et al. Single ascending dose study of a short interfering RNA targeting lipoprotein(a) production in individuals with elevated plasma lipoprotein(a) levels. JAMA. 2022 May 3;327(17):1679–1687. doi: 10.1001/jama.2022.5050
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Nissen SE, Fleming C, et al. Muvalaplin, an oral small molecule inhibitor of lipoprotein(a) formation: a randomized clinical trial. JAMA. 2023 Sep 19;330(11):1042–1053. doi: 10.1001/jama.2023.16503
   PubMed Web of Science ®Google Scholar
• Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and LDL-C-Lowering LDLR variants with risk of coronary heart disease. JAMA. 2019 Jan 29;321(4):364–373. doi: 10.1001/jama.2018.20045
   PubMed Web of Science ®Google Scholar
• Bloomfield Rubins H, Davenport J, Babikian V, et al. Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT). Circulation. 2001 Jun 12;103(23):2828–2833. doi: 10.1161/01.CIR.103.23.2828
   PubMed Web of Science ®Google Scholar
• Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans affairs high-density lipoprotein cholesterol intervention trial study group. N Engl J Med. 1999 Aug 5;341(6):410–418. doi: 10.1056/NEJM199908053410604
   PubMed Web of Science ®Google Scholar
• Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001 Mar 24;357(9260):905–910. doi: 10.1016/S0140-6736(00)04209-4
   PubMed Web of Science ®Google Scholar
• Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005 Nov 26;366(9500):1849–1861. doi: 10.1016/S0140-6736(05)67667-2
   PubMed Web of Science ®Google Scholar
• Robins SJ, Collins D, Wittes JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA. 2001 Mar 28;285(12):1585–1591. doi: 10.1001/jama.285.12.1585
   PubMed Web of Science ®Google Scholar
• Lee M, Saver JL, Towfighi A, et al. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis. 2011 Aug;217(2):492–498. doi: 10.1016/j.atherosclerosis.2011.04.020
   PubMed Web of Science ®Google Scholar
• Das Pradhan A, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med. 2022 Nov 24;387(21):1923–1934. doi: 10.1056/NEJMoa2210645
   PubMed Web of Science ®Google Scholar
• Mason RP, Libby P, Bhatt DL. Emerging mechanisms of cardiovascular protection for the Omega-3 fatty acid Eicosapentaenoic acid. Arterioscler Thromb Vasc Biol. 2020 May;40(5):1135–1147. doi: 10.1161/ATVBAHA.119.313286
   PubMed Web of Science ®Google Scholar
• Bang HO, Dyerberg J, Sinclair HM. The composition of the Eskimo food in north western Greenland. Am J Clin Nutr. 1980 Dec;33(12):2657–2661. doi: 10.1093/ajcn/33.12.2657
   PubMed Web of Science ®Google Scholar
• Dolecek TA. Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the multiple risk factor intervention trial. Proc Soc Exp Biol Med. 1992 Jun;200(2):177–182. doi: 10.3181/00379727-200-43413
   PubMed Web of Science ®Google Scholar
• Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999 Aug 7;354(9177):447–455. doi: 10.1016/S0140-6736(99)07072-5
   PubMed Web of Science ®Google Scholar
• Aung T, Halsey J, Kromhout D, et al. Associations of Omega-3 fatty acid supplement use with cardiovascular disease risks: Meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 2018 Mar 1;3(3):225–234. doi: 10.1001/jamacardio.2017.5205
   PubMed Web of Science ®Google Scholar
• Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11–22. doi: 10.1056/NEJMoa1812792
   PubMed Web of Science ®Google Scholar
• Doi T, Langsted A, Nordestgaard BG. A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs. Eur Heart J. 2021 Dec 14;42(47):4807–4817. doi: 10.1093/eurheartj/ehab555
   PubMed Web of Science ®Google Scholar
• Saito Y, Yokoyama M, Origasa H, et al. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis. 2008 Sep;200(1):135–140. doi: 10.1016/j.atherosclerosis.2008.06.003
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose Omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: The STRENGTH Randomized Clinical Trial. JAMA. 2020 Dec 8;324(22):2268–2280. doi: 10.1001/jama.2020.22258
   PubMed Web of Science ®Google Scholar
• Kalstad AA, Myhre PL, Laake K, et al. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized, controlled trial. Circulation. 2021 Feb 9;143(6):528–539. doi: 10.1161/CIRCULATIONAHA.120.052209
   PubMed Web of Science ®Google Scholar
• Tg, Hdl Working Group of the Exome Sequencing Project NHL, Blood I, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014 Jul 3;371(1):22–31. doi: 10.1056/NEJMoa1307095
   PubMed Web of Science ®Google Scholar
• Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol. 2017 Apr 25;69(16):2054–2063. doi: 10.1016/j.jacc.2017.02.030
   PubMed Web of Science ®Google Scholar
• [cited 2021 Dec 24]. Available from: https://www.europeanpharmaceuticalreview.com/news/154004/evinacumab-shows-promise-in-severe-hypertriglyceridemia-trial/
   Google Scholar
• Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E, et al. Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome. N Engl J Med. 2024 Apr 7;390(19):1781–1792. doi: 10.1056/NEJMoa2400201
   PubMedGoogle Scholar
• Gaudet D, Gipe DA, Pordy R, et al. ANGPTL3 Inhibition in Homozygous Familial Hypercholesterolemia. N Engl J Med. 2017 Jul 20;377(3):296–297. doi: 10.1056/NEJMc1705994
   PubMed Web of Science ®Google Scholar
• Digenio A, Dunbar RL, Alexander VJ, et al. Antisense-mediated lowering of plasma apolipoprotein C-III by Volanesorsen improves dyslipidemia and insulin sensitivity in type 2 diabetes. Diabetes Care. 2016 Aug;39(8):1408–1415. doi: 10.2337/dc16-0126
   PubMed Web of Science ®Google Scholar
• Gaudet D, Alexander VJ, Baker BF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med. 2015 Jul 30;373(5):438–447. doi: 10.1056/NEJMoa1400283
   PubMed Web of Science ®Google Scholar
• Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014 Dec 4;371(23):2200–2206. doi: 10.1056/NEJMoa1400284
   PubMed Web of Science ®Google Scholar
• Gaudet D, Pall D, Watts GF, et al. Plozasiran (ARO-APOC3) for severe hypertriglyceridemia: The SHASTA-2 randomized clinical trial. JAMA Cardiol. 2024 Apr 7. doi: 10.1001/jamacardio.2024.0959
   PubMedGoogle Scholar
• Bergmark BA, Marston NA, Prohaska TA, et al. Olezarsen for hypertriglyceridemia in patients at high cardiovascular risk. N Engl J Med. 2024 Apr 7;390(19):1770–1780. doi: 10.1056/NEJMoa2402309
   PubMedGoogle Scholar
• Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977 May;62(5):707–714. doi: 10.1016/0002-9343(77)90874-9
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Cutri B, Worthley SG, et al. Impact of short-term administration of high-density lipoproteins and atorvastatin on atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2416–2421. doi: 10.1161/01.ATV.0000184760.95957.d6
   PubMed Web of Science ®Google Scholar
• cited 2013 Feb 15]. Available from: http://www.thrivestudy.org/HPS2THRIVE%20RELEASEUSWIREVERSIONfinal.pdf
   Google Scholar
• Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017 May 18;376(20):1933–1942. doi: 10.1056/NEJMoa1609581
   PubMed Web of Science ®Google Scholar
• Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Meta-Analysis Research Support, N.I.H. Extramural Research Support, Non-U.S. Gov’t. Lancet. 2012 Aug 11;380(9841):572–580. doi: 10.1016/S0140-6736(12)60312-2
   PubMed Web of Science ®Google Scholar
• Khera AV, Cuchel M, de la Llera-Moya M, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011 Jan 13;364(2):127–135. doi: 10.1056/NEJMoa1001689
   PubMed Web of Science ®Google Scholar
• Bhattacharyya T, Nicholls SJ, Topol EJ, et al. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA. 2008 Mar 19;299(11):1265–1276. doi: 10.1001/jama.299.11.1265
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Andrews J, Kastelein JJP, et al. Effect of serial infusions of CER-001, a pre-beta high-density lipoprotein mimetic, on coronary atherosclerosis in patients following acute coronary syndromes in the CER-001 atherosclerosis regression acute coronary syndrome trial: a randomized clinical trial. JAMA Cardiol. 2018 Sep 1;3(9):815–822. doi: 10.1001/jamacardio.2018.2121
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Puri R, Ballantyne CM, et al. Effect of infusion of high-density lipoprotein mimetic containing recombinant Apolipoprotein A-I milano on coronary disease in patients with an acute coronary syndrome in the MILANO-PILOT trial: a randomized clinical trial. JAMA Cardiol. 2018 Sep 1;3(9):806–814. doi: 10.1001/jamacardio.2018.2112
   PubMed Web of Science ®Google Scholar
• Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003 Nov 5;290(17):2292–2300. doi: 10.1001/jama.290.17.2292
   PubMed Web of Science ®Google Scholar
• Gibson CM, Duffy D, Korjian S, et al. Apolipoprotein A1 infusions and cardiovascular outcomes after acute myocardial infarction. N Engl J Med. 2024 Apr 6;390(17):1560–1571. doi: 10.1056/NEJMoa2400969
   PubMedGoogle Scholar
• Povsic TJ, Korjian S, Bahit MC, et al. Effect of reconstituted human apolipoprotein A-I on recurrent ischemic events in survivors of acute MI. J Am Coll Cardiol. 2024 Mar 25;83(22):2163–2174. doi: 10.1016/j.jacc.2024.03.396
   PubMedGoogle Scholar
• Ridker PM, Buring JE, Shih J, et al. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation. 1998 Aug 25;98(8):731–733. doi: 10.1161/01.CIR.98.8.731
   PubMed Web of Science ®Google Scholar
• Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005 Jan 6;352(1):29–38. doi: 10.1056/NEJMoa042000
   PubMed Web of Science ®Google Scholar
• Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005 Jan 6;352(1):20–28. doi: 10.1056/NEJMoa042378
   PubMed Web of Science ®Google Scholar
• Cupido AJ, Asselbergs FW, Natarajan P, et al. Dissecting the IL-6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R. Br J Clin Pharmacol. 2022 Jun;88(6):2875–2884. doi: 10.1111/bcp.15191
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Kastelein JJ, Schwartz GG, et al. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial. Research Support, Non-U.S. Gov’t. JAMA. 2014 Jan 15;311(3):252–262. doi: 10.1001/jama.2013.282836
   PubMed Web of Science ®Google Scholar
• Investigators S, White HD, Held C, et al. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med. 2014 May 1;370(18):1702–1711. doi: 10.1056/NEJMoa1315878
   PubMed Web of Science ®Google Scholar
• Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with Canakinumab for atherosclerotic disease. N Engl J Med. 2017 Sep 21;377(12):1119–1131. doi: 10.1056/NEJMoa1707914
   PubMed Web of Science ®Google Scholar
• Nidorf SM, Eikelboom JW, Budgeon CA, et al. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013 Jan 29;61(4):404–410. doi: 10.1016/j.jacc.2012.10.027
   PubMed Web of Science ®Google Scholar
• Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020 Nov 5;383(19):1838–1847. doi: 10.1056/NEJMoa2021372
   PubMed Web of Science ®Google Scholar
• Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019 Dec 26;381(26):2497–2505. doi: 10.1056/NEJMoa1912388
   PubMed Web of Science ®Google Scholar
• Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2019 Feb 21;380(8):752–762. doi: 10.1056/NEJMoa1809798
   PubMed Web of Science ®Google Scholar
• Ridker PM, Devalaraja M, Baeres FMM, et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021 May 29;397(10289):2060–2069. doi: 10.1016/S0140-6736(21)00520-1
   PubMed Web of Science ®Google Scholar
• Anand SS, Bosch J, Eikelboom JW, 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 Jan 20;391(10117):219–229. doi: 10.1016/S0140-6736(17)32409-1
   PubMed Web of Science ®Google Scholar
• Libby P, Pasterkamp G, Crea F, et al. Reassessing the mechanisms of acute coronary syndromes. Circ Res. 2019 Jan 4;124(1):150–160. doi: 10.1161/CIRCRESAHA.118.311098
   PubMed Web of Science ®Google Scholar