Search

A 56-year-old white man with hypertension and a strong family history of cardiovascular disease was referred to a lipid-specialty clinic secondary to a statin intolerance (ie, myalgias) and dyslipidemia. The patient was initiated on ezetimibe 10 mg daily and experienced a supratherapeutic response. His baseline low-density lipoprotein cholesterol was reduced by 52% after 8 months of ezetimibe therapy, with no other explanation for the marked reduction. Recent studies have indicated a wide range of response to ezetimibe with different genetic variations. It is likely that this patient has a genetic variation that resulted in a hyperresponse to ezetimibe. [ABSTRACT FROM AUTHOR]

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a proinflammatory participant in atherosclerosis and a potential biomarker for coronary heart disease. The effects of low-density lipoprotein (LDL) apheresis on Lp-PLA(2) levels were evaluated in 8 patients with cardiovascular disease. Each patient received 5 LDL apheresis treatments over a 3-month period. The mean direct LDL cholesterol level reduction was 60% (252 to 100 mg/dl). LDL apheresis acutely reduced Lp-PLA(2) by 21.4%. Over the course of treatment, Lp-PLA(2) levels were reduced by 29%. Chronic LDL apheresis significantly reduces Lp-PLA(2) independent of LDL cholesterol, which may be a potential mechanism by which LDL apheresis diminishes coronary heart disease risk. [ABSTRACT FROM AUTHOR]

Despite the availability of multiple classes of lipoprotein-lowering medications, some high-risk patients have persistent hypercholesterolemia and may require nonpharmacologic therapy. Lipoprotein apheresis (LA) is a valuable but underused adjunctive therapeutic option for low-density lipoprotein cholesterol and lipoprotein(a) lowering, particularly in children and adults with familial hypercholesterolemia. In addition to lipid lowering, LA reduces serum levels of proinflammatory and prothrombotic factors, reduces blood viscosity, increases microvascular myocardial perfusion, and may provide beneficial effects on endothelial function. Multiple observational studies demonstrate strong evidence for improved cardiovascular outcomes with LA; however, use in the United States is limited to a fraction of its Food and Drug Administration-approved indications. In addition, there are limited data regarding LA benefit for refractory focal segmental glomerulosclerosis. In this scientific statement, we review the history of LA, mechanisms of action, cardiovascular and renal outcomes data, indications, and options for treatment.

Background: It is unknown whether clinical benefit of proprotein convertase subtilisin/kexin type 9 inhibitors is associated with baseline or on-treatment triglyceride concentrations., Objectives: This study sought to examine relations between triglyceride levels and the effect of alirocumab vs placebo on cardiovascular outcomes using prespecified and post hoc analyses of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial., Methods: Patients with recent acute coronary syndrome (ACS) (n = 18,924) and elevated atherogenic lipoproteins despite optimized statin therapy were randomized to alirocumab 75 to 150 mg or matching placebo every 2 weeks subcutaneously. Major adverse cardiovascular events (MACE) were examined in relation to continuous or dichotomous triglyceride concentrations., Results: Median baseline triglyceride concentration was 129 mg/dL. In both treatment groups, a 10-mg/dL higher baseline concentration was associated with an adjusted MACE HR of 1.008 (95% CI: 1.003-1.013; P < 0.005). Baseline triglycerides ≥150 vs <150 mg/dL were associated with a HR of 1.184 (95% CI: 1.080-1.297; P < 0.005). Versus placebo, alirocumab reduced low-density lipoprotein cholesterol from baseline (average, 54.7%) and reduced MACE (HR: 0.85; 95% CI: 0.78-0.93). At month 4, triglyceride levels were reduced from baseline by median 17.7 mg/dL (P < 0.001) and 0.9 mg/dL (P = NS) with alirocumab and placebo, respectively. A 10-mg/dL decline from baseline in triglycerides was associated with lower subsequent risk of MACE with placebo (HR: 0.988; 95% CI: 0.982-0.995; P < 0.005) but not with alirocumab (HR: 0.999; 95% CI: 0.987-1.010; P = 0.82)., Conclusions: Among patients with recent ACS on optimized statin therapy, baseline triglycerides was associated with cardiovascular risk. However, the reduction in triglycerides with alirocumab did not contribute to its clinical benefit. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402)., Competing Interests: Funding Support and Author Disclosures This analysis was funded by Regeneron Pharmaceuticals, Inc. The ODYSSEY OUTCOMES trial was funded by Regeneron Pharmaceuticals, Inc, and Sanofi. The trial was designed by an academic steering committee in conjunction with the sponsors. The sponsors were involved in the collection verification, and analysis of the data provided in the manuscript. All authors participated in the interpretation of the data. Dr Zahger has served as national coordinator for the ODYSSEY OUTCOMES trial and the SCORED trial, both funded by Sanofi; and has served as consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Sanofi. Dr Schwartz has received research support to the University of Colorado from AstraZeneca, Sanofi, Silence Therapeutics, and The Medicines Company; and is a coinventor of pending U.S. patent 62/806,313 (“Methods for Reducing Cardiovascular Risk”) assigned in full to the University of Colorado. Drs Du, Manvelian, Pordy, Fazio, and Geba are all employees of and shareholders in Regeneron Pharmaceuticals, Inc. Dr Szarek has received salary support from CPC, a nonprofit academic research organization affiliated with the University of Colorado that receives research grant/consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol Myers Squibb, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, Everly Health, Faraday, Fortress Biotech, HDL Therapeutics, HeartFlow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, MedPace, Medtronic, Moderna, Novate Medical, Novo Nordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Biosciences, Regeneron Pharmaceuticals, Inc, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, University of Pittsburgh, Worldwide Clinical Trials, Wraser, and Yale Cardiovascular Research Group; has received fees for performing analyses, steering committee fees, and travel support from Sanofi and Regeneron Pharmaceuticals, Inc; has received consulting fees from CiVi, Lexicon, Amarin, and Esperion Therapeutics; has received Data Safety and Monitoring Board membership fees from Resverlogix and Janssen; and is a member of the Journal of the American College of Cardiology Editorial Board. Dr Bhatt has served on the advisory board for Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; has served on the Board of Directors for Angiowave (with stock options), Boston VA Research Institute, Bristol Myers Squibb (with stock), DRS.LINQ (with stock options), High Enroll (with stock), Society of Cardiovascular Patient Care, and TobeSoft; has served as the Inaugural Chair of the American Heart Association Quality Oversight Committee; has served as a consultant for Broadview Ventures and Hims; has served on the Data Monitoring Committee for Acesion Pharma, Assistance Publique–Hôpitaux de Paris, the Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), the Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, the Population Health Research Institute, and Rutgers University (for the National Institutes of Health–funded MINT trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, the Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and U.S. national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); has served as the Deputy Editor of Clinical Cardiology; has served as the Chair of the NCDR-ACTION Registry Steering Committee and the VA CART Research and Publications Committee; holds a patent for sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither Dr Bhatt nor Brigham and Women's Hospital receives any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Eli Lilly and Company, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron Pharmaceuticals, Inc, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); has served as a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; is a trustee of the American College of Cardiology; and conducted unfunded research for FlowCo and Takeda. Dr Bittner has received grant support from Sanofi, AstraZeneca, DalCor, Esperion, Bayer, Novartis, and Amgen, all paid direct to her institution; and has received personal fees from Sanofi and Pfizer. Dr Budaj has received personal fees and nonfinancial support from Sanofi, Bristol Myers Squibb/Pfizer, Bayer, and AstraZeneca; and has received personal fee from Novartis, Amgen, and Novo Nordisk. Dr Diaz has received research grants from Sanofi, DalCor Pharmaceuticals, the Population Health Research Institute, Duke Clinical Research Institute, the TIMI group, Amgen, Cirius, the Montreal Health Innovations Coordinating Center, and Lepetit; and has received personal fees, as a member of the Executive Steering Committee, from Amgen and Cirius. Dr Goodman has received research grants from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly and Comapny, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, and Sanofi; has received honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly and Company, Esperion Therapeutics, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, JAMP Pharma, Janssen/Johnson & Johnson, Merck, Novartis, Novo Nordisk A/C, Pendopharm, Pfizer, Regeneron Pharmaceuticals, Inc, Sanofi, Servier, Valeo Pharma, the Canadian Heart Research Centre and MD Primer, the Canadian VIGOUR Centre, the Cleveland Clinic Coordinating Centre for Clinical Research, the Duke Clinical Research Institute, the New York University Clinical Coordinating Centre, the PERFUSE Research Institute, and the TIMI Study Group (Brigham Health); and has served as a consultant or on the advisory board (or both) for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Janssen/Johnson & Johnson, Merck, Novartis, Pendopharm, Pfizer, Regeneron Pharmaceuticals, Inc, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma. Dr Jukema has received research grants from the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Commission Seventh Framework Programme; and has received research support from Amgen, Astellas, AstraZeneca, Daiichi-Sankyo, Eli Lilly and Company, Merck-Schering-Plough, Pfizer, Roche, and Sanofi. Dr Harrington has received research grants (all data safety and monitoring board related) from AstraZeneca, Janssen, and Bristol Myers Squibb; has served on the advisory board for Gilead (uncompensated) and WebMD; and has served on the board of directors (unpaid) for the American Heart Association and Stanford HealthCare. Dr Moriarty has received research grants to his institution for the participation in the ODYSSEY OUTCOMES trial; has received financial fees for serving as a medical monitor for the trial and associated support for travel related to trial meetings from Sanofi; has received consulting and speaking fees from Regeneron Pharmaceuticals, Inc, and Amgen; has received consulting fees from Esperion, Kaneka, and Stage II innovations; has received speaker fees from Amarin; has received advisor fees from Novartis for serving on their advisory committee; and has received research grants to his institution from Ionis, FH Foundation, GB Life Sciences, Aegerion, Amgen, Kowa, Novartis, and Regeneron Pharmaceuticals, Inc. Dr Scemama is an employee of Sanofi and may hold shares and/or stock options in the company. Dr White has received grant support paid to his institution for serving on a Steering Committee for the ODYSSEY OUTCOMES trial from Sanofi and Regeneron Pharmaceuticals, Inc, for the ACCELERATE study from Eli Lilly and Company, for the STRENGTH trial from Omthera Pharmaceuticals, for the CAMELLIA-TIMI study from Eisai, for the HEART-FID study from American Regent, and for the ISCHEMIA Trial and the MINT Trial from the National Institutes of Health; has received grants to his institution and personal fees as Steering Committee member for the dal-GenE study from DalCor Pharma UK Inc, for the AEGIS-II study from CSL Behring, for the SCORED trial and the SOLOIST-WHF trial from Sanofi Australia Pty Ltd, and for the CLEAR Outcomes Study from Esperion Therapeutics Inc; and has served on the advisory board for CSL Behring and Genentech (an affiliate of F. Hoffmann-La Roche Ltd, “Roche”; Lytics Post-PCI Advisory Board at European Society of Cardiology). Dr Zeiher has received fees for serving on a steering committee for the ODYSSEY OUTCOMES trial from Sanofi; and has received advisory board and speaker fees from Sanofi, Amgen, Boehringer Ingelheim, Bayer, Novartis, Pfizer, AstraZeneca, and Vifor. Dr Steg has received grants and nonfinancial support (co-Chair of the ODYSSEY OUTCOMES trial; as such, he received no personal fees, but his institution has received funding for the time he has devoted to trial coordination, and he has received support for travel related to trial meetings) from Sanofi; has received research grants and personal fees from Bayer (Steering Committee MARINER, grant for epidemiological study), Merck (speaker fees, grant for epidemiological studies), Sanofi (co-Chair of the ODYSSEY OUTCOMES trial; co-Chair of the SCORED trial; consulting; speaking), Servier (Chair of the CLARIFY registry; grant for epidemiological research), and Amarin (executive steering committee for the REDUCE-IT trial [Disease Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial]; consulting); has received personal fees from Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, Idorsia, MyoKardia, Novo Nordisk, Novartis, Regeneron Pharmaceuticals, Inc, and AstraZeneca; and has a European application number/patent number, issued on October 26, 2016 (no. 15712241.7), for a method for reducing cardiovascular risk, with all royalties assigned to Sanofi. Dr Kiss has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study., Methods: The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks., Results: Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related., Conclusions: Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04233918., Competing Interests: Disclosures A.W. reports payment or honoraria for lectures, presentations, speakers’ bureaus, article writing, or educational events from Novartis and Algorithm; participation in a data safety monitoring board or advisory board for Amryt Pharma; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for Novartis; and research support for pharmaceutical trials from Amgen, Regeneron Pharmaceuticals, Inc, Novartis, Silence Therapeutics, Esperion, and Ultragenyx. S.G.-P. reports receiving research support from Amgen. S.A., J.M., S.B., P.B., R.T.G., B.H., and R.P. are employees of and stockholders in Regeneron Pharmaceuticals, Inc. E.A.B. is a steering committee member for the REDUCE-IT (Amarin) and PROMINENT (Kowa) trials, and receives research support from Regeneron Pharmaceuticals, Inc. He has received speaking or consulting honoraria from 89Bio, Amarin, Amgen, Amryt, Dalcor, Esperion, Immunovant, Ionis, Merck, New Amsterdam, and Pfizer. M.-J.C. reports honoraria from AstraZeneca, Merck Sharp & Dohme, Pfizer, Amgen, and Sanofi. C.B.-S. reports honoraria for presentations from the National Association of Continuing Medical Education and the Cardiometabolic Health Congress. S.B. reports funding or consulting fees from Amgen, Altimmune, Axcella, Regeneron Pharmaceuticals, Inc, Ionis Pharmaceuticals, Boehringer Ingelheim, Esperion, Lilly, Madrigal, Merck, and Novartis. J.B. reports funding or consulting fees from Regeneron Pharmaceuticals, Inc. P.M.M. reports receipt of research grants to his institution for the participation in the ODYSSEY OUTCOMES trial, as well as financial fees for serving as a medical monitor for the trial and associated support for travel related to trial meetings from Sanofi; consulting fees from Regeneron Pharmaceuticals, Inc, Amgen, Esperion, Kaneka, and Stage II Innovations; advisor fees from Novartis for serving on their advisory committee; and research grants to his institution from Ionis, FH Foundation, GB Life Sciences, Aegerion, Amgen, Kowa, Novartis, and Regeneron Pharmaceuticals, Inc. The other authors report no conflicts.

Purpose of Review: Lipoprotein (a) [Lp(a)] is a likely causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve disease, confirmed by Mendelian randomization. With reliable assays, it has been established that Lp(a) is linearly associated with ASCVD. Current low-density lipoprotein cholesterol (LDL-C) lowering therapies do not or minimally lower Lp(a). This review focuses on the clinical importance and therapeutic consequences of Lp(a) measurement., Recent Findings: Development of RNA-based Lp(a) lowering therapeutics has positioned Lp(a) as one of the principal residual risk factors to target in the battle against lipid-driven ASCVD risk. Pelacarsen, which is a liver-specific antisense oligonucleotide, has shown Lp(a) reductions up to 90% and its phase 3 trial is currently underway. Olpasiran is a small interfering RNA targeting LPA messenger RNA, which is being investigated in phase 2 and has already shown dose-dependent Lp(a) reductions up to 90%., Summary: Lp(a) should be measured in every patient at least once to identify patients with very high Lp(a) levels. These patients could benefit from Lp(a) lowering therapies when approved. In the meantime, therapy in high Lp(a) patients should focus on further reducing LDL-C and other ASCVD risk factors., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: Familial hypercholesterolemia (FH) and hyperlipoproteinemia(a) are relatively common disorders, posing a significant health burden due to increased risk of atherosclerotic cardiovascular disease (ASCVD). Development of electronic health record-based strategies with a linkage to the genetic test results has increased awareness, detection, and control of heritable lipid disorders. This review attempts to critically examine available data to provide a summary of the current evidence for lipoprotein apheresis in FH and elevated lipoprotein(a) (Lp(a))., Review Findings: Availability and indications for lipoprotein apheresis vary across the globe. On average, greater than 60% of atherogenic apoB-containing lipoproteins are immediately reduced following a single procedure, translating in substantial reduction of incident ASCVD events, and preventing accelerated vascular aging. Simultaneous lipid-lowering therapy targeting low-density lipoprotein (LDL) and Lp(a) enhances the efficacy of lipoprotein apheresis. Lipoprotein apheresis alters the proteomics of the lipoprotein particles, including reduction in the concentration of the oxidized-LDL and Lp(a) particles, and proinflammatory apoE bound to HDL particles and remnant lipoproteins. Other effects attributed to lipoprotein apheresis include improvement in blood rheology, endothelial function, microvascular flow, myocardial perfusion, reduction in circulating inflammatory markers. Development of lipoprotein apheresis registries provides data on benefits, challenges, and barriers to inform pertinent healthcare policies. Lipoprotein apheresis is a safe and effective procedure for lowering cholesterol in patients with combined and isolated FH and elevated Lp(a). It reduces the burden of ASCVD and improves long-term prognosis. A team approach is required by the patient, medical staff, and healthcare provider to initiate and maintain a lipoprotein apheresis program., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In 2022, the European Atherosclerosis Society (EAS) published a new consensus statement on lipoprotein(a) [Lp(a)], summarizing current knowledge about its causal association with atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. One of the novelties of this statement is a new risk calculator showing how Lp(a) influences lifetime risk for ASCVD and that global risk may be underestimated substantially in individuals with high or very high Lp(a) concentration. The statement also provides practical advice on how knowledge about Lp(a) concentration can be used to modulate risk factor management, given that specific and highly effective mRNA-targeted Lp(a)-lowering therapies are still in clinical development. This advice counters the attitude: "Why should I measure Lp(a) if I can't lower it?". Subsequent to publication, questions have arisen relating to how the recommendations of this statement impact everyday clinical practice and ASCVD management. This review addresses 30 of the most frequently asked questions about Lp(a) epidemiology, its contribution to cardiovascular risk, Lp(a) measurement, risk factor management and existing therapeutic options., Competing Interests: Declaration of competing interest Potential conflicts of interest outside the submitted work are summarized below. The following authors report participation in trials; receipt of fellowships, or grants for travel, research or staffing support; and/or personal honoraria for consultancy or lectures/speaker’s bureau from: Abbott (KKR, LST, BG Nordestgaard [BGN]), Abcentra (M Koschinsky [MK]), Abdi-Ibrahim (LST), Actelion (LST), Aegerion (ALC, PM Moriarty [PMM]), Affiris AG (G Lambert [GL]), Akcea (ALC, BGN, KG Parhofer [KGP], ESGS), Amarin (ALC, PMM, BGN, KGP), Amgen (ALC, BA Ference [BAF], F Kronenberg [FK], F Mach [FM], PMM, P Natarajan [PN], BGN, KGP, KKR, ESGS, LST, GF Watts [GFW]), Amgen Germany (A von Eckardstein [AvE]), Amgen Switzerland (AvE), Amryt (ALC), Amundsen/Amgen (FM), Apple (PN), Arrowhead (GFW), Ayma Therapeutics (MK), AstraZeneca (ALC, PN, BGN, KKR, GFW), Bayer (LST), Berlin-Chemie (KGP), Boehringer-Ingelheim (KKR), Boston Scientific (PN), CiVi Pharma (BAF), Daiichi-Sankyo (ALC, BAF, FM, KGP, KKR, LST), Daiichi Switzerland (AvE), dalCOR (BAF), Denka (BGN), Eli Lilly (ALC, BAF, MK, KKR), Esperion (ALC, BAF, PMM, BGN, KKR, ESGS, GFW), FH Foundation (PMM), Foresite Labs (PN), Fresenius (FK), GB Life Sciences (PMM), Genentech (PN), Genzyme (ALC), Horizon/Novartis (FM, BGN), Ionis Pharmaceuticals (BA, ALC, BAF, BGN, MK, PMM), Jupiter Bioventures (MR Dweck [MRD]), Kaneka (FK, PMM), Kowa (ALC, BGN, KKR), KrKa Phama (BAF), Lupin (KKR), Menarini (ALC), Merck (ALC, BAF), MSD (KGP), Mylan (ALC, BAF, LST), New Amsterdam (KKR), Noetic Insights (MK), Novartis (B Arsenault [BA], ALC, MRD, BAF, FK, FM, CJ McNeal [CJMN], PMM, PN, BGN, KGP, KKR, ESGS, LST, GFW), Novartis Canada (MK), NovoNordisk (BAF, CJMN, BGN, KKR, ES, LST), Nyrada Inc (GL), Pfizer (BA, MRD, BAF, MK,SM, KKR, LST, GFW), Quest Diagnostics (SM), Recordati (ALC, LST), Regeneron (ALC, BAF, PMM, BGN, KKR, ESGS), Renew (PMM), Resverlogix (KKR), Sandoz (ALC), Sanofi (ALC, BAF, FM, BGN, KGP, KKR, ESGS, LST, GFW), Sanofi-Aventis Switzerland (AvE), Sanofi-Regeneron (GL, ESGS), Servier (LST), Sigma Tau (ALC), Silence Therapeutics (BA, MRD, BAF, BGN, KKR, GFW), The Medicines Co (BAF) and UltraGenyx (BGN). PN declares spousal employment at Vertex and KGP is a member of the Data Monitoring and Safety Board at Boehringer-Ingelheim. SSV declares an honorarium from the American College of Cardiology (Associate Editor for Innovations, acc.org), and grant funding from the U.S. Department of Veterans Affairs, National Institutes of Health, World Heart Federation, and Tahir and Jooma Family. Manuscripts have been published in collaboration with non-academic co-authors by PN and LST (Fitbit), GFW (Amgen), and BA (Pfizer). Equity interests including income from stocks, stock options, royalties, or from patents or copyrights were reported from AstraZeneca (JKS), Boston Scientific (L Berglund [LB]), Cargene Therapeutics (KKR), Gilead Sciences (LB), J & J (LB), GSK (JKS), Medtronic (LB), New Amsterdam Pharma (KKR), NovoNordisk (LB), Pemi31 Therapeutics (KKR), and Pfizer (LB).KKR is President of the European Atherosclerosis Society. LST is Past-President of the European Atherosclerosis Society and an Editorial Board Member, The European Heart Journal., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by early-onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a "real-world" setting. Untreated low-density lipoprotein cholesterol levels were lower in adults than children (533 versus 776 mg/dL; P =0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow-up, despite multiple lipid-lowering treatment, low-density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid-lowering treatments were prescribed for 18%; 40% were on no lipid-lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid-lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.

Background: Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain., Methods: We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization., Results: A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels., Conclusions: Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.)., (Copyright © 2023 Massachusetts Medical Society.)

Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations (n = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations (n = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations (n = 19). Fifty-one patients (males, n = 27; females, n = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg -1 or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of -27.1% (37.4) (95% confidence interval -71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228 ., (© 2023. The Author(s).)

Background: Severe hypertriglyceridemia is often caused by variants in genes of triglyceride metabolism. These variants include rare, heterozygous pathogenic variants (PVs), or multiple common, small-effect single nucleotide polymorphisms that can be quantified using a polygenic risk score (PRS). The role of genetic testing to examine PVs and PRS in predicting risk for pancreatitis and severity of hypertriglyceridemia is unknown., Methods: We examined the relationship of PVs and PRSs associated with hypertriglyceridemia with the highest recorded plasma triglyceride level and risk for acute pancreatitis in 363 patients from 3 academic lipid clinics who underwent genetic testing (GBinsight's Dyslipidemia Comprehensive Panel). Categories of hypertriglyceridemia included: normal triglyceride (<200 mg/dL), moderate (200-499 mg/dL), severe (500-999 mg/dL), or very severe (≥1000 mg/dL)., Results: PVs and high PRSs were identified in 37 (10%) and 59 (16%) individuals, respectively. Patients with both had increased risk for very severe hypertriglyceridemia compared with those with neither genetic risk factor. Risk for acute pancreatitis was also increased in individuals with both genetic risk factors (odds ratio, 5.1 [ P =0.02] after controlling for age, race, sex, body mass index, and highest triglyceride level), but not in individuals with PV or high PRS alone., Conclusions: The presence of both PV and high PRS significantly increased risk for very severe hypertriglyceridemia and acute pancreatitis, whereas PV or PRS alone only modestly increased risk. Genetic testing may help identify patients with hypertriglyceridemia who have the greatest risk for developing pancreatitis and may derive the greatest benefit from novel triglyceride-lowering therapies.

This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis., Competing Interests: Conflict of interest: Potential conflicts of interest outside the submitted work are summarized as follows. The following authors report participation in trials; receipt of fellowships, or grants for travel, research or staffing support; and/or personal honoraria for consultancy or lectures/speaker’s bureau from: Abbott (K.K.R., L.S.T.), Abcentra (M.K.), Abdi-Ibrahim (L.S.T.), Actelion (L.S.T.), Aegerion (A.L.C., P.M.M.), Affiris AG (G.L.), Akcea (A.L.C., B.G.N., K.G.P., E.S.G.S.), Amarin (A.L.C., P.M.M., B.G.N., K.G.P.), Amgen (A.L.C., B.A.F., F.K., F.M., P.M.M., P.N., B.G.N., K.G.P., K.K.R., E.S.GS., L.S.T., G.F.W.), Amgen Germany (A.v.E.), Amgen Switzerland (A.v.E.), Amryt (A.L.C.), Amundsen/Amgen (F.M.), Apple (P.N.), Arrowhead (G.F.W.), Ayma Therapeutics (M.K.), AstraZeneca (A.L.C., P.N., B.G.N., K.K.R., G.F.W.), Bayer (L.S.T.), Berlin-Chemie (K.G.P.), Boehringer-Ingelheim (K.K.R.), Boston Scientific (P.N.), CiVi Pharma (B.A.F.), Daiichi-Sankyo (A.L.C., B.A.F., F.M., K.G.P., K.K.R., L.S.T.), Daiichi Switzerland (A.v.E.), dalCOR (B.A.F.), Denka (B.G.N.), Eli Lilly (A.L.C., B.A.F., M.K., K.K.R.), Esperion (A.L.C., B.A.F., P.M.M., B.G.N., K.K.R., E.S.G.S., G.F.W.), FH Foundation (P.M.M.), Foresite Labs (P.N.), Fresenius (F.K.), GB Life Sciences (P.M.M.), Genentech (P.N.), Genzyme (A.L.C.), Horizon/Novartis (F.M., B.G.N.), Ionis Pharmaceuticals (B.A., A.L.C., B.A.F., M.K., P.M.M.), Jupiter Bioventures (M.R.D.), Kaneka (F.K., P.M.M.), Kowa (A.L.C., B.G.N., K.K.R.), KrKa Phama (B.A.F.), Lupin (K.K.R.), Menarini (A.L.C.), Merck (A.L.C., B.A.F.), MSD (K.G.P.), Mylan (A.L.C., B.A.F., L.S.T.), New Amsterdam (K.K.R.), Noetic Insights (M.K.), Novartis (B.A., A.L.C., M.R.D., B.A.F., F.K., F.M., C.J.M.N., P.M.M., P.N., B.G.N., K.G.P., K.K.R., E.S.G.S., L.S.T., G.F.W.), Novartis Canada (M.K.), NovoNordisk (B.A.F., C.J.M.N., B.G.N., K.K.R., E.S., L.S.T.), Nyrada Inc (G.L.), Pfizer (B.A., M.R.D., B.A.F., M.K., S.M., K.K.R., L.S.T., G.F.W.), Quest Diagnostics (S.M.), Recordati (A.L.C., LS.T.), Regeneron (A.L.C., B.A.F., P.M.M., B.G.N., K.K.R., E.S.G.S.), Renew (P.M.M.), Resverlogix (K.K.R.), Sandoz (A.L.C.), Sanofi (A.L.C., B.A.F., F.M., B.G.N., K.G.P., K.K.R., E.S.G.S., L.S.T., G.F.W.), Sanofi-Aventis Switzerland (A.v.E.), Sanofi-Regeneron (G.L., E.S.G.S.), Servier (L.S.T.), Sigma Tau (A.L.C.), Silence Therapeutics (B.A., M.R.D., B.A.F., B.G.N., K.K.R., G.F.W.), and The Medicines Co (B.A.F.). P.N. declares spousal employment at Vertex and K.G.P. is a member of the Data Monitoring and Safety Board at Boehringer-Ingelheim. S.S.V. declares an honorarium from the American College of Cardiology (Associate Editor for Innovations, acc.org), and grant funding from the U.S. Department of Veterans Affairs, National Institutes of Health, World Heart Federation, and Tahir and Jooma Family. Manuscripts have been published in collaboration with non-academic co-authors by P.N. and L.S.T. (Fitbit), G.F.W. (Amgen), and B.A. (Pfizer). Equity interests including income from stocks, stock options, royalties, or from patents or copyrights were reported from AstraZeneca (J.K.S.), Boston Scientific (L.B.), Cargene Therapeutics (K.K.R.), Gilead Sciences (L.B)., J & J (L.B.), GSK (J.K.S.), Medtronic (L.B.), New Amsterdam Pharma (K.K.R.), NovoNordisk (L.B.), Pemi31 Therapeutics (K.K.R.), and Pfizer (L.B.). K.K.R. is President of the European Atherosclerosis Society. L.S.T. is past-president of the European Atherosclerosis Society and an Editorial Board Member, The European Heart Journal., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Elevated red blood cell distribution width (RDW) is associated with increased risk for major adverse cardiovascular events (MACE) and death in patients with cardiovascular disease. The ODYSSEY OUTCOMES trial compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome (ACS) and elevated atherogenic lipoproteins despite optimized statin treatment. This post hoc analysis determined whether RDW independently predicts risk of MACE and death in patients after recent ACS, whether RDW influences MACE reduction with alirocumab, and whether alirocumab treatment affects RDW. Associations of baseline RDW with risk of MACE and death were analyzed in the placebo group in adjusted proportional hazards models. Interactions of RDW and treatment on the risk of MACE and death were evaluated. An increasing quartile of RDW was associated with characteristics that predicted risk of MACE and death including age, hypertension, diabetes, atherosclerotic conditions and events, revascularizations, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. After adjusting for baseline characteristics associated with the risk of MACE or death, baseline RDW remained independently associated with the risk of MACE and death in the placebo group (hazard ratios [95% confidence intervals] 1.08 [1.02-1.15] and 1.13 [1.03-1.24] per 1% increase of RDW, respectively, both p <0.001). There was no interaction of RDW and treatment on MACE or death, nor did alirocumab affect RDW. RDW was associated with an increased risk of MACE and death, independent of established risk factors., (Copyright © 2022. Published by Elsevier Inc.)

Background: Olezarsen is a hepatocyte-targeted, GalNAc-modified antisense oligonucleotide that decreases plasma levels of apolipoprotein C-III (apoC-III) and triglyceride-rich lipoproteins (TRLs)., Objective: To define the effect of olezarsen on NMR-derived lipoprotein particle size and concentration., Methods: Patients (n=114) with or at risk for atherosclerotic cardiovascular disease and fasting triglycerides ≥200 and <500 mg/dL received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. NMR LipoProfile® analysis was performed in frozen EDTA plasma samples collected at baseline and at the primary analysis timepoint (PAT) at 6 months., Results: A dose-dependent relationship was generally noted with increasing cumulative doses of olezarsen in TRL particle (TRLP), LDL particle (LDL-P) and HDL (HDL-P) particle concentrations. In the 50 mg every 4 weeks dose, compared to placebo, olezarsen resulted in a significant reduction in total TRL-P (51%, P<0.0001) with largest reductions in large-size (68%, P<0.0001) and medium-size (63%, P<0.0001) TRL-P. Total LDL-P concentration was not changed, but large LDL-P increased by 186% (p=0.0034), and small LDL-P decreased by 39% (p=0.0713). Total HDL-P concentration increased by 15% (P=0.0006), driven primarily by a 32% increase in small HDL subspecies (diameters <8.3 nm) (P=0.0008)., Conclusion: Olezarsen results in favorable changes in lipoprotein concentration and particle size, primarily manifested by reduction in TRLs, remodeling to larger LDL particles, and increase in small HDL-P. These findings suggest that apoC-III inhibition improves the overall atherogenic risk profile., Competing Interests: Disclosures EKP, VJB, SX, and ST are employees of Ionis Pharmaceuticals. J-C T received research grants from Amarin, AstraZeneca, DalCor, Esperion, Ionis, Pfizer and Servier; honoraria from Amarin, DalCor, Pfizer, Sanofi and Servier; minor equity interest in DalCor. DG reports grants and personal fees from Akcea Therapeutics, Ionis Pharmaceuticals during the conduct of the study, Arrowhead and Regeneron, and grants from Kowa and Acasti and grants from Uniqure outside the submitted work. CMB has received grant/research support (to his institution) from Abbott Diagnostic, Akcea, Amgen, Esperion, Ionis, Novartis, Regeneron, and Roche Diagnostic, and has been a consultant for Abbott Diagnostics, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Corvidia, Denka Seiken, Esperion, Genentech, Gilead, Matinas BioPharma Inc, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostic, and Sanofi-Synthelabo. MDS serves on scientific advisory boards: Amgen, Esperion, Novartis. PMM is a consultant, speaker, or received Research grants from Amgen, Esperion, Kaneka, Amarin, Stage II Innovations/Renew, Novartis, Ionis, FH Foundation, GB Life Sciences, Aegerion. SJB is consultant on scientific advisory board or speaker for Altimmune, Akcea, Amgen, AstraZeneca, Boehringer Ingelheim, Axcella, Eli Lilly, Esperion, Madrigal, Novartis, Regeneron, Sanofi. JDO is an employee of LabCorp. JLW is a consultant to Ionis. JLW and ST are co-inventors and receive royalties from patents owned by UCSD on oxidation-specific antibodies and of biomarkers related to oxidized lipoproteins and are co-founders and have an equity interest in Oxitope, Inc and its affiliates (“Oxitope”) as well as in Kleanthi Diagnostics, LLC (“Kleanthi”). ST is a co-founder of Covicept Therapeutics. Although these relationships have been identified for conflict of interest management based on the overall scope of the project and its potential benefit to Oxitope and Kleanthi, the research findings included in this particular publication may not necessarily relate to the interests of Oxitope and Kleanthi. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. The other authors have no disclosures. All authors have approved the final article should be true and included in the disclosure., (Copyright © 2022. Published by Elsevier Inc.)

The extent of intervention effects on carotid intima-media thickness (CIMT) can predict the degree of atherosclerotic cardiovascular risk-reduction. We hypothesized that regular lipoprotein apheresis over the course of 10 years might slow down progression of CIMT in patients with severe hypercholesterolemia. This case series describes 10 Caucasian patients (mean age 60 ± 9 years, 70% female, 80% statin intolerant) with a severe hypercholesterolemia phenotype treated with lipoprotein apheresis between 2005 and 2020 (mean duration, 10 ± 4 years). The median pretreatment low-density lipoprotein cholesterol (LDL-C) level was 214 mg/100 ml (95% confidence interval, 145 to 248), lipoprotein(a) (Lp[a]), 26 mg/100 ml (15 to 109; 40% with Lp(a)>60 mg/100 ml). Three patients were diagnosed with a monogenic cause. The baseline mean CIMT was 850 ± 170 µm, and maximum CIMT was 1,040 ± 220 µm across the age range of 46 to 70 years. Acute effects of lipoprotein apheresis determined as a difference before and immediately after the procedure were estimated as a median of 72 ± 8% and 75 ± 7% reduction in the LDL-C and Lp(a) levels, respectively. Using the imputed trajectories, period-specific on-treatment time-weighted averages for LDL-C and Lp(a) were 141 mg/100 ml (interquartile range, 89 to 152; 38% reduction from the baseline) and 24 mg/100 ml (interquartile range, 12 to 119; 19% reduction from baseline), respectively. The number of patients with CIMT above their "vascular age" decreased from 80% to 30% over the treatment course. In conclusion, an increase in CIMT seen with advanced age and severe hypercholesterolemia was halted with lipoprotein apheresis with an estimated annual rate of change in mean common CIMT of -4 µm/y and maximum CIMT of -3 µm/y., Competing Interests: Disclosures PMM reports modest honoraria from Kaneka Medical America LLC. The other authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose of Review: Lipoprotein(a) (Lp[a]) is a likely causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve disease, confirmed by Mendelian randomization. With reliable assays, it has been established that Lp(a) is linearly associated with ASCVD. Current low-density lipoprotein cholesterol (LDL-C) lowering therapies do not or minimally lower Lp(a). This review focuses on the clinical importance and therapeutic consequences of Lp(a) measurement., Recent Findings: Development of RNA-based Lp(a) lowering therapeutics has positioned Lp(a) as one of the principal residual risk factors to target in the battle against lipid-driven ASCVD risk. Pelacarsen, which is a liver-specific antisense oligonucleotide, has shown Lp(a) reductions up to 90% and its phase 3 trial is currently underway. Olpasiran is a small interfering RNA targeting LPA messenger RNA which is being investigated in phase 2 and has already shown dose-dependent Lp(a) reductions up to 90%., Summary: Lp(a) should be measured in every patient at least once to identify patients with very high Lp(a) levels. These patients could benefit from Lp(a) lowering therapies when approved. In the meantime, therapy in high Lp(a) patients should focus on further reducing LDL-C and other ASCVD risk factors., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established cardiovascular disease., Methods and Results: A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200-500 mg/dL (2.26-5.65 mmol/L). Patients received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. The primary endpoint was the percent change in fasting triglyceride levels from baseline to Month 6 of exposure. Baseline median (interquartile range) fasting triglyceride levels were 262 (222-329) mg/dL [2.96 (2.51-3.71) mmol/L]. Treatment with olezarsen resulted in mean percent triglyceride reductions of 23% with 10 mg every 4 weeks, 56% with 15 mg every 2 weeks, 60% with 10 mg every week, and 60% with 50 mg every 4 weeks, compared with increase by 6% for the pooled placebo group (P-values ranged from 0.0042 to <0.0001 compared with placebo). Significant decreases in apoC-III, very low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were also observed. There were no platelet count, liver, or renal function changes in any of the olezarsen groups. The most common adverse event was mild erythema at the injection site., Conclusion: Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease., Trial Registration Number: NCT03385239., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Importance: Intense interest exists in novel ω-3 formulations with high bioavailability to reduce blood triglyceride (TG) levels., Objective: To determine the phase 3 efficacy and safety of a naturally derived krill oil with eicosapentaenoic acid and docosahexaenoic acid as both phospholipid esters (PLs) and free fatty acids (FFAs) (ω-3-PL/FFA [CaPre]), measured by fasting TG levels and other lipid parameters in severe hypertriglyceridemia., Design, Setting, and Participants: This study pooled the results of 2 identical randomized, double-blind, placebo-controlled trials. TRILOGY 1 (Study of CaPre in Lowering Very High Triglycerides) enrolled participants at 71 US centers from January 23, 2018, to November 20, 2019; TRILOGY 2 enrolled participants at 93 US, Canadian, and Mexican centers from April 6, 2018, to January 9, 2020. Patients with fasting TG levels from 500 to 1500 mg/dL, with or without stable treatment with statins, fibrates, or other agents to lower cholesterol levels, were eligible to participate., Interventions: Randomization (2.5:1.0) to ω-3-PL/FFA, 4 g/d, vs placebo (cornstarch) for 26 weeks., Main Outcomes and Measures: The primary outcome was the mean percentage of change in TG levels at 12 weeks; persistence at 26 weeks was the key secondary outcome. Other prespecified secondary outcomes were effects on levels of non-high-density lipoprotein cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), HDL-C, and low-density lipoprotein cholesterol (LDL-C); safety and tolerability; and TG level changes in prespecified subgroups., Results: A total of 520 patients were randomized, with a mean (SD) age of 54.9 (11.2) years (339 men [65.2%]), mean (SD) body mass index of 31.5 (5.1), and baseline mean (SD) TG level of 701 (222) mg/dL. Two hundred fifty-six patients (49.2%) were of Hispanic or Latino ethnicity; 275 (52.9%) had diabetes; and 248 (47.7%) were receiving statins. In the intention-to-treat analysis, TG levels were reduced by 26.0% (95% CI, 20.5%-31.5%) in the ω-3-PL/FFA group and 15.1% (95% CI, 6.6%-23.5%) in the placebo group at 12 weeks (mean treatment difference, -10.9% [95% CI, -20.4% to -1.5%]; P = .02), with reductions persisting at 26 weeks (mean treatment difference, -12.7% [95% CI, -23.1% to -2.4%]; P = .02). Compared with placebo, ω-3-PL/FFA had no significant effect at 12 weeks on mean treatment differences for non-HDL-C (-3.2% [95% CI, -8.0% to 1.6%]; P = .18), VLDL-C (-3.8% [95% CI, -12.2% to 4.7%]; P = .38), HDL-C (0.7% [95% CI, -3.7% to 5.1%]; P = .77), or LDL-C (4.5% [95% CI, -5.9% to 14.8%]; P = .40) levels; corresponding differences at 26 weeks were -5.8% (95% CI, -11.3% to -0.3%; P = .04) for non-HDL-C levels, -9.1% (95% CI, -21.5% to 3.2%; P = .15) for VLDL-C levels, 1.9% (95% CI, -4.8% to 8.6%; P = .57) for HDL-C levels, and 6.3% (95% CI, -12.4% to 25.0%; P = .51) for LDL-C levels. Effects on the primary end point did not vary significantly by age, sex, race and ethnicity, country, qualifying TG level, diabetes, or fibrate use but tended to be larger among patients taking statins or cholesterol absorption inhibitors at baseline (mean treatment difference, -19.5% [95% CI, -34.5% to -4.6%]; P = .08 for interaction) and with lower (less than median) baseline blood eicosapentaenoic acid plus docosahexaenoic acid levels (-19.5% [95% CI, -33.8% to -5.3%]; P = .08 for interaction). ω-3-PL/FFA was well tolerated, with a safety profile similar to that of placebo., Conclusions and Relevance: This study found that ω-3 -PL/FFA, a novel krill oil-derived ω-3 formulation, reduced TG levels and was safe and well tolerated in patients with severe hypertriglyceridemia., Trial Registration: ClinicalTrials.gov Identifiers: NCT03398005 and NCT03361501.

Compelling evidence supports a causal role for lipoprotein(a) (Lp(a)) in cardiovascular disease. No pharmacotherapies directly targeting Lp(a) are currently available for clinical use. Here we report the discovery and development of olpasiran, a first-in-class, synthetic, double-stranded, N-acetylgalactosamine-conjugated small interfering RNA (siRNA) designed to directly inhibit LPA messenger RNA translation in hepatocytes and potently reduce plasma Lp(a) concentration. Olpasiran reduced Lp(a) concentrations in transgenic mice and cynomolgus monkeys in a dose-responsive manner, achieving up to over 80% reduction from baseline for 5-8 weeks after administration of a single dose. In a phase 1 dose-escalation trial of olpasiran (ClinicalTrials.gov: NCT03626662 ), the primary outcome was safety and tolerability, and the secondary outcomes were the change in Lp(a) concentrations and olpasiran pharmacokinetic parameters. Participants tolerated single doses of olpasiran well and experienced a 71-97% reduction in Lp(a) concentration with effects persisting for several months after administration of doses of 9 mg or higher. Serum concentrations of olpasiran increased approximately dose proportionally. Collectively, these results validate the approach of using hepatocyte-targeted siRNA to potently lower Lp(a) in individuals with elevated plasma Lp(a) concentration., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background and Aims: Thrombosis is a major driver of adverse outcome and mortality in patients with Coronavirus disease 2019 (COVID-19). Hypercoagulability may be related to the cytokine storm associated with COVID-19, which is mainly driven by interleukin (IL)-6. Plasma lipoprotein(a) [Lp(a)] levels increase following IL-6 upregulation and Lp(a) has anti-fibrinolytic properties. This study investigated whether Lp(a) elevation may contribute to the pro-thrombotic state hallmarking COVID-19 patients., Methods: Lp(a), IL-6 and C-reactive protein (CRP) levels were measured in 219 hospitalized patients with COVID-19 and analyzed with linear mixed effects model. The baseline biomarkers and increases during admission were related to venous thromboembolism (VTE) incidence and clinical outcomes in a Kaplan-Meier and logistic regression analysis., Results: Lp(a) levels increased significantly by a mean of 16.9 mg/dl in patients with COVID-19 during the first 21 days after admission. Serial Lp(a) measurements were available in 146 patients. In the top tertile of Lp(a) increase, 56.2% of COVID-19 patients experienced a VTE event compared to 18.4% in the lowest tertile (RR 3.06, 95% CI 1.61-5.81; p < 0.001). This association remained significant after adjusting for age, sex, IL-6 and CRP increase and number of measurements. Increases in IL-6 and CRP were not associated with VTE. Increase in Lp(a) was strongly correlated with increase in IL-6 (r = 0.44, 95% CI 0.30-0.56, p < 0.001)., Conclusions: Increases in Lp(a) levels during the acute phase of COVID-19 were strongly associated with VTE incidence. The acute increase in anti-fibrinolytic Lp(a) may tilt the balance to VTE in patients hospitalized for COVID-19., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Lipoprotein apheresis (LA) tolerability is a key factor for the utilization of this therapy. Common reactions to LA are hypotension and nausea. Serious reactions include severe hypotension and anaphylactoid reactions (0.13%-1.3% and 0.2%-0.4%, respectively). The bradykinin response drives these reactions and can worsen with the use of angiotensin-converting-enzyme inhibitors. Efforts to mitigate these reactions are necessary for the tolerability of LA with a dextran sulfate-adsorption (DSA) system., Materials and Methods: In an effort to increase apheresis tolerability, seven patients at The University of Kansas, Department of Clinical Pharmacology, who had prior anaphylactoid reactions (defined as general cutaneous flushing, nausea/vomiting, tongue swelling, lightheadedness, and hypotension) to the DSA despite pharmacologic intervention, were treated with pre-LA intravenous magnesium adapted from a protocol developed by co-author Eliaz. This protocol consists of 1.5 g of magnesium sulfate administered over 45 minutes. All seven patients were treated with intravenous magnesium sulfate immediately before LA., Results: No episodes of anaphylactoid reactions during LA have been reported to date., Conclusions: Magnesium infusion before DSA can be utilized to establish tolerability in patients with prior anaphylactoid reactions to LA. Proposed mechanisms include temporary stabilization of the negative-positive interactions of the dextran sulfate filter leading to a reduction of circulating bradykinin, reduction of nitric oxide, and reduction of the sympathetic response to LA., (© 2021 Wiley Periodicals LLC.)

Although statins play a pivotal role in the prevention of atherosclerotic cardiovascular disease, many patients fail to achieve recommended lipid levels due to statin-associated muscle symptoms. Bempedoic acid is an oral pro-drug that is activated in the liver and inhibits cholesterol synthesis in hepatocytes, but is not activated in skeletal muscle which has the potential to avoid muscle-related adverse events. Accordingly, this agent effectively lowers atherogenic lipoproteins in patients who experience statin-associated muscle symptoms. However, the effects of bempedoic acid on cardiovascular morbidity and mortality have not been studied. STUDY DESIGN: Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes is a randomized, double-blind, placebo-controlled clinical trial. Included patients must have all of the following: (i) established atherosclerotic cardiovascular disease or have a high risk of developing atherosclerotic cardiovascular disease, (ii) documented statin intolerance, and (iii) an LDL-C ≥100 mg/dL on maximally-tolerated lipid-lowering therapy. The study randomized 14,014 patients to treatment with bempedoic acid 180 mg daily or matching placebo on a background of guideline-directed medical therapy. The primary outcome is a composite of the time to first cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. The trial will continue until 1620 patients experience a primary endpoint, with a minimum of 810 hard ischemic events (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) and minimum treatment duration of 36 months and a projected median treatment exposure of 42 months. CONCLUSIONS: CLEAR Outcomes will determine whether bempedoic acid 180 mg daily reduces the incidence of adverse cardiovascular events in high vascular risk patients with documented statin intolerance and elevated LDL-C levels., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Volanesorsen is an antisense oligonucleotide that targets hepatic apolipoprotein C-III synthesis and reduces plasma triglyceride concentration. The aim of this study was to explore the safety and efficacy of volanesorsen in patients with multifactorial chylomicronaemia syndrome., Methods: The COMPASS trial was a randomised, placebo-controlled, double-blind, phase 3 study done at 38 international clinical sites in Canada, France, Germany, the Netherlands, UK, and USA. Eligible patients were aged 18 years or older with multifactorial severe hypertriglyceridaemia or familial chylomicronaemia syndrome, who had a BMI of 45 kg/m 2 or less and fasting plasma triglyceride of 500 mg/dL or higher. Patients were randomly assigned (2:1) with an interactive response system using an allocation sequence and permuted block randomisation to receive subcutaneous volanesorsen (300 mg) or a matched volume of placebo (1·5 mL) once a week for 26 weeks. After 13 weeks of treatment, dosing was changed to 300 mg of volanesorsen or placebo every 2 weeks for all patients, except those who had completed 5 months or more of treatment as of May 27, 2016. Participants, investigators, sponsor personnel, and clinical research staff were all masked to the treatment assignments. The primary outcome was percentage change from baseline to 3 months in fasting triglyceride in the full analysis set (all patients who were randomly assigned and received at least one dose of study drug and had a baseline fasting triglyceride assessment). This trial is registered with ClinicalTrials.gov, NCT02300233 (completed)., Findings: Between Feb 5, 2015, and Jan 24, 2017, 408 patients were screened for eligibility. 294 were excluded and 114 randomly assigned to receive either volanesorsen (n=76) or placebo (n=38). One patient in the volanesorsen group discontinued before receiving the study drug. The total number of dropouts was 28 (four in the placebo group and 24 in the treatment group). Volanesorsen reduced mean plasma triglyceride concentration by 71·2% (95% CI -79·3 to -63·2) from baseline to 3 months compared with 0·9% (-13·9 to 12·2) in the placebo group (p<0·0001), representing a mean absolute reduction of fasting plasma triglycerides of 869 mg/dL (95% CI -1018 to -720; 9·82 mmol/L [-11·51 to -8·14]) in volanesorsen compared with an increase in placebo of 74 mg/dL (-138 to 285; 0·83 mmol/L [-1·56 to 3·22]; p<0·0001). In the key safety analysis, five adjudicated events of acute pancreatitis occurred during the study treatment period, all in three of 38 patients in the placebo group. The most common adverse events were related to tolerability and included injection-site reactions (average of 24% of all volanesorsen injections vs 0·2% of placebo injections), which were all mild or moderate. One participant in the volanesorsen group had a platelet count reduction to less than 50 000 per μL and one patient had serum sickness, both of which were regarded as serious adverse events., Interpretation: Volanesorsen significantly reduced triglyceride concentrations in patients with multifactorial chlyomicronaemia and might reduce acute pancreatitis events in these patients., Funding: Ionis Pharmaceuticals and Akcea Therapeutics., Competing Interests: Declaration of interests IG-B has received personal honoraria for consulting from Amgen, Akcea Therapeutics, Regeneron, Aegereon, Daiichi-Sankyo, Novartis, and Sanofi; and non-financial support from Amgen, Akcea Therapeutics, and Sanofi. VJA and QY are employees and stockholders of Ionis Pharmaceuticals. EH and LSLO are employees of Akcea Therapeutics. ES-T has received personal honoraria for advisory boards from Akcea Therapeutics and Novartis; and personal honoraria for lectures from Novartis, Daiichi-Sankyo, and Amgen. PMM has received grants from Regeneron, Sanofi, Amgen, Kaneka, Ionis Pharmaceuticals, Akcea Therapeutics, FH Foundation, GB Life Sciences, Aegerion, Gempshire, and Pfizer; and personal honoraria for consulting from Regeneron, Sanofi, Amgen, Kaneka, Ionis Pharmaceuticals, Esperion, Amarin, Stage II Innovations Renew, and Novartis. SGH has received personal honoraria for consulting from Akcea Therapeutics and Ionis Pharmaceuticals and was an employee of Ionis Pharmaceuticals during the conduct of this study. DG has received grants and personal honoraria for consulting from Akcea Therapeutics, Ionis Pharmaceuticals, Arrowhead, and Regeneron; and grants from Acasti, Kowa, and Uniqure. RAH has received personal honoraria for consulting from Ionis Pharmaceuticals, Akcea Therapeutics, Acasti, Aegerion, Amgen, HLS Therapeutics, Novartis, Pfizer, Regeneron, and Sanofi. ESGS has received personal honoraria for advisory boards and lectures from Amgen, Sanofi, Regeneron, Esperion, Akcea Therapeutics, Ionis Pharmaceuticals, Novartis, and Novo Nordisk. ST is an employee of Ionis Pharmaceuticals and the University of California San Diego. ST and JLW are co-inventors receiving royalties from patents owned by the University of California San Diego and are co-founders of Oxitope and Kleanthi Diagnostics. JLW has received personal honoraria for consulting from Ionis Pharmaceuticals., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose of Review: Summarize recent recommendations on clinical management of adults and youth with elevated lipoprotein(a) [Lp(a)] who are at-risk of or affected by cardiovascular disease (CVD)., Recent Findings: There is ample evidence to support elevated Lp(a) levels, present in approximately 20% of the general population, as a causal, independent risk factor for CVD and its role as a significant risk enhancer. Several guidelines and position statements have been published to assist in the identification, treatment and follow-up of adults with elevated levels of Lp(a). There is growing interest in Lp(a) screening and strategies to improve health behaviors starting in youth, although published recommendations for this population are limited. In addition to the well established increased risk of myocardial infarction, stroke and valvular aortic stenosis, data from the coronavirus pandemic suggest adults with elevated Lp(a) may have a particularly high-risk of cardiovascular complications. Lp(a)-specific-lowering therapies are currently in development. Despite their inability to lower Lp(a), use of statins have been shown to improve outcomes in primary and secondary prevention., Summary: Considerable differences exist amongst published guidelines for adults on the use of Lp(a) in clinical practice, and recommendations for youth are limited. With increasing knowledge of Lp(a)'s role in CVD, including recent observations of COVID-19-related risk of cardiovascular complications, more harmonized and comprehensive guidelines for Lp(a) in clinical practice are required. This will facilitate clinical decision-making and help define best practices for identification and management of elevated Lp(a) in adults and youth., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Lipoprotein(a) [Lp(a)] has risen to the level of an accepted cardiovascular disease risk factor, but final proof of causality awaits a randomized trial of Lp(a) lowering. Inhibiting apolipoprotein(a) production in the hepatocyte with ribonucleic acid therapeutics has emerged as an elegant and effective solution to reduce plasma Lp(a) levels. Phase 2 clinical trials have shown that the antisense oligonucleotide pelacarsen reduced mean Lp(a) levels by 80%, allowing 98% of subjects to reach on-treatment levels of <125 nmol/l (∼50 mg/dl). The phase 3 Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD) outcomes trial is currently enrolling approximately 7,680 patients with history of myocardial infarction, ischemic stroke, and symptomatic peripheral arterial disease and controlled low-density lipoprotein cholesterol to pelacarsen versus placebo. The co-primary endpoints are major adverse cardiovascular events in subjects with Lp(a) >70 mg/dl and >90 mg/dl, in which either of the two being positive will lead to a successful trial. Additional ribonucleic acid-targeted therapies to lower Lp(a) are in preclinical and clinical development. The testing of the Lp(a) hypothesis will provide proof whether Lp(a)-mediated risk can be abolished by potent Lp(a) lowering., Competing Interests: Funding Support and Author Disclosures Dr.Tsimikas has received research support from the Fondation Leducq and partial support from National Institutes of Health grants HL136275, HL106579, HL108735, HL136098, HL128550, and HL135737. Dr. Tsimikas is an employee of the University of California-San Diego and of Ionis Pharmaceuticals; is a co-inventor and receives royalties from patents owned by the University of California San Diego on diagnostic and therapeutic applications; and is a co-founder and has an equity interest in Oxitope and its affiliates (“Oxitope”) as well as in Kleanthi Diagnostics (“Kleanthi”) (although these relationships have been identified for conflict-of-interest management based on the overall scope of the project and its potential benefit to Oxitope and Kleanthi, the research findings included in this particular publication may not necessarily relate to the interests of Oxitope and Kleanthi; the terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies). Dr. Moriarty has served as an advisor, consultant, and received research support from Regeneron, Sanofi, Amgen, Esperion, Kaneka, Amarin, Stage II Innovations/Renew, Novartis, Ionis, Akcea, FH Foundation, GB Life Sciences, Aegerion, Gemphire, and Pfizer. Dr. Stroes has received fees paid to his institution from Amgen, Akcea, Athera, Sanofi-Regeneron, Esperion, Novo Nordisk, Lily, and Novartis., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background Conventional "low-density lipoprotein cholesterol (LDL-C)" assays measure cholesterol content in both low-density lipoprotein and lipoprotein(a) particles. To clarify the consequences of this methodological limitation for clinical care, our study aimed to compare associations of "LDL-C" and corrected LDL-C with risk of cardiovascular disease and to assess the impact of this correction on the classification of patients into guideline-recommended LDL-C categories. Methods and Results Lipoprotein(a) cholesterol content was estimated as 30% of lipoprotein(a) mass and subtracted from "LDL-C" to obtain corrected LDL-C values (LDL-C corr30 ). Hazard ratios for cardiovascular disease (defined as coronary heart disease, stroke, or coronary revascularization) were quantified by individual-patient-data meta-analysis of 5 statin landmark trials from the Lipoprotein(a) Studies Collaboration (18 043 patients; 5390 events; 4.7 years median follow-up). When comparing top versus bottom quartiles, the multivariable-adjusted hazard ratio for cardiovascular disease was significant for "LDL-C" (1.17; 95% CI, 1.05-1.31; P =0.005) but not for LDL-C corr30 (1.07; 95% CI, 0.93-1.22; P =0.362). In a routine laboratory database involving 531 144 patients, reclassification of patients across guideline-recommended LDL-C categories when using LDL-C corr30 was assessed. In "LDL-C" categories of 70 to <100, 100 to <130, 130 to <190, and ≥190 mg/dL, significant proportions (95% CI) of participants were reassigned to lower LDL-C categories when LDL-C corr30 was used: 30.2% (30.0%-30.4%), 35.1% (34.9%-35.4%), 32.9% (32.6%-33.1%), and 41.1% (40.0%-42.2%), respectively. Conclusions " LDL-C" was associated with incident cardiovascular disease only when lipoprotein(a) cholesterol content was included in its measurement. Refinement in techniques to accurately measure LDL-C, particularly in patients with elevated lipoprotein(a) levels, is warranted to assign risk to the responsible lipoproteins.

Aims: Lipoprotein(a) concentration is associated with first cardiovascular events in clinical trials. It is unknown if this relationship holds for total (first and subsequent) events. In the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab reduced lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), and cardiovascular events compared with placebo. This post hoc analysis determined whether baseline levels and alirocumab-induced changes in lipoprotein(a) and LDL-C [corrected for lipoprotein(a) cholesterol] independently predicted total cardiovascular events., Methods and Results: Cardiovascular events included cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina or heart failure, ischaemia-driven coronary revascularization, peripheral artery disease events, and venous thromboembolism. Proportional hazards models estimated relationships between baseline lipoprotein(a) and total cardiovascular events in the placebo group, effects of alirocumab treatment on total cardiovascular events by baseline lipoprotein(a), and relationships between lipoprotein(a) reduction with alirocumab and subsequent risk of total cardiovascular events. Baseline lipoprotein(a) predicted total cardiovascular events with placebo, while higher baseline lipoprotein(a) levels were associated with greater reduction in total cardiovascular events with alirocumab (hazard ratio Ptrend = 0.045). Alirocumab-induced reductions in lipoprotein(a) (median -5.0 [-13.6, 0] mg/dL) and corrected LDL-C (median -51.3 [-67.1, -34.0] mg/dL) independently predicted lower risk of total cardiovascular events. Each 5-mg/dL reduction in lipoprotein(a) predicted a 2.5% relative reduction in cardiovascular events., Conclusion: Baseline lipoprotein(a) predicted the risk of total cardiovascular events and risk reduction by alirocumab. Lipoprotein(a) lowering contributed independently to cardiovascular event reduction, supporting the concept of lipoprotein(a) as a treatment target after ACS., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The previously published ODYSSEY ESCAPE trial demonstrated a significant reduction in the use of lipoprotein apheresis for heterozygous familial hypercholesterolemia (HeFH) patients when placed on alirocumab 150 mg every 2 weeks. In patients with HeFH who have consistently elevated levels of low-density lipoprotein cholesterol (LDL-C) despite maximally tolerated statin therapy, current lipid guidelines recommend apheresis. Although apheresis reduces LDL-C levels by 50%-75%, it must be repeated, as frequently as every 1-2 weeks., Objective: To assess clinical experience with apheresis and alirocumab for patients in a real-world practice setting., Methods: This retrospective review included patients from 5 apheresis centers who were treated with apheresis and had started alirocumab therapy. In addition to LDL-C levels, total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, and particle numbers were evaluated if data were available., Results: Eleven of the 25 (44%) patients discontinued apheresis completely after initiation of alirocumab therapy, having achieved LDL-C <70 mg/dL or >50% reduction from baseline levels. Among the 14 patients who remained on apheresis, seven decreased the frequency of apheresis sessions. No significant safety problems were reported., Conclusion: Alirocumab lowered LDL-C levels by an average of 55.5% in patients receiving apheresis for elevated LDL-C. Seventy-two percent of patients on alirocumab therapy discontinued or reduced the frequency of apheresis treatment. However, some patients continued to require apheresis due to elevated lipoprotein(a), extremely elevated LDL-C, or if alirocumab therapy was discontinued due to less than anticipated LDL-C reduction., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

The ability to interpret others' emotions is a critical skill for children's socioemotional functioning. Although research has emphasized facial emotion expressions, children are also constantly required to interpret vocal emotion expressed at or around them by individuals who are both familiar and unfamiliar to them. The current study examined how speaker familiarity, specific emotions, and the acoustic properties that comprise affective prosody influenced children's interpretations of emotional intensity. Participants were 51 7- and 8-year-olds presented with speech stimuli spoken in happy, angry, sad, and nonemotional prosodies by both each child's mother and another child's mother unfamiliar to the target child. Analyses indicated that children rated their own mothers as more intensely emotional compared with the unfamiliar mothers and that this effect was specific to angry and happy prosodies. Furthermore, the acoustic properties predicted children's emotional intensity ratings in different patterns for each emotion. The results are discussed in terms of the significance of the mother's voice in children's development of emotional understanding., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose of Review: The COVID-19 pandemic has infected over > 11 million as of today people worldwide and is associated with significant cardiovascular manifestations, particularly in subjects with preexisting comorbidities and cardiovascular risk factors. Recently, a predisposition for arterial and venous thromboses has been reported in COVID-19 infection. We hypothesize that besides conventional risk factors, subjects with elevated lipoprotein(a) (Lp(a)) may have a particularly high risk of developing cardiovascular complications., Recent Findings: The Lp(a) molecule has the propensity for inhibiting endogenous fibrinolysis through its apolipoprotein(a) component and for enhancing proinflammatory effects such as through its content of oxidized phospholipids. The LPA gene contains an interleukin-6 (IL-6) response element that may induce an acute phase-type increase in Lp(a) levels following a cytokine storm from COVID-19. Thus, subjects with either baseline elevated Lp(a) or those who have an increase following COVID-19 infection, or both, may be at very high risk of developing thromboses. Elevated Lp(a) may also lead to acute destabilization of preexisting but quiescent atherosclerotic plaques, which might induce acute myocardial infarction and stroke. Ongoing studies with IL-6 antagonists may be informative in understanding this relationship, and registries are being initiated to measure Lp(a) in subjects infected with COVID-19. If indeed an association is suggestive of being causal, consideration can be given to systematic testing of Lp(a) and prophylactic systemic anticoagulation in infected inpatients. Therapeutic lipid apheresis and pharmacotherapy for the reduction of Lp(a) levels may minimize thrombogenic potential and proinflammatory effects. We propose studies to test the hypothesis that Lp(a) may contribute to cardiovascular complications of COVID-19.

Background: Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C)., Objectives: A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE)., Methods: One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina., Results: Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081)., Conclusions: Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels., Methods: We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-L Rx , referred to here as APO(a)-L Rx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses)., Results: The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-L Rx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-L Rx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions., Conclusions: APO(a)-L Rx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: The 24-week randomized, double-blind ODYSSEY ALTERNATIVE trial (NCT01709513) demonstrated significant low-density lipoprotein cholesterol (LDL-C) reductions with the PCSK9 inhibitor alirocumab vs ezetimibe in statin-intolerant patients, with significantly fewer skeletal muscle events (SMEs; 32.5%) vs atorvastatin (46.0%; hazard ratio: 0.61, 95% confidence interval: 0.38 to 0.99, P = .042)., Objective: ALTERNATIVE participants could enter an open-label treatment period (OLTP) for assessment of long-term safety., Methods: Two hundred and eighty one patients entered the OLTP; 93.7%, 84.0%, and 92.9% of patients who received atorvastatin, ezetimibe, and alirocumab, respectively, during double-blind treatment, including 216 patients (76.9%) who completed double-blind treatment, as well as patients who either prematurely discontinued treatment due to SME (n = 51 [18.1%]) or other reasons (n = 14 [5.0%]) but completed week 24 assessments. All patients in the OLTP received alirocumab (75 or 150 mg every 2 weeks based on investigator decision) for ∼3 years or until commercial availability, whichever came first., Results: SMEs were reported by 38.4% of patients in the OLTP. Safety results from the OLTP were similar to those of the alirocumab group in the double-blind period, except for a lower rate of discontinuations due to SMEs observed with alirocumab in the OLTP (3.2% vs 15.9% in the double-blind period). At OLTP week 8, mean LDL-C reduction from baseline (=week 0 of double-blind period) was 52.0%, with reductions sustained through to the end-of-treatment visits (55.4% and 53.7% reduction at weeks 100 and 148, respectively)., Conclusions: In this population of statin-intolerant patients, alirocumab was well tolerated and produced durable LDL-C reductions over 3 years., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: The 2018 US cholesterol management guidelines recommend additional lipid-lowering therapies for secondary prevention in patients with low-density lipoprotein cholesterol ≥70 mg/dL or non-high-density lipoprotein cholesterol ≥100 mg/dL despite maximum tolerated statin therapy. Such patients are considered at very high risk (VHR) based on a history of >1 major atherosclerotic cardiovascular disease (ASCVD) event or a single ASCVD event and multiple high-risk conditions. We investigated the association of US guideline-defined risk categories with the occurrence of ischemic events after acute coronary syndrome and reduction of those events by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor., Methods: In the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), patients with recent acute coronary syndrome and residual dyslipidemia despite optimal statin therapy were randomly assigned to alirocumab or placebo. The primary trial outcome (major adverse cardiovascular events, ie, coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) was examined according to American College of Cardiology/American Heart Association risk category., Results: Of 18 924 participants followed for a median of 2.8 years, 11 935 (63.1%) were classified as VHR: 4450 (37.3%) had multiple prior ASCVD events and 7485 (62.7%) had 1 major ASCVD event and multiple high-risk conditions. Major adverse cardiovascular events occurred in 14.4% of placebo-treated patients at VHR versus 5.6% of those not at VHR. In the VHR category, major adverse cardiovascular events occurred in 20.4% with multiple prior ASCVD events versus 10.7% with 1 ASCVD event and multiple high-risk conditions. Alirocumab was associated with consistent relative risk reductions in both risk categories (hazard ratio=0.84 for VHR; hazard ratio=0.86 for not VHR; P interaction =0.820) and by stratification within the VHR group (hazard ratio=0.86 for multiple prior ASCVD events; hazard ratio=0.82 for 1 major ASCVD event and multiple high-risk conditions; P interaction =0.672). The absolute risk reduction for major adverse cardiovascular events with alirocumab was numerically greater (but not statistically different) in the VHR group versus those not at VHR (2.1% versus 0.8%; P interaction =0.095) and among patients at VHR with multiple prior ASCVD events versus a single prior ASCVD event (2.4% versus 1.8%; P interaction =0.661)., Conclusions: The US guideline criteria identify patients with recent acute coronary syndrome and dyslipidemia who are at VHR for recurrent ischemic events and who may derive a larger absolute benefit from treatment with alirocumab., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402.

Background: Elevated lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease (CVD). In the United States, lipoprotein apheresis (LA) therapy is approved for patients with familial hypercholesterolemia. Germany uses LA therapy for patients with an Lp(a) > 60 mg/dL, normal low-density lipoprotein cholesterol (LDL-C) levels, and CVD. LA therapy in this population demonstrated a >70% reduction in CVD events. In the United States, LA is only approved for patients with elevated LDL-C levels, regardless of Lp(a) level., Objective: The objective of the study was to evaluate clinical significance of Lp(a) reduction with LA therapy in the United States., Methods: A retrospective cohort study at one LA site in the United States evaluated 14 CVD patients with elevated Lp(a) and near normal LDL-C levels. Patient data was analyzed to demonstrate possible clinical benefit in reducing Lp(a) levels with LA to mitigate risk of major adverse cardiovascular events., Results: Pre-LA patients' mean LDL-C and Lp(a) were 80 mg/dL and 138 mg/dL, respectively. LA therapy demonstrated a reduction of mean LDL-C to 29 mg/dL and Lp(a) to 51 mg/dL. These represent a percent reduction of 64% and 63% for LDL-C and Lp(a), respectively. There was a 94% reduction in major adverse cardiovascular events over a mean treatment period of 48 months., Conclusion: The treatment of CVD patients with an elevated Lp(a) and near normal LDL-C with LA in a U.S. treatment center demonstrated a significant reduction in future CVD events. LA should be considered for patients in the United States suffering from an elevated Lp(a) and progressive CVD., (Copyright © 2019. Published by Elsevier Inc.)

Context: In the ODYSSEY CHOICE I trial, alirocumab 300 mg every 4 weeks (Q4W) was assessed in patients with hypercholesterolemia. Alirocumab efficacy and safety were evaluated in a patient subgroup with type 2 diabetes mellitus (T2DM) and who were receiving maximally tolerated statins with or without other lipid-lowering therapies., Methods: Participants received either alirocumab 300 mg Q4W (n = 458, including 96 with T2DM) or placebo (n = 230, including 50 with T2DM) for 48 weeks, with alirocumab dose adjustment to 150 mg every 2 weeks at Week (W) 12 if W8 low-density lipoprotein cholesterol (LDL-C) levels were ≥70 mg/dL or ≥ 100 mg/dL, depending on cardiovascular risk, or if LDL-C reduction was <30% from baseline. Efficacy end points included percentage change from baseline to W24 for lipids, and time-averaged LDL-C over W21 to W24., Results: In individuals with T2DM, LDL-C reductions from baseline to W24 and the average of W21 to W24 were significantly greater with alirocumab (-61.6% and -68.8%, respectively) vs placebo. At W24, alirocumab significantly reduced levels of non-high-density lipoprotein cholesterol (HDL-C) and other lipids. At W24, 85.9% and 12.5% of individuals in the alirocumab and placebo groups, respectively, reached both non-HDL-C <100 mg/dL and LDL-C <70 mg/dL. At W12, In total, 18% of alirocumab-treated participants received dose adjustment. The most common treatment-emergent adverse events were upper respiratory tract infection and injection-site reaction. No clinically significant changes in fasting plasma glucose and glycated hemoglobin were observed., Conclusion: In individuals with T2DM, alirocumab 300 mg Q4W was generally well tolerated and efficacious in reducing atherogenic lipoproteins., (Copyright © 2019 Endocrine Society.)