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Background: The anti-DFS70 autoantibodies are one of the most commonly and widely described agent of unknown clinical significance, frequently detected in healthy individuals. It is not known whether the DFS70 autoantibodies are protective or pathogenic. One of the factors suspected of inducing the formation of anti-DFS70 antibodies is increased oxidative stress. We evaluated the coexistence of anti-DFS70 antibodies with selected markers of oxidative stress and investigated whether these antibodies could be considered as indirect markers of oxidative stress., Methods: The intensity of oxidative stress was measured in all samples via indices of free-radical damage to lipids and proteins such as total oxidant status (TOS), concentrations of lipid hydroperoxides (LPH), lipofuscin (LPS), and malondialdehyde (MDA). The parameters of the non-enzymatic antioxidant system, such as total antioxidant status (TAS) and uric acid concentration (UA), were also measured, as well as the activity of superoxide dismutase (SOD). Based on TOS and TAS values, the oxidative stress index (OSI) was calculated. All samples were also tested with indirect immunofluorescence assay (IFA) and 357 samples were selected for direct monospecific anti DFS70 enzyme-linked immunosorbent assay (ELISA) testing., Results: The anti-DFS70 antibodies were confirmed by ELISA test in 21.29% of samples. Compared with anti-DFS70 negative samples we observed 23% lower concentration of LPH ( P  = .038) and 11% lower concentration of UA ( P  = .005). TOS was 20% lower ( P  = .014). The activity of SOD was up to 5% higher ( P  = .037). The Pearson correlation showed weak negative correlation for LPH, UA, and TOS and a weak positive correlation for SOD activity., Conclusion: In samples positive for the anti-DFS70 antibody a decreased level of oxidative stress was observed, especially in the case of samples with a high antibody titer. Anti-DFS70 antibodies can be considered as an indirect marker of reduced oxidative stress or a marker indicating the recent intensification of antioxidant processes., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Jacek J. Jóźwiak and Maciej Banach have received an unrestricted educational grant from Valeant, and has served as a consultant or speaker for Valeant. Paweł Krzemień is employed by Euroimmun Polska Sp. z o.o. (Wroclaw, Poland), whose autoantibody reagents were used in the study. Peter E. Penson owns 4 shares in AstraZeneca PLC and has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT, Link Medical, Mylan, Napp, Sanofi. All others authors declare no conflicts of interest concerning the results of this analysis., (© The Author(s) 2022.)

The Food and Drug Administration recommends prognostic enrichment of randomized controlled trials (RCTs), aimed at restricting the study population to participants most likely to have events and therefore derive benefit from a given intervention. The coronary artery calcium (CAC) score is powerful discriminator of cardiovascular risk, and in this review we discuss how CAC may be used to augment widely used prognostic enrichment paradigms of RCTs of add-on therapies in primary prevention. We describe recent studies in this space, with special attention to the ability of CAC to further stratify risk among guideline-recommended candidates for add-on risk-reduction therapies. Given the potential benefits in terms of sample size, cost reduction, and overall RCT feasibility of a CAC-based enrichment strategy, we discuss approaches that may help maximize its advantages while minimizing logistical barriers and other challenges. Specifically, use of already existing CAC data to avoid the need to re-scan participants with previously documented high CAC scores, use of increasingly available, large clinical CAC databases to facilitate the identification of potential RCT participants, and implementation of machine learning approaches to measure CAC in existing computed tomography images performed for other purposes, will most likely boost the implementation of a CAC-based enrichment paradigm in future RCTs., Competing Interests: Declaration of conflicts of interest Dr Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, MyoKardia, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), 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), 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, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA 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); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. The other authors declare that they have no conflicts of interest relevant to the content of this manuscript., (Copyright © 2021. Published by Elsevier Inc.)

Amyloid fibrils are structurally heterogeneous protein aggregates that are implicated in a wide range of neurodegenerative and other proteopathic diseases. These fibrils exist in a variety of different tertiary and higher-level structures, and this exhibited polymorphism greatly complicates any structural study of amyloid fibrils. In this work, we demonstrate a method of using polarization-resolved microscopy to directly observe the structural heterogeneity of individual amyloid fibrils using amyloid-bound fluorophores. We formulate a mathematical quantity, helical anisotropy, which utilizes the polarized emission of amyloid-bound fluorophores to report on the local structure of individual fibrils. Using this method, we show how model amyloid fibrils generated from short peptides exhibit diverse structural properties both between different fibrils and within a single fibril, in a manner that is replicated for fibrils assembled from longer proteins. Our method represents an accessible and easily adaptable technique by which polymorphism in the structure of amyloid fibrils can be probed. Additionally, the methodology we describe here can be easily extended to the study of other fibrillar and otherwise ordered supramolecular structures.

Purpose of Review: Lipid registry-based research is a valuable tool for assessing current lipid management in patients at risk of cardiovascular disease (CVD). Results of several registries are useful for improving clinical practice highlight gaps between guidelines and their implementation and potential impact on population health. We summarize recent clinical studies based on lipid registries., Recent Findings: Current guidelines for lipid management recommend high-intensity statins and concomitant therapies such as ezetimibe and proprotein convertase subtilisin-kexin type 9 inhibitors for high-risk patients. However, recent observational studies show that the majority of patients received inadequate lipid-lowering therapy (LLT), and the low-density lipoprotein-cholesterol (LDL-C) goal attainment rates are still unsatisfactory., Summary: There is a clear gap between lipid guidelines and lipid management in clinical practice. Clinical studies based on registry databases represent real-world conditions, as opposed to clinical trials. Contemporary registry data reveal that only half of the patients received high-intensity statins, and less than half achieve the LDL-C <70 mg/dL in secondary prevention. In addition, the major reasons for insufficient therapy have been shown to be not only side effects of LLT, but poor adherence by patients to medication regimens and low use of combination therapies by physicians. The real-world evidence from lipid registries clarifies gaps, areas for focus for implementation, to improve CVD prevention., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

A nationwide cross-sectional study, LIPIDOGRAM2015, was carried out in Poland in the years 2015 and 2016. A total of 438 primary care physicians enrolled 13,724 adult patients that sought medical care in primary health care practices. The prevalence of hypertension, diabetes mellitus, dyslipidaemia, and CVD were similar in urban and rural areas (49.5 vs. 49.4%; 13.7 vs. 13.1%; 84.2 vs. 85.2%; 14.4 vs. 14.2%, respectively). The prevalence of obesity (32.3 vs. 37.5%, p < 0.01) and excessive waist circumference (77.5 vs. 80.7%, p < 0.01), as well as abdominal obesity (43.2 vs. 46.4%, p < 0.01), were higher in rural areas in both genders. Mean levels of LDL-C (128 vs. 130 mg/dL, p = 0.04) and non-HDL-C (147 vs. 148 mg/dL, p = 0.03) were slightly higher in rural populations. Altogether, 14.3% of patients with CVD from urban areas and 11.3% from rural areas reached LDL <70 mg/dL ( p = 0.04). There were no important differences in the prevalence of hypertension, diabetes, dyslipidaemia, and CVD, or in mean levels of blood pressure, cholesterol fractions, glucose, and HbA1c between Polish urban and rural primary care patient populations. A high proportion of patients in cities and an even-higher proportion in rural areas did not reach the recommended targets for blood pressure, LDL-C, and HbA1c, indicating the need for novel CVD-prevention programs.

Detecting familial hypercholesterolemia (FH) early and "normalizing" low-density lipoprotein (LDL) cholesterol values are the 2 pillars for effective cardiovascular disease prevention in FH. Combining lipid-lowering therapies targeting synergistic/complementary metabolic pathways makes this feasible, even among severe phenotypes. For LDL receptor-dependent treatments, PCSK9 remains the main target for adjunctive therapy to statins and ezetimibe through a variety of approaches. These include protein inhibition (adnectins), inhibition of translation at mRNA level (antisense oligonucleotides or small interfering RNA), and creation of loss-of-function mutations through base-pair editing. For patients with little LDL receptor function, LDL receptor-independent treatment targeting ANGPTL3 through monoclonal therapies are now available, or in the future, antisense/small interfering RNA-based approaches offer alternative approaches. Finally, first-in-human studies are ongoing, testing adenovirus-mediated gene therapy transducing healthy LDLR DNA in patients with HoFH. Further development of the CRISPR cas technology, which has shown promising results in vivo on introducing PCSK9 loss-of-function mutations, will move a single-dose, curative treatment for FH closer., Competing Interests: Funding Support and Author Disclosures Dr Brandts has received research grant support from AstraZeneca; and has received speaker honoraria from Amgen. Dr Ray has received support from the National Institute for Health Research Imperial Biomedical Research Centre and additional support from the National Institute for Health Research ARC for northwest London; has received grants from Amgen during the conduct of the study; has received grants and personal fees from Amgen, Sanofi/Regeneron, Pfizer, Merck Sharp & Dohme, Daiichi-Sankyo; has received personal fees from Aegerion, AstraZeneca, Cerenis, Akcea, The Medicines Company, Kowa, Novartis, Cipla, Lilly, Algorithm, Takeda, Boehringer Ingelheim, Abbvie, Silence Therapeutics, Dr Reddys, Bayer, Esperion, Abbvie, Zuelling Pharma, and Silence Therapeutics outside of the submitted work., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Diagnosis rates of familial hypercholesterolemia (FH) remain low. We implemented FH ALERT to assess whether alerting physicians for the possibility of FH impacted additional diagnostic activity. The study was conducted from SYNLAB laboratory Weiden (Bavaria). Beyond common reporting of LDL-C or TC, 1411 physicians covering approximately a population of 1.5 million people were eligible to receive an alert letter (AL) including information on FH, if laboratory results exceeded thresholds as follows: adults LDL-C ≥ 190-250 mg/dl (to convert into mmol/l multiply with 0.0259), TC ≥ 250 to ≤ 310 mg/dl (probable suspicion); LDL-C > 250 mg/dl and TC > 310 mg/dl (strong suspicion). Persons below 18 years were alerted for LDL-C  140 mg/dl and TC ≥ 200 mg/dl (strong suspicion). Patients above 60 years were excluded. Our readouts were characteristics of involved physicians, rate of ALs issued, acceptance, and subsequent diagnostic activity. Physicians were mainly general practitioners in ambulatory care. 75% of the ordered tests were for TC, 25% for LDL-C. We issued 3512 ALs (~ 5% of tests) triggered by 2846 patients. 86% of eligible physicians stayed with the initiative, 32.7% were alerted, and 70% were positive upon call-center survey. We registered 101 new visitors of www.fhscore.eu and sent out 93 kits for genetics. Thereof, 26 were returned and 5 patients were positive for FH. Physicians were in general open to our approach. Although genetic testing was taken up with caution, this 3-months pilot examination resulted in a greater rate of patients with FH diagnosed than previous screening projects. Further education on FH in primary care is required to improve FH detection in the community., (© 2021. The Author(s).)

Background and Aims: Central and Eastern Europe (CEE) is a largely understudied region, despite having the highest cardiovascular disease mortality in Europe. This analysis aimed to assess the proportion of patients in CEE who achieved their LDL-C goals based on individual cardiovascular risk recommended by the 2016 and 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines., Methods: The DA VINCI study was a cross-sectional observational study of primary and secondary prevention patients receiving lipid-lowering therapy across Europe between June 2017 and November 2018., Results: In total, 2154 patients were enrolled from the Czech Republic (n = 509), Hungary (n = 319), Poland (n = 460), Romania (n = 259), Slovakia (n = 123) and Ukraine (n = 484). At LDL-C measurement, most patients were on either moderate- or high-intensity statin monotherapy (53% and 32%, respectively). Despite this, only 44% of patients achieved risk-based LDL-C goals recommended by the 2016 ESC/EAS guidelines, ranging from 21% in Ukraine to 50% in Hungary and Romania. Only 24% of patients overall achieved the risk-based LDL-C goals recommended by the 2019 ESC/EAS guidelines, ranging from 11% in Ukraine to 32% in Poland., Conclusions: Among patients receiving lipid-lowering therapy, more than half did not achieve their 2016 LDL-C goals. In one of the first comparative analyses evaluating 2019 risk-based goal attainment among countries in CEE, three-quarters of patients did not meet their 2019 LDL-C goals, highlighting a significant gap between guidelines and clinical practice for lipid management in CEE., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The purpose of the study was to evaluate secondary stroke prevention in Poland and its association with sociodemographic factors, place of residence, and concomitant cardiovascular risk factors., Material and Methods: From all patients in LIPIDOGRAM2015 Study ( n = 13,724), 268 subjects had a history of ischaemic stroke and were included., Results: 165 subjects (61.6%) used at least one preventive medication. Oral antiplatelet and anticoagulation agents were used by 116 (43.3%) and 70 (26.1%) patients, respectively. Only 157 (58.6%) participants used lipid-lowering drugs, and 205 (76.5%) were treated with antihypertensive drugs. Coronary heart disease (CHD) and dyslipidaemia were associated with antiplatelet treatment ( p = 0.047 and p = 0.012, respectively). A history of atrial fibrillation, CHD, and previous myocardial infarction correlated with anticoagulant treatment ( p = 0.001, p = 0.011, and p < 0.0001, respectively). Age, gender, time from stroke onset, place of residence, and level of education were not associated with antiplatelet or anticoagulant treatment. Only 31.7% of patients were engaged in regular physical activity, 62% used appropriate diet, and 13.6% were current smokers., Conclusions: In Poland drugs and lifestyle modification for secondary stroke prevention are not commonly adhered to. Educational programmes for physicians and patients should be developed to improve application of effective secondary prevention of stroke.

Aims: To provide contemporary data on the implementation of European guideline recommendations for lipid-lowering therapies (LLTs) across different settings and populations and how this impacts low-density lipoprotein cholesterol (LDL-C) goal achievement., Methods and Results: An 18 country, cross-sectional, observational study of patients prescribed LLT for primary or secondary prevention in primary or secondary care across Europe. Between June 2017 and November 2018, data were collected at a single visit, including LLT in the preceding 12 months and most recent LDL-C. Primary outcome was the achievement of risk-based 2016 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL-C goal while receiving stabilized LLT; 2019 goal achievement was also assessed. Overall, 5888 patients (3000 primary and 2888 secondary prevention patients) were enrolled; 54% [95% confidence interval (CI) 52-56] achieved their risk-based 2016 goal and 33% (95% CI 32-35) achieved their risk-based 2019 goal. High-intensity statin monotherapy was used in 20% and 38% of very high-risk primary and secondary prevention patients, respectively. Corresponding 2016 goal attainment was 22% and 45% (17% and 22% for 2019 goals) for very high-risk primary and secondary prevention patients, respectively. Use of moderate-high-intensity statins in combination with ezetimibe (9%), or any LLT with PCSK9 inhibitors (1%), was low; corresponding 2016 and 2019 goal attainment was 53% and 20% (ezetimibe combination), and 67% and 58% (PCSK9i combination)., Conclusion: Gaps between clinical guidelines and clinical practice for lipid management across Europe persist, which will be exacerbated by the 2019 guidelines. Even with optimized statins, greater utilization of non-statin LLT is likely needed to reduce these gaps for patients at highest risk., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose of Review: To describe the INTERASPIRE scientific protocol-an international survey of secondary prevention of coronary heart disease (CHD)., Recent Findings: This international survey is being conducted through National Societies of Cardiology in selected countries from each of the six WHO regions and has the following overall aims: (i) describe prevalence of cardiometabolic and renal risk factors together with biomarkers in CHD patients; (ii) describe current risk factor management through lifestyle changes and cardioprotective drug therapies; (iii) provide an objective assessment of clinical implementation of preventive care by comparison with the lifestyle and risk factor targets defined in international and national guidelines; (iv) investigate the reasons for variation in preventive cardiology practice between regions and countries; and (v) promote the principles of best preventive cardiology practice. This international survey will provide a unique picture of CHD patients; their cardiometabolic, renal and biomarker status; lifestyle and therapeutic management; and the quality of preventive care provided in all WHO regions., (© 2021. The Author(s).)

Background and Aims: Clinical practice before 2019 suggests a substantial proportion of high and very high CV risk patients taking lipid-lowering therapy (LLT) would not achieve the new LDL-C goals recommended in the 2019 ESC/EAS guidelines (<70 and < 55 mg/dL, respectively). To what extent practice has changed since the last ESC/EAS guideline update is uncertain, and quantification of remaining implementation gaps may inform health policy., Methods: The SANTORINI study is a multinational, multicentre, prospective, observational, non-interventional study documenting patient data at baseline (enrolment) and at 12-month follow-up. The study recruited 9606 patients ≥18 years of age with high and very high CV risk (as assigned by the investigators) requiring LLT, with no formal patient or comparator groups. The primary objective is to document, in the real-world setting, the effectiveness of current treatment modalities in managing plasma levels of LDL-C in high- and very high-risk patients requiring LLT. Key secondary effectiveness objectives include documenting the relationship between LLT and levels of other plasma lipids, high-sensitivity C-reactive protein (hsCRP) and overall predicted CV risk over one year. Health economics and patient-relevant parameters will also be assessed., Conclusions: The SANTORINI study, which commenced after the 2019 ESC/EAS guidelines were published, is ideally placed to provide important contemporary insights into the evolving management of LLT in Europe and highlight factors contributing to the low levels of LDL-C goal achievement among high and very high CV risk patients. It is hoped the findings will help enhance patient management and reduce the burden of ASCVD in Europe., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (© 2021 The Authors.)

Importance: In patients treated with ω-3 fatty acids, it remains uncertain whether achieved levels of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) are associated with cardiovascular outcomes., Objective: To determine the association between plasma levels of EPA and DHA and cardiovascular outcomes in a trial of ω-3 fatty acids compared with corn oil placebo., Design, Setting, and Participants: A double-blind, multicenter trial enrolled patients at high cardiovascular risk with elevated triglyceride levels and low levels of high-density lipoprotein cholesterol at 675 centers (enrollment from October 30, 2014, to June 14, 2017; study termination January 8, 2020; last visit May 14, 2020)., Interventions: Participants were randomized to receive 4 g daily of ω-3 carboxylic acid (CA) or an inert comparator, corn oil., Main Outcomes and Measures: The primary prespecified end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The primary outcome measure was the hazard ratio, adjusted for baseline characteristics, for patients treated with the ω-3 CA compared with corn oil for the top tertile of achieved EPA and DHA plasma levels 12 months after randomization., Results: Of the 13 078 total participants, 6539 (50%) were randomized to receive ω-3 CA and 6539 (50%) randomized to corn oil. ω-3 Fatty acid levels were available at both baseline and 12 months after randomization in 10 382 participants (5175 ω-3 CA patients [49.8%] and 5207 corn oil-treated patients [50.2%]; mean [SD] age, 62.5 [8.9] years, 3588 [34.6%] were women, 9025 [86.9%] were White, and 7285 [70.2%] had type 2 diabetes). The median plasma levels at 12 months in ω-3 CA patients were 89 μg/mL (interquartile range [IQR], 46-131 μg/mL) for EPA and 91 μg/mL (IQR, 71-114 μg/mL) for DHA with top tertile levels of 151 μg/mL (IQR, 132-181 μg/mL) and 118 μg/mL (IQR, 102-143 μg/mL), respectively. Compared with corn oil, the adjusted hazard ratios for the highest tertile of achieved plasma levels were 0.98 (95% CI, 0.83-1.16; P = .81) for EPA, and 1.02 (95% CI, 0.86-1.20; P = .85 for DHA. Sensitivity analyses based on changes in plasma and red blood cell levels of EPA and DHA and primary and secondary prevention subgroups showed similar results., Conclusions and Relevance: Among patients treated with ω-3 CA, the highest achieved tertiles of EPA and DHA were associated with neither benefit nor harm in patients at high cardiovascular risk., Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.

Many patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels with statins alone; others are unable to tolerate statin therapy. Additional non-statin treatment options including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bile acid sequestrants are often necessary to further reduce the risk of atherosclerotic cardiovascular disease. This review provides practical guidance as to the use of bempedoic acid to lower LDL-C and includes direction as to which patients may benefit and advice for safety monitoring during treatment. Bempedoic acid, a new class of agent, is a prodrug converted to bempedoyl-CoA by very long-chain acyl-CoA synthetase 1, an enzyme with high expression in the liver but that is undetectable in the skeletal muscle. Bempedoic acid inhibits the enzyme adenosine triphosphate (ATP)-citrate lyase, which lies two steps upstream from β-hydroxy β-methylglutaryl-CoA reductase in the cholesterol biosynthesis pathway. In clinical trials conducted in patients with or at risk for atherosclerotic cardiovascular disease or familial heterozygous hypercholesterolemia, bempedoic acid in combination with statins and/or ezetimibe significantly reduced LDL-C, apolipoprotein B, and high-sensitivity C-reactive protein compared with placebo. Bempedoic acid is generally well tolerated with no clinically meaningful increase in muscle-related symptoms relative to placebo, even in patients taking maximally tolerated statins. A small increase in serum uric acid (mean increase 0.8 mg/dL) is the most noteworthy adverse effect. Bempedoic acid provides an effective and generally well-tolerated medication to further reduce LDL-C in patients taking maximally tolerated statins or manage LDL-C levels in those who are unable to take statins. The potential for a reduced incidence of major cardiovascular events with bempedoic acid is being investigated in the CLEAR Outcomes trial, with results expected in 2023.

Inclisiran is a siRNA inhibiting hepatic PCSK9 synthesis. As a first-in-class therapy, inclisiran has been assessed within the ORION trial program for its low-density lipoprotein cholesterol (LDL-C) lowering efficacy and clinical safety. Phase II and III trials have shown that inclisiran lowers LDL-C by about 50% with an infrequent dosing schedule in patients with established atherosclerotic cardiovascular disease and those at high risk, including patients with heterozygous familial hypercholesterolemia. Ongoing Phase III trials will provide evidence on longer-term safety and effectiveness, and inclisiran's efficacy in patients with homozygous familial hypercholesterolemia. Furthermore, the ORION-4 trial will assess inclisiran's impact on cardiovascular outcomes.

Introduction: Oxidative stress is one of many factors suspected to promote antinuclear autoantibody (ANA) formation. Reactive oxygen species can induce changes in the antigenic structure of macromolecules, causing the immune system to treat them as "neo-antigens" and start production of autoantibodies. This study was designed to evaluate the relationship between oxidative stress markers, lifestyle factors and the detection of ANA., Material and Methods: We examined measures of oxidative stress indices of free-radical damage to lipids and proteins, such as total oxidant status (TOS), concentration of protein thiol groups (PSH), and malondialdehyde (MDA), activity of superoxide dismutase (SOD) in 1731 serum samples. The parameters of the non-enzymatic antioxidant system, such as total antioxidant status (TAS) and uric acid (UA) concentration, were also measured and the oxidative stress index (OSI-index) was calculated. All samples were tested for the presence of ANA using an indirect immunofluorescence assay (IIFA)., Results: The presence of ANA in women was associated with lower physical activity ( p = 0.036), less frequent smoking ( p = 0.007) and drinking of alcohol ( p = 0.024) accompanied by significant changes in SOD isoenzymes activity ( p < 0.001) and a higher uric acid (UA) concentration ( p < 0.001). In ANA positive males we observed lower concentrations of PSH ( p = 0.046) and increased concentrations of MDA ( p = 0.047)., Conclusions: The results indicate that local oxidative stress may be associated with increased probability of ANA formation in a sex-specific manner., Competing Interests: JJJ and MB have received an unrestricted educational grant from Valeant, and have served as consultants or speakers for Valeant. PK is employed by Euroimmun Polska Sp. z o.o., (Wroclaw, Poland), whose autoantibody reagents were used in the study. PEP owns four shares in AstraZeneca PLC and has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT, Link Medical, Mylan, Napp, Sanofi. All other authors have no conflict of interest concerning the results of this analysis., (Copyright: © 2021 Termedia & Banach.)

Background: In stable patients with type 2 diabetes (T2D), insulin treatment is associated with elevated risk for major adverse cardiovascular events (MACE). Patients with acute coronary syndrome (ACS) and T2D are at particularly high risk for recurrent MACE despite evidence-based therapies. It is uncertain to what extent this risk is further magnified in patients with recent ACS who are treated with insulin. We examined the relationship of insulin use to risk of MACE and modification of that risk by apabetalone, a bromodomain and extra-terminal (BET) protein inhibitor., Methods: The analysis utilized data from the BETonMACE phase 3 trial that compared apabetalone to placebo in patients with T2D, low HDL cholesterol, andACS. The primary MACE outcome (cardiovascular death, myocardial infarction, or stroke) was examined according to insulin treatment and assigned study treatment. Multivariable Cox regression was used to determine whether insulin use was independently associated with the risk of MACE., Results: Among 2418 patients followed for median 26.5 months, 829 (34.2%) were treated with insulin. Despite high utilization of evidence-based treatments including coronary revascularization, intensive statin treatment, and dual antiplatelet therapy, the 3-year incidence of MACE in the placebo group was elevated among insulin-treated patients (20.4%) compared to those not-treated with insulin (12.8%, P = 0.0001). Insulin treatment remained strongly associated with the risk of MACE (HR 2.10, 95% CI 1.42-3.10, P = 0.0002) after adjustment for demographic, clinical, and treatment variables. Apabetalone had a consistent, favorable effect on MACE in insulin-treated and not insulin-treated patients., Conclusion: Insulin-treated patients with T2D, low HDL cholesterol, and ACS are at high risk for recurrent MACE despite the use of evidence-based, contemporary therapies. A strong association of insulin treatment with risk of MACE persists after adjustment for other characteristics associated with MACE. There is unmet need for additional treatments to mitigate this risk. Trial registration ClinicalTrials.gov NCT02586155, registered October 26, 2015.

LDL cholesterol (LDL-C) plays a central role in the progression of atherosclerosis. Statin therapy for lowering LDL-C reduces the risk of atherosclerotic cardiovascular disease and is the recommended first-line treatment for patients with high LDL-C levels. However, some patients are unable to achieve an adequate reduction in LDL-C with statins or are statin-intolerant; thus, PCSK9 inhibitors were developed to reduce LDL-C levels, instead of statin therapy. PCSK9 monoclonal antibodies dramatically reduce LDL-C levels and cardiovascular risk, and promising new PCSK9 inhibitors using different mechanisms are currently being developed. The absolute benefit of LDL-C reduction depends on the individual absolute risk and the achieved absolute reduction in LDL-C. Therefore, PCSK9 inhibitors may provide the greatest benefits from further LDL-C reduction for the highest risk patients. Here, we focus on PCSK9-targeted therapies and discuss the challenges of LDL-C reduction for prevention of atherosclerotic cardiovascular disease., (© 2019 The British Pharmacological Society.)

Background and Objectives: CKD and type 2 diabetes mellitus interact to increase the risk of major adverse cardiovascular events ( i.e. , cardiovascular death, nonfatal myocardial infarction, or stroke) and congestive heart failure. A maladaptive epigenetic response may be a cardiovascular risk driver and amenable to modification with apabetalone, a selective modulator of the bromodomain and extraterminal domain transcription system. We examined this question in a prespecified analysis of BETonMACE, a phase 3 trial., Design, Setting, Participants, & Measurements: BETonMACE was an event-driven, randomized, double-blind, placebo-controlled trial comparing effects of apabetalone versus placebo on major adverse cardiovascular events and heart failure hospitalizations in 2425 participants with type 2 diabetes and a recent acute coronary syndrome, including 288 participants with CKD with eGFR <60 ml/min per 1.73 m 2 at baseline. The primary end point in BETonMACE was the time to the first major adverse cardiovascular event, with a secondary end point of time to hospitalization for heart failure., Results: Median follow-up was 27 months (interquartile range, 20-32 months). In participants with CKD, apabetalone compared with placebo was associated with fewer major adverse cardiovascular events (13 events in 124 patients [11%] versus 35 events in 164 patients [21%]; hazard ratio, 0.50; 95% confidence interval, 0.26 to 0.96) and fewer heart failure-related hospitalizations (three hospitalizations in 124 patients [3%] versus 14 hospitalizations in 164 patients [9%]; hazard ratio, 0.48; 95% confidence interval, 0.26 to 0.86). In the non-CKD group, the corresponding hazard ratio values were 0.96 (95% confidence interval, 0.74 to 1.24) for major adverse cardiovascular events, and 0.76 (95% confidence interval, 0.46 to 1.27) for heart failure-related hospitalization. Interaction of CKD on treatment effect was P =0.03 for major adverse cardiovascular events, and P =0.12 for heart failure-related hospitalization. Participants with CKD showed similar numbers of adverse events, regardless of randomization to apabetalone or placebo (119 [73%] versus 88 [71%] patients), and there were fewer serious adverse events (29% versus 43%; P =0.02) in the apabetalone group., Conclusions: Apabetalone may reduce the incidence of major adverse cardiovascular events in patients with CKD and type 2 diabetes who have a high burden of cardiovascular disease., (Copyright © 2021 by the American Society of Nephrology.)

Biophysics experiments performed at single-molecule resolution provide exceptional insight into the structural details and dynamic behavior of biological systems. However, extracting this information from the corresponding experimental data unequivocally requires applying a biophysical model. In this review, we discuss how to use probability theory to apply these models to single-molecule data. Many current single-molecule data analysis methods apply parts of probability theory, sometimes unknowingly, and thus miss out on the full set of benefits provided by this self-consistent framework. The full application of probability theory involves a process called Bayesian inference that fully accounts for the uncertainties inherent to single-molecule experiments. Additionally, using Bayesian inference provides a scientifically rigorous method of incorporating information from multiple experiments into a single analysis and finding the best biophysical model for an experiment without the risk of overfitting the data. These benefits make the Bayesian approach ideal for analyzing any type of single-molecule experiment.

Objectives: This study sought to assess the value, in terms of sample size and cost, of using the coronary artery calcium (CAC) score to enrich the study population of primary prevention randomized controlled trials (RCTs) with participants at high absolute risk of atherosclerotic cardiovascular disease (ASCVD) events., Background: The feasibility of RCTs assessing the efficacy of novel add-on therapies for primary prevention among high-risk individuals treated with statins may be limited by sample size and cost., Methods: We evaluated 3,075 statin-naive participants from the MESA (Multi-Ethnic Study of Atherosclerosis) with estimated 10-year ASCVD risk of ≥7.5%. CAC of >100, CAC of >400, high sensitivity C-reactive protein levels of >2 and >3 mg/l, ankle-brachial index of <0.9, and triglyceride levels of >175 mg/dl were each evaluated as enrichment criteria on top of estimated ASCVD risk of ≥7.5%, ≥10%, ≥15% and ≥20%. For each criterion, using the observed 5-year incidence of CVD, we projected the incidence of CVD assuming a 28% relative risk reduction with high-intensity statin therapy and after addition of novel therapy with additive relative risk reductions of 15% and 25%. Sample size and cost of a hypothetical primary prevention 5-year RCT of a novel therapy on top of statins versus statins alone were then computed by using the projected incidences. Yearly costs per included participant of $6,000 to $9,000 and of $500/$600 per screened nonparticipant were assumed., Results: CAC of >400, present in 15% to 23% participants, consistently identified the subgroups with highest 5-year incident events and outperformed the other features yielding the smallest projected sample size, ranging 33% to 58% lower than using risk estimations alone for participant selection. CAC of >400 also yielded the lowest projected RCT costs, at least $40 million lower than using risk estimations alone. CAC of >100 showed the second-best performance in most scenarios., Conclusions: High CAC scores used as study entry criteria can improve the efficiency and feasibility of primary prevention RCTs evaluating the incremental efficacy of novel add-on therapies., Competing Interests: Funding Support and Author Disclosures This research was supported by contracts HHSN268201500003I and N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, and UL1-TR-001881 from the National Center for Advancing Translational Sciences. Dr. Ray acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre and Imperial College London is grateful for support from the NIHR Applied Research Collaboration for North West London. Dr. Bhatt has served on the Advisory Board of Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; has served on the Board of Directors for Boston Veterans Affairs Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; has served as chair of the American Heart Association Quality Oversight Committee; has served on the Data Monitoring Committee for the Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), and Population Health Research Institute; has received honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; vice chair, ACC Accreditation Committee), 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), 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), Medtelligence/ReachMD (continuing medical education [CME] steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, and steering committee and U.S. national coleader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees); reports the following roles: Clinical Cardiology (deputy editor), National Cardiovascular Data Registry (NCDR)-ACTION Registry Steering Committee (chair), Veteran Affairs Clinical Assessment, Reporting and Tracking Program (VA CART) Research and Publications Committee (chair); has received research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; has received royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease) has served as site coinvestigator for Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; has served as trustee for the American College of Cardiology; and has performed unfunded research for FlowCo, Merck, Novo Nordisk, and Takeda. Dr. Ray reports personal fees from Aegerion, grants and personal fees from Amgen, Sanofi/Regeneron, Pfizer, and Merck Sharp & Dohme Corp. (MSD), personal fees from AstraZeneca, Cerenis, Akcea, The Medicines Company, Kowa, Novartis, Cipla, Lilly, Algorithm, Takeda, Boehringer Ingelheim, AbbVie, and Silence Therapeutics. Dr. Reddy’s has received personal fees from Bayer, Daiichi Sankyo, Esperion, AbbVie, Zuelling Pharma, and Resverlogix, outside the submitted work. Dr. Nasir is on the Advisory Boards of Amgen, Novartis, and The Medicine Company; and his research is partly supported by the Jerold B. Katz Academy of Translational Research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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 and Aims: Several medications targeting PCSK9 reduce LDL-cholesterol (LDL-C) in heterozygous familial hypercholesterolemia (HeFH). We aimed to assess in patients diagnosed clinically as HeFH, whether LDL-C reduction varied by different therapeutic approaches to PCSK9-targeting or by the underlying genetic variant., Methods: We conducted a random-effects meta-analysis of randomised clinical trials assessing PCSK9-targeting therapies, namely alirocumab, evolocumab and inclisiran, in patients with clinically diagnosed HeFH and restricted analyses to those patients in whom genotypic data were available. A search of MEDLINE and Embase identified eligible trials published between inception and June 29, 2020. We included trials of sufficient duration to allow for a stable treatment effect: ~12 weeks for monoclonal antibodies (mAbs) (alirocumab, evolocumab) and ~1 year for small interfering RNA (siRNA) (inclisiran). Single-moderator meta-regression comparing mean percentage LDL-C reduction between mAbs and siRNA as well as PCSK9-targeting therapies between different genotypes was used to assess heterogeneity., Results: Eight trials of HeFH met our inclusion criteria, including 1887 genotyped patients. Among monogenic HeFH cases (N = 1347) the LDL-C reduction from baseline was 46.12% (95%CI 48.4-43.9) for siRNA and 50.4% (59.3-41.4) for mAbs compared to control, without evidence of significant heterogeneity between treatment (Q M  = 0.32, df = 1, p = 0.57). Irrespective of therapeutic approach to PCSK9-targeting, reductions in LDL-C were generally consistent across genetic variants (LDL-Receptor variants, LDL-Receptor variants of unknown significance, Apolipoprotein B variants, two variants and no variant) (Q M  = 8.3, df = 4, p = 0.08)., Conclusions: Among patients with HeFH, the LDL-C-lowering effect of PCSK9-targeting medications did not show statistical heterogeneity across different drug-classes and across genetic variants., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: Despite trial evidence, high intensity statins are underutilized in routine clinical practice. This study sought to assess the individual and joint contributions of the TRS2P score as a measure of residual risk and LDL-C levels to benefits from further LDL-C lowering in the TNT trial., Methods: A total of 9980 patients were divided into 4 groups based on TRS2P and LDL-C at baseline: median (7.2%, group 4), NNT 78 vs. 14 (p-interaction <0.0001)., Conclusions: Measures of residual risk as well LDL-C identify patients who remain at high risk despite statins with the combination identifying those who derive the greatest benefits from even modest additional LDL-C lowering. Attention to residual risk as well as LDL-C may further help to optimize guideline implementation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Inclisiran is a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin-kexin type 9 (PCSK9) translation in the liver, leading to sustained reductions in low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins with twice-yearly dosing., Objectives: The purpose of this study was to conduct a patient-level pooled analysis from 3 phase 3 studies of inclisiran., Methods: Participants with heterozygous familial hypercholesterolemia (ORION-9 [Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)]), atherosclerotic cardiovascular disease (ASCVD) (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]), or ASCVD and ASCVD risk equivalents (ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]) taking maximally tolerated statin therapy, with or without other LDL-C-lowering agents, were randomly assigned in a 1:1 ratio to receive either inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter for 540 days. The coprimary endpoints were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 to day 540. Levels of other atherogenic lipoproteins and treatment-emergent adverse events were also assessed., Results: A total of 3,660 participants (n = 482, n = 1,561, and n = 1,617 from ORION-9, -10, and -11, respectively) underwent randomization. The placebo-corrected change in LDL-C with inclisiran at day 510 was -50.7% (95% confidence interval: -52.9% to -48.4%; p < 0.0001). The corresponding time-adjusted change in LDL-C was -50.5% (95% confidence interval: -52.1% to -48.9%; p < 0.0001). Safety was similar in both groups. Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups., Conclusions: These pooled safety and efficacy data show that inclisiran, given twice yearly in addition to maximally tolerated statin therapy with or without other LDL-C lowering agents, is an effective, safe, and well-tolerated treatment to lower LDL-C in adults with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk equivalents., Competing Interests: Funding Support and Author Disclosures The analyses presented here were funded by Novartis Pharma AG. Statistical analysis was carried out by Summit Analytical, with funding from Novartis Pharma AG, Basel. Dr. Wright has received support from the Mayo Clinic and U.S. Department of Health and Human Services (HHS), Biomedical Advanced Research and Development Authority (BARDA) contract 75A50120C00096; has received fees for serving on steering committees from Boehringer Ingelheim and The Medicines Company; and has nonfinancial conflicts with AstraZeneca and Novartis. Dr. Ray has received support from the NIHR Imperial Biomedical Research Centre; has received lecture fees from Aegerion Pharmaceuticals, Kowa, Cipla, Algorithm, and Zuelling Pharma; has received grant support, paid to his institution, lecture fees, and advisory board fees from Amgen, Regeneron Pharmaceuticals/Sanofi, and Pfizer; has received lecture fees and fees for serving on steering committees for trials from AstraZeneca and Eli Lilly; has received fees for serving on steering committees for trials from Cerenis Therapeutics, The Medicines Company, and Esperion; has received advisory board fees from Akcea Therapeutics, Novartis, Silence Therapeutics, Bayer, and Daiichi-Sankyo; has received lecture fees and advisory board fees from Takeda, Boehringer Ingelheim, and Dr. Reddy’s Laboratories; has received grant support and advisory board fees from Merck Sharp & Dohme; has received fees for serving on a clinical events adjudication committee from AbbVie; and has received fees for serving as principal investigator for a trial from Resverlogix. Dr. Raal has received advisory board fees and lecture fees from Amgen, Sanofi, Regeneron Pharmaceuticals, and The Medicines Company. Dr. Kallend was employed by and held stock options in The Medicines Company at the time of study; and was employed by DalCor Pharmaceuticals at the time of publication. Dr. Jaros has received fees for providing statistical analysis for trials from The Medicines Company and Novartis. Dr. Koenig has received consulting fees and lecture fees from AstraZeneca, Novartis, and Amgen; has received consulting fees from Pfizer, The Medicines Company, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, and Daiichi-Sankyo; has received lecture fees from Berlin-Chemie, Bristol Myers Squibb, and Sanofi; and has received grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr. Beckmann Pharma. Dr. Leiter has received grant support paid to his institution, advisory board fees, and fees for CME from Amgen, Eli Lilly, and Regeneron Pharmaceuticals/Sanofi; has received fees for serving on a steering committee from Esperion; has received grant support paid to his institution and fees for serving on a steering committee from Kowa, The Medicines Company, and Novartis; has received advisory board fees and fees for CME from Merck; and has received advisory board fees from HLS Therapeutics. Dr. Landmesser has received lecture fees and advisory fees from AstraZeneca, Amgen, Sanofi, Berlin Chemie, Novartis, and Abbott; has received advisory fees from The Medicines Company; and has received grant support, lecture fees, and advisory fees from Bayer. Dr. Schwartz has received research support, paid to his institution, from AstraZeneca, Resverlogix, Roche, and The Medicines Company; and has a patent (62/806313) on a method for reducing cardiovascular risk assigned in full to the University of Colorado. Dr. Friedman was employed by and held shares and stock options in The Medicines Company at the time of the study; and was employed by Novartis at the time of publication. Dr. Wijngaard was employed by and held shares and stock options in The Medicines Company at the time of the study; and was employed by and held shares and stock options in Novartis at the time of publication. Dr. Kastelein has received consulting fees from Akcea Therapeutics, AstraZeneca, CiVi Biopharma, Corvidia Therapeutics, CSL Behring, Daiichi-Sankyo, Draupnir Bio, Esperion, Gemphire Therapeutics, Madrigal Pharmaceuticals, Matinas BioPharma, NorthSea Therapeutics, Novo Nordisk, Novartis, Regeneron Pharmaceuticals, REGENXBIO, Staten Biotechnology, and 89bio. Dr. Garcia Conde was employed by Novartis at the the time of publication., (Copyright © 2021 American College of Cardiology Foundation. All rights reserved.)

Background and Aims: Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype., Methods: The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C <4.9 and ≥ 4.9 mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of "premature CAD" and "family history of CAD". Participants having both are defined as having an FH phenotype., Results: 2267 and 2164 participants had LDL-C <4.9 and ≥ 4.9 mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1-4.3% for mortality endpoints, versus 2.5-2.8%). LDL-C reductions were similar among the 4 subgroups with levels ≥4.9 mmol/L. Participants with FH phenotype (n = 152) appeared to derive greater relative benefits with simvastatin than the other three subgroups (all-cause death: 84% relative risk reduction, p = 0.046; MCE: 55% reduction, p = 0.0297); statistical interaction was non-significant. Participants with FH phenotype derived greater ARR than any other group with simvastatin versus placebo (all-cause mortality: 6.6% ARR; MCE 13.2%; versus 3.8% and 8.3%, respectively, among participants with LDL-C ≥4.9 mmol/L but without features suggestive of FH)., Conclusions: The FH phenotype appeared to be associated with greater clinical benefits from a given magnitude of LDL-C reduction as compared to individuals without FH phenotype., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied., Methods: We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m 2 of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding., Results: Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo., Conclusions: In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Patients with diabetes and acute coronary syndrome (ACS) are at high risk for subsequent heart failure. Apabetalone is a selective inhibitor of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression. Preclinical data suggest that apabetalone exerts favorable effects on pathways related to myocardial structure and function and therefore could impact subsequent heart failure events. The effect of apabetalone on heart failure events after an ACS is not currently known., Methods: The phase 3 BETonMACE trial was a double-blind, randomized comparison of apabetalone versus placebo on the incidence of major adverse cardiovascular events (MACE) in 2425 patients with a recent ACS and diabetes. This prespecified secondary analysis investigated the impact of apabetalone on hospitalization for congestive heart failure, not previously studied., Results: Patients (age 62 years, 74.4% males, 90% high-intensity statin use, LDL-C 70.3 mg/dL, HDL-C 33.3 mg/dL and HbA1c 7.3%) were followed for an average 26 months. Apabetalone treated patients experienced the nominal finding of a lower rate of first hospitalization for heart failure (2.4% vs. 4.0%, HR 0.59 [95%CI 0.38-0.94], P = 0.03), total number of hospitalizations for heart failure (35 vs. 70, HR 0.47 [95%CI 0.27-0.83], P = 0.01) and the combination of cardiovascular death or hospitalization for heart failure (5.7% vs. 7.8%, HR 0.72 [95%CI 0.53-0.98], P = 0.04)., Conclusion: Apabetalone treatment was associated with fewer hospitalizations for heart failure in patients with type 2 diabetes and recent ACS. Future studies are warranted to define the potential for BET inhibition with apabetalone to prevent heart failure in patients with diabetes and ACS.

Aims: Small-interfering RNA (siRNA)-based targeting of proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a novel therapeutic approach that may provide a convenient, infrequent, and safe dosing schedule to robustly lower low-density lipoprotein cholesterol (LDL-C). Given the long duration of action, however, establishing safety in particular with respect to immunogenicity is of paramount importance. In earlier clinical studies of other RNA-targeted treatment approaches (antisense oligonucleotide therapy) immunological and haematological adverse effects, in particular thrombocytopenia and pro-inflammatory effects, have been reported. Here, we present the pre-specified safety analysis from ORION-1 evaluating platelets, immune cells, immunological markers, antidrug antibodies, and clinical immunogenicity adverse events (AEs) under PCSK9 siRNA treatment with inclisiran., Methods and Results: The pre-specified safety analysis from ORION-1 was performed in six different inclisiran dosing regimens in patients at high risk of cardiovascular disease with elevated LDL-C levels. Patients received either a single dose (SD: 200 mg, n = 60; 300 mg, n = 62 or 500 mg, n = 66) or double-dose starting regimen (DD: 100 mg, n = 62; 200 mg, n = 63; or 300 mg, n = 61 on days 1 and 90) of inclisiran or placebo (SD: n = 65; DD: n = 62). The effects of inclisiran on haematological parameters including platelet counts, lymphocytes, and monocytes as well as on the immune markers interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were examined after 180 days. Immunogenicity was further evaluated by analysis of anti-drug-antibodies (ADAs) towards inclisiran in 6068 study samples and by careful analysis of immunogenicity AEs as part of the pharmacovigilance strategy. At day 180, no significant alterations of platelet counts were observed in any of the dosing groups (change from baseline, SD: 200 mg: 0.8%; 300 mg: -0.5%; 500 mg: -1.8%; DD: 100 mg: 1.3%; 200 mg: -0.5%; 300 mg: 1.0%; no significant difference for any group as compared with placebo). No significant effects on other immune cells, including leucocytes, monocytes, or neutrophils were detected. Notably, no significant increase of inflammatory biomarkers (IL-6 or TNF-α) with either the SD or DD regimen became evident. There was no evidence for immunogenicity based on ADA level analysis and careful review of clinical immunogenicity AEs in none of the treatment regimens., Conclusion: In this pre-specified safety analysis of ORION-1 for the siRNA therapeutic inclisiran, no adverse effects on measures of inflammation or immune activation nor adverse effects on platelets or clinical immunogenicity AEs were observed over at least 6-month treatment. These safety findings in the largest analysis of an RNAi study in humans to date provide strong reassurance about the safety of inclisiran and the potential of cardiovascular RNA-targeted therapies., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer's disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic "readers" that may distort normal gene expression and contribute to chronic disorders., Objective: To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE)., Methods: The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. 464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score≥26 (normal performance), MoCA score 25-22 (mild cognitive impairment), and MoCA score≤21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group., Results: Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of≤21 (p = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%)., Conclusion: In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.

Importance: It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk., Objective: To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk., Design, Setting, and Participants: A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa., Interventions: Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins., Main Outcomes and Measures: The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization., Results: When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%)., Conclusions and Relevance: Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients., Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.

Background and Aim: To estimate the prevalence of cardiovascular (CV) disease and CV risk factors among Polish patients., Methods: A nationwide cross-sectional study, LIPIDOGRAM2015, was carried out in Poland in the 4th quarter of 2015 and 1st and 2nd quarters of 2016; 438 primary care physicians enrolled 13,724 adult patients that sought medical care in primary health care practices., Results: Nearly 19% of men and approximately 12% of women had cardiovascular disease (CVD). Over 60% of the recruited patients had hypertension (HTN), >80% had dyslipidaemia and <15% of patients were diagnosed with diabetes (DM). All of these disorders were more frequent in men. In 80% of patients the waist circumference exceed norm for the European population. Less than half of the patients were current smokers or had smoked in the past. Patients with CVD had significantly higher blood pressure and glucose levels but lower low density lipoprotein-cholesterol level., Conclusions: The prevalence of CVD and CV risk factors among patients in Poland is high. CVD is more common in men than in women. The most common CV risk factors are excess waist circumference, dyslipidaemia and HTN. Family physicians should conduct activities to prevent, diagnose early and treat CVD in the primary health care population., Competing Interests: Declaration of competing interest JJJ has received research grant/support from Valeant, and has served as a consultant or speaker for Valeant, Amgen, Teva, Servier, Boehringer Ingelheim, Celgene, Bioton, Microlife and ALAB Laboratories. TT has served as a consultant or speaker for Boehringer Ingelheim, Novartis, Shire, Biofarm, Eli Lilly. AW has served as a consultant or speaker for Merck, Boehringer Ingelheim, Sanofi Aventis, Bausch Health. ALC reports grants from Amgen, Sanofi, Regeneron personal fees from Merck, Sanofi, Regeneron, AstraZeneca, Amgen, Novartis, outside the submitted work. DPM has given talks and attended conferences sponsored by Amgen, Novonordisk and Libytec. MTM has no direct competing interests in regards to this paper. His dept holds or has held research grants from Pfizer, Amgen, Ipsen, Shire, Teijin & Menarini. He was or has been the principal investigator on trials paid for by: Pfizer, Novartis, Ipsen, Teijin & Menarini. In the last 5 years have been paid consulting or speakers fees by Novartis, Takeda, Shire, &AstraZeneca. ŁS has given talks and attended conferences sponsored by Janssen-Cilag, Pfizer, Krka. SK has served as a speaker for Novartis. MB has received research grant(s)/support from Amgen, Mylan, Sanofi and Valeant, and has served as a consultant for Amgen, Daiichi-Sankyo, Esperion, Freia Pharmaceuticals, Herbapol, Kogen, KRKA, Mylan, Novartis, Novo-Nordisk, Polfarmex, Polpharma, Sanofi-Aventis, Servier, and Zentiva., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The evidence of the causal role of low-density lipoprotein cholesterol in the development of atherosclerotic cardiovascular disease is well-established. The clearly identified common position of the European guidelines proclaims necessity to decrease LDL-C concentrations based on a proper risk stratification. However, current worldwide situation with the lipid management still demonstrates inadequate dyslipidemia control, that is probably related to a healthcare system issues. As the need to standardize and implement approaches following the guidelines into clinical practice remains a challenge, the EAS initiates the Lipid Clinics Network project, aiming to provide a structure to establish uniform EU-wide standards of diagnosis, management and treatment of patients with lipid disorders, based on the ESC/EAS Guidelines on management of dyslipidaemias., Competing Interests: Declaration of competing interest None relevant to the work described in this manuscript., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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.)

Despite consensus that excessive circulating concentrations of apoB-lipoproteins is a key driver for the atherosclerotic process and that treatments that low-density lipoprotein cholesterol lowering by up-regulation of low-density lipoprotein cholesterol receptor expression reduces that risk, divergent viewpoints on interpretation of study data have resulted in substantial differences in European and American lipid guideline recommendations. This article explores those differences and highlights the importance of understanding guideline-based lipid management to improve patient care and reduce the risk of clinical atherosclerotic cardiovascular disease.

Background: Global trends in cardiovascular disease (CVD) exhibit considerable interregional and interethnic differences, which in turn affect long-term CVD risk across diverse populations. An in-depth understanding of the interplay between ethnicity, socioeconomic status, and CVD risk factors and mortality in a contemporaneous population is crucial to informing health policy and resource allocation aimed at mitigating long-term CVD risk. Generating bespoke large-scale and reliable data with sufficient numbers of events is expensive and time-consuming but can be circumvented through utilization and linkage of data routinely collected in electronic health records (EHR)., Objective: We aimed to characterize the burden of CVD risk factors across different ethnicities, age groups, and socioeconomic groups, and study CVD incidence and mortality by EHR linkage in London., Methods: The proposed study will initially be a cross-sectional observational study unfolding into prospective CVD ascertainment through longitudinal follow-up involving linked data. The government-funded National Health System (NHS) Health Check program provides an opportunity for the systematic collation of CVD risk factors on a large scale. NHS Health Check data on approximately 200,000 individuals will be extracted from consenting general practices across London that use the Egton Medical Information Systems (EMIS) EHR software. Data will be analyzed using appropriate statistical techniques to (1) determine the cross-sectional burden of CVD risk factors and their prospective association with CVD outcomes, (2) validate existing prediction tools in diverse populations, and (3) develop bespoke risk prediction tools across diverse ethnic groups., Results: Enrollment began in January 2019 and is ongoing with initial results to be published mid-2021., Conclusions: There is an urgent need for more real-life population health studies based on analyses of routine health data available in EHRs. Findings from our study will help quantify, on a large scale, the contemporaneous burden of CVD risk factors by geography and ethnicity in a large multiethnic urban population. Such detailed understanding (especially interethnic and sociodemographic variations) of the burden of CVD risk and its determinants, including heredity, environment, diet, lifestyle, and socioeconomic factors, in a large population sample, will enable the development of tailored and dynamic (continuously learning from new data) risk prediction tools for diverse ethnic groups, and thereby enable the personalized provision of prevention strategies and care. We anticipate that this systematic approach of linking routinely collected data from EHRs to study CVD can be conducted in other settings as EHRs are being implemented worldwide., International Registered Report Identifier (irrid): PRR1-10.2196/17548., (©Kanika Dharmayat, Maria Woringer, Nikolaos Mastellos, Della Cole, Josip Car, Sumantra Ray, Kamlesh Khunti, Azeem Majeed, Kausik K Ray, Sreenivasa Rao Kondapally Seshasai. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 02.10.2020.)

Aims: Guidelines recommend targeting non-high-density lipoprotein cholesterol to reduce cardiovascular risk. We assessed the impact of baseline triglycerides on non-high-density lipoprotein cholesterol goal attainment in 10 phase 3 trials with alirocumab versus control ( n  = 4983)., Methods: Trials were grouped into four pools based on alirocumab dose (75-150 mg every 2 weeks), control (placebo/ezetimibe) and statin use. Baseline triglyceride quintiles were built within each pool. Non-high-density lipoprotein cholesterol goal attainment (very high risk: <100 mg/dl; moderate/high risk: <130 mg/dl), low-density lipoprotein cholesterol goal attainment (very high risk: <70 mg/dl; moderate/high risk: <100 mg/dl) and changes from baseline in lipid parameters were assessed at Week 24 among baseline triglyceride quintiles., Results: Higher baseline triglycerides were associated with a worse cardiovascular risk profile. Low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol increased with higher triglycerides, but the magnitude in non-high-density lipoprotein cholesterol was three- to four-fold higher compared with the increase in low-density lipoprotein cholesterol. Non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol percentage reductions from baseline with alirocumab were similar regardless of baseline triglycerides. A greater proportion of alirocumab-treated patients attained non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol goals compared with placebo or ezetimibe. Unlike low-density lipoprotein cholesterol goal attainment, non-high-density lipoprotein cholesterol goal attainment significantly declined with increasing baseline triglycerides ( p  < 0.05 for trend tests). A single standard deviation increase in baseline log(triglycerides) was significantly associated with lower odds ratios of attaining non-high-density lipoprotein cholesterol goals in the different pools and treatment (alirocumab/placebo/ezetimibe) groups, unlike low-density lipoprotein cholesterol goal attainment., Conclusion: Individuals with increased triglycerides have higher non-high-density lipoprotein cholesterol levels and lower rates of non-high-density lipoprotein cholesterol goal attainment (unlike low-density lipoprotein cholesterol goal attainment). Alirocumab improves non-high-density lipoprotein cholesterol goal attainment in this population. These results highlight the impact of triglycerides on non-high-density lipoprotein cholesterol and the need for novel therapies targeting triglyceride-related pathways.

Importance: Additional lipid-lowering therapy options are needed for patients who cannot achieve sufficient decreases in low-density lipoprotein cholesterol (LDL-C) levels using statins alone or for those who are statin intolerant., Objective: To conduct a pooled analysis of phase 3 randomized clinical trials of bempedoic acid vs placebo., Design, Setting, and Participants: This analysis pooled data from 4 double-blind, placebo-controlled randomized clinical trials conducted from 2016 to 2018. Patients were enrolled in North America and Europe. Eligibility criteria included hypercholesterolemia while receiving stable lipid-lowering therapy and high cardiovascular risk or hypercholesterolemia and statin intolerance., Interventions: Patients were randomized 2:1 to bempedoic acid, 180 mg (n = 2425), or placebo (n = 1198) once daily for 12 to 52 weeks., Main Outcomes and Measures: Primary efficacy end point was percentage change from baseline in LDL-C level at week 12 in the intention-to-treat population. Patients were parsed into 2 groups according to enrollment criteria: (1) patients with hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) or with heterozygous familial hypercholesterolemia (HeFH) or with both and receiving statins and (2) patients with hypercholesterolemia who were statin intolerant receiving maximally tolerated statins., Results: In this analysis of 3623 patients, the overall mean (SD) patient age was 65.5 (9.2) years (similar in both pools). Among patients with ASCVD or HeFH or both, the mean (SD) baseline LDL-C level was 107.6 (32.7) mg/dL. At week 12, the LDL-C level percentage change from baseline was -16.0% with bempedoic acid vs 1.8% with placebo (difference, -17.8%; 95% CI, -19.5% to -16.0%; P < .001). Patients with statin intolerance had a mean (SD) baseline LDL-C level of 144.4 (38.8) mg/dL. The percentage changes in LDL-C levels at week 12 were -23.0% in the bempedoic acid group and 1.5% in the placebo group (difference, -24.5%; 95% CI, -27.8% to -21.1%; P < .001). The decrease in LDL-C levels with bempedoic acid was sustained during long-term follow-up in both pools (patients with ASCVD or HeFH or both receiving a maximally tolerated statin, difference of -12.7% at week 52; patients with statin intolerance, difference of -22.2% at week 24). Decreases in non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein levels were greater with bempedoic acid vs placebo. Treatment-emergent adverse events associated more frequently with bempedoic acid than with placebo included increased blood uric acid level (2.1% vs 0.5%), gout (1.4% vs 0.4%), decreased glomerular filtration rate (0.7% vs <0.1%), and increased levels of hepatic enzymes (2.8% vs 1.3%)., Conclusions and Relevance: Bempedoic acid added to maximally tolerated statins, including moderate- or high-intensity statins or no background statin, was associated with decreased LDL-C levels vs placebo in patients with hypercholesterolemia with an acceptable safety profile. As a nonstatin adjunct or statin alternative, bempedoic acid has potential for use in a broad spectrum of patients., Trial Registration: ClinicalTrials.gov Identifiers: NCT02666664, NCT02991118, NCT03001076, and NCT02988115.

Background: An ongoing need exists for safe and effective lipid-lowering therapies (LLTs) for patients unable to achieve desired lipid levels with current treatment options., Objective: The objective of this study was to describe the safety profile of bempedoic acid, an oral, first-in-class, adenosine triphosphate (ATP)-citrate lyase inhibitor that significantly reduces low-density lipoprotein cholesterol (LDL-C) levels by 17.4%-28.5% vs placebo., Methods: This was a pooled analysis of four phase 3, randomized (2:1), double-blind, placebo-controlled studies in patients with hypercholesterolemia who required additional LDL-C lowering, despite stable maximally-tolerated LLT. Patients received 180 mg of bempedoic acid (n = 2424) or placebo (n = 1197) once daily for 12 to 52 weeks. Assessments included treatment-emergent adverse events (TEAEs) and clinical laboratory tests., Results: Of 3621 patients (the median drug exposure: 363 days), exposure-adjusted TEAE rates were 87.1/100 and 82.9/100 person-years (PY) for bempedoic acid and placebo, respectively. No single TEAE influenced the difference in rates. TEAEs leading to discontinuation occurred at rates of 13.4/100 and 8.9/100 PY for bempedoic acid vs placebo, with the most common cause being myalgia, which occurred less frequently with bempedoic acid vs placebo (1.5/100 vs 2.0/100 PY). Rates of myalgia and muscle weakness were comparable vs placebo. Bempedoic acid was associated with mild increases in blood urea nitrogen, creatinine, and uric acid and decreases in hemoglobin. These laboratory abnormalities were apparent by week 4, stable over time, and reversible after treatment cessation. Gout incidence was 1.6/100 vs 0.5/100 PY in the bempedoic acid vs placebo groups. New-onset diabetes/hyperglycemia occurred less frequently with bempedoic acid vs placebo (4.7/100 vs 6.4/100 PY). The safety profile was consistent across subgroups., Conclusions: Bempedoic acid is generally safe and well tolerated among patients with hypercholesterolemia who require additional LLT., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Apabetalone is the first selective BET protein inhibitor in the field of cardiovascular diseases (CVD). BET proteins are epigenetic regulators that link upstream epigenetic modifications to downstream gene expression. Inhibition of BET proteins by apabetalone has been shown to modulate reverse cholesterol transport, coagulation, inflammation and vascular calcification. Furthermore, apabetalone reduces circulating markers of CVD risk and plaque vulnerability. Post-hoc pooled analyses suggest a potential reduction in risk of major adverse cardiac events (MACE) in patients with Type 2 diabetes (T2D) and stable CVD. However, the current cardiovascular outcomes trial BET-on-MACE failed to detect the assumed 30% reduction of MACE by apabetalone in patients with T2D after an acute coronary syndrome.

Background With the availability of new lipid-lowering therapy options, there is a need to compare the expected clinical benefit of different treatment strategies in different patient populations and over various time frames. We aimed to develop a time-dependent model from published randomized controlled trials summarizing the relationship between low-density lipoprotein cholesterol lowering and cardiovascular risk reduction and to apply the model to investigate the effect of treatment scenarios over time. Methods and Results A cardiovascular treatment benefit model was specified with parameters as time since treatment initiation, magnitude of low-density lipoprotein cholesterol reduction, and additional patient characteristics. The model was estimated from randomized controlled trial data from 22 trials for statins and nonstatins. In 15 trials, the new time-dependent model had better predictions than cholesterol treatment trialists' estimations for a composite of coronary heart disease death, nonfatal myocardial infarction, and ischemic stroke. In explored scenarios, absolute risk reduction ≥2% with intensive treatment with high-intensity statin, ezetimibe, and high-dose proprotein convertase subtilisin/kexin type 9 inhibitor compared with high- or moderate-intensity statin alone were achieved in higher-risk populations with 2 to 5 years of treatment, and lower-risk populations with 9 to 11 years of treatment. Conclusions The time-dependent model accurately predicted treatment benefit seen from randomized controlled trials with a given lipid-lowering therapy by incorporating patient profile, timing, duration, and treatment type. The model can facilitate decision making and scenario analyses with a given lipid-lowering therapy strategy in various patient populations and time frames by providing an improved assessment of treatment benefit over time.

Purpose of Review: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a new strategy to reduce LDL cholesterol (LDL-C), that is currently pursued by mAbs. A promising novel approach to target PCSK9 is using small interfering RNAs to inhibit hepatic PCSK9 synthesis. The first small interfering RNA developed for this purpose is inclisiran. Here, we review its clinical trial data and potential impact on patient management., Recent Findings: Inclisiran achieves sustained, additional 50% LDL-C reduction in patients receiving background statin therapy. Resulting LDL-C changes can be maintained by an infrequent dosing regimen with twice per year injections, that appear safe and well tolerated. Thus far, inclisiran has been studied in patients with established cardiovascular disease, high-risk primary prevention and in patients with familial hypercholesterolemia., Summary: High and very high-risk individuals may benefit from the additional LDL-C-lowering effect of inclisiran when added to current lipid-lowering therapies. Furthermore, the simple dosing regimen may improve the convenience for users and facilitate patient adherence to therapy. The safety and convenience of inclisiran may offer new opportunities for population health.