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Background and Aims: Utilising real-world data, we quantified the burden of cardiovascular risk factors and long-term residual risk of atherothrombotic events among routine care cohorts with coronary (CAD) or peripheral (PAD) artery disease or ischemic stroke (IS) on guideline-recommended antiplatelet monotherapy (APMT)., Methods: Retrospective cohort study using data (2010-2020) from the United Kingdom Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics, including adults with CAD, PAD or IS who were first prescribed APMT (CAD/IS: aspirin; PAD: clopidogrel). Primary outcomes (recurrent events): major adverse cardiovascular events (MACE) for CAD/PAD/IS cohorts, major adverse limb events (MALE) for PAD., Results: 266,478 CAD, 13,162 PAD, and 14,788 IS patients were included (mean age: 71 years; women 37.7%-47.5 %). Risk factor burden was high and attainment of recommended goals was low. There were 73,691, 3,121 and 7,137 MACE among CAD, PAD and IS patients, respectively (median follow-up: 89.9, 42.4 and 75.9 months, respectively), and 4,767 MALE among PAD patients. MACE incidence rate per 1000 person-years was higher in IS (268.7; 95%CI 265.3-272.0) than CAD (92.9; 95%CI 92.5-93.4) or PAD cohorts (97.2; 95%CI 94.6-99.8). MALE incidence rate was 195.9 (95%CI 192.2-199.6) per 1000 person-years. IS patients presented a lower rate of hospitalisations and longer time-to-first hospitalisation, but once hospitalised, they had a longer length-of-stay. PAD patients had the highest hospitalisation rate., Conclusions: Among a contemporary cohort with cardiovascular disease on APMT, long-term residual atherothrombotic risk remains high despite being on APMT. Greater attention to risk factor control and use of appropriate evidence-based therapy is required to reduce residual risk among this very high-risk population., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AJVV: personal fees for consulting from Bayer, during the conduct of the study; current or past participation in research grants to Imperial College London from Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron, outside the submitted work; and personal fees for consulting from Regeneron and honoraria for lectures from Amgen, Mylan, Akcea, and Ferrer, outside the submitted work. KID: personal fees for consulting from Bayer, during the conduct of the study; grants from Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron, outside the submitted study; and personal fees from Regeneron, outside the submitted work. NN,CCand STF:Bayer plc employees. MJF,ETand CL: none to report. KKR: personal fees for consulting from Bayer, during the conduct of the study; grants and personal fees from Aegerion, Amgen, Daiichi Sankyo, MSD, Pfizer, and Sanofi/Regeneron, and personal fees from Abbvie, Akcea, Algorithm, Astra Zeneca, Bayer, Boehringer Ingelheim, Cerenis Therapeutcics, Cipla, Dr Reddy's Laboratories, Esperion, Kowa, Lilly, Novartis, Silence Therapeutics, Takeda, and Zuellig Pharma, outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Inclisiran, an siRNA therapy, consistently reduces low-density lipoprotein cholesterol (LDL-C) with twice-yearly dosing. Potential cardiovascular benefits of implementing inclisiran at a population level, added to statins, were evaluated through simulation., Methods: For each participant in the ORION-10 and ORION-11 trials comparing inclisiran with placebo, baseline 10-year cardiovascular risk was estimated using the SMART equation. The time-adjusted LDL-C difference from baseline observed 90-540 days after baseline was assumed to persist and used to estimate potential reduction in 10-year cardiovascular risk. Impact on 500,000 ORION-like individuals was simulated with Monte-Carlo., Results: Mean baseline LDL-C and predicted 10-year major vascular risk among patients randomized to inclisiran (n = 1288) versus placebo (n = 1264) were 2.66 mmol/L versus 2.60 mmol/L and 24.9% versus 24.6%, respectively. Placebo-corrected time-adjusted absolute reduction in LDL-C with inclisiran was -1.32 mmol/L (95% CI -1.37 to -1.26; p < 0.001), which predicted a 10-year cardiovascular risk of 18.1% with inclisiran versus 24.7% with placebo (absolute difference [95% CI], -6.99% [-7.33 to -6.66]; p < 0.001) NNT 15. Extrapolating to 500,000 inclisiran-treated individuals, the model predicted large population shifts towards lower quintiles of risk with fewer remaining in high-risk categories; 3350 to 471 (≥80% risk), 11,793 to 3332 (60-<80% risk), 52,142 to 22,665 (40-<60% risk), 197,752 to 141,014 (20-<40% risk), and more moving into the lowest risk category (<20%) from 234,963 to 332,518., Conclusions: Meaningful gains in population health might be achieved over 10 years by implementing at-scale approaches capable of providing substantial and sustained reductions in LDL-C beyond those achievable with statins., Competing Interests: Declaration of competing interest Kausik K. Ray reports unrestricted research grants to Imperial College London from Amgen, Daiichi Sankyo, Regeneron, Sanofi, and SC, EC or advisory board honoraria from Novartis, Esperion, Daiichi Sankyo, Abbott, Bayer, Eli Lilly, Silence Therapeutics, CSL Behring, New Amsterdam Pharma, Sanofi, Amgen, Novo Nordisk, BI, Scribe, Vaxxinity, CRISPR, AZ, Kowa, and Cargene, honoraria for CME and non-CME from Novartis, Novo Nordisk, BI, AZ, Viatris, Daiichi Sankyo, Amgen, and Sanofi, and stock options from PEMI-31; Laura H. Gunn has no conflict of interests to declare; Lorena Garcia Conde is an employee of Novartis; Frederick J. Raal reports receiving advisory board fees and lecture fees from Amgen, Sanofi-Aventis, Regeneron Pharmaceuticals, The Medicines Company, and Novartis; R. Scott Wright reports receiving advisory board fees from Boehringer Ingelheim and past fees for consulting on lipid issues with The Medicines Company; Nathalie H. Gosselin is an employee of Certara, consulting division; Lawrence A. Leiter reports grant support paid to his institution, advisory board fees, and fees for CME from Amgen and Novartis, fees for serving on a steering committee, and advisory board fees from Esperion, grant support paid to his institution, and fees for serving on a steering committee from Kowa, The Medicines Company, and Novartis; advisory board fees and fees for CME from Amarin, Astra Zeneca, HLS, Merck, Pfizer, and Sanofi; Wolfgang Koenig reports receiving consulting fees and lecture fees from AstraZeneca, Novartis, and Amgen, consulting fees from Pfizer, The Medicines Company, Novartis, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, Esperion, Genentech, OMEICOS, Novo Nordisk, LIB Therapeutics, New Amsterdam Pharma, TenSixteen Bio, and Daiichi Sankyo, lecture fees from Berlin-Chemie, Bristol-Myers Squibb, and Sanofi, and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr Beckmann Pharma; Gregory G. Schwartz reports receiving research support, paid to his institution from AstraZeneca, Resverlogix, Sanofi, Silence Therapeutics, and The Medicines Company, and a patent (62/806313) on a method for reducing cardiovascular risk assigned in full to the University of Colorado; Ulf Landmesser reports receiving lecture fees and advisory fees from AstraZeneca, Amgen, Sanofi, Berlin Chemie, and Abbott, advisory fees from The Medicines Company, and grant support, lecture fees, and advisory fees from Bayer and Novartis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Among patients with prior myocardial infarction (MI), the risk of future ischaemic cardiovascular events is increased, and intensive lipid-lowering therapy (LLT) is indicated to achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals. Here, the efficacy and safety of inclisiran, a small interfering ribonucleic acid, were evaluated in patients with or without prior MI from the pooled ORION-10 and ORION-11 Phase 3 trials., Methods: Patients (n = 2636) were randomised 1:1 to receive 284 mg inclisiran (300 mg inclisiran sodium) or placebo on Day 1, Day 90, and 6-monthly thereafter over 18 months, along with background oral LLT, including statins. Of these, 1643 (62.3%) patients had an MI prior to randomisation, stratified as recent (>3 months to <1 year) or remote (≥1 year), and 993 (37.7%) patients were without a prior MI. The percentage change in LDL-C from baseline and safety were assessed., Results: Baseline characteristics were well balanced across the treatment arms and MI strata. The mean (95% confidence interval) placebo-corrected LDL-C reductions from baseline to Day 510 with inclisiran were 52.6% (40.1, 65.1), 50.4% (47.0, 53.8), and 51.6% (47.4, 55.9) for recent, remote, and no prior MI, respectively. Corresponding time-adjusted LDL-C reductions were 50.0% (41.4, 58.7), 52.2% (49.8, 54.7), and 51.2% (48.1, 54.2). In each MI stratum, treatment-emergent adverse events (TEAEs) at the injection site (all mild to moderate) were observed more in inclisiran-treated patients than placebo, without an excess of other TEAEs., Conclusions: Inclisiran provided effective and consistent LDL-C lowering, irrespective of MI status., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ulf Landmesser reports receiving lecture fees and advisory fees from AstraZeneca, Boehringer, Sanofi, Berlin-Chemie, and Abbott; advisory fees from The Medicines Company; and grant support, lecture fees, and advisory fees from Amgen, Bayer and Novartis. Wolfgang Koenig reports receiving consulting fees and lecture fees from AstraZeneca, Novartis, and Amgen; consulting fees from Pfizer, The Medicines Company and Novartis, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, Esperion, Genentech, OMEICOS, Novo Nordisk, LIB Therapeutics, Daiichi Sankyo; New Amsterdam Pharma and TenSixteen Bio; lecture fees from Berlin-Chemie, Bristol-Myers Squibb, and Sanofi; and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr Beckmann Pharma. Lawrence A Leiter reports receiving grant support paid to his institution and advisory board fees and fees for CME from Amgen and Novartis; fees for serving on a steering committee and advisory board fees from Esperion; grant support paid to his institution and fees for serving on a steering committee from Kowa and The Medicines Company and Novartis; and advisory board fees and fees for CME from Amarin, AstraZeneca, HLS, Merck, Pfizer, and Sanofi. Frederick J Raal reports receiving advisory board fees and lecture fees from Amgen, Sanofi-Aventis, Regeneron Pharmaceuticals, Novartis, and LIB Therapeutics. Kausik K Ray reports receiving support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre. His institution (Imperial College London) receives support from the NIHR Applied Research Collaboration Northwest London. Prof. Ray also reports receiving lecture fees from Aegerion Pharmaceuticals, Kowa, Cipla, Algorithm, and Zuelling Pharma; grant support paid to his institution, lecture fees, and advisory board fees from Amgen, Regeneron Pharmaceuticals/Sanofi, and Pfizer; lecture fees and fees for serving on steering committees for trials from AstraZeneca and Eli Lilly; fees for serving on steering committees for trials from Cerenis Therapeutics, The Medicines Company, and Esperion; advisory board fees from Akcea Therapeutics, Novartis, Silence Therapeutics, Bayer, and Daiichi Sankyo; lecture fees and advisory board fees from Takeda, Boehringer Ingelheim, and Dr Reddy's Laboratories; grant support and advisory board fees from Merck Sharp & Dohme; fees for serving on a clinical events adjudication committee from AbbVie; and fees for serving as a principal investigator for a trial from Resverlogix. R Scott Wright reports receiving advisory board fees from Boehringer Ingelheim and fees for consulting on lipid issues with The Medicines Company. Jackie Han reports being employed by Novartis at the time of publication. Lorena Garcia Conde reports being employed by Novartis at the time of publication. Gregory G Schwartz reports receiving research support paid to his institution from AstraZeneca, Resverlogix, Sanofi, Silence Therapeutics, and The Medicines Company; and a patent (62/806313) on a method for reducing cardiovascular risk assigned in full to the University of Colorado., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Dyslipidemia refers to unhealthy changes in blood lipid composition and is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Usually, low-density lipoprotein-cholesterol (LDL-C) is the primary goal for dyslipidemia management. However, non-high-density lipoprotein cholesterol (non-HDL-C) has gained attention as an alternative, reliable goal. It encompasses all plasma lipoproteins like LDL, triglyceride-rich lipoproteins (TRL), TRL-remnants, and lipoprotein a [Lp(a)] except high-density lipoproteins (HDL). In addition to LDL-C, several other constituents of non-HDL-C have been reported to be atherogenic, aiding the pathophysiology of atherosclerosis. They are acknowledged as contributors to residual ASCVD risk that exists in patients on statin therapy with controlled LDL-C levels. Therefore, non-HDL-C is now considered an independent risk factor or predictor for CVD. The popularity of non-HDL-C is attributed to its ease of estimation and non-dependency on fasting status. It is also better at predicting ASCVD risk in patients on statin therapy, and/or in those with obesity, diabetes, and metabolic disorders. In addition, large follow-up studies have reported that individuals with higher baseline non-HDL-C at a younger age (<45 years) were more prone to adverse CVD events at an older age, suggesting a predictive ability of non-HDL-C over the long term. Consequently, non-HDL-C is recommended as a secondary goal for dyslipidemia management by most international guidelines. Intriguingly, geographical patterns in recent epidemiological studies showed remarkably high non-HDL-C attributable mortality in high-risk countries. This review highlights the independent role of non-HDL-C in ASCVD pathogenesis and prognosis. In addition, the need for a country-specific approach to dyslipidemia management at the community/population level is discussed. Overall, non-HDL-C can become a co-primary or primary goal in dyslipidemia management., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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

Background and Aims: High-sensitivity C-reactive protein (hsCRP), a marker for atherosclerotic cardiovascular disease risk, is reduced by bempedoic acid. We assessed the relationship between changes in low-density lipoprotein cholesterol (LDL-C) and hsCRP in relation to baseline statin use., Methods: Pooled data from four phase 3 trials (patients on maximally tolerated statins [Pool 1] and patients receiving no or low-dose statins [Pool 2]) were used to determine the proportion of patients with baseline hsCRP ≥2 mg/L who achieved hsCRP <2 mg/L at week 12. The percentage of patients who achieved hsCRP <2 mg/L and guideline-recommended LDL-C (Pool 1, <70 mg/dL; Pool 2, <100 mg/dL) was determined for patients on statins in Pool 1 and those not on statins in Pool 2, as was the correlation between percent changes in hsCRP and LDL-C., Results: Overall, 38.7% in Pool 1 and 40.7% in Pool 2 with baseline hsCRP ≥2 mg/L achieved hsCRP <2 mg/L with bempedoic acid, with little effect from background statin. Among patients taking a statin in Pool 1 or not taking a statin in Pool 2, 68.6% and 62.4% achieved hsCRP <2 mg/L. Both hsCRP <2 mg/L and United States guideline-recommended LDL-C were achieved more often with bempedoic acid vs. placebo (20.8% vs. 4.3%, respectively, in Pool 1 and 32.0% vs. 5.3%, in Pool 2). Changes in hsCRP and LDL-C were only weakly correlated (Pool 1, r = 0.112; Pool 2, r = 0.173)., Conclusions: Bempedoic acid significantly reduced hsCRP irrespective of background statin therapy; the effect was largely independent of LDL-C lowering., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Stroes has received research grant(s)/support to his institution from Amgen, Sanofi, Resverlogix, and Athera and has received lecturing/advisory board fees from Amgen, Sanofi, Akcea/IONIS, Esperion Therapeutics, Inc., and Novartis. Dr. Bays’s research site has received research grants from 89Bio, Acasti, Akcea, Allergan, Alon Medtech/Epitomee, Amarin, Amgen, AstraZeneca, Axsome, Boehringer Ingelheim, Civi, Eli Lilly, Esperion Therapeutics, Inc., Evidera, Gan and Lee, Home Access, Janssen, Johnson and Johnson, Lexicon, Matinas, Merck, Metavant, Novartis, NovoNordisk, Pfizer, Regeneron, Sanofi, Selecta, TIMI, and Urovant. He has served as a consultant/advisor for 89Bio, Amarin, Esperion Therapeutics, Inc., Matinas, and Gelesis and as a speaker for Esperion. Dr. Banach has received research grant(s)/support from Amgen, Sanofi, Valeant, and Viatris, has served as a consultant for or received honoraria from Abbott Medical, Abbott Vascular, Amgen, Esperion Therapeutics, Inc., Freia Pharmaceuticals, Herbapol, Kogen, KRKA, Mylan/Viatris, Novartis, Novo Nordisk, Polpharma, Polfarmex, Regeneron, Sanofi-Aventis, Servier, Valeant, Daichii Sankyo, Teva, and Zentiva, and is CMO at Nomi Biotech Corporation Ltd. Dr. Catapano has received research grant(s)/support from Sanofi, Sanofi Regeneron, Amgen, Amarin, Mylan, and Menarini (all paid to the institution, not to the individual), and has served as a consultant for or received honoraria from Akcea, Amarin, Amgen, Sanofi, Esperion Therapeutics, Inc., Kowa, Novartis, Ionis Pharmaceuticals, Medco, Mylan, Menarini, MSD, Recordati, Regeneron, and Daiichi Sankyo. Dr. Duell has received institutional research grant(s)/support from Travere/Retrophin and Regenxbio, and served as a consultant for Akcea/Ionis, Kaneka, Novo Nordisk, Retrophin, and Regeneron. Dr. Laufs has served as a consultant for Amgen, Daiichi Sankyo, Esperion Therapeutics, Inc., and Sanofi. Dr. Mancini received research grant(s)/support from Merck, AstraZeneca, Amgen, Sanofi, Novo Nordisk, Boehringer Ingelheim, Lilly, Pfizer, HLS Therapeutics, and Bayer and has served as a consultant for these companies as well as for Esperion Therapeutics, Inc., Novartis, and Servier. Dr. Ray has received research grant(s)/support from Amgen, Daiichi Sankyo, MSD, Pfizer, Regeneron, and Sanofi (all paid to the institution, not to the individual), and served as a consultant for or received honoraria from AbbVie, Akcea, Algorithm, Amgen, AstraZeneca, Boehringer Ingelheim, Cerenis, Cipla, Daiichi Sankyo, Dr. Reddy’s Laboratories, Lilly, Esperion Therapeutics, Inc., Kowa, Medco, MSD, Novo Nordisk, Pfizer, Regeneron, Resverlogix, Sanofi, Takeda, and Zuellig Pharma. Dr. Gotto is an Esperion Therapeutics, Inc. board member and Akcea DSMB chair. He has also served as a consultant for Kowa. Dr. Sasiela is a former employee of Esperion Therapeutics, Inc., and may hold stock and/or stock options. He is currently the principal of Cardiometabolic Consulting, LLC. Dr. Zhang was an employee of Esperion Therapeutics, Inc. when the analysis was carried out and may hold stock and/or stock options., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The European Atherosclerosis Society (EAS) Lipid Clinics Network promoted a survey in order to identify and understand how and when lipoprotein(a) [Lp(a)] is tested and clinically evaluated in lipid clinics throughout Europe, and the challenges that may prevent evaluation from being carried out., Methods: This survey was divided into three areas of inquiry: background and clinical setting information of clinicians, questions for doctors who claimed not to measure Lp(a), in order to understand what were the reasons for not ordering the test, and questions for doctors who measure Lp(a), to investigate the use of this value in the management of patients., Results: A total of 151 centres clinicians filled in the survey, out of 226 invited. The proportion of clinicians who declare to routinely measure Lp(a) in clinical practice was 75.5%. The most common reasons for not ordering the Lp(a) test were the lack of reimbursement or of treatment options, the non-availability of Lp(a) test, and the high cost of performing the laboratory test. The availability of therapies targeting this lipoprotein would result in a greater propensity of clinicians to start testing Lp(a). Among those who declared to routinely measure Lp(a), the Lp(a) measurement is mostly requested to further stratify patients' cardiovascular risk, and half of them recognized 50 mg/dL (approx. 110 nmol/L) as the threshold for increased cardiovascular risk due., Conclusions: These results warrant for a great deal of effort from scientific societies to address the barriers that limit the routine use of the measurement of Lp(a) concentration and to recognise the importance of Lp(a) as a risk factor., Competing Interests: Declaration of competing interest All authors declare no support from any organization for the submitted work; no other relationships or activities that could appear to have influenced the submitted work. E.O., M.G., and M.C. report no disclosures. A.L.C. received research funding and/or honoraria for advisory boards, consultancy or speaker bureau from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Mediolanum, Merck or MSD, Pfizer, Recordati, Rottapharm, Sanofi-Regeneron, Sigma-Tau. L.T. received research funding and/or honoraria for advisory boards, consultancy or speaker bureau from Abbott, Astra Zeneca, Novartis, Sanofi, MSD, Novo Nordisk, Amgen, Bayer, Daiichi Sankyo, Janssen, Pfizer, Recordati. M.B. speakers bureau: Amgen, Daichii-Sankyo, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo-Nordisk, Pfizer, Sanofi-Aventis, Teva, Zentiva; consultant to Amgen, Daichii Sankyo, Esperion, Freia Pharmaceuticals, NewAmsterdam, Novartis, Novo-Nordisk, Polfarmex, Sanofi-Aventis; Grants from Amgen, Daichii-Sankyo, Mylan/Viatris, Sanofi and Valeant; CMDO at Longevity Group (Luxemburg). K.K.R. received research funding and/or honoraria for advisory boards, consultancy or speaker bureau from Amgen, Daiichi Sankyo, Regeneron, Sanofi, Novartis, Esperion, Abbott, Bayer, Eli Lilly, Silence Therapeutics, CSL Behring, New Amsterdam Pharma, Novo Nordisk, BI, Scribe, Vaxxinity, CRISPR, AZ, Kowa, Cargene and Viatris., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Aims: Variability in low-density lipoprotein-cholesterol (LDL-C) level control at a population level is associated with poor cardiovascular outcomes. Limited data exist on LDL-C level variability or long-term persistence with the monoclonal antibody evolocumab in routine clinical practice. Using data from the HEYMANS registry, this analysis aimed to assess evolocumab persistence and discontinuation over 30 months of evolocumab treatment and to evaluate at a population level the variability in LDL-C level reductions during the study period., Methods: HEYMANS was a prospective registry of adults initiating evolocumab in routine clinical practice in 12 European countries. Data were collected for up to and including 6 months before evolocumab initiation and up to 30 months after. Evolocumab discontinuation was analysed for two time periods: 0-12 months and 12-30 months., Results: In total, 1951 patients were included in the study. The median reduction in LDL-C levels was 58% within 3 months after evolocumab initiation; this reduction was maintained over 30 months. More than 90% of patients continued receiving evolocumab at 12 months and 30 months of follow-up. Of patients with an LDL-C level measurement during follow-up, approximately 85% achieved a ≥30% reduction from baseline at each follow-up visit and approximately 60% achieved a ≥50% reduction., Conclusions: Evolocumab therapy was associated with sustained LDL-C level reductions up to 30 months, and persistence with evolocumab remained high, both at 12 and 30 months. Expanding the use of monoclonal antibodies such as evolocumab could provide improvements in LDL-C level control at a population level in European clinical practice., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: K.K.R. reports grants/personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cargene, Daiichi Sankyo, Esperion, Kowa, Lilly, New Amsterdam Pharma, Novartis, Pfizer, Sanofi-Regeneron, Silence Therapeutics and Scribe Therapeutics. E.B. reports consulting fees from Aegerion, AKCEA, Amarin, Amgen, Genfit, Ionis-pharmaceuticals, Lilly, MSD, Mylan, Novartis, Regeneron, Sanofi and Servier. P.P.F. reports consulting and speakers fees from Amgen. C.E. reports grants and personal fees from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk and Sanofi. A.V. reports grants from Amgen, Novartis and Sanofi-Regeneron; and personal fees from Aegerion, Akcea, Amgen, Amryt, Daiichi Sankyo, Novartis and Sanofi-Regeneron. I.B. is an employee of Amgen Ltd and a stockholder of Amgen. N.D. is an employee of Amgen Inc and a stockholder of Amgen. M.S. is an employee of Amgen (Europe) GmbH and a stockholder of Amgen., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The SAFEHEART tool has shown good discrimination in predicting cardiovascular events in a bespoke genotyped cohort with familial hypercholesterolaemia (FH). We assessed whether the tool could aid clinical decision making in an English routine care cohort with FH., Methods: A historical (2000-2017) open cohort of 3643 participants aged 18-79 years and ≥6-months since FH diagnosis was derived from the Clinical Practice Research Datalink. Individual 10-year cardiovascular risks were predicted using the SAFEHEART model, with multiple imputation used to manage missing data. Outcomes were the first occurrence of myocardial infarction, coronary revascularisation, ischaemic stroke, carotid revascularisation, peripheral arterial revascularisation, non-traumatic lower limb amputation, or cardiovascular death. Model performance was assessed using standard measures of calibration and discrimination, and decision curve analysis., Results: 147 outcome events were observed over a median 3.73 (IQR 1.59-6.48) years follow-up. While the model had some discriminatory value (Harrell's c-statistic 0.67 (95% CI 0.61-0.72)), observed outcome risks departed substantially from predicted risks. Calibration slopes for men and women by age decile were 10.09 (95% CI 7.40-12.77) and 2.85 (1.25-4.45), respectively. Recalibration-in-the-large led to closer alignment of observed and predicted risks (recalibration slopes 3.48 (2.55-4.41) and 1.14 (0.50-1.79), respectively). Decision curve analysis suggested the recalibrated model had net benefit at predicted risks of 10-30%., Conclusions: The original SAFEHEART model has limited generalisability to the routinely identifiable English primary care FH population. With recalibration it appears to have moderate utility at 10-30% predicted risk. It may have greater validity in more bespoke genetically defined FH populations., Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kausik Ray has acted as a consultant for Amgen, Sanofi, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Kowa, Silence Therapeutics, New Amsterdam, Esperion, Daiichi Sankyo, Bayer, Abbott and Resverlogix; and as a speaker for Novartis, Amgen, Viatris, Pfizer, AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Sanofi. He has received research grants from Amgen, Sanofi, Daiichi Sankyo, Regeneron, and Pfizer through his institution. No conflicts of interest are reported by the other team members., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Disorders of plasma lipids remain key risk factors for the development of atherosclerotic cardiovascular disease (ASCVD) in the Middle East and are estimated to increase more dramatically in the next decade than in any other global region except Africa. This statement is an update to the 2016 consensus clinical recommendations for the management of plasma lipid disorders in the Middle East, following the evaluation of newer cholesterol-lowering agents in randomised controlled cardiovascular outcome trials, as well as the publication of revised international guidelines., Methods: A multidisciplinary panel of regional experts was convened to update the consensus clinical recommendations for the management of plasma lipids in the Middle East. The recommendations constructed in 2016 were reviewed against emerging research since publication., Results: Newly developed Middle East ASCVD risk categories were established using the multiple risk group categories from the recently updated international guidelines and the epidemiological evidence from the Gulf Region. These consensus recommendations support a more intensive reduction of LDL-C across cardiovascular risk categories. Alongside low-density lipoprotein cholesterol, we recommend non-high-density lipoprotein cholesterol as a primary treatment target. Lifestyle modifications remain the first-line treatment recommendation for all patients. The first-line pharmacological treatment in patients with dyslipidaemia is statin therapy, with a number of second-line agents available. The selection of a second lipid-lowering agent for combination therapy with statin should be based on the lipid-lowering target of the patient. Guidance is also provided on the management of underlying conditions and special populations; of particular pertinence in the region are familial hypercholesterolaemia, diabetes and metabolic dyslipidaemia. New therapies have emerged from research that found positive outcomes in reducing low-density lipoprotein cholesterol levels. The initial results of these newly researched drugs strongly indicate their inclusion as future therapies in dyslipidaemia management in the Middle East., Conclusions: These updated consensus clinical recommendations provide practicing clinicians with comprehensive, region-specific guidance to improve the detection and management of plasma lipid disorders in patients in the Middle East., (Copyright © 2021. Published by Elsevier B.V.)

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 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 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 and Aims: In patients with cardiovascular disease, considerable residual risk remains despite evidence-based secondary prevention measures. Alkaline phosphatase (ALP) has been suggested as a modifiable cardiovascular risk factor. We sought to determine whether cardiovascular risk reduction by the bromodomain and extra-terminal (BET) protein inhibitor apabetalone is associated with the concomitant lowering of serum ALP., Methods: In a post-hoc analysis of 795 patients with established coronary heart disease and statin treatment, who participated in phase 2 placebo-controlled trials of apabetalone, we determined the effect of assigned treatment for up to 24 weeks on the incidence of major adverse cardiovascular events (MACE) and serum ALP., Results: Baseline ALP (median 72 U/L) predicted MACE (death, non-fatal myocardial infarction, coronary revascularization, or hospitalization for cardiovascular causes), independent of high-sensitivity C-reactive protein (hsCRP), sex, age, race, study, cardiovascular risk factors, chronic kidney disease (CKD), liver function markers and treatment allocation (hazard ratio [HR] per standard deviation [SD] 1.6, 95% CI 1.19-2.16, p = 0.002). Mean placebo-corrected decreases in ALP from baseline were 9.2% (p < 0.001) after 12-14 weeks and 7.7% (p < 0.001) after 24-26 weeks of apabetalone treatment. In the apabetalone group, a 1-SD reduction in ALP was associated with a HR for MACE of 0.64 (95% CI 0.46-0.90, p = 0.009)., Conclusions: Serum ALP predicts residual cardiovascular risk, independent of hsCRP, established cardiovascular risk factors and CKD, in patients with cardiovascular disease on statin treatment. Apabetalone lowers serum ALP, which was associated with a lower risk of cardiovascular events. Whether the beneficial cardiovascular effects of apabetalone are causally related to ALP reduction remains undetermined., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Guidelines recommend high-intensity statins for patients with atherosclerotic cardiovascular disease (ASCVD). Subgroups with comorbidities that increase cardiovascular risk, such as diabetes mellitus (DM), chronic kidney disease (CKD) or polyvascular disease (PoVD), may derive greater absolute benefit from addition of non-statin therapies. We assessed the relationship between lower low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) risk reduction during alirocumab phase III ODYSSEY trials among these subgroups., Methods: Patient data were pooled from nine trials comparing alirocumab with control (placebo/ezetimibe), predominantly on background maximally tolerated statin. Patients with baseline ASCVD were stratified into subgroups with DM, CKD or PoVD, or without comorbidities, and between-group relative and absolute benefits were compared., Results: Among 3505 patients with ASCVD, 1573 had no comorbidities, 981 had DM, 660 had CKD and 943 had PoVD, with overlap between comorbidities; mean baseline LDL-C levels were 119 (ASCVD overall), 123, 117, 114 and 113 mg/dL, respectively. Overall, each 39 mg/dL lower on-study LDL-C was associated with a 25% lower MACE risk, hazard ratio 0.75 (95% confidence interval, 0.62-0.90, p = 0.0023), with a similar lower risk observed in each very high-risk subgroup (DM, CKD or PoVD; 30-35%) but not in the subgroup without these comorbidities (9%). Absolute benefits were greater for very high-risk subgroups; lowering LDL-C from 120 to 40 mg/dL would result in 2.76-4.35 fewer MACE/100 patient-years versus 0.3 for no comorbidities., Conclusions: Among patients with ASCVD and mean baseline LDL-C >100 mg/dL, patients with DM, CKD or PoVD appeared to derive greater absolute cardiovascular benefits from further LDL-C reduction than those without., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Elevated lipoprotein(a) [Lp(a)] levels are considered a causal factor for cardiovascular disease. In phase 3 ODYSSEY trials, alirocumab reduced levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a), with concomitant reductions in the risk of major adverse cardiovascular events (MACE). We assessed whether lower on-study and greater percentage reductions in Lp(a) are associated with a lower risk of MACE., Methods: Post-hoc analysis of data pooled from 10 phase 3 ODYSSEY trials comparing alirocumab with control (placebo or ezetimibe) in patients (n = 4983) with cardiovascular disease and/or risk factors, and hypercholesterolemia despite statin/other lipid-lowering therapies., Results: Median (Q1, Q3) baseline Lp(a) levels were 23.5 (8.0, 67.0) mg/dL. Median Lp(a) changes from baseline with alirocumab were -25.6% vs. -2.5% with placebo (absolute reductions 6.8 vs. 0.5 mg/dL) in placebo-controlled trials, and -21.4% vs. 0.0% with ezetimibe (4.5 vs. 0.0 mg/dL) in ezetimibe-controlled trials. During follow-up (6699 patient-years), 104 patients experienced MACE. A 12% relative risk reduction in MACE per 25% reduction in Lp(a) (p=0.0254) was no longer significant after adjustment for LDL-C changes: hazard ratio per 25% reduction: 0.89 (95% confidence interval, 0.79-1.01; p=0.0780). In subgroup analysis, the association between Lp(a) reduction and MACE remained significant in a fully adjusted model among participants with baseline Lp(a) ≥50 mg/dL (p-interaction vs. Lp(a) < 50 mg/dL: 0.0549)., Conclusions: In this population, Lp(a) reductions were not significantly associated with MACE independently of LDL-C reductions. Reducing the risk of MACE by targeting Lp(a) may require greater reductions in Lp(a) with more potent therapies and/or higher initial Lp(a) levels., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Patients with familial hypercholesterolaemia (FH) may require proprotein convertase subtilisin/kexin-type 9 (PCSK9) mAb as add-on therapy to achieve LDL-cholesterol (LDL-C) goals. However, the current cost of these therapies means that choosing suitable patients is based on consensus or clinical judgement rather than a quantitative risk assessment. We used the SAFEHEART Risk Equation (RE) to estimate the number needed to treat (NNT) at different risk thresholds and baseline LDL-C to identify those FH patients more likely to derive the greatest benefit from PCSK9 mAb., Methods: Five-year event rates were calculated using the SAFEHEART-RE for every patient, overall and across LDL-C strata. A 60% reduction of LDL-C after theoretical treatment with PCSK9 mAb was assumed. Individual absolute risk simulating the effects of PCSK9 inhibition was calculated using the SAFEHEART-RE and, in a similar way, by using the Cholesterol Treatment Trialists' (CTT) Collaboration criteria. Absolute risk reduction and NNTs were calculated., Results: Of the total SAFEHEART population, 2,153 were FH cases aged 18 years or older, on maximum tolerated lipid lowering treatment. NNTs were dependent of both baseline predicted risk and baseline LDL-C level ranging from 44 to 17 for those with 5-year risk of ≥1 to ≥5. The smallest NNT (12) was observed among those with 5-year risk of ≥5% and LDL-C ≥160 mg/dl. Using the CTT criteria produced similar results., Conclusions: The SAFEHEART-RE may provide a useful quantitative tool for rationalising the selection of FH patients who might derive greater absolute benefits from PCSK9 mAb., (Copyright © 2019. Published by Elsevier B.V.)

Familial hypercholesterolaemia (FH) is a genetic disorder affecting the metabolism of low-density lipoprotein (LDL) particles, leading to high LDL-cholesterol levels maintained over time and higher risk of cardiovascular disease (CVD) early in life. Contemporary studies have challenged prior estimations of FH prevalence and suggest this condition to be more frequent than previously considered, with an overall prevalence rate of 1:200-300 individuals in the general population (1:160,000-300,000 for homozygous FH). However, prevalence of FH varies around the world. In part this is due to an artefact of approaches of detection and methods used to diagnose FH (e.g. lack of gold standard for diagnosis of FH, different criteria applied, availability of genetic testing). But also due to intrinsic characteristic of different populations, e.g. higher presence of founder effects or rates of consanguinity. Additionally, results from many regions are lacking and it is estimated that only a small percentage of subjects with FH would have been diagnosed overall. FH entails a significantly higher risk of CVD, reported to be higher than that estimated by conventional risk assessment tools for the general population. This risk is mainly driven by coronary heart disease. Despite this evidence, low rates of patients meet therapeutic targets for cardiovascular prevention, and implementation of therapy (high intensity statins, combination therapy) is needed. The introduction of novel lipid-lowering therapies may improve this situation. In the present review, we discuss the epidemiology of FH overall, with special attention to different aspects related to prevalence, cardiovascular risk and prognosis, and treatment of FH., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries., Methods: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management., Results: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ∼2/3 countries. Lipoprotein-apheresis is offered in ∼60% countries, although access is limited., Conclusions: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Familial hypercholesterolaemia (FH) is the commonest monogenic disorder that accelerates atherosclerotic cardiovascular disease. We compared and contrasted the characteristics of patients from three specialist centres in the southern hemisphere., Methods: Adult index-cases with molecularly diagnosed heterozygous FH attending specialist lipid centres in Cape Town, Perth and São Paulo were studied. Myocardial infarction, revascularisation, hypertension, diabetes, smoking and lipid-lowering treatment were recorded at the time of diagnosis and compared across the three centres., Results: The spectrum of genetic variants causative of FH was significantly different in patients attending the centres in South Africa compared with Australia and Brazil. Hypertension and diabetes were more prevalent in Brazilian and Australian patients, than in South African patients, but the frequency of smoking was significantly greater in South Africa than the other two centres (p<0.01). Age, male sex and smoking were significant independent predictors of coronary artery disease (CAD) in all three countries (p<0.05)., Conclusions: Patients with FH in three specialist centres in the southern hemisphere exhibit a high prevalence of non-cholesterol cardiovascular disease risk factors. Older age, male sex and smoking were more common among subjects with CAD. In all three countries, there should be vigorous programmes for the control of risk factors beyond good control of hypercholesterolaemia among patients with FH. Promotion of a healthy lifestyle, especially anti-smoking advice, is of paramount importance., (Copyright © 2018. Published by Elsevier B.V.)

Background and Aims: Familial hypercholesterolaemia (FH) is widely underdiagnosed. Cascade testing (CT) of relatives has been shown to be feasible, acceptable and cost-effective in the UK, but requires a supply of index cases. Feasibility of universal screening (US) at age 1-2 years was recently demonstrated. We examined whether this would be a cost-effective adjunct to CT in the UK, given the current and plausible future undiagnosed FH prevalence., Methods: Seven cholesterol and/or mutation-based US ± reverse cascade testing (RCT) alternatives were compared with no US in an incremental analysis with a healthcare perspective. A decision model was used to estimate costs and outcomes for cohorts exposed to the US component of each strategy. RCT case ascertainment was modelled using recent UK CT data, and probabilistic Markov models estimated lifetime costs and health outcomes for the cohorts screened under each alternative. 1000 Monte Carlo simulations were run for each model, and average outcomes reported. Further uncertainty was explored deterministically. Threshold analysis investigated the association between undiagnosed FH prevalence and cost-effectiveness., Results: A strategy involving cholesterol screening followed by diagnostic genetic testing and RCT was the most cost-effective modelled (incremental cost-effectiveness ratio (ICER) versus no US £12,480/quality adjusted life year (QALY); probability of cost-effectiveness 96·8% at £20,000/QALY threshold). Cost-effectiveness was robust to both deterministic sensitivity analyses and threshold analyses that modelled ongoing case ascertainment at theoretical maximum levels., Conclusions: These findings support implementation of universal cholesterol screening followed by diagnostic genetic testing and RCT for FH, under a UK conventional willingness-to-pay threshold., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Overt atherosclerotic cardiovascular disease (ASCVD) warrants aggressive lipid lowering. Imaging for ambiguous symptoms suggesting ischemia or for clarification of CV risk in asymptomatic individuals often uncovers previously unknown ASCVD. Guidelines do not provide clear recommendations for aggressive lipid lowering in such cases. We explored physicians' perception, as influenced by tests that detect ASCVD, regarding appropriateness of getting to lipid goals and for theoretically accessing proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i)., Methods: A questionnaire was developed including cases of low to high CV risk, chronic kidney disease (CKD) or type 2 diabetes mellitus (T2DM). Each case was considered with or without angina symptoms and, in turn, whether testing identified previously unknown advanced, early/subclinical or no ASCVD. Synthesis of responses was facilitated by using a scale for perceived appropriateness from 1 (lowest) to 9 (highest)., Results: Getting to goal and, if not achieved by statins and/or ezetimibe, accessing PCSK9i was considered appropriate in patients with T2DM with preclinical or advanced ASCVD, patients with moderate or high CV risk and advanced ASCVD, patients with CKD or low CV risk with angina symptoms and advanced ASCVD. For most of the remaining cases adding PCSK9i was considered only possibly appropriate., Conclusions: Physicians' perception of appropriateness for achieving lipid goals, including access to PCSK9i, is markedly influenced by detection of previously unknown ASCVD. Since these commonly encountered scenarios do not clearly meet current indications for PCSK9i, our data identify pressing areas requiring further research., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The optimal approaches to management of patients treated with moderate statin doses on lipid parameters are unknown. The ACCENTUATE study aimed to compare the effects of adding the cholesteryl ester transfer protein inhibitor (CETP) evacetrapib, ezetimibe or increasing statin dose in atorvastatin-treated high-vascular risk patients on lipid parameters., Methods: 366 patients with atherosclerotic cardiovascular disease (ASCVD) and/or diabetes were treated with atorvastatin 40 mg/day for 28 days prior to randomization to atorvastatin 40 mg plus evacetrapib 130 mg, atorvastatin 80 mg, atorvastatin 40 mg plus ezetimibe 10 mg or atorvastatin 40 mg plus placebo, daily for 90 days at 64 centers in the United States. Lipid parameters, safety and tolerability were measured., Results: Addition of evacetrapib significantly reduced LDL-C (-33%) compared with ezetimibe (-27%, p=0.045), increasing statin dose (-6%) and statin alone (0%, p<0.001). Evacetrapib also decreased apoB by 23% compared to 19% with ezetimibe (p=0.06) and 7% with increased statin dose (p<0.001), and reduced Lp(a) by 29% (p<0.001 vs. other groups). Evacetrapib increased HDL-C (+125%), apoA-I (+46%), apoC-III (+50%) and apoE (+28%) (p<0.001 vs. other groups). Non-ABCA1-mediated efflux increased by 53% (p<0.001 vs. other groups) with evacetrapib. ABCA1-mediated efflux also increased by 13% with evacetrapib (p<0.001 vs. ezetimibe, p=0.002 vs. increasing statin dose, and p=0.004 vs. statin alone). Addition of evacetrapib to atorvastatin produced an increase in hsCRP compared with ezetimibe (p=0.02)., Conclusions: While evacetrapib improved traditional atherogenic and putative protective lipid measures compared with ezetimibe and increasing statin dose in patients with ASCVD and/or diabetes, it also adversely affected novel atherogenic risk factors. These findings may contribute to the lack of clinical benefit observed in the ACCELERATE trial., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Aims: The effect of statin therapy on plasma adiponectin levels has not been conclusively studied. Therefore, we aimed to evaluate this effect through a systematic review and meta-analysis of available randomized controlled trials (RCTs)., Methods: Quantitative data synthesis was performed using a random-effects model with weighted mean difference (WMD) and 95% confidence interval (CI) as summary statistics., Results: In 30 studies (43 study arms) with 2953 participants, a significant increase in plasma adiponectin levels was observed after statin therapy (WMD: 0.57 μg/mL, 95% CI: 0.18, 0.95, p = 0.004). In subgroup analysis, atorvastatin, simvastatin, rosuvastatin, pravastatin and pitavastatin were found to change plasma adiponectin concentrations by 0.70 μg/mL (95% CI: -0.26, 1.65), 0.50 μg/mL (95% CI: -0.44, 1.45), -0.70 μg/mL (95% CI: -1.08, -0.33), 0.62 μg/mL (95% CI: -0.12, 1.35), and 0.51 μg/mL (95% CI: 0.30, 0.72), respectively. With respect to duration of treatment, there was a significant increase in the subset of trials lasting ≥12 weeks (WMD: 0.88 μg/mL, 95% CI: 0.19, 1.57, p = 0.012) but not in the subset of <12 weeks of duration (WMD: 0.18 μg/mL, 95% CI: -0.23, 0.58, p = 0.390). Random-effects meta-regression suggested a significant association between statin-induced elevation of plasma adiponectin and changes in plasma low density lipoprotein cholesterol levels (slope: 0.04; 95% CI: 0.01, 0.06; p = 0.002)., Conclusions: The meta-analysis showed a significant increase in plasma adiponectin levels following statin therapy. Although statins are known to increase the risk for new onset diabetes mellitus, our data might suggest that the mechanism for this is unlikely to be due to a reduction in adiponectin expression., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Clinical trials have been instrumental in reducing the morbidity and mortality associated with cardiovascular disease, especially in the developed world. Recently however this improvement has plateaued, highlighting the importance of optimising current strategies and considering alternative practises. Inequalities in global healthcare, the changing patient profile as a result of an obesity and diabetes epidemic, and inadequate utilisation of evidence-based treatments are partly responsible. Despite pharmacotherapies such as statins having substantial evidence for cardiovascular benefit, patient response may be variable with genetic factors thought to be partly responsible. Although randomised controlled trials remain the backbone of clinical research, they have limitations including time taken to complete a trial and the financial costs associated with it. In this opinion-based paper, we discuss some of the key considerations for the future of cardiovascular disease prevention., (Crown Copyright © 2016. Published by Elsevier Ireland Ltd. All rights reserved.)

Introduction: Circulating lipoprotein (a) (Lp(a)) is a recognized risk factor for cardiovascular disease (CVD). Tibolone, a synthetic steroid, may lower Lp(a) levels; however, evidence of the effects of tibolone on Lp(a) still remain to be defined. Therefore, we investigated the effects of tibolone treatment on circulating Lp(a) levels in postmenopausal women., Methods: The search included PUBMED, Web of Science, Scopus, and Google Scholar (up to January 31st, 2015) to identify controlled clinical studies investigating the effects of oral tibolone treatment on Lp(a) levels in postmenopausal women. Random-effects meta-regression was performed using unrestricted maximum likelihood method for the association between calculated weighted mean difference (WMD) and potential moderators., Results: Meta-analysis of data from 12 trials (16 treatment arms) suggested a significant reduction of Lp(a) levels following tibolone treatment (WMD: -25.28%, 95% confidence interval [CI]: -36.50, -14.06; p < 0.001). This result was robust in the sensitivity analysis and its significance was not influenced after omitting each of the included studies from the meta-analysis. When the studies were categorized according to the tibolone dose, there were consistent significant reductions of Lp(a) in the subsets of studies with doses <2.5 mg/day (WMD: -17.00%, 95%CI: -30.22, -3.77; p < 0.012) and 2.5 mg/day (WMD: -29.18%, 95%CI: -45.02, -13.33; p < 0.001). Likewise, there were similar reductions in the subsets of trials with follow-up either <24 months (WMD: -26.79%, 95%CI: -38.40, -15.17; p < 0.001) or ≥24 months (WMD: -23.10%, 95%CI: -40.17, -6.03; p = 0.008)., Conclusions: This meta-analysis shows that oral tibolone treatment significantly lowers circulating Lp(a) levels in postmenopausal women. Further studies are warranted to explore the mechanism of this effect and the potential value and place of tibolone or its analogues in the treatment of elevated Lp(a) in individuals at risk of CVD., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: Whether adverse effect of statins on glycaemic indices is common to all statins remains controversial and as yet data for pitavastatin are limited. We sought to assess the effects of pitavastatin on glycaemia and new-onset diabetes (NOD) in non-diabetic individuals using data from RCT pooled together by means of a meta-analysis., Materials and Methods: We searched Medline, Cochrane, Embase and clinical trials registries websites until November-2014 for ≥12-week follow-up placebo or statin-controlled RCT of pitavastatin that included participants without diabetes and reported on fasting blood glucose (FBG), HbA1c or NOD. We additionally sought studies by consulting with Kowa Ph. Ltd. The association of pitavastatin with the outcomes were estimated by random-effects meta-analyses. Heterogeneity was assessed by the I(2) statistic and sensitivity and subgroup analyses, and publication bias with funnel plots and Egger and Harbord Tests., Results: 15 studies (approx. 1600 person-years) were included. No significant differences associated with pitavastatin (vs. control) were observed for FBG (MD -0.01 mg/dL [95%CI -0.77, 0.74], I(2) = 0%), HbA1c (MD -0.03% [95%CI -0.11, 0.05], I(2) = 43%) or NOD (RR 0.70 [95%CI 0.30, 1.61]; RD 0.0 [95%CI -0.004, 0.003]; I(2) = 0%). Sensitivity and subgroup analyses (including type of control [placebo or other statin], pitavastatin dose or follow-up] did not yield significant results. Potential publication bias may occur for NOD., Conclusions: In the present meta-analysis pitavastatin did not adversely affect glucose metabolism or diabetes development compared with placebo or other statins., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Raised plasma endothelin-1 (ET-1) levels may be a risk factor for vascular dysfunction and cardiovascular (CV) disease. This meta-analysis assessed the effect of statins on circulating ET-1 concentrations., Methods and Results: The search included PUBMED, Cochrane Library, Web of Science, Scopus, and EMBASE up to September 30, 2014 to identify randomized controlled trials (RCTs) with ET-1 measurement during statin therapy. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Data from 15 RCTs showed that statin therapy significantly reduces plasma ET-1 concentrations (WMD: -0.30 pg/mL, 95%CI: -0.47, -0.13; p < 0.01). This effect was robust in sensitivity analysis, and not largely affected by the duration of statin therapy (<12 weeks - WMD: -0.51 pg/mL, 95%CI: -0.89, -0.14, p < 0.01; >12 week -WMD: -0.19 pg/mL, 95%CI: -0.36, -0.02; p < 0.05) or by dose of statins (<40 mg/day - WMD: -0.27 pg/mL, 95%CI: -0.49, -0.05; p = 0.01; >40 mg/day - WMD: -0.38 pg/mL, 95%CI: -0.68, -0.08; p = 0.01). Lipophilic (atorvastatin, simvastatin, fluvastatin, and cerivastatin - WMD: -0.34 pg/mL, 95%CI: -0.55, -0.13; p < 0.01), but not a hydrophilic statin (pravastatin - WMD: -0.18 pg/mL, 95%CI: -0.44 -0.08; p > 0.05) had a significant effect in promoting ET-1 reduction., Conclusions: Statin therapy significantly reduces circulating ET-1 concentrations, regardless of treatment duration or dose of statins. This effect of statins may be influenced by statin lipophilicity. There is a need to establish whether lowering ET-1 levels has a beneficial effect on CV events., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: Non-HDL cholesterol represents the pro-atherogenic, apo-B-containing lipoprotein fraction of circulating lipids, and represents a secondary target for CVD prevention in people with diabetes. We therefore assessed the proportion of individuals with diabetes and CVD who attain a non-HDL-C goal of <2.6 mmol/L, the extent to which triglycerides influence this goal attainment, and their relationship with HDL-C and triglyceride-rich lipoproteins (TRL)., Methods and Results: Of 2674 diabetic subjects with baseline CVD in the Hungarian MULTI-GAP programme (mean age 64.8 years, mean HbA1c 7.2%), an LDL-C goal <1.8 and non-HDL-C goal <2.6 mmol/L was attained in 13.5% and 17.7% individuals, respectively. Non-HDL-C goal attainment declined at higher triglyceride concentrations; and graphically this relationship appeared to be continuously and inversely associated with triglyceride concentrations. In contrast, the relationship between LDL-C goal attainment was inversely and continuously associated with triglyceride levels up to about 2.5 mmol/L, after which the graphical appearance plateaued such that no further difference in LDL-C were observed beyond triglyceride levels of 2.5 mmol/L. With increasing triglyceride concentrations, non-HDL-C increased continuously, HDL-C decreased initially but later plateaued (at 1.5-2.0 [men] or 2.0-2.5 mmol/L [women]), LDL-C levels plateaued at about 2.0-2.5 mmol/L, and TRL-cholesterol (non-HDL-C minus LDL-C) rose continuously. In multivariable-adjusted models, elevated triglyceride concentrations, non-specialist care and uncontrolled blood pressure were inversely associated with non-HDL-C goal attainment. Triglyceride levels were more strongly associated with non-HDL-C than with LDL-C goal attainment (ORs per 1-SD increase in log-triglycerides was 0.74, 95% CI 0.61-0.89, for LDL-C goal attainment, and 0.49, 95% CI 0.38-0.61, for non-HDL-C goal attainment)., Conclusion: Non-HDL-C goal attainment was suboptimal in people with diabetes and co-existing CVD. This was most marked at higher triglyceride levels, possibly due to higher levels of TRL., (Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.)