Search

Significant advances in atherosclerotic cardiovascular (ASCVD) risk stratification and treatment have occurred over the past 10 years. While the lipid panel continues to be the basis of risk estimation, imaging for coronary artery calcium is now widely used in estimating risk at the individual level. Statins remain first-line agents for ASCVD risk reduction but in high-risk patients, ezetimibe, proprotein convertase subtilisin kexin-9 inhibitors, and bempedoic acid can be added to further reduce individual cardiovascular risk based on results of cardiovascular outcomes trials. Results of randomized control trials do not support use of medications targeted at triglyceride lowering for ASCVD risk reduction, but icosapent ethyl can be considered., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Statin-intolerance (SI) has prevalence between 8.0 % and 10 %, and muscular complaints are the most common reason for discontinuation. Bempedoic acid (BA), an ATP citrate lyase inhibitor, decreases hepatic generation of cholesterol, upregulates low-density lipoprotein (LDL) receptor expression in the liver, and eventually clears circulating LDL-cholesterol from the blood. Multiple randomized clinical trials studying BA demonstrate a reduction in LDL levels by 17-28 % in SI. The CLEAR OUTCOME trial established significant cardiovascular benefits with BA. A dose of 180 mg/day of BA showed promising results. BA alone or in combination with ezetimibe is US Food and Drug Administration-approved for use in adults with heterozygous familial hypercholesterolemia and/or established atherosclerotic cardiovascular disease. BA reduced HbA1c by 0.12 % (p < 0.0001) in patients with diabetes. Adverse events of BA include myalgia (4.7 %), anemia (3.4 %), and increased aminotransferases (0.3 %). BA can cause up to four times higher risk of gout in those with a previous gout diagnosis or high serum uric acid levels. Reports of increased blood urea nitrogen and serum creatinine were noted. Current evidence does not demonstrate a reduction in deaths from cardiovascular causes. More studies that include a diverse population and patients with both high and low LDL levels should be conducted. We recommend that providers consider BA as an adjunct to statin therapy in patients with a maximally tolerated dosage to specifically target LDL levels., Competing Interests: Declaration of competing interest Authors confirm that there is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: There is ample evidence of the benefits and safety of low-density lipoprotein (LDL)-lowering therapies in the prevention of atherosclerotic cardiovascular disease. While statins remain the first-line agent for LDL reduction, several new therapies are now available. This narrative review provides an overview of currently available non-statin LDL-lowering agents, specifically mechanisms of action and data on efficacy and safety. It also discusses recommendations on their use in clinical practice., Recent Findings: Ezetimibe, PCSK9 inhibitors, and bempedoic acid have proven safe and efficacious in reducing cardiovascular events in large randomized controlled trials. Inclisiran is a promising agent that suppresses PCSK9 mRNA translation and is currently under investigation in a large clinical outcomes randomized controlled trial assessing its effect on clinical outcomes. Expert consensus advocates for lower LDL targets in higher risk patients and escalation to or a combination of non-statin therapies as needed to achieve these goals., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: Bempedoic acid is a novel therapeutic agent that is designed to reduce levels of low-density lipoprotein cholesterol (LDL-C). The purpose of this review is to provide the background for development of bempedoic acid, findings from clinical trials and to discuss clinical implications., Recent Findings: Bempedoic acid inhibits ATP citrate lyase within the liver and reduces cholesterol synthesis, with the potential to avoid muscle symptoms experienced by patients treated with statins. Early clinical studies demonstrated that administration of bempedoic acid resulted in lowering of LDL-C by 20-30% as monotherapy and by 40-50% when combined with ezetimibe, in addition to lowering of high sensitivity C-reactive protein by 20-30%. The CLEAR Outcomes trial of high cardiovascular risk patients, with elevated LDL-C levels and either unable or unwilling to take statins demonstrated that bempedoic acid reduced the rate of major adverse cardiovascular events. A greater incidence of elevation of hepatic transaminase and creatinine, gout, and cholelithiasis were consistently observed in bempedoic acid-treated patients. Bempedoic acid presents an additional therapeutic option to achieve more effective lowering of LDL-C levels and reduction in cardiovascular risk., (© 2024. The Author(s).)

Non-statin drugs find utility in the management of dyslipidaemia in mixed dyslipidaemia, patients with statin intolerance, and when guidelines directed low-density lipoprotein cholesterol (LDL-C) target cannot be achieved despite maximally tolerated statin. The most definite indication of fenofibrate monotherapy is fasting serum triglyceride >500 mg/dl to reduce the risk of acute pancreatitis It offers a modest reduction in cardiovascular events. The statin-ezetimibe combination is commonly used for lipid lowering particularly after ACS. Fish oils reduce serum triglycerides by about 25 %. EPA (and not DHA) seems to have cardioprotective effects. Despite cardiovascular outcome benefits, bile-exchange resins have limited use due to poor tolerance. Bempedoic acid added to maximally tolerated statin therapy is approved to lower LDL-C in adults with primary hypercholesterolemia or mixed dyslipidaemias, HeFH, in patients with ASCVD who require additional lowering of LDL-C, and in patients who are statin-intolerant. Inclisiran is a long-acting double-stranded small interfering RNA (siRNA) that inhibits the transcription of PCSK-9 leading to a decrease in PCSK9 generation in hepatocytes and an increase in LDL receptor expression in the liver cell membrane leading to about 50 % reduction in serum LDL-C levels. Lomitapide lowers plasma levels of all ApoB-containing lipoproteins, including VLDL, LDL, and chylomicrons by inhibiting the enzyme microsomal triglyceride transfer protein (MTP) and approved for the treatment of adult patients with homozygous familial hypercholesterolemia (HoFH). Close monitoring for hepatotoxicity is required. Mipomersen is a single-stranded synthetic antisense oligonucleotide (ASO) that affects the production and secretion of apoB-containing lipoproteins with demonstrated efficacy in both homozygous and heterozygous FH patients. It is approved for restricted use due to risk of hepatotoxicity. Pelacarsen is an antisense oligonucleotide that reduces the production of apo(a) in the liver., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Cardiological Society of India. Published by Elsevier, a division of RELX India, Pvt. Ltd. All rights reserved.)

Aims: We performed quality control of lipid-lowering therapy (LLT) in patients with acute coronary syndrome (ACS), with a view to proposing corrective actions., Methods and Results: Using a Define Measure Analysis Improve Control (DMAIC) approach applied to data from the ACS EuroPath IV survey, we measured attainment of two quality indicators (QIs) related to lipid-lowering treatment: (i) prescription of high-intensity statins (or equipotent treatment) before discharge, and (ii) proportion with LDL-cholesterol <55 mg/dL (1.4 mmol/L) during follow-up. A total of 530 European cardiologists responded and provided data for up to 5 patients from their centre, for acute and follow-up phases. Corrective measures are proposed to increase the rate of attainment of both QIs. Attainment of the first QI was measured in 929 acute-phase patients, 99% had LLT prescribed at discharge and 75% of patients fulfilled the first QI. Attainment of the second QI was assessed in 1721 patients with follow-up. The second QI was reached in 31% of patients. The DMAIC approach yielded 10 potential changes in prescription, 3 for the first and 7 for the second QI. The overall strategy is 'Fire to Target', i.e. early intensification of the LLT using statins, ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type-9 inhibitors, and is presented as an algorithm for routine application., Conclusion: Quality control for LLT, based on the ACS EuroPath IV survey, detected 10 potential changes in prescription that could enhance attainment of 2 QIs. Whether the Fire to Target strategy will be adopted and effective needs to be assessed in further steps of the EuroPath Quality programme., Competing Interests: Conflict of interest: F.S. has received research grants from and/or was speaker (with or without lecture fees) on a.o. (CME accredited) meetings sponsored by Amgen, Bayer, Novartis, Novo Nordisk, Sanofi Aventis, Recordati, Servier, Mylan, and AstraZeneca. A.S. has received honoraria, lecture fees, or research grants from Amgen, Daiichi Sankyo, Ferrer, Getinge, Novartis, Pfizer, Sanofi, and Zoll. A.L.C. has received honoraria, lecture fees, or research grants from: AstraZeneca, Aegerion, Amryt, Amarin, Daiichi Sankyo, Esperion, Ionis Pharmaceuticals, Kowa, Medscape, Mylan, Merck, Menarini, Novartis, Peer Voice, Pfizer, Recordati, Regeneron, Sandoz, Sanofi, and The Corpus. The work of A.L.C. relevant to this publication is supported by Ministero della salute Ricerca corrente. R.D.C. has received honoraria, lecture fees, or research grants from Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi Sankyo, Roche, Novartis, AstraZeneca, Milestone, Menarini, Guidotti, Lilly, Merck, and Portola. U.L. has received honoraria, lecture fees, or research grants from Amgen, Daiichi Sankyo, Novartis, and Sanofi. A.Z. has received honoraria, consulting, or lecture fees from Sanofi, Amgen, and Novartis. J.W.J. and his department has received research grants from and/or was speaker (with or without lecture fees) on a.o. (CME accredited) meetings sponsored by Amarin, Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, The Netherlands Heart Foundation, CardioVascular Research The Netherlands (CVON), The Netherlands Heart Institute, and the European Community Framework KP7 Programme., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Despite the proven effects of statins in preventing cardiovascular disease, their diabetogenic effect has caused concern. The mechanism of this diabetogenic effect is unknown. We suggest a novel mechanism that may contribute to the diabetogenic effect of statins, through an effect of statins that has apparently escaped previous consideration. Briefly, by inhibiting HMG-CoA reductase, statins may cause accumulation of acetate, which through FFA2 and FFA3 stimulation may inhibit insulin secretion., (© 2023. The Author(s).)

Introduction: Bempedoic acid (BA) has shown significant progress in reducing cholesterol levels and is relatively free from the many side effects encountered with the use of other hyperlipidemic drugs such as statins. However, its efficacy in patients with statin intolerance is controversial with inconsistent results among studies., Materials and Methods: An electronic literature search was performed using various databases such as Medline, Google Scholar, and the International Registry of Clinical Trials. The primary endpoint was the change in LDL-C levels. The secondary endpoints included changes in HDL-C, non-HDL-C, triglycerides (TG), clinical outcomes such as MACE, all-cause mortality (ACM), cardiovascular mortality, myocardial infarction (MI), and additional safety outcomes. The least-square mean (LSM) percent change for assessing changes in lipid parameter levels from the baseline and the risk ratio (RR) were used for the evaluation of binary endpoints, with statistical significance set at p<0.05. Random-effects meta-analyses were performed for all the outcomes., Results: Our analysis included 5 randomized controlled trials (RCTs) with a total of 18,848 participants. BA showed a significant reduction in LDL-C [LSM difference in %: -25.24; 95 % CI: -30.79 to -19.69; p < 0.00001], total cholesterol [LSM difference in %:-21.28; 95 % CI:-30.58 to-11.98; p < 0.00001], non-HDL-C [LSM difference in %: -23.27; 95 % Cl: -29.80 to -16.73 p < 0.00001], and HDL-C [LSM difference in %:-3.37, 95 % CI:-3.73 to-3.01, p < 0.00001] compared to placebo. In terms of clinical efficacy, BA was associated with a lower risk of coronary revascularization [RR:0.81; 95 % CI:0.66 to 0.99; p = 0.04], hospitalization for unstable angina [RR:0.67; 95 % CI:0.50 to 0.88; p = 0.005], and myocardial infarction [RR:0.76; 95 % CI:0.66 to 0.88;p = 0.0004]. No significant difference was observed in MACE [RR:0.81; p = 0.15], ACM [RR:0.86; p = 0.46], cardiovascular-related mortality [RR:0.79; p = 0.44], and stroke [RR:0.83; p = 0.08] between the two groups. In terms of safety efficacy, the risk for myalgia was significantly lower in BA-treated patients than in placebo [RR:0.80; p = 0.0002], while the risk for gout [RR:1.46; p < 0.0001] and hyperuricemia [RR:1.93; p < 0.00001] was higher for BA than for placebo. The risks for other adverse effects, such as neurocognitive disorder, nasopharyngitis urinary tract infection, upper respiratory infection, muscular disorder, and worsening hyperglycemia/DM were comparable between the two groups., Conclusion: Our analysis demonstrated that BA significantly reduced the levels of LDL-C, total cholesterol, non-HDL-C, HDL-C, ApoB, and hs-CRP compared with the placebo group. Additionally, patients who received BA had a lower likelihood of coronary revascularization and hospitalization due to unstable angina, MI, and myalgia. Further large-scale RCTs are required to generate more robust evidence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: The management of LDL-C levels is pivotal in the prevention of cardiovascular morbidity, particularly among patients at high risk or those intolerant to statins. Bempedoic acid emerges as a novel agent in this therapeutic arena., Objectives: This systematic review and meta-analysis endeavor to quantify the effectiveness of Bempedoic acid in attenuating LDL-C levels and explore its impact on cardiovascular morbidity, emphasizing its role as an adjunctive or alternative therapy in statin-intolerant or high-risk patients., Methods: A comprehensive search spanning PubMed, Google Scholar, and Cochrane Library databases furnished studies for this review. The inclusion was critiqued based on predefined PICOS parameters, ensuring a robust analytical framework., Results: Bempedoic acid showcased a significant plunge in LDL-C levels (MD -20.69 %, 95 % CI [-23.20, -18.19]), outperforming placebo and ezetimibe monotherapy. The cardioprotective effect was further echoed with a reduced risk of major adverse cardiac events (MACE) in the Bempedoic acid cohort (RR 0.86, 95 % CI [0.80, 0.94]). However, a dive into the safety profile revealed no substantial augmentation in adverse events, affirming its tolerance and efficacy., Conclusions: Bempedoic acid represents a potent therapeutic ally, affirming its capacity to significantly pare down LDL-C levels and curtail cardiovascular events. Its favorable safety profile underscores its suitability, especially among those with statin intolerance or individuals categorized within the high-risk vascular bracket, necessitating a paradigm shift in current lipid management strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Statins play a significant role in the prevention of cardiovascular (CV) diseases (CVDs); however, non-adherence with statin treatment or statin intolerance (mainly attributed to muscleassociated side effects) is not uncommon. New agents such as bempedoic acid (BA) can provide more treatment options. BA is administered orally, once daily, at a dose of 180 mg in current clinical practice. It can decrease circulating low-density lipoprotein cholesterol (LDL-C) levels by nearly 30% as monotherapy or by 20% as an add-on to statins. CV outcome studies have shown that BA decreases major adverse CV event risk in patients with established CVD or high CV risk by 13%. When patients with high CV risk were analyzed alone, the risk reduction was 30%. Its side effects include a rise in serum uric acid levels and liver enzyme activity, whereas it does not increase diabetes risk as statins do. BA can be used as adjunctive therapy to statins in patients at high CV risk in whom lipid targets cannot be achieved or as an alternative to statins in patients with statin intolerance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: Statin intolerance and myopathy is a major issue with prolonged use of statins myopathy. Bempedoic acid can be a good alternative for those intolerant to statins. This systematic review aims to observe incidence of major adverse cardiovascular events (MACE) and other adverse events, in high-risk statin intolerant patients receiving bempedoic acid. Methods: Literature search was conducted via Google Scholar, Science Direct and PubMed, after which screening, selection and data extraction of articles was done. Meta-analysis was performed on RevMan 5.4. Subgroup analysis was also conducted and heterogeneity was evaluated. Risk of bias was performed using ROB2 assessment scale. (CRD42024536827). Results: Only six randomized controlled trials were used in final analysis consisting of 17,844 patients. Treatment with bempedoic acid was associated with a reduced risk of MACE compared with placebo (RR 0.86; 95% CI [0.79, 0.94] p  = 0.0005), with myocardial infarction significantly reduced. Incidence of adverse effects was increased with bempedoic acid (RR: 1.02; 95% [1.00, 1.03] p  = 0.01) but no significant difference was observed. Incidence of myalgia was reduced in bempedoic group as well. Conclusion: Bempedoic acid is a safe and effective alternative to statins in high-risk patients intolerant to statins, decreasing the risk of MACE.

Background: Low-density lipoproteins are now proven to be causal for atherosclerosis. Pharmacological treatment focuses on an increase of low-density lipoprotein (LDL) receptors, particularly in the hepatocyte, which leads to uptake of LDL from blood, thereby reducing the burden to the arterial wall. This mechanism has first been proven by statins to be effective to reduce cardiovascular morbidity and mortality. The concept of "the lower, the better" was shown by high-intensity statins and new compounds like ezetimibe, PCSK9 antibodies, inclisiran, and ultimately bempedoic acid., Summary: Although first considered only a relatively weak LDL-C lowering drug, bempedoic acid proved to be very effective, for example, in statin-intolerant patients to reduce cardiovascular events in the CLEAR-Outcomes study. In the era of personalized medicine, it should not be forgotten that the individual response to a LDL-C lowering drug can vary considerably. Bempedoic acid has a favorable safety profile, particularly it does not induce muscle problems because its precursor is not metabolized to the active drug in the muscle, and it does not induce hyperglycemia. Bempedoic acid probably is best used in combination with ezetimibe, which leads to LDL-C reductions in the range of moderately intensive statins; in an oral triple combination with a high-intensity statin, LDL-C reductions in the range of two-thirds can be achieved., Key Messages: Bempedoic acid is a further weapon against the atherogenic effect of LDL cholesterol - in both primary and secondary prevention., (© 2023 S. Karger AG, Basel.)

Background: Bempedoic acid is an oral adenosine triphosphate citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) blood levels. The Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes study demonstrated that bempedoic acid reduced cardiovascular (CV) risk in patients at high risk for CV events who were unwilling or unable to take guideline-recommended doses of statins., Objective: To describe detailed safety information from CLEAR Outcomes, including events in the United States (US) prescribing information based on previous phase 3 hyperlipidemia studies., Methods: CLEAR Outcomes was a double-blind trial conducted in 13,970 patients randomized to oral bempedoic acid 180 mg daily or placebo and followed for a median of 3.4 years., Results: In patients who received at least one dose (7,001 bempedoic acid, 6,964 placebo), treatment emergent adverse events (AE) occurred in 86.3 % and 85 % of patients, respectively. COVID-19 was the most frequently reported AE in both groups. Changes in serum creatinine, blood urea nitrogen, hemoglobin, aminotransaminases, and uric acid were consistent with the known safety profile of bempedoic acid. Gout or gouty arthritis occurred in 3.2 % of bempedoic acid and 2.2 % of placebo patients. AE associated with tendinopathies, including tendon rupture, occurred in 2 % of patients in both treatment groups. Cholelithiasis occurred in 2.2 % of bempedoic acid and 1.2 % of placebo patients; AE related to gallbladder disease were similar between treatment groups., Conclusions: Bempedoic acid was well-tolerated compared with placebo. Safety data from the long-term CLEAR Outcomes study reinforce the positive benefit-risk profile of bempedoic acid., (Copyright © 2023. Published by Elsevier Inc.)

Background and Aims: Bempedoic Acid (BA) is a novel Lipid-Lowering Therapy (LLT). We performed a systematic review and meta-analysis to assess the efficacy and safety of BA in patients with hypercholesterolemia., Methods: PubMed, Scopus, and Cochrane library databases were searched for randomised controlled trials evaluating the efficacy and/or safety of BA compared with placebo. Trials investigating dosages other than 180 mg/die were excluded. Major adverse cardiovascular events (MACE) were the primary efficacy endpoint. LDL-cholesterol reduction was the primary laboratory endpoint. Pre-specified safety endpoints included muscle-related adverse events, new-onset diabetes, and gout. The protocol was registered on PROSPERO (temporary ID:399,867)., Results: Study search identified 275 deduplicated results. 11 studies, encompassing 18,315 patients (9854 on BA vs 8461 on placebo/no treatment) were included. BA was associated with a reduced risk of MACE (OR 0.86, 95% CI 0.79-0.95), myocardial infarction (OR 0.76, 95% CI 0.64-0.88) and unstable angina (OR 0.69, 95% CI 0.54-0.88) compared to control, over a median follow up of 87 (15-162) weeks. BA was associated with a reduction of LDL-Cholesterol (mean difference [MD]-22.42,95% CI - 24.02% to - 20.82%), total cholesterol (- 16.50%,95% - 19.21% to - 13.79%), Apo-B lipoprotein (- 19.55%, - 22.68% to - 16.42%) and high-sensitivity CRP (- 27.83%, - 31.71% to - 23.96%) at 12 weeks. BA was associated with a higher risk of gout (OR 1.55, 95% CI 1.27-1.90) as compared with placebo. Efficacy on laboratory endpoints was confirmed, with a variable extent, across patients on statin or ezetimibe background therapy., Conclusions: The improved cholesterol control achieved with BA translates into a reduced risk of MACE, including myocardial infarction and coronary revascularisation. The drug has a satisfactory safety profile except for an increased risk of gout., (© 2023. The Author(s).)

Aim: This systematic review and meta-analysis was conducted to synthesize the efficacy and safety of bempedoic acid in patients requiring lipid-lowering therapy., Methods: PubMed, Embase, and Scopus databases were searched for randomized controlled trials from inception till June 2023. The primary outcome was major adverse cardiovascular events (MACE), and secondary outcomes were all-cause mortality, serum lipid profile, and adverse events between bempedoic acid and comparators. ROB2 was used for risk of bias assessment. We pooled mean differences or relative risks (RR) along with 95% confidence intervals (random-effects model)., Results: Five-hundred and thirty-one studies were screened and 17 (n = 21,131) were included for review. There was a significant reduction in the risk of MACE [RR, 0.88 (95% CI: 0.77 to 0.99), p = 0.03)] and all-cause mortality [RR, 0.90 (95% CI: 0.82 to 0.98), p = 0.02] following bempedoic acid treatment. Treatment with bempedoic acid led to a significant reduction in the mean serum total cholesterol [- 34.41 mg/dl (95% CI: - 42.43 to - 26.39), p < 0.001], low-density lipoprotein cholesterol (LDL-C) [- 33.91 mg/dl (95% CI: - 39.66 to - 28.17), p < 0.001], as well as high-density lipoprotein cholesterol (HDL-C) [- 2.40 mg/dl (95% CI: - 3.09 to - 1.71), p < 0.001] levels. However, there was a significant increase in the risk of hyperuricemia [RR, 2.05 (95% CI: 1.81 to 2.33), p < 0.001] following bempedoic acid treatment. The number needed to harm was large for all safety outcomes. The GRADE of evidence was moderate for all outcomes., Conclusion: Bempedoic acid reduces the risk of MACE and all-cause mortality, lowers serum total cholesterol and LDL-C levels, and has a favorable safety profile. Trial registration ClinicalTrial.gov Identifier: CRD42023412837., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Machine learning has potential to improve the management of lipid disorders. We explored the utility of machine learning in high-risk patients in primary care receiving cholesterol-lowering medications. Methods: Machine learning algorithms were created based on lipid management guidelines for England [National Institute for Health and Care Excellence (NICE) CG181] to reproduce the guidance with >95% accuracy. Natural language processing and therapy identification algorithms were applied to anonymized electronic records from six South London primary care general practices to extract medication information from free text fields. Results: Among a total of 48,226 adult patients, a subset of 5630 (mean ± standard deviation, age = 67 ± 13 years; male:female = 55:45) with a history of lipid-lowering therapy were identified. Additional major cardiometabolic comorbidities included type 2 diabetes in 13% ( n  = 724) and hypertension in 32% ( n  = 1791); all three risk factors were present in a further 28% ( n  = 1552). Of the 5630 patients, 4290 (76%) and 1349 (24%) were in primary and secondary cardiovascular disease prevention cohorts, respectively. Statin monotherapy was the most common current medication (82%, n  = 4632). For patients receiving statin monotherapy, 71% ( n  = 3269) were on high-intensity therapy aligned with NICE guidance with rates being similar for the primary and secondary prevention cohorts. In the combined cohort, only 46% of patients who had been prescribed lipid-lowering therapy in the previous 12 months achieved the NICE treatment goal of >40% reduction in non-high-density lipoprotein cholesterol from baseline pretreatment levels. Based on the most recent data entry for patients not at goal the neural network recommended either increasing the dose of statin, adding complementary cholesterol-lowering medication, or obtaining an expert lipid opinion. Conclusions: Machine learning can be of value in (a) quantifying suboptimal lipid-lowering prescribing patterns, (b) identifying high-risk patients who could benefit from more intensive therapy, and (c) suggesting evidence-based therapeutic options.

Purpose of Review: It is clear from epidemiological studies that patients at high and very-high risk of atherosclerotic cardiovascular diseases (ASCVD) risk do not reach lipid guideline-recommended targets. Thus, fixed-dose combinations of statins/ezetimibe, bempedoic acid/ezetimibe and statins/fibrates may represent a further armamentarium in the field of lipid-lowering approaches in these individuals., Recent Findings: The combination therapy of moderate-intensity statin with ezetimibe is not inferior to high-intensity statin monotherapy in reducing cardiovascular outcomes. Drug discontinuation or dose reduction is inferior with fixed-dose combination. The fixed-dose combination of bempedoic acid with ezetimibe is superior to bempedoic acid in monotherapy in lowering LDL-C and in reducing high-sensitivity C-reactive protein concentrations. The combination fenofibrate with atorvastatin is superior to monotherapies in lowering triglycerides. Lipid-lowering fixed-dose combinations may guarantee a higher therapy adherence, representing a better approach to control plasma lipids and thus ameliorate ASCVD burden. Additional studies will define the advantages on cardiovascular outcomes in high and very high-risk patients., (© 2023. The Author(s).)

Purpose of Review: To provide an updated review of bempedoic acid's clinical application in lowering LDL-C in the setting of statin intolerance and the recent findings in the CLEAR Outcomes trial as well as summarize and synthesize the current state of knowledge regarding bempedoic acid while providing an in-depth analysis of the drug's pharmacological properties, mechanism of action, clinical trials, safety, and efficacy., Recent Findings: The CLEAR Outcomes trial has provided evidence to support bempedoic acid as a viable alternative to statins for the primary and secondary prevention of cardiovascular disease. Bempedoic acid is a promising treatment option for patients with hypercholesterolemia who are unable to tolerate statin therapy or require additional LDL-C reduction in the treatment of cardiovascular disease, with the newest lipid-lowering cardiovascular outcomes trials expanding on their generalizability particularly in the inclusion of women., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Atherosclerotic cardiovascular disease is the leading cause of death globally. LDL cholesterol is a key risk factor for cardiovascular disease.  The most common group of medicines for lowering LDL cholesterol are the statins, as they reduce the risk of cardiovascular events.  However, some subjects are statin-intolerant and remain at high risk., Areas Covered: CLEAR Outcomes; a phase 3 clinical trial of bempedoic acid, an ATP citrate lyase (ACL) inhibitor, in subjects who do not tolerate statins or are unable to take the recommended dose. It enrolled subjects with prior cardiovascular events (secondary prevention) and at high risk (primary prevention). The primary endpoint was a composite of major adverse cardiovascular events, and this occurred in less subjects in the bempedoic acid than the placebo group., Expert Opinion: Bempedoic acid is suitable for use as monotherapy in the prevention of cardiovascular events in statin intolerant subjects, and it has a good safety profile in most subjects.However, the effects of bempedoic acid in lowering LDL cholesterol and cardiovascular events are modest.  This suggests that more benefits may ensue ifbempedoic acid was used in combination with other lipid lowering agents to cause larger decreases in LDL cholesterol.

Background and Aims: Bempedoic acid significantly lowers low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia but its effects in patients with metabolic syndrome (MetS) have not been well characterized. We sought to determine the efficacy and safety of bempedoic acid in patients with hypercholesterolemia by baseline MetS status., Methods: This study used pooled data from four phase 3 studies. Using modified International Atherosclerosis Society guidelines, patients were grouped into two pools: those with and those without MetS. Patients with diabetes were excluded. Endpoints assessed change from baseline to week 12 in lipid and glycemic parameters and high-sensitivity C-reactive protein (hsCRP), and safety., Results: The study included 936 patients with MetS (bempedoic acid, 648; placebo, 288) and 1573 without MetS (bempedoic acid, 1037; placebo, 536). Significant placebo-corrected reductions in LDL-C were observed with bempedoic acid (p < 0.0001), with a slightly larger decrease in patients with vs. without MetS (-22.3% vs. -18.4%; interaction p = 0.0472). Compared with placebo, bempedoic acid significantly (p < 0.0001) lowered total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and hsCRP, with a similar magnitude of benefit observed between MetS categories. Triglycerides increased with bempedoic acid but only to a lesser extent than with placebo in patients without MetS (placebo-corrected difference, -4.4%; p = 0.02). Only patients with MetS experienced decreases in glycated hemoglobin (-0.07%; p < 0.0001) and fasting plasma glucose (-2.4 mg/dL; p = 0.002). Safety was comparable between MetS categories and treatment groups., Conclusions: These data suggest that bempedoic acid is a suitable therapy for patients with and without MetS who require additional lipid lowering., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MDS has received research grant(s)/support paid to his institution from Amgen, Esperion Therapeutics, Ionis Pharmaceuticals, the National Institutes of Health, NewAmsterdam Pharma, and Novartis, and honoraria for consultancy from EmendoBio, Ionis Pharmaceuticals, Novartis, and Regeneron Pharmaceuticals. He has also served on scientific advisory boards for Amgen, Novartis, and Precision BioSciences. PRT has received funding/grant support from the American Heart Association, the National Institutes of Health, and the Federal Emergency Management Agency, and honoraria for consultancy from Amgen, Bayer, Boehringer Ingelheim, Esperion Therapeutics, Medtronic, Novartis, Novo Nordisk, and Sanofi. MJL is an employee of Esperion Therapeutics, Inc. LL is a consultant for Esperion Therapeutics, Inc. CMB has received research grant(s)/support paid to his institution from Abbott Diagnostics, Akcea Therapeutics, Amarin, Amgen, Esperion Therapeutics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, Roche Diagnostics, Sanofi Synthelabo, the National Institutes of Health, the American Heart Association, and the American Diabetes Association; he has also served as a consultant for Abbott Diagnostics, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Intercept Pharmaceuticals, Ionis Pharmaceuticals, Matinas BioPharma Holdings, Merck, Novartis, Novo Nordisk, Regeneron Pharmaceuticals, Roche Diagnostics, and Sanofi Synthelabo., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Cardiovascular disease (CVD) is a chronic non-communicable disease (NCD) and the predominant cause of morbidity and mortality worldwide. Substantial reductions in the CVD prevalence have been achieved in recent years by the attenuation of risk factors (particularly hypertension and dyslipidaemias) in primary and secondary prevention. Despite the remarkable success of lipid lowering treatments, and of statins in particular, in reducing the risk of CVD, there is still an unmet clinical need for the attainment of guideline lipid-targets in even 2/3 of patients. Bempedoic acid, the first in-class inhibitor of ATP-citrate lyase presents a new approach to lipid-lowering therapy. By reducing the endogenous production of cholesterol, upstream of the rate-limiting enzyme HMG-CoA-reductase, i.e., the target of statins, bempedoic acid reduces circulating plasma concentrations of low-density lipoprotein cholesterol (LDL-C), and major adverse CVD events (MACE). Bempedoic acid has the potential to contribute to the reduction of CVD risk not only as monotherapy, but even further as part of a lipid-lowering combination therapy with ezetimibe, reducing LDL-C cholesterol up to 40%. This position paper of the International Lipid Expert Panel (ILEP) summarises the recent evidence around the efficacy and safety of bempedoic acid and presents practical recommendations for its use, which complement the 'lower-is-better-for-longer' approach to lipid management, which is applied across international guidelines for the management of CVD risk. Practical evidence-based guidance is provided relating to the use of bempedoic acid in atherosclerotic CVD, familial hypercholesterolaemia, and statin intolerance. Although there are still no sufficient data avilable for the role of bempedoic acid in the primary prevention of CVD, its favourable effects on plasma glucose and inflammatory markers makes this drug a rational choice in the patient-centred care of specific groups of primary prevention., Competing Interests: Declaration of Competing Interest MB: speakers bureau: Amgen, Daiichi Sankyo, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo-Nordisk, Pfizer, Sanofi-Aventis, Teva, Zentiva; consultant to Adamed, Amgen, Daiichi Sankyo, Esperion, NewAmsterdam, Novartis, Novo-Nordisk, Sanofi-Aventis; Grants from Amgen, Daiichi Sankyo, Mylan/Viatris, Sanofi and Valeant; CMDO at Longevity Group (Luxemburg); PEP owns four shares in AstraZeneca PLC and has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT; MF reports having received consulting fees and/or honoraria and delivering lectures for Abbott, Amarin, Amgen, AstraZeneca, Ajanta, Kowa, Merck and Co, Organon, Pfizer, Recordati, Sanofi/Regeneron, Servier, SMB, Ultragenyx and Viatris; GL: has given talks, attended conferences, received consultancy fees and participated in trials sponsored by Abbott Laboratories, Amgen, Astra-Zeneca, Berlin Chemie, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Grindex, KRKA, MSD, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi, Servier Laboratories, Siemens Laboratories, Zentiva; PP; Grants from Akcea, Amgen. Scientific expert for: Amgen, Akcea, PRD Therapeutics; ŽR: has received honoraria from Novartis, Sanofi-Aventis and Swixx; MV has given talks, attended conferences, received consultancy fees and participated in trials sponsored by Amgen, Astra-Zeneca, Bayer, Boehringer Ingelheim, KRKA, MSD, Novartis, Novo Nordisk, Pfizer, Sanofi, Servier, Viatris, Zentiva; all other authors do not declare any conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The low-density lipoprotein cholesterol goals in the 2019 European Society of Cardiology/European Atherosclerosis Society dyslipidaemia guidelines necessitate greater use of combination therapies. We describe a real-world cohort of patients in Austria and simulate the addition of oral bempedoic acid and ezetimibe to estimate the proportion of patients reaching goals., Methods: Patients at high or very high cardiovascular risk on lipid-lowering treatments (excluding proprotein convertase subtilisin/kexin type 9 inhibitors) from the Austrian cohort of the observational SANTORINI study were included using specific criteria. For patients not at their risk-based goals at baseline, addition of ezetimibe (if not already received) and subsequently bempedoic acid was simulated using a Monte Carlo simulation., Results: A cohort of patients (N = 144) with a mean low-density lipoprotein cholesterol of 76.4 mg/dL, with 94% (n = 135) on statins and 24% (n = 35) on ezetimibe monotherapy or in combination, were used in the simulation. Only 36% of patients were at goal (n = 52). Sequential simulation of ezetimibe (where applicable) and bempedoic acid increased the proportion of patients at goal to 69% (n = 100), with a decrease in the mean low-density lipoprotein cholesterol from 76.4 mg/dL at baseline to 57.7 mg/dL overall., Conclusions: The SANTORINI real-world data in Austria suggest that a proportion of high and very high-risk patients remain below the guideline-recommended low-density lipoprotein cholesterol goals. Optimising use of oral ezetimibe and bempedoic acid after statins in the lipid-lowering pathway could result in substantially more patients attaining low-density lipoprotein cholesterol goals, likely with additional health benefits., (© 2023. The Author(s).)

Statins are first-line therapy for treating dyslipidemia because of their low-density lipoprotein cholesterol (LDL-C) lowering efficacy, superior event-reduction data and unrivaled cost-effectiveness. Yet, many people are intolerant of statins, whether due to true adverse events or the nocebo effect, so within one year about two-thirds of primary prevention patients and one-third of secondary prevention patients are no longer taking their prescription. Statins still dominate this landscape, but other agents, often used in combination, potently reduce LDL-C levels, regress atherosclerosis and lower risk of major adverse cardiovascular events (MACE). Ezetimibe lowers LDL-C by reducing intestinal absorption of cholesterol. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) lower LDL-C by increasing the number and durability of hepatic LDL receptors. Bempedoic acid reduces hepatic cholesterol synthesis. Ezetimibe, PCSK9i and bempedoic are evidence-based, non-statin therapies that synergistically lower LDL-C and reduce risk of MACE; they also have benign side-effect profiles and are generally well tolerated., Competing Interests: Conflict of interest SPG / ELO – no conflicts of interest. JHO – Speaker Bureau for Amgen. CJL – Speaker Bureau for Amgen, Esperion, and consultant for Novartis., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Aims: We aimed to understand the impact of physicians' perception about LDL-cholesterol (LDLc) control on the management of patients with dyslipidemia in Spain., Methods: We performed a cross-sectional and multicenter study, in which 435 healthcare professionals participated in face-to-face meetings, collecting qualitative and quantitative information related to hypercholesterolemia management. Additionally, aggregated anonymized data of the last 10 patients with hypercholesterolemia attended by each physician were collected., Results: A total of 4,010 patients (8%, 13%, 16% and 61% with low, moderate, high, and very high cardiovascular [CV] risk) were included. Physicians' perception was that 62% of their patients attained LDLc goals (66%, 63%, 61% and 56%, for low, moderate, high and very high CV risk, respectively). However, when looking into the data only 31% (vs 62% p<0.01) of patients attained the LDLc goals (47%, 36%, 22% and 25%, respectively). Overall, 33% of patients were taking high intensity statins, 32% statin/ezetimibe, 21% low/moderate intensity statins and 4% PCSK9 inhibitors. These numbers were 38%, 45%, 8% and 6% for very high risk patients and 44%, 21%, 21% and 4% for high CV risk patients. In 32% of patients, a change in lipid lowering therapy was performed after the visit, mainly combining statins/ezetimibe (55%)., Conclusions: In Spain, most patients with dyslipidemia do not achieve the recommended LDLc goals because of an insufficient intensification of lipid lowering therapy. On the one hand, this is in part due to physicians misperception on preventive LDLc control and the need for repeated advice to patient, and, on the other, to the lack of patient adherence., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Juan Cosin-Sales: has received conference fees from Almirall, Amgen, Daiichi-Sankyo, Ferrer, MSD, Novartis, Organon, Rovi and Sanofi; has participated in advisory services for Almirall, Amgen, MSD and Sanofi; and has received research grants from Amgen, Ferrer, MSD and Sanofi. Raquel Campuzano: has received conference fees from Amgen, Daiichi-Sankyo, Ferrer, Mylan, MSD, Organon, Sanofi, Servier and Novartis; has participated in advisory services for Novartis, Amgen, Sanofi and Servier; and has received collaborations to scientific or research projects from Amgen, Daiichi-Sankyo, Ferrer, Organon, Servier and Novartis. José Luis Díaz: has received fees for presentations, advisory services or scientific collaborations from Amgen, Bayer, Boëringher, BMS, Lilly, MSD, Mylan, Novartis, Novo-Nordisk, Pfizer, Rovi, Rubió, Sanofi, Daiichi-Sankyo and Servier. Carlos Escobar: has received fees for conferences/advisory services from: Almirall, Amgen, Daiichi-Sankyo, Esteve, Ferrer, MSD, Novartis, Organon, Rovi, Sanofi, Servier and Viatris. María Rosa Fernández: has received fees for conferences from Amgen, Sanofi, Ferrer, Daiichi-Sankyo, Organon and Rovi; has participated in advisory services for Novartis, Amgen, Sanofi and Amarin. Juan José Gómez-Doblas: has received fees for conferences from Amgen, Sanofi, Daiichi-Sankyo, Organon and MSD; has participated in advisory services for Amgen, Sanofi and Amarin; and has received collaborations to scientific or research projects from Amgen, Sanofi, Ferrer and Daiichi-Sankyo. José María Mostaza: has participated in advisory services and/or conferences, or has carried out projects for Pfizer, Amarin, Ferrer, Sanofi, Amgen, Alter, Servier, Novartis and Daiichi-Sankyo. Juan Pedro-Botet: has received fees for conferences from Amarin, Amgen, Daiichi-Sankyo, Esteve, MSD, Sanofi and Viatris; and has participated in advisory services for Amarin, Amgen, Daiichi-Sankyo, Esteve, Ferrer, Sanofi and Viatris. Núria Plana: has received fees for conferences from Amgen, Sanofi, Daiichi-Sankyo Mylan and Alexion. Pedro Valdivielso: has received fees for conferences from Amgen, Sanofi, Ferrer, Amarin, Akcea, Sobi, MSD, Novartis and Daiichi-Sankyo; has participated in advisory services for Daiichi-Sankyo, Amgen, Sanofi, Akcea and Amarin; and has received research grants from Ferrer and Akcea., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose of Review: To summarize selected late-breaking science on cardiovascular (CV) disease prevention presented at the 2023 American College of Cardiology (ACC) conference., Recent Findings: The CLEAR outcomes randomized control trial (RCT) compared bempedoic acid to placebo in patients at high-risk of cardiovascular disease (CVD) or prevalent CVD and statin intolerance for CV outcomes. The YELLOW III was a single-arm study that evaluated the effect of Evolocumab on coronary plaque characteristics in patients with stable coronary artery disease (CAD). A cohort evaluated the association between a self-reported low-carbohydrate high-fat (ketogenic) diet and serum lipid levels as compared to a standard diet. The LOADSTAR trial compared CV outcomes with targeted low-density lipoprotein cholesterol (LDL-C) approach vs. high-intensity statin in patients with CAD. The PCDS statin cluster randomized trial compared the effectiveness of an electronic reminder to the clinician on a high-intensity statin use among patients with a history of ASCVD as compared to no reminder. A prospective cohort study compared the extent of coronary atherosclerosis among lifelong endurance athletes and healthy non-athletes. A causal artificial intelligence study combined polygenic risk scores with data from large CV prevention RCTs to guide systolic blood pressure and LDL-C reduction targets to reach average CV risk. The ACCESS trial evaluated the impact of eliminating copayment for low-income older adults in Canada with chronic CV diseases on composite CV outcomes. A pooled analysis of 3 large RCTs evaluated the association between residual inflammatory risk and CV outcomes, as compared to residual elevated cholesterol risk in patients receiving statin therapy. A Phase 2B RCT compared the efficacy of an oral PCSK9i, MK-0616, in reducing LDL-C as compared to a placebo. The late-breaking clinical science presented at the 2023 conference of the ACC paves the way for an evidence-based alternative to statin therapy and provides data on several common clinical scenarios encountered in daily practice., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The relative risk reduction of cardiovascular events is proportional to the absolute reduction in LDL-C levels, the primary target of therapy, no matter the way of reduction. During the last decades, the therapeutic regimens for reducing the LDL-C levels have been immerged and improved, with favorable effects on the atherosclerotic process and clinical benefits of various cardiovascular outcomes. From a practical view of point, this review is focusing only on the current available lipid lowering agents: statins, ezetimibe, anti PCSK9 monoclonal antibodies, the small interfering RNA (siRNA) agent, Inclisiran, and Bempedoic acid. The recent changes in lipid lowering regimens, including the early combination of lipid lowering agents and "Low LDL-C" levels <30 mg/dL for high/very high cardiovascular risk patients will also be discussed., Competing Interests: Declarations of Competing Interest The author declare he has no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality, and statins have become a cornerstone in its treatment and prevention. Despite the well-documented benefits of statins, many patients stop taking them, with adverse muscle symptoms being a commonly cited reason. Although some statin-associated adverse muscle effects are real, some can be attributed to the nocebo effect, which is the patient's perception of harm. The purpose of this article is to review the literature on statin safety, particularly that related to muscle, to analyze adverse effects, and to propose various treatment strategies for the statin intolerant patient., Competing Interests: Declaration of competing interest Alexandra Martirossian has no conflicts of interest to disclose. She was supported by an NIH training grant, T32 DK007120. Anne Goldberg reports research funding from Amgen, IONIS, Regeneron, Novartis, Sanofi, Pfizer, Arrowhead, Amarin, and New Amsterdam. Honoraria from Esperion, Novartis, Amgen, Merck, AKCEA, and Regeneron. She receives a stipend as Chief Science Officer for the National Lipid Association., (Copyright © 2022. Published by Elsevier Ltd.)

Primarily a consequence of sedentary lifestyle, atherosclerosis has already reached pandemic proportions, and with every year the burden of it is only increasing. As low-density lipoprotein cholesterol (LDL-C) represents a crucial factor in atherosclerosis formation and progression, stringent lipid-lowering therapy could conceivably be the key to preventing the unfavorable outcomes that arise as a consequence of atherosclerosis. The use of statins in lipid-lowering is often burdened by adverse events or is insufficient to prevent cardiovascular events as a monotherapy. Therefore, in the present review, the authors aimed to discuss the underlying mechanisms of dyslipidemia and associated atherosclerotic cardiovascular disease (ASCVD) and preclinical and clinical trials of novel therapeutic approaches to its treatment, some of which are still in the early stages of development. Apart from novel therapies, a novel change in perspective is needed. Specifically, the critical objective in the future management of ASCVD is to embrace emerging evidence in the field of atherosclerosis, because clinicians are often burden by common practice and personal experience, both of which have so far been shown to be futile in the setting of atherosclerosis.

Statins have contributed to the prevention of numerous atherosclerotic cardiovascular (CV) events and cardiovascular deaths in the past three decades. The benefit of statins is mainly mediated by the lowering of LDLc. According to scientific evidence, the current international guidelines recommend very low LDLc goals in patients at high/very high cardiovascular risk because they are associated with fewer CV events and improvements in atherosclerotic plaques. However, these goals often cannot be obtained with statins alone. Recent RCTs have demonstrated that these CV benefits can also be obtained with nonstatin LDLc-lowering drugs such as PCSK9 inhibitors (alirocumab and evolocumab), ezetimibe and bempedoic acid, while evidence with inclisiran is upcoming. Icosapent ethyl, a lipid metabolism modifier, has also shown an effect on event reduction. Physicians should take advantage of the currently available lipid-lowering therapies, choosing the drug or combination of drugs that is most appropriate for each patient according to his or her CV risk and baseline LDLc concentration. Strategies implementing combination therapies from early stages or even from the outset may increase the number of patients attaining LDLc goals, thereby preventing new CV episodes and improving existing atherosclerotic lesions., Competing Interests: Declaration of Competing Interest L.M.: Fees for lectures and/or advisory work from Amgen, Amarin, Amryt, Daiichi-Sankyo, Ferrer, Novartis, Sanofi, Servier, Viatris. D.I.: Fees for Lectures Viatris, Ferrer, Sanofi. N.P.: Fees for lectures from Amgen, Viatris, Sanofi.N.A.: no competing financial interest to declare. A,L.C,: Prof. Catapano has received honoraria, lecture fees, or research grants from: Aegerion, Amgen, Amryt, Astrazeneca, Bayer, Daiichi-Sankyo, Eli Lilly, Genzyme, Ionis Pharmaceutical, Kowa, Mediolanum, Medscape, Menarini, Merck, Mylan, Novartis,PeerVoice, Pfizer, Recordati, Regeneron, Sanofi, Sigma-Tau, The Corpus., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

While bempedoic acid (BA), an inhibitor of ATP citrate lyase, lowers high-sensitivity C-reactive protein (hsCRP) and low-density lipoprotein cholesterol (LDL-C), the mechanisms underlying the potential anti-inflammatory effects of BA are uncertain, as are effects of this agent on lipoprotein(a).  To address these issues, we conducted a secondary biomarker analysis of the randomized placebo-controlled multi-center CLEAR Harmony trial which included 817 patients with known atherosclerotic disease and/or heterozygous familial hypercholesterolemia who were taking maximally tolerated statin therapy and had residual inflammatory risk, defined as a baseline hsCRP ≥2 mg/L. Participants were randomly allocated in a 2:1 ratio to oral BA 180 mg once daily or matching placebo.  Placebo-corrected median percent changes (95% CI) from baseline to 12 weeks associated with BA were -21.1% (-23.7 to -18.5) for LDL-C; -14.3% (-16.8 to -11.9) for non-high-density lipoprotein cholesterol; -12.8% (-14.8 to -10.8) for total cholesterol; -8.3% (-10.1 to -6.6) for high-density lipoprotein cholesterol (HDL-C); -13.1% (-15.5 to -10.6) for apolipoprotein B; 8.0% (3.7 to 12.5) for triglycerides; -26.5% (-34.8 to -18.4) for hsCRP; 2.1% (-2.0 to 6.4) for fibrinogen, -3.7% (-11.5, 4.3) for interleukin-6; and 2.4% (0.0 to 4.8) for lipoprotein(a). There was no correlation between BA associated lipid changes and BA associated change in hsCRP (all r<0.05), except for a weak correlation with HDL-C (r = 0.12). Thus, the pattern of lipid lowering and inflammation inhibition with BA is almost identical to what is observed with statin therapy suggesting that BA could be a useful treatment option to address both residual cholesterol risk and residual inflammatory risk. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02666664; https://clinicaltrials.gov/ct2/show/NCT02666664., (Copyright © 2023. Published by Elsevier Inc.)

The clinical benefit of LDL cholesterol (LDL-C) lowering for cardiovascular disease prevention is well documented. This paper from the Italian Study Group on Atherosclerosis, Thrombosis and Vascular Biology summarizes current recommendations for treatment of hypercholesterolemia, barriers to lipid-lowering therapy implementation and tips to overcome them, as well as available evidence on the efficacy and safety of bempedoic acid. We also report an updated therapeutic algorithm for pharmacological LDL-C lowering in view of the introduction of bempedoic acid in clinical practice., (Copyright © 2022. Published by Elsevier Inc.)

After experiencing an acute coronary syndrome (ACS), patients are at a high risk of suffering from recurrent ischaemic cardiovascular events, especially in the very early phase. Low density lipoprotein-cholesterol (LDL-C) is causally involved in atherosclerosis and a clear, monotonic relationship between pharmacologic LDL-C lowering and a reduction in cardiovascular events post-ACS has been shown, a concept termed 'the lower, the better'. Current ESC guidelines suggest an LDL-C guided, step-wise initiation and escalation of lipid-lowering therapy (LLT). Observational studies consistently show low rates of guideline-recommended LLT adaptions and concomitant low rates of LDL-C target goal achievement, leaving patients at residual risk, especially in the vulnerable post-ACS phase. In addition to the well-established 'the lower, the better' approach, a 'strike early and strike strong' approach in the early post-ACS phase with upfront initiation of a combined lipid-lowering approach using high-intensity statins and ezetimibe seems reasonable. We discuss the rationale, clinical trial evidence and experience for such an approach and highlight existing knowledge gaps. In addition, the concept of acute initiation of PCSK9 inhibition in the early phase is reviewed. Ultimately, we focus on hurdles and solutions to provide high-quality, evidence-based follow-up care in post-ACS patients., Competing Interests: Conflicts of interest: K.A.K. was a member of the advisory boards at Novartis, Sanofi, and Amgen and received speaker fees from Amgen. S. H. received speaker honoraria from Sanofi and Novartis. C.H. is Chair of the Danish Heart Foundation and received grants from the Danish Heart Foundation, Lundbaek foundation and NNF. K. H. received consultant and lecture fees for AstraZeneca, Amgen, Novartis and Sanofi Aventis. F.S. received speaker honoraria fees from Amgen, Bayer, Novartis, Novonordisk, Organon, Servier, Recordati and Sanofi and consulting fees from Amgen, Bayer, Servier and Sanofi. A.G.S. has received speaker honoraria and/or consulting fees from AbbVie, Bayer, Eli Lilly, Novartis Amgen, Pfizer and Sanofi. A.S. received speaker honoraria from Bayer, Daiichi-Sankyo, Ferrer, Pfizer, Sanofi, Servier and consulting fees from Sanofi. M.J.C. received Consulting & speakers' fees from Amgen, Sanofi, Novartis and Bayer. J.A.B. has received funding for Educational activities from AstraZeneca, NovoNordisk and Sanofi. P. S. received Consulting & speakers' fees from Amgen, Sanofi, Pfizer and BMS. A.C. received honoraria and lecture fees from Sigma-Tau, Manarini, Kowa, Recordati, Eli Lilly, Astrazeneca, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, Amgen, Genzyme, Bayer, Sanofi, Regeneron and Daiichi-Sankyo. The other authors declare no potential conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Atherosclerotic heart disease is the leading cause of mortality and morbidity in the USA. Low density lipoprotein (LDL) has been the target for many hypolipidemic agents to modify atherosclerotic risk. Bempedoic acid is a novel hypolipidemic drug that inhibits the enzymatic activity of ATP citrate lyase in the cholesterol synthesis pathway. CLEAR Harmony, CLEAR Wisdom, CLEAR Tranquillity and CLEAR Serenity have shown safety and efficacy associated with long term administration of this drug. Studies have shown effectiveness in reducing LDL-C in both statin intolerant patients and in patients on maximally tolerated doses of statin. The fixed drug combination of bempedoic acid and ezetimibe in a recent phase III showed significant reduction in LDL compared with placebo, which might be a promising future for LDL reduction among statin intolerant patients. Bempedoic acid also reduced inflammatory markers like hs-CRP. Given these results, bempedoic acid alone and in combination with ezetimibe received the USA FDA approval for adults with heterozygous familial hypercholesterolaemia or established atherosclerotic cardiovascular disease. We present a comprehensive review exploring the underlying mechanism, pre-clinical studies, and clinical trials of bempedoic acid and discuss the potential future role of the drug in treating hyperlipidaemia.

Background: An elevated low-density lipoproteincholesterol (LDL-C) level is one of the most important modifiable cardiovascular risk factors. Despite potent combination treatment, the LDL‑C target values are not achieved in many high-risk patients., Objective: Presentation of the rationale for lowering LDL‑C, the current status of lipid-lowering treatment and established and novel approaches to lower LDL‑C., Current Data: Based on the large outcome trials with ezetimibe and antibodies against proprotein convertase subtilisin-kexin type 9 (PCSK9), the professional societies recommend LDL‑C target values depending on the individual cardiovascular risk. For patients with manifest atherosclerosis, the LDL‑C target value is < 55 mg/dL (1.4 mmol/L). The LDL‑C target values are only achieved in the minority of patients. The reasons for this include a lack of awareness among treating physicians, low medication adherence, restrictions in prescriptions and intolerance. On the basis of a healthy lifestyle, statins are the cornerstone of LDL-C-lowering treatment. If LDL‑C targets are not achieved, the cholesterol absorption inhibitor ezetimibe is additionally recommended. As a third step, PCSK9 antibodies are added. A novel drug to lower LDL‑C is the orally available bempedoic acid, which acts on the same metabolic pathway as statins but is specifically activated in the liver and not in the skeletal muscle. Another novel drug is inclisiran, which acts as an intracellular PCSK9 inhibitor through RNA interference. Inclisiran is administered subcutaneously only every 6 months and has potential advantages regarding adherence. According to the new recommendations, active substances should be combined and fixed-dose combinations should be used early for lowering of LDL‑C., Conclusion: Using established and novel LDL-C-lowering drugs, the recommended LDL‑C target values can be achieved in the majority of patients with a high cardiovascular risk., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Purpose of Review: Cardiovascular disease is the leading cause of death in the United States with incidence expected to increase in the coming decades. Recent years have produced a variety of new and novel therapeutics aimed at reducing the global burden of cardiovascular disease. This review highlights these recent advancements., Recent Findings: In addition to more rigorous therapeutic thresholds for traditional LDL lowering agents such as statins, recent studies have developed new pathways of lipid lowering for both typical cardiovascular disease and complex, genetic lipid disorders. This includes inhibition of the cholesterol synthesis enzyme ATP citrate lyase with bempedoic acid, prevention of PCSK9 mRNA translation with inclisiran, inhibition of the lipoprotein lipase inhibitor angiopoetin like 3 protein with evinacumab and the use of anti-sense oligonucleotides to lower lipoprotein(a) levels. Icosapent ethyl, while remaining a topic of debate and controversy, demonstrates efficacy in cardiovascular risk reduction when all available data are examined. Lastly fibrate therapy continues to produce negative results in terms of cardiovascular disease reduction., Summary: Recent years have yielded breadth and depth to cardiovascular treatments. This expanded armamentarium will allow for more effective and more consistent treatment and prevention of cardiovascular disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Dyslipidemia is a major modifiable risk factor for developing atherosclerotic cardiovascular disease. Despite increasing high intensity statin prescription and adherence to statin therapy, a considerable number of patients will not reach the guideline directed goals due to statin intolerance, lack of adherence or treatment efficacy. Several new lipid lowering medications have received approval by regulatory agencies in the past decade including proprotein convertase subtilisin/kexin type 9 modulators, ATP-citrate lyase inhibitors, angiopoietin-like 3 inhibitors, lomitapide, and icosapent ethyl. Although approved by regulatory agencies, these medications are still under-prescribed worldwide which may be related to cost issues, lack of cardiovascular outcome results, or clinicians not being familiar with their use. In this review, we propose a practical stepwise approach including each class' efficacy, place in therapy, adverse effects, warnings and precautions, and monitoring parameters. This information can help the clinicians to prescribing these novel lipid lowering medications to achieve treatment goals and reduce the risk of atherosclerotic cardiovascular disease. The aim is to shift the paradigm for high-intensity statins from watch and wait to initial combination therapy for high-risk patients., Competing Interests: Declaration of Competing Interest Hessam Kakavand: none declared Maryam Aghakouchakzadeh: none declared Ali Shahi: none declared Salim S. Virani: Grant support: Department of Veterans Affairs, NIH, World Heart Federation, Tahir and Jooma Family; Honorarium: American College of Cardiology (Associate Editor for Innovations, acc.org) Dave L. Dixon: none declared Benjamin W. Van Tassell: none declared Azita H. Talasaz: none declared., (Copyright © 2022. Published by Elsevier Inc.)

Purpose of Review: The aim of creating an orally active non-statin cholesterol-lowering drug was achieved with bempedoic acid, a small linear molecule providing both a significant low-density lipoprotein cholesterol (LDL-C) reduction and an anti-inflammatory effect by decreasing high-sensitivity C-reactive protein. Bempedoic acid antagonizes ATP citrate-lyase, a cytosolic enzyme upstream of HMGCoA reductase which is the rate-limiting step of cholesterol biosynthesis. Bempedoic acid is a pro-drug converted to its active metabolite by very-long-chain acyl-CoA synthetase 1 which is present mostly in the liver and absent in skeletal muscles. This limits the risk of myalgia and myopathy. The remit of this review is to give clinical insights on the safety and efficacy of bempedoic acid and to understand for whom it should be prescribed., Recent Findings: Bempedoic acid with a single daily dose (180 mg) reduces LDL-C by a mean 24.5% when given alone, by 18% when given on top of a major statin and by 38-40% when given in a fixed-dose combination with ezetimibe. Bempedoic acid does not lead to the risk of new-onset diabetes, and moderately improves the glycaemic profile. The extensive knowledge on bempedoic acid mechanism, metabolism and side effects has led to an improved understanding of the potential benefits of this agent and offers a possible alternative to cardiologists and clinical practitioners somewhat worn out today by the occurrence of the muscular side effects of statins., (© 2022. The Author(s).)

Background Lowering low-density lipoprotein cholesterol (LDL-C) levels decreases major cardiovascular events and is recommended for patients at elevated cardiovascular risk. However, appropriate doses of statin therapy are often insufficient to reduce LDL-C in accordance with current guidelines. In such cases, treatment could be supplemented with nonstatin lipid-lowering therapy. Methods and Results A systematic literature review and network meta-analysis were conducted on randomized controlled trials of nonstatin lipid-lowering therapy added to maximally tolerated statins, including statin-intolerant patients. The primary objective was to assess relative efficacy of nonstatin lipid-lowering therapy in reducing LDL-C levels at week 12. Secondary objectives included the following: LDL-C level reduction at week 24 and change in non-high-density lipoprotein cholesterol and apolipoprotein B at week 12. There were 48 randomized controlled trials included in the primary network meta-analysis. All nonstatin agents significantly reduced LDL-C from baseline versus placebo, regardless of background therapy. At week 12, evolocumab, 140 mg every 2 weeks (Q2W)/420 mg once a month, and alirocumab, 150 mg Q2W, were the most efficacious regimens, followed by alirocumab, 75 mg Q2W, alirocumab, 300 mg once a month, inclisiran, bempedoic acid/ezetimibe fixed-dose combination, and ezetimibe and bempedoic acid used as monotherapies. Primary end point results were generally consistent at week 24, and for other lipid end points at week 12. Conclusions Evolocumab, 140 mg Q2W/420 mg once a month, and alirocumab, 150 mg Q2W, were consistently the most efficacious nonstatin regimens when added to maximally tolerated statins to lower LDL-C, non-high-density lipoprotein cholesterol, and apolipoprotein B levels and facilitate attainment of guideline-recommended risk-stratified lipoprotein levels.

This article reviews the safety of statins and non-statin medications for management of dyslipidemia. Statins have uncommon serious adverse effects: myopathy/ rhabdomyolysis, which resolve with statin discontinuation, and diabetes, usually in people with risk factors for diabetes. The CVD benefit of statins far exceeds the risk of diabetes. Statin myalgia, without CK elevation, is likely caused by muscle symptoms with another etiology, or the nocebo effect. Notable adverse effects of non-statin medicines include injection site reactions (alirocumab, evolocumab, inclisiran), increased uric acid and gout (bempedoic acid), atrial fibrillation/flutter (omega-3-fatty acids), and myopathy in combination with a statin (gemfibrozil)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose of Review: There have been recent developments of novel therapeutic agents for lipid lowering. This article reviews treatment concepts for two of the newest lipid-lowering medications., Recent Findings: Bempedoic acid inhibits adenosine citrate lyase, decreasing intracellular lipogenesis. This oral medication is a prodrug and requires activation by enzymes present in hepatocytes but absent in the skeletal muscle. Clinical trials demonstrated additive benefit with statin therapy, and it was well tolerated in statin-intolerant populations. Inclisiran uses RNA interference to prevent translation of PCSK9 mRNA. Due to its stability, it can be given as an injection every 6 months and produces consistent, durable, and potent cholesterol lowering. Bempedoic acid and inclisiran represent new avenues of treatment for the prevention and treatment of cardiovascular disease. This will allow for more comprehensive care by addressing challenges with medication adherence, such as adverse effects to prior medications as well as ease of dosing., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Experimental and clinical studies have conclusively demonstrated that lowering elevated low-density lipoprotein cholesterol levels results in fewer major adverse cardiac events. Over the past few decades, statins have become the mainstay of lipid-lowering therapy, contributing significantly to the reduction of lipids, and providing patients with a cost-effective approach. However, with growing evidence in support of combination therapies providing increased benefits to certain patient populations, such as those intolerant to statins, there is an urgent need to investigate the safety and efficacy of alternative lipid-lowering drugs. In this paper, we review the current alternative and adjuvant cholesterol targeting agents. We further discuss the clinical trials that have evaluated the safety and efficacy of these alternative and adjuvant therapies as well as their implications for practical use. These drugs target levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or lipoprotein(a) as treatments for hyperlipidemia and atherosclerotic cardiovascular disease., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: Despite the high incidence of patients with statin tolerance problems, randomized evaluations of nonstatin oral treatment options for lowering of low-density lipoprotein cholesterol (LDL-C) in this population are sparse., Objective: To assess the LDL-C lowering effect of bempedoic acid in patients not taking statins., Methods: This was a pooled analysis of data from patients enrolled in four phase 3 bempedoic acid studies (12 to 52 weeks in duration) who were not taking concomitant statins (Phase 3 No Statin Cohort) and a phase 3 bempedoic acid plus ezetimibe fixed-dose combination study (BA+EZE FDC No Statin Cohort). The primary endpoint for all studies was the percent change from baseline to week 12 in LDL-C levels. Safety and tolerability were assessed by laboratory values and adverse events., Results: In the Phase 3 No Statin Cohort, bempedoic acid (n = 394) lowered LDL-C levels at week 12 significantly more than placebo (n = 192; -26.5% [95% CI, -29.7%, -23.2%]; P<0.001). The fixed-dose combination of bempedoic acid with ezetimibe lowered LDL-C by 39.2% (95% CI, -51.7% to -26.7%; P<0.001). Muscle-related disorders occurred at a rate of 26.4 and 28.6 per 100 person-years with bempedoic acid and placebo, respectively., Conclusions: In patients with hypercholesterolemia unable to take statins, bempedoic acid lowered LDL-C levels by a mean of 26.5% vs placebo and bempedoic acid + ezetimibe fixed-dose combination lowered LDL-C by 39.2%. The treatments were generally well tolerated, suggesting that bempedoic acid may be efficacious and well tolerated in this challenging-to-treat patient population., (Copyright © 2022. Published by Elsevier Inc.)

Patients at high or very high cardiovascular risk should have a LDL cholesterol level as low as possible, a target that may be difficult to be reached with statin monotherapy, especially when this treatment is not well tolerated. It is generally recommended to use pharmacological combinations to reach more and more strict objectives. Bempedoic acid is a new oral cholesterol-lowering medication that reduces hepatic cholesterol synthesis by inhibiting the enzyme adenosine triphosphate (ATP)-citrate lyase enzyme. Because this medication is a prodrug that is selectively activated in the liver, it is deprived of any muscular adverse effect. This article summarizes the mode of action, pharmacokinetics, efficacy, safety profile, indications and reimbursement conditions of bempedoic acid. This novel cholesterol-lowering drug is indicated in combination with statins (with or without ezetimibe) in patients who do not attain LDL goals despite administration of a statin at the maximum tolerated dose or in case of statin intolerance.

An increase in the level of cholesterol day by day is easily seen in most people just because of poor life style, food with high cholesterol, lack of physical work, etc. There are lots of molecules available, which lower down the cholesterol level. In this field a new molecule has been introduced that is bimpedoic acid. Researches indicate that bempedoic acid has the same mechanism of action as statins, which means that it also inhibits the HMG-CoA reductase enzyme. This article is my best collection of published scientific data on bempedoic acid till now. It also includes the chemistry, pharmacodynamic and pharmacokinetic parameters of the mentioned new molecule., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Lipid management for prevention and treatment of cardiovascular disease remains insufficient for many with currently available therapies., Objective: Evaluate real-world use of bempedoic acid., Methods: Retrospective study of patients in our Center for Preventive Cardiology who were prescribed bempedoic acid between February 2020 and July 2021. Patients were managed according to clinical standards of care, with lipid assessments at months ≤3, 6, and 12 post-bempedoic acid initiation., Results: Seventy-three patients were prescribed bempedoic acid, with 64 initiating therapy. The majority had atherosclerosis (89%), familial hypercholesterolemia (64%), and statin intolerance (74%), with baseline low-density lipoprotein cholesterol (LDL-C) 120 mg/dL. Prior authorization requests and appeals of denials were required in 90% and 19% of cases, respectively. Cost-mitigating strategies reduced median monthly drug costs from $432 pre-insurance approval to $80 post-insurance approval, to $10 after financial assistance intervention. Bempedoic acid reduced LDL-C by -36.7%, -31%, and -20.3% at ≤3, 6, and 12, respectively, with >20% achieving LDL-C <70 mg/dL. There was substantial inter-individual heterogeneity in LDL-C lowering. We observed high rates of drug discontinuation (35.9%), mostly related to treatment-emergent adverse events (TEAEs) (32.8%), primarily musculoskeletal complaints. Use of reduced dose bempedoic acid (<180 mg) was associated similar LDL-C lowering but TEAE and drug discontinuation were still common., Conclusions: Real-world use of bempedoic acid was limited by insurance and cost barriers requiring substantial post-prescription interventions. In patients at heightened risk for atherosclerotic events and statin intolerance, bempedoic acid was associated with clinically meaningful LDL-C lowering, but high rates of TEAEs and drug discontinuations., Competing Interests: Declaration of Competing Interest BAW reports institutional grant from Akcea. PBD has been a consultant for Akcea, Amryt, Esperion, Kaneka, Regeneron, and has received institutional research grants from Regeneron, Regenxbio, and Retrophin. JQP reports clinical trial work with Amgen, Novartis, and Akcea. SF is an employee of Regeneron and has no current disclosures. Prior disclosures were for single-event consultations with Amarin, Kowa, Novo Nordisk, Esperion, Bio89, and Novartis., (Copyright © 2021. Published by Elsevier Inc.)

Purpose of Review: For many years, the lipid-lowering armamentarium consisted of statins and/or ezetimibe and/or bile acid sequestrants and/or fibrates. Now, with the availability of new drugs mostly injectables, the field has changed and the role of oral non-statin drugs (including bempedoic acid) must be reevaluated., Recent Findings: Ezetimibe remains a very important combination partner for statins with continuously increasing treatment numbers. Bempedoic acid is another interesting combination partner for statin/ezetimibe or ezetimibe alone but lacks in contrast to ezetimibe evidence from outcome trials. The role of fibrates is less clear as they have shown disappointing results in outcome trials but may still be used in selected, high-risk patients with combined dyslipidemia. Bile acid sequestrants are now rarely used as there are stronger, better tolerable ways to lower LDL-cholesterol. With the introduction of new injectable lipid-lowering drugs, some oral drugs such as ezetimibe and bempedoic acid still have an important spot in our treatment algorithm others such as fibrates have a less clear role while again others are now rarely used., (© 2021. The Author(s).)

Purpose: The lowered LDL-C treatment goal of the 2019 European Society of Cardiology dyslipidemia guidelines results in a significant increase in the projected need for cost-intensive proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Addition of bempedoic acid (BA) to established oral lipid-lowering medication (LLM) has the potential to enable affordable LDL-C goal attainment, particularly in patients with statin intolerance (SI). The goal of this study was to quantify the target populations for BA and PCSK9 inhibitors as well as the related treatment costs to achieve the LDL-C goal of <55 mg/dL and a ≥50% reduction assuming the addition of BA to LLM., Methods: This study included 1922 patients with coronary artery disease (CAD) from the contemporary observational cohort study INTERCATH. A Monte Carlo simulation incorporating an algorithm adding sequentially a statin, ezetimibe, optionally BA, and a PCSK9 inhibitor was applied to achieve the LDL-C treatment goal, with consideration of both partial and total SI. Two scenarios were simulated for both a moderate (2% full and 10% partial) and a high (12% full) rate of SI: (1) without BA; and (2) with BA., Findings: Patients' mean age was 69.3 years, and the median baseline LDL-C level was 86.0 mg/dL. The need for a PCSK9 inhibitor would be 41.4% for a moderate rate of SI and 46.1% for a high rate of SI. Addition of BA would: (1) reduce the need for a PCSK9 inhibitor to 25.3% and 29.4%, thus lowering the annual overall treatment cost incurred through PCSK9 inhibitor ± BA per 1 million patients with CAD by 13.3% and 10.5%; (2) lower the cost per prevented event in the entire cohort (-5.0% and -6.3%), although at the price of fewer prevented events (-8.7% and -4.5%); and (3) reduce the cost per prevented event (-6.8% for both rates of SI) while preventing more events (7.6% and 6.9%) in the subpopulation of patients with full SI., Implications: Use of BA is projected to reduce the need for PCSK9 inhibitors as well as the treatment cost for add-on LLM. The subpopulation of patients with full SI might profit particularly., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose of Review: Elevation in apolipoprotein B-containing lipoproteins in the blood is a cause of atherosclerosis. Statins have changed the preventive cardiology scenario, and more recently monoclonal proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors were added as robust agents to further reduce pro-atherogenic lipoproteins and therefore prevent cardiovascular events. However, despite this many dyslipidemic individuals persist with inadequate LDL-C levels and still at risk. The purpose of this review was to discuss current status and describe advances in therapies beyond statins and monoclonal PCSK9 inhibitors., Recent Findings: Ezetimibe and lomitapide have been used for many years to further reduce LDL-C and longer term data reinforce their safety. Bempedoic acid, an inhibitor of adenosine triphosphate-citrate lyase, has been shown to add LDL-C reduction on top of statins and ezetimibe, furthermore it may be an alternative for statin intolerant patients. Inclisiran is a small interfering ribonucleic acid inhibitor that reduces the hepatic production of PCSK9 that induces robust LDL-C lowering, similar to monoclonal antibodies, with the advantage of 2 or 3 injections per year. So far, no safety signs were seen with its use. Evinacumab, a monoclonal antibody that binds angiopoietin-like protein 3 (ANGPTL3), induces robust LDL-C lowering in either homozygous familial hypercholesterolemia or severe hypercholesterolemia patients with good tolerability. Many high-risk individuals persist with elevated LDL-C, newer medications further lower LDL-C on top of standard lipid-lowering therapies and are well tolerated. Ongoing clinical trials may prove if these novel medications will reduce cardiovascular events with safety.