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Importance: Many patients with coronary artery disease (CAD) do not achieve the guideline-directed goals for low-density lipoprotein cholesterol (LDL-C) levels., Objective: To estimate reductions in the rates of adverse events associated with CAD in a large US military veteran population that may be achieved through use of optimized statin therapy alone or with ezetimibe compared with the prevailing lipid-lowering therapy (LLT)., Design, Setting, and Participants: In this observational cohort study, US military veterans with CAD were identified by coronary angiography between June 2015 and September 2020 across 82 US Department of Veterans Affairs health care facilities., Exposures: The exposures were observed LLT, LLT with an optimized statin regimen, and LLT with optimized statin and ezetimibe., Main Outcomes and Measures: Observed rates of death, myocardial infarction, stroke, and coronary revascularization, and potential reductions in those outcomes with optimized LLT based on expected further reductions in LDL-C levels and application of formulas from The Cholesterol Treatment Trialists' Collaboration., Results: The analysis cohort comprised 111 954 veterans (mean [SD] age, 68.4 [8.8] years; 109 390 men [97.7%]; 91 589 White patients [81.8%]; 17 592 Black patients [15.7%]). The median (IQR) observation period for this study was 3.4 (2.1-4.0) years. At the time of index angiography, 66 877 patients (59.7%) were treated with statin therapy, and 623 patients (0.6%) were treated with ezetimibe. At 6 months, the number of patients with statin prescriptions increased to 74 400 (68.7%), but the number of patients with high-intensity statin prescriptions was only 57 297 (52.9%). At 6 months, ezetimibe use remained low (n = 1168 [1.1%]), and LDL-C levels were 70 mg/dL or more in 56 405 patients (52.1%). At 4 years, observed incidences of death, myocardial infarction, stroke, and coronary revascularization were 21.6% (95% CI, 21.3%-21.8%), 5.0% (95% CI, 4.9%-5.2%), 2.2% (95% CI, 2.1%-2.3%), and 15.4% (95% CI, 15.2%-15.7%), respectively. With optimized statin treatment, projected absolute reductions in these incidences were 1.3% (95% CI, 0.9%-1.7%), 0.8% (95% CI, 0.7%-1.0%), 0.2% (95% CI, 0.1%-0.3%), and 2.3% (95% CI, 2.0%-2.7%), respectively. With optimized statin and ezetimibe treatment, projected absolute reductions were 1.8% (95% CI, 1.2%-2.4%), 1.1% (95% CI, 0.9%-1.3%), 0.3% (95% CI, 0.2%-0.4%), and 3.1% (95% CI, 2.6%-3.6%), respectively., Conclusions and Relevance: In this cohort study of veterans with CAD, suboptimal LLT was prevalent in the clinical setting. Optimization of statin therapy was projected to produce clinically relevant reductions in the risks of death and cardiovascular events. Despite a lesser lipid-lowering efficacy of ezetimibe, its widespread use on a population level in conjunction with optimized statin therapy may be associated with further meaningful reductions in cardiovascular risk.

Although studies of nonstatin lipid-lowering therapies have demonstrated cardiovascular benefits; whether these benefits provide good value has not been evaluated in type 2 diabetes mellitus patients. A systematic review was performed to include studies on the cost-effectiveness of non-statin lipid-lowering therapies in type 2 diabetes mellitus patients with/without cardiovascular disease. Thirteen studies were included; ezetimibe (n = 8), proprotein convertase subtilisin/kexin type 9 inhibitors (n = 4), fenofibrate (n = 2), nicotinic acid (n = 1), extended-release niacin/laropiprant (n = 1), and icosapent ethyl (n = 1). Six studies considered ezetimibe + statin to be a cost-effective compared to statins monotherapy, three studies suggested that proprotein convertase subtilisin/kexin type 9inhibitors + statins were not cost-effective compared to statin + ezetimibe. Fenofibrate was a cost-effective either as monotherapy or combined with a statin compared to statin or fenofibrate monotherapy. Nicotinic acid and proprotein convertase subtilisin/kexin type 9 compared to statin monotherapy were also cost-effective. Icosapent ethyl was cost-effective compared to standard care but not using the wholesale acquisition cost., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This review aims to examine the complex interaction between dyslipidemia, platelet function, and related drug treatments. In particular, the manuscript provides an overview of the effects of major hypolipidemic drugs on platelet function. Indeed, growing evidence supports the view that statins, ezetimibe, PCSK9 inhibitors, inclisiran, and icosapent ethyl also act as antithrombotics. It is known that platelets play a key role not only in the acute phase of coronary syndromes but also in the early phase of atherosclerotic plaque formation. The goal of cholesterol-lowering therapy is to reduce cardiovascular events. The direct effects of cholesterol-lowering drugs are widely described in the literature. Lowering LDL-c (low-density lipoprotein cholesterol) by 1 mmol/L results in a 22-23% reduction in cardiovascular risk. Numerous studies have examined the direct antithrombotic effects of these drugs on platelets, endothelium, monocytes, and smooth muscle cells, and thus, potentially independent of blood LDL-cholesterol reduction. We reviewed in vitro and in vivo studies evaluating the complex interaction between hypercholesterolemia, hypertriglyceridemia, platelet function, and related drug treatments. First, we discussed the role of statins in modulating platelet activation. Discontinuation of statin therapy was associated with increased cardiovascular events with increased ox-LDL, P-selectin, and platelet aggregation. The effect of PCSK9-I (inhibitors of proprotein convertase subtilisin/kexin type 9, PCSK9 involved in the degradation of LDL receptors in the liver) was associated with a statistically significant reduction in platelet reactivity, calculated in P2Y12 reaction units (PRU), in the first 14 days and no difference at 30 days compared to placebo. Finally, in patients with hypertriglyceridemia, the REDUCE-IT study showed that icosapent ethyl (an ethyl ester of eicosapentaenoic acid that reduces triglyceride synthesis and improves triglyceride clearance) resulted in a 25% reduction in ischemic events and cardiovascular death. However, to date, there is not yet clear clinical evidence that the direct antithrombotic effects of the drugs may have a beneficial impact on outcomes independently from the reduction in LDL-C or triglycerides.

Background: Obicetrapib, a selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein particles, and apolipoproteins, when added to high-intensity statin in patients with dyslipidemia., Objective: To evaluate the safety and lipid-altering efficacy of obicetrapib plus ezetimibe combination therapy as an adjunct to high-intensity statin therapy., Methods: This double-blind, randomized, phase 2 trial administered 10 mg obicetrapib plus 10 mg ezetimibe (n = 40), 10 mg obicetrapib (n = 39), or placebo (n = 40) for 12 weeks to patients with LDL-C >70 mg/dL and triglycerides (TG) <400 mg/dL, on stable high-intensity statin. Endpoints included concentrations of lipids, apolipoproteins, lipoprotein particles, and proprotein convertase subtilisin kexin type 9 (PCSK9), safety, and tolerability., Results: Ninety-seven patients were included in the primary analysis (mean age 62.6 years, 63.9% male, 84.5% white, average body mass index of 30.9 kg/m 2 ). LDL-C decreased from baseline to week 12 by 63.4%, 43.5%, and 6.35% in combination, monotherapy, and placebo groups, respectively (p<0.0001 vs. placebo). LDL-C levels of <100, <70, and <55 mg/dL were achieved by 100%, 93.5%, and 87.1%, respectively, of patients taking the combination. Both active treatments also significantly reduced concentrations of non-HDL-C, apolipoprotein B, and total and small LDL particles. Obicetrapib was well tolerated and no safety issues were identified., Conclusion: The combination of obicetrapib plus ezetimibe significantly lowered atherogenic lipid and lipoprotein parameters, and was safe and well tolerated when administered on top of high-intensity statin to patients with elevated LDL-C., (Copyright © 2023. Published by Elsevier Inc.)

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).)

Background: Lipid-lowering therapy (LLT) in patients with cardiovascular disease (CVD) is insufficient despite clear guideline recommendations. Lipid clinics have specialized in patients with dyslipidemia, but the magnitude and reduction of low-density lipoprotein cholesterol (LDL-C) in lipid clinics has not yet been studied in depth., Objective: To assess LDL-C reduction in very high-risk CVD patients achieved in a lipid clinic through different forms of LLT in comparison to standard care without the initiation of PSCK9 inhibitors., Methods: Data from 96 lipid clinic patients were analyzed retrospectively and compared to 84 standard care patients. Very high-risk patients were defined according to the European Society of Cardiology (ESC). Different combinations of LLT focusing on statins and ezetimibe were investigated. Achievement of LDL-C treatment goals according to ESC guidelines as well as LDL-C reduction were assessed., Results: Baseline and follow-up data of 180 very high-risk CVD patients (mean age 67.7 (±9.8) y; 60.6% male) were used. Achievement of the LDL-C goal in lipid clinic patients increased significantly from 14.6% at baseline to 41.7% at the latest visit (p<0.001) while standard care patients improved from 21.4% to 33.3% (p=0.08). The largest relative LDL-C reduction via an adjustment in LLT was achieved by initiation of high-intensity statins (50.8 ± 4.9%, n = 5, p < 0.05)., Conclusion: Treatment in a lipid clinic leads to a superior LDL-C goal achievement in very high-risk CVD patients as compared to standard care with the highest reduction under LLT with high-intensity statins and ezetimibe. Referral algorithms have to be established for high-risk patients., (Copyright © 2023. Published by Elsevier Inc.)

Sustained inflammation after a traumatic spinal cord injury (TSCI) triggers oxidative stress and neuronal apoptosis, hindering functional recovery. Ezetimibe (EZE) has been reported to have anti-inflammatory and antioxidative properties in hepatology-related diseases, but its potential role in SCI remains unclear. In this study, we evaluated the therapeutic effect of EZE on inflammatory microglia and in an SCI model and elucidated the underlying mechanism. First, we stimulated the BV2 microglia cell line with LPS, and we also induced moderate spinal cord injuries in adult male C57BL/6 mice. Both the cells and mice were treated with EZE, and we investigated inflammation, oxidative stress, neurologic damage, and motor function in vitro and in vivo, respectively. Our findings demonstrated that EZE administration attenuates inflammation in microglia by regulating the AMPK/Nrf2 axis. Furthermore, EZE treatment reduced inflammation and oxidative stress levels in the injured spinal cord. Additionally, treatment with EZE decreased glial scarring and improved motor function recovery, indicating the protective role of EZE in SCI. EZE was found to have anti-inflammatory and antioxidative effects on SCI, and it modulated the AMPK/Nrf2 pathway in microglia. Moreover, EZE prevented histological destruction of the spinal cord tissue. In conclusion, EZE shows promise as a drug to protect neurologic integrity following post-SCI.

The objective was to assess the role of the combination approach with ezetimibe 10 mg/simvastatin 20 mg versus atorvastatin 40 mg in predicting atrial fibrillation (AF) in type 2 diabetes mellitus patients with acute coronary syndrome and acute ischemic stroke. The authors formed a cohort of diabetic patients with extensive vascular diseases between 2000 and 2018 using data from the National Health Insurance Research Database in Taiwan. AF was the outcome of interest in this study. Cox proportional hazards regression analysis was performed to estimate the hazard ratios and 95% confidence intervals in the analysis. After controlling for sex, age, comorbidities and medications, the patients coexisting with type 2 diabetes mellitus, acute coronary syndrome and acute ischemic stroke with ezetimibe 10 mg/simvastatin 20 mg treatment were not significantly at risk of AF, compared to the patients with atorvastatin 40 mg treatment (adjusted hazard ratio, 0.85; 95% confidence interval, 0.52-1.38). A similar effect for AF risk between ezetimibe 10 mg/simvastatin 20 mg and atorvastatin 40 mg users was observed in the current investigation., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

YES. In patients with known cardiovascular disease (CVD), ezetimibe with a statin decreases major adverse cardiovascular events (MACE) but has no effect on all-cause and cardiovascular mortality, compared to a statin alone (strength of recommendation [SOR], A; meta-analysis of randomized controlled trials [RCTs] including 1 large RCT). In adults with atherosclerotic CVD (ASCVD), the combination of ezetimibe and a moderate-intensity statin (rosuvastatin 10 mg) was noninferior at decreasing cardiovascular death, major cardiovascular events, and nonfatal stroke, but was more tolerable, compared to a high-intensity statin (rosuvastatin 20 mg) alone (SOR, B; 1 RCT).

The management of patients with coronary artery disease (CAD) is complex, especially after they have been discharged from hospital after an acute coronary syndrome (ACS), because each patient may have numerous healthcare providers, and follow-up after discharge may be disjointed, or even incomplete. During follow-up after ACS, few patients have treatment intensification; rather, there is actually a major tendency towards reductions in treatment intensity, to the potential detriment of outcomes. We present here guidance from a French expert panel for the optimal management of lipid-lowering therapy up to 1 year after ACS. A French expert panel provides a practical guide for the implementation of guidelines for the management of post-ACS patients in routine practice, from hospital discharge up to one year after the index event, focusing in particular on the achievement of target LDL cholesterol (LDL-C) levels. We discuss the early follow-up (up to 6 months after discharge) and review the lipid-lowering treatment strategies that should be implemented. We discuss the evidence underpinning the prescription of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as well as recent evidence about icosapent ethyl. This review should facilitate implementation of a clear and effective lipid-lowering strategy for all patients after ACS. The panel recommends early use of high-intensity statins, in combination with ezetimibe for patients with LDL-c above 100 mg/dL at baseline. PCSK9i should be rapidly added during the first 3 months in high-risk diabetic patients with residual LDL-C above 70 mg/dL (with further benefit for those with residual LDL-C above ≥100 mg/dL) despite maximal tolerated dose statin and ezetimibe, patients with recent ACS, and patients with recurrent ischemic events under optimal medical therapy, multivessel coronary disease (MVD) and/or polyvascular disease (PVD), especially symptomatic PAD diabetic patients. Concerning icosapent ethyl (EPA), this drug should be introduced in patients ≥45 years of age with clinical atherosclerotic cardiovascular disease (ASCVD) or already on high-intensity or maximally tolerated statin therapy or with fasting triglycerides 135-499 mg/dL (with or without ezetimibe). Lipid-lowering treatment should be introduced as early as possible to obtain a rapid and profound decrease of LDL-c from baseline, using high-intensity statins (atorvastatin or rosuvastatin) and ezetimibe in fixed combination before discharge. Then, the strategy should be rapidly intensified by adding a PCSK9 inhibitor if the patient does not reach LDL-c levels below 55 mg/dL. We advocate this intensive strategy, which has demonstrated a further reduction in ischemic events, without safety concerns, even for patients who reach very low LDL-cholesterol levels. This approach, comprising few therapeutic steps, aims to rapidly reach LDL-c goals, improve patient compliance, and is an efficient method to fight therapeutic inertia, which remains a major issue.

Background: Guidelines advocate for intensive lipid-lowering in patients with atherosclerotic cardiovascular disease (ASCVD). In May 2020, evolocumab, a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, became government subsidised in Australia for patients with ASCVD requiring further low-density lipoprotein cholesterol (LDL-C) lowering., Aim: To identify barriers to prescribing PCSK9 inhibitors in hospitalised patients with ASCVD., Methods: A retrospective 3-month, single-site, observational analysis was conducted in consecutive patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery. Lipid-lowering therapy prescriptions, including PSCK9 inhibitors, were assessed using electronic medical records, compared against the Australian Pharmaceutical Benefits eligibility criteria, and barriers to PCSK9 inhibitor use identified., Results: Of 331 patients, 244 (73.7%) underwent PCI and 87 (26.3%) underwent CABG surgery. A lipid profile during or within 8 weeks of admission was measured for 202 (82.8%) patients undergoing PCI and 59 (67.8%) undergoing CABG surgery. In patients taking high-intensity statins on admission (n = 109), LDL-C ≥1.4, ≥1.8 and >2.6mmol/L was seen in 64 (58.7%), 44 (40.4%) and 19 (17.4%) patients respectively. High-intensity statin prescribing at discharge was high (>80%); however, ezetimibe was initiated in zero patients with LDL-C ≥1.4 mmol/L. There was variable advice given by clinicians for LDL-C targets. No patients met the criteria for subsidised PSCK9 inhibitor therapy, largely due to lack of qualifying lipid levels following combined statin and ezetimibe therapy., Conclusion: Prescribing of non-statin LDL-C-lowering therapies remains low in patients with ASCVD. Underprescribing of ezetimibe and suboptimal lipid testing rates are barriers to accessing subsidised PCSK9i therapy using current Australian eligibility criteria., (© 2022 Royal Australasian College of Physicians.)

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.)

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.)

Aim    To evaluate the frequency and structure of lipid-lowering therapy and of achieving the goal of low-density lipoprotein cholesterol (LDL-C) in patients with very high cardiovascular risk (CVR) who were monitored at the outpatient stage. Material and methods    A retrospective snapshot analysis was performed by continuous sampling method for 136 medical records of outpatient patients (71 men, 65 women) aged 42 to 91 years [median, 68 years; 25th and 75th percentiles (59; 78)].Results    134 (98,53 %) patients took statins; 8 (5.88 %) patients took a combination of statin and ezetimibe; 2 (1.47 %) patients took proprotein convertase subtilisin/kexin type 9 enzyme inhibitors (PCSK9): 2 (1.47 %) patients took evolocumab and 1 (0.74%) of 2 PCSK9-treated patients took a combination of PCSK9 inhibitor and statin. Atorvastatin at a dose of 20 (20; 40) mg as recommended at the hospital was the most frequently prescribed statin. 5 (3.68%) patients achieved the goal LDL-C of ≤1.4 mmol/l.Conclusion    Statins prevail in the structure of lipid-lowering therapy in patients with very high CVR. The frequency of combination therapy (statin/ezetimibe, 5.88%; PCSK9 inhibitor/statin, 0.74%) and PCSK9 inhibitors was noted to be low. Only 3.68% of patients achieved the goal LDL-C during the lipid-lowering treatment.

Background: The gap between the targets recommended by current guidelines and the lipid values observed in the real world among patients at very high or extreme cardiovascular risk has called into question the effectiveness of the stepwise lipid-lowering strategy. The BEST (Best Evidence with Ezetimibe/statin Treatment) project supported an expert panel of Italian cardiologists to investigate the different clinical-therapeutic pathways in the management of the residual lipid risk of post-acute coronary syndrome (ACS) patients at discharge and to analyze potential critical issues., Methods: Among the members of the panel, 37 cardiologists were selected to participate in a consensus process using the mini-Delphi technique. A 9-statement questionnaire, focusing on the early use of combination lipid-lowering therapies in post-ACS patients, was built up based on a previous survey that involved all members of the BEST project. For each proposed statement, participants anonymously expressed their personal level of disagreement/agreement, according to a 7-point Likert scale. The relative degree of agreement and consensus was calculated based on the median and the 25th percentile values and the interquartile range (IQR). The administration of the questionnaire was repeated twice: the second one after general discussion and analysis of the answers given in the first round in order to obtain as much consensus as possible., Results: With the exception of a single item, the responses of the participants were in agreement with a broad consensus already at the first round with a median value of 6, a 25th percentile of 5 and an IQR of 2. This trend resulted more evident at the second round (median 7, 25th percentile 6, IQR 1). In particular, there was unanimous agreement (median 7, IQR 0-1) on the statements in favor of a lipid-lowering therapy that guarantees the achievement of the targets as much and as soon as possible by the systematic early utilization of the high-dose/intensity statin + ezetimibe combination and, when needed, PCSK9 inhibitors. The percentage of the experts who changed their responses between the first and second round was 39% overall, ranging from 16% to 69%., Conclusions: According to the mini-Delphi results, there is a broad agreement and consensus to manage the lipid risk in post-ACS patients by lipid-lowering treatments that guarantee an early and "robust" lipid reduction which can be achieved only by the systematic use of combination therapies.

Nearly two-thirds of individuals with atherosclerotic cardiovascular disease (ASCVD) do not reach target low-density lipoprotein cholesterol despite statin therapy. Three novel lipid-lowering therapies have proven to further reduce ASCVD beyond statins, including: ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), and icosapent ethyl. This study evaluated the use of these three agents in 728,423 individuals with ASCVD from 89 US health systems from 01/2018 through 03/2021 using the electronic health record. As of 2021, only 6.0% of ASCVD patients were on ezetimibe, 1.6% were on a PCSK9i, and 1.3% on icosapent ethyl, with utilization only marginally increasing over the study period. Addressing the underutilization of non-statin lipid-lowering therapy for secondary prevention is a critical step in improving the treatment gap of patients with residual risk of ASCVD., (Copyright © 2023. Published by Elsevier Inc.)

Background: Even though many oral glucose-lowering or lipid-lowering agents have already been reported to improve hepatic steatosis to some degree, which drug had a more beneficial effect on hepatic steatosis among those drugs has not been precisely explored. We analysed the effect of empagliflozi, a selective sodium-glucose cotransporter 2 inhibitor, and ezetimibe on developing hepatic steatosis., Methods and Results: Using 4005,779 patients with type 2 diabetes mellitus (T2DM) or dyslipidemia provided by the Korean National Health Insurance Service (NHIS) between January 2015 and December 2015, we analyzed the odds ratio (OR) of fatty liver development (fatty liver index [FLI] >60). Additionally, we examined the metabolic effects of ezetimibe and empagliflozin in mice fed with a choline-deficient high-fat diet, mimicking the features of human NAFLD. The experiment for agents was performed for the non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) mouse models independently. In the NHIS data, ORs for the development of fatty liver were significantly lower in all treatment groups than in the reference group, which did not receive ezetimibe or empagliflozin. (Ezetimibe therapy; OR=0.962, empagliflozin therapy; OR=0.527, ezetimibe plus empagliflozin; OR=0.509 compared to reference therapy). Unlike non-alcoholic steatohepatitis mouse model, ezetimibe, empagliflozin, and combination therapy also reduced liver steatosis in the non-alcoholic fatty liver mouse model., Conclusions: Compared with other agents, empagliflozin and/or ezetimibe treatment reduced the risk of developing hepatic steatosis. Our data suggest that empagliflozin or ezetimibe can be primarily considered in type 2 DM or dyslipidemia patients to prevent hepatic steatosis., Competing Interests: Conflict of interest statement All authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Dyslipidemia is a major risk factor for stroke, following hypertension, diabetes, and smoking, and is an important risk factor for the prevention and treatment of coronary artery disease and peripheral vascular disease, including stroke. Recent guidelines recommend considering low-density lipoprotein cholesterol (LDL-C)-lowering therapies, such as statins (preferably), ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to prevent the occurrence or recurrence of stroke, adhering to the "lower is better" approach. In this review, we examined the evidence supporting lipid-lowering medications like statins, ezetimibe, and PCSK9 inhibitors for secondary stroke prevention and dyslipidemia management in different stroke subtypes. Stroke guidelines advocate for administering the maximum tolerable dose of statins as the primary treatment and as soon as possible despite the potential for new-onset diabetes mellitus and possible muscle and liver toxicity due to their demonstrated benefits in secondary prevention of cardiovascular diseases and mortality reduction. When statin use is insufficient for LDL lowering, ezetimibe and PCSK9 inhibitors are recommended as complementary therapies. It is essential to establish lipid-lowering therapy goals based on the stroke subtype and the presence of comorbidities.

Objectives: Attainment of low-density lipoprotein cholesterol (LDL-C) therapeutic goals in statin-treated patients remains suboptimal. We quantified the health economic impact of delayed lipid-lowering intensification from an Australian healthcare and societal perspective., Methods: A lifetime Markov cohort model (n = 1000) estimating the impact on coronary heart disease (CHD) of intensifying lipid-lowering treatment in statin-treated patients with uncontrolled LDL-C, at moderate to high risk of CHD with no delay or after a 5-year delay, compared with standard of care (no intensification), starting at age 40 years. Intensification was tested with high-intensity statins or statins + ezetimibe. LDL-C levels were extracted from a primary care cohort. CHD risk was estimated using the pooled cohort equation. The effect of cumulative exposure to LDL-C on CHD risk was derived from Mendelian randomization data. Outcomes included CHD events, quality-adjusted life-years (QALYs), healthcare and productivity costs, and incremental cost-effectiveness ratios (ICERs). All outcomes were discounted annually by 5%., Results: Over the lifetime horizon, compared with standard of care, achieving LDL-C control with no delay with high-intensity statins prevented 29 CHD events and yielded 30 extra QALYs (ICERs AU$13 205/QALY) versus 22 CHD events and 16 QALYs (ICER AU$20 270/QALY) with a 5-year delay. For statins + ezetimibe, no delay prevented 53 CHD events and gave 45 extra QALYs (ICER AU$37 271/QALY) versus 40 CHD events and 29 QALYs (ICER of AU$44 218/QALY) after a 5-year delay., Conclusions: Delaying attainment of LDL-C goals translates into lost therapeutic benefit and a waste of resources. Urgent policies are needed to improve LDL-C goal attainment in statin-treated patients., (Copyright © 2022. Published by Elsevier Inc.)

Background/aim: To provide longitudinal data on the evolution of lipid levels and the intake of lipid-lowering therapies in patients with stable coronary artery disease., Methods: Single-centre retrospective study with inclusion of 350 patients with a first coronary artery event in 2014 or earlier and outpatient cardiac clinic follow-up in 2015 and 2019. Lipid levels were collected within a time frame of 3 months of their visits.This retrospective study protocol (2020.086) was approved by the ethical committee and by the Data Privacy Officer of AZ Maria Middelares Ghent. For this type of study, formal consent is not required, following local law and regulations., Results: Average LDL levels were 82 (±26) mg/dl in 2015 and 70 (±24) mg/dl in 2019 ( p  < 0.001). Most patients included were already on statin treatment before inclusion in the trial (94%), with a significant increase in high-intensity statin use (45% vs. 58%) after a 5-year follow-up. At the same time, we observed a significant increase in ezetimibe use (in combination with statin therapy or in monotherapy) (8% vs. 22%) during follow-up. LDL ≤70 mg/dl was 34% in 2015 and 53% in 2019. LDL ≤55 mg/dl was 13% in 2015 and 28% in 2019., Conclusion: This study shows significant intensification of lipid-lowering therapy use during follow-up, and a significant lipid level lowering after 5-year follow-up, in an outpatient cardiac clinic follow-up. Further improvement in lipid control is still desirable, especially after the European Society of Cardiology recommend stricter lipid levels in the 2021 Prevention Guidelines.

Introduction: Almost one third of U.S. adults have elevated low-density lipoprotein cholesterol, increasing their risk of atherosclerotic cardiovascular disease. The 2018 American College of Cardiology/American Heart Association Multisociety Cholesterol Management Guideline recommends maximally tolerated statin for those at increased atherosclerotic cardiovascular disease risk and add-on therapies (ezetimibe and PCSK9 inhibitors) in those at very high risk and low-density lipoprotein cholesterol ≥70 mg/dL. Prescription fill trends are unknown., Methods: Using national outpatient retail prescription data from the first quarter of 2017 to the first quarter of 2022, authors determined counts of patients who filled low-, moderate-, or high-intensity statins alone and with add-on therapies. The overall percentage change and joinpoint regression were used to assess trends. Analyses were conducted in March 2022-May 2022., Results: During the first quarter of 2017 to the first quarter of 2022, patients filling a statin increased by 25.0%, with the greatest increase in high-intensity statins (64.1%, range=6.6-10.9 million). Low-intensity statins decreased by 29.2% (range=3.3-2.4 million). Concurrent fills of high-intensity statin and ezetimibe rose by 210% to 579,012 patients by the first quarter of 2022, with an increase in slope by the first quarter of 2019 for all statin intensities (p<0.01). Concurrent fills of a statin and PCSK9 inhibitor increased to 2,629, 16,169, and 28,651 by the first quarter of 2022 for low-, moderate-, and high-intensity statins, respectively. For patients on all statin intensities and PCSK9 inhibitor, there were statistically significant increases in slope in the second quarter of 2019 and decreases in the first quarter of 2020., Conclusions: Patients filling moderate- and high-intensity statins and add-on ezetimibe and PCSK9 inhibitors have increased, indicating uptake of guideline-concordant lipid-lowering therapies. Improvements in the initiation and continuity of these therapies are important for atherosclerotic cardiovascular disease prevention., (Published by Elsevier Inc.)

Aims: This study evaluated the effect of moderate-intensity statin with ezetimibe combination therapy vs. high-intensity statin monotherapy among patients with diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD)., Methods and Results: This was a pre-specified, stratified subgroup analysis of the DM cohort in the RACING trial. The primary outcome was a 3-year composite of cardiovascular death, major cardiovascular events, or non-fatal stroke. Among total patients, 1398 (37.0%) had DM at baseline. The incidence of the primary outcome was 10.0% and 11.3% among patients with DM randomized to ezetimibe combination therapy vs. high-intensity statin monotherapy (hazard ratio: 0.89; 95% confidence interval: 0.64-1.22; P = 0.460). Intolerance-related discontinuation or dose reduction of the study drug was observed in 5.2% and 8.7% of patients in each group, respectively (P = 0.014). LDL cholesterol levels <70 mg/dL at 1, 2, and 3 years were observed in 81.0%, 83.1%, and 79.9% of patients in the ezetimibe combination therapy group, and 64.1%, 70.2%, and 66.8% of patients in the high-intensity statin monotherapy group (all P < 0.001). In the total population, no significant interactions were found between DM status and therapy regarding primary outcome, intolerance-related discontinuation or dose reduction, and the proportion of patients with LDL cholesterol levels <70 mg/dL., Conclusion: Ezetimibe combination therapy effects observed in the RACING trial population are preserved among patients with DM. This study supports moderate-intensity statin with ezetimibe combination therapy as a suitable alternative to high-intensity statins if the latter cannot be tolerated, or further reduction in LDL cholesterol is required among patients with DM and ASCVD., Clinical Trial Registration: ClinicalTrials.gov, Identifier:NCT03044665., Competing Interests: Conflict of interest: S.C.Y. is a chief technical officer of PHI Digital Healthcare and has received consulting fee from IQVIA; B.-K.K. has received speaker’s fees from Medtronic and Abbott Vascular; M.-K.H. has received speaker’s fees from Medtronic, Abbott Vascular, and Pfizer, Y.J. has received institutional research grants from Biotronik and Hanmi, and J.-S.K. has received proctoring fees from Abbott Vascular. All other authors declare no competing interests., (© 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.)

Purpose of Review: The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated the clinical benefit of the combination of ezetimibe-simvastatin compared to placebo-simvastatin following acute coronary syndrome (ACS). This review highlights key findings from this study with particular attention to the practice-changing impact on guidelines for low-density lipoprotein cholesterol (LDL-C) reduction after ACS, especially among high-risk populations., Recent Findings: Consistent reductions in LDL-C have been reported with newer lipid-lowering therapies (proprotein convertase subtilisin/kexin type 9 inhibitors, cholesterol ester transfer proteins, bempedoic acid) in combination with statin in high-risk subgroups. Since high-risk subgroups remain a focus of guidelines, exploration of high-risk subgroups can help define the optimal use of new therapies. Ezetimibe reduced the LDL-C by 16.7 mg/dL compared to placebo at 1 year, resulting in a significant reduction in the primary composite endpoint (absolute risk difference 2.0%; relative risk difference 6.4%, hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P = 0.016). The benefits achieved with ezetimibe in both LDL-C reduction and the primary clinical composite across 10 pre-specified high-risk subgroups, including the elderly; women; patients with diabetes, prior coronary artery bypass graft, history of stroke, polyvascular disease, low baseline LDL-C, renal dysfunction, prior heart failure, and an elevated TIMI risk score for secondary prevention, were similar or greater than in the corresponding non-high-risk subgroups. Safety events were similar between ezetimibe and placebo across the high-risk subgroups. These data support the addition of ezetimibe to statin therapy in high-risk patients who require additional therapy to lower the LDL-C post-ACS., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Atherosclerosis and cardiovascular events can be prevented, or treated, using statin therapy, either alone or in combination with ezetimibe. Chronic inflammation, vascular proliferation, and the development of atherosclerosis are also influenced by 25-hydroxycholesterol (25-OHC). The aim of the study was to compare the direct pleiotropic effects of two commonly-used statins (atorvastatin, rosuvastatin), ezetimibe, and their combinations, on the mRNA expression of pro-inflammatory IL1β, IL-18 and IL-23 and anti-inflammatory TGFβ, IL-35 (EBI3, IL-12 subunits), IL-10 and IL-37, in endothelial cells damaged by 25-OHC. It also analyzed IL-35 expression at the protein level. HUVECs were stimulated with atorvastatin (5 μM), rosuvastatin (10 μM), ezetimibe (1.22 μM), atorvastatin-ezetimibe (5 μM + 1.22 μM) or rosuvastatin-ezetimibe (10 μM + 1.22 μM), with or without pre-incubation with 10 μg/mL 25-OHC. mRNA expression was analyzed by real-time PCR. The protein level of IL-35 was analyzed by ELISA. In the pre-stimulated HUVECs, atorvastatin and rosuvastatin decreased mRNA expression of IL1β, IL-18, IL-23, TGFβ, IL35 and increased mRNA expression of IL-10 and IL-37 compared to 25-OHC. Furthermore, only incubation with rosuvastatin and rosuvastatin-ezetimibe decreased IL-35 mRNA and protein levels. Ezetimibe down-regulated only IL1β. Treatment with rosuvastatin-ezetimibe and atorvastatin-ezetimibe reversed the effect of 25-OHC in IL1β, IL-18 and IL-35 mRNA expression. In conclusion, rosuvastatin has the strongest anti-inflammatory effects and is the best at reducing the effect of oxysterols. Both statins exert a greater anti-inflammatory effect than ezetimibe. The anti-inflammatory effect of the combination therapies appears to be based on the effects of the statins alone and not their combination with ezetimibe., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Woźniak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Adults with atherosclerotic cardiovascular disease (ASCVD) are recommended high-intensity statins, with those at very high risk for recurrent events recommended adding ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor if their low-density lipoprotein cholesterol (LDL-C) is ≥70 mg/dL. We estimated the number of recurrent ASCVD events potentially averted if all adults in the United States (US) ≥45 years of age with ASCVD achieved an LDL-C <70 mg/dL., Methods: The number of US adults with ASCVD and LDL-C ≥70 mg/dL was estimated from the National Health and Nutrition Examination Survey 2009-2016 (n = 596). The 10-year cumulative incidence of recurrent ASCVD events was estimated from the REasons for Geographic And Racial Differences in Stroke study (n = 5390), weighted to the US population by age, race, and sex. The ASCVD risk reduction by achieving an LDL-C <70 mg/dL was estimated from meta-analyses of lipid-lowering treatment trials., Results: Overall, 14.7 (95% CI, 13.7-15.8) million US adults had ASCVD, of whom 11.6 (95% CI, 10.6-12.5) million had LDL-C ≥70 mg/dL. The 10-year cumulative incidence of ASCVD events was 24.3% (95% CI, 23.2-25.6%). We projected that 2.823 (95% CI, 2.543-3.091) million ASCVD events would occur over 10 years among US adults with ASCVD and LDL-C ≥70 mg/dL. Overall, 0.634 (95% CI, 0.542-0.737) million ASCVD events could potentially be averted if all US adults with ASCVD achieved and maintained LDL-C <70 mg/dL., Conclusion: A substantial number of recurrent ASCVD events could be averted over 10 years if all US adults with ASCVD achieved, and maintained, an LDL-C <70 mg/dL., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Background Randomized clinical trials (RCTs) might not be representative of the real-world population because of unreasonable exclusion criteria. We sought to determine which groups of patients are excluded from RCTs that included lipid-lowering therapy. Methods and Results We retrieved all trials from the Cholesterol Treatment Trialists Collaboration and systematically searched for large (≥1000 participants) lipid-lowering therapy RCTs, defined as statins, ezetimibe, and PCSK9 inhibitors. We predefined groups: older adults (>70 or >75 years), women, non-Whites, chronic kidney failure, heart failure, immunosuppression, cancer, dementia, treated thyroid disease, chronic obstructive pulmonary disease, mental illness, atrial fibrillation, multimorbidity (≥2 chronic diseases), and polypharmacy. We counted the number of RCTs excluding patients of the predefined groups and meta-analyzed the prevalence of included patients to obtain pooled estimates with a random-effects model. We included 42 RCTs (298 605 patients). Eighty-one percent of trials excluded patients with severe and 76% those with moderate kidney failure. Seventy-one percent of trials excluded groups of women, 64% excluded patients with moderate to severe heart failure, 64% those with immunosuppressant conditions, 48% those with cancer, 29% those with dementia, and 29% of trials excluded older adults. The pooled prevalence for patients >70 years of age was 25% (95% CI, 0%-49%), 11% (3%-18%) for >75 years of age, and 51% (38%-63%) for multimorbidity. Conclusions The majority of lipid-lowering therapy trials excluded patients with common diseases, such as moderate-to-severe kidney disease or heart failure or with immunosuppression. Underrepresenting certain populations, including women and older adults, might lead to limited transportability of study results and uncertainty on possible side-effects and efficacy in these groups. Future trials should promote diversity in the recruitment strategies and improve equity in cardiovascular research. Registration URL: ClinicalTrials.gov; Unique Identifier: CRD42021253909.

The use of lipid-modifying agents (LMAs) other than statins has rarely been reported in real clinical settings. We aimed to compare the initiation and subsequent use of LMA classes for prevention of cardiovascular diseases. Using the national claims database, this retrospective cohort study was conducted on patients aged ≥55 years who initiated to use statins, ezetimibe, or fibrates between Fiscal Years (FYs) 2014 and 2017 as the first pharmacotherapy for dyslipidemia in Japan. A permissible gap for defining persistence was set as the median days of supply of a class to an individual. Kaplan-Meier estimates were calculated for rates. Cohorts for primary prevention without/with risk and secondary prevention comprised 1307438, 908378, and 503059 initiators for statins; 44116, 34206, and 11373 for ezetimibe; and 124511, 96380, and 27751 for fibrates. The persistence rates declined shortly after the therapy initiation regardless of the classes, which was approximately 50% at 1 year for any class for primary prevention without risk. A notable sex difference in terms of persistence rates was observed only for statins of secondary prevention. The restarting rates were similar between prevention settings: approximately 50-60% for statins and 30-40% for ezetimibe and fibrates 1 year after first discontinuation. For ezetimibe and fibrates, approximately 10% of initiators were added or switched to statins within 1 year of initiation. Collectively, any class tended to be discontinued early and some restarted; however, there were some unique classes. The findings are useful for improvement of dyslipidemia therapy.

Introduction: The 2019 European Society of Cardiology and European Atherosclerosis Society (2019 ESC/EAS) guidelines stress the importance of managing low-density lipoprotein cholesterol (LDL-C) after myocardial infarction (MI) to reduce the risk of cardiovascular events. Information on guideline implementation is limited. The aim of this survey was to describe current clinical practice regarding LDL-C management in the first year post-MI across Europe, improving understanding of the role of ESC/EAS guidelines on clinical practice., Methods: A qualitative web-based cross-sectional physician survey about the patient pathway and LDL-C management post-MI was conducted in 360 physicians from France, Italy, Germany, The Netherlands, Spain, and the UK (n = 60/country) between December 2019 and June 2020. Secondary and primary care physicians (SCPs/PCPs) described their experiences treating patients post-MI over the preceding 2 months., Results: Physicians reported that on average 90.7% of patients not prescribed lipid-lowering therapy (LLT) before an MI initiated LLT as inpatients; for patients already taking LLT, treatment was intensified for 64.7% of inpatients post-MI. SCPs reported prescribing higher-intensity statins and/or ezetimibe for between 72.3% (Italy) and 88.6% (UK) of patients post-MI. More than 80.0% of SCPs and 51.2% of PCPs stated that they would initiate a change in LLT immediately if patients did not achieve their LDL-C treatment goal by 12 weeks post-MI; 82.0% of SCPs and 55.1% of PCPs reported referring to 2019 ESC/EAS guidelines for management of patients post-MI. Barriers to initiating PCSK9 inhibitors (PCSK9is) included prior prescription of a maximally tolerated dose of statin (49.4%) and/or ezetimibe (38.9%), requirement to reach threshold LDL-C levels (44.9%), and pre-authorization requirements (30.4%)., Conclusion: Differences in clinical practice post-MI were reported across the countries surveyed, including divergence between 2019 ESC/EAS and local guidelines. Increased use of innovative medicines to achieve LDL-C goals should reduce risk of subsequent cardiovascular events in very high-risk patients post-MI., (© 2022. The Author(s).)

Abstract: Lipid-modifying agents steadily lower low-density lipoprotein cholesterol (LDL-C) levels with the aim of reducing mortality. A systematic review and meta-analysis were conducted to determine whether all-cause or cardiovascular (CV) mortality effect size for lipid-lowering therapy varied according to the magnitude of LDL-C reduction. Electronic databases were searched, including PubMed and ClinicalTrials.gov , from inception to December 31, 2019. Eligible studies included randomized controlled trials that compared lipid-modifying agents (statins, ezetimibe, and PCSK-9 inhibitors) versus placebo, standard or usual care or intensive versus less-intensive LDL-C-lowering therapy in adults, with or without known history of CV disease with a follow-up of at least 52 weeks. All-cause and CV mortality as primary end points, myocardial infarction, stroke, and non-CV death as secondary end points. Absolute risk differences [ARD (ARDs) expressed as incident events per 1000 person-years], number needed to treat (NNT), and rate ratios (RR) were assessed. Sixty randomized controlled trials totaling 323,950 participants were included. Compared with placebo, usual care or less-intensive therapy, active or more potent lipid-lowering therapy reduced the risk of all-cause death [ARD -1.33 (-1.89 to -0.76); NNT 754 (529-1309); RR 0.92 (0.89-0.96)]. Intensive LDL-C percent lowering was not associated with further reductions in all-cause mortality [ARD -0.27 (-1.24 to 0.71); RR 1.00 (0.94-1.06)]. Intensive LDL-C percent lowering did not further reduce CV mortality [ARD -0.28 (-0.83 to 0.38); RR 1.02 (0.94-1.09)]. Our findings indicate that risk reduction varies across subgroups and that overall NNTs are high. Identifying patient subgroups who benefit the most from LDL-C levels reduction is clinically relevant and necessary., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aim: This study examined whether survival and causes of death differed between participants enrolled from Australia (AUS), Malaysia (MYL), and New Zealand (NZ) in extended follow-up of the Study of Heart and Renal Protection (SHARP), a randomized controlled trial (RCT) of participants with moderate to severe chronic kidney disease comparing placebo to combination therapy with Simvastatin and Ezetimibe., Methods: All participants alive at final SHARP study visit in participating centres were eligible for inclusion. Consenting participants were re-enrolled following final SHARP Study visit and followed for 5 years. Data collection included: significant medical events, hospital admissions and requirement for kidney replacement therapy. Data linkage was performed to national kidney and mortality registries. The primary outcome was all-cause mortality compared across the three countries., Results: The SHARP trial randomized 2029 participants from AUS (1043/2029, 51%), MYL (701/2029, 35%), and NZ (285/2029, 14%), with 1136 participants alive and eligible for extended follow-up at the end of SHARP. In multivariable analysis, risk of death was increased for participants in MYL (HR 1.37, 95% CI 1.17-1.61, p < .001) and NZ (HR 1.28, 95% CI 1.04-1.57, p = .02) when compared to AUS participants. Adjustment for kidney transplantation as a competing risk did not explain the variation seen between countries., Conclusion: This study allows a better understanding of the differences in long-term mortality risk across participants from AUS, MYL, and NZ in extended follow-up of the SHARP study and demonstrates the feasibility and value of extended follow-up of participants enrolled in RCTs., (© 2022 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Background: Chronic kidney disease (CKD) is a known risk factor of atherosclerotic cardiovascular disease (ASCVD). Per the 2018 American Heart Association/American College of Cardiology cholesterol guidelines, high-risk ASCVD patients with CKD and low-density lipoprotein cholesterol (LDL-C) levels  ≥ $\ge $  70 mg/dL should take a high-intensity statin with ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i)., Objective/methods: We examined the changes in use of lipid lowering therapies (LLT) over two years in 3304 patients with ASCVD and CKD in the Getting to an imprOved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) observational cohort study., Results: Of those with eGFR <60 ml/min/1.73 m 2 , 21.6% (171/791) had intensification of LLT while 10.4% (82/791) had de-escalation of LLT. Notably, 61.6% (487/791) had no change in LLT regimen over 2 years. Statin use was 83.2% (785/944) at baseline and 80.1% (634/791) at 2 years. Statin/ezetimibe use increased from 2.9% (27/944) to 4.9% (39/791). Statin discontinuation at 2 years was greater with lower eGFR levels across all cohorts., Conclusion: Despite the recommendations of multiscociety guidelines, statin use, while high, is not ubiquitous and rates of high-intensity statin and ezetimibe use remain low in patients with CKD. There remains a significant opportunity to optimize LLT and achieve atheroprotective cholesterol levels in the CKD population., (© 2022 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

Dyslipidemia, specifically elevated low-density lipoprotein (LDL) cholesterol levels, causes atherosclerotic cardiovascular disease (ASCVD) and increases the risk of myocardial infarction and stroke. Statins, a class of drugs that exert their effects by inhibiting HMG-CoA reductase, a key enzyme in the synthesis of cholesterol, have been the mainstay of therapy for the primary prevention of cardiovascular disease and lipids reduction. Statins are associated with side effects, most commonly myopathy and myalgias, despite their proven efficacy. This review explores non-statin lipid-lowering therapies and examines recent advances and emerging research. Over the previous decades, several lipid-lowering therapies, both as monotherapy and adjuncts to statin therapy and lipid-targeting gene therapy, have emerged, thus redefining how we treat dyslipidemia. These drugs include Bile acids sequestrants, Fibrates, Nicotinic acid, Ezetimibe, Bempedoic acid, Volanesoren, Evinacumab, and the PCSK 9 Inhibitors Evolocumab and Alirocumab. Emerging gene-based therapy includes Small interfering RNAs, Antisense oligonucleotides, Adeno-associated virus vectors, CRISPR/Cas9 based therapeutics, and Non-coding RNA therapy. Of all these therapies, Bempedoic acid works most like statins by working through a similar pathway to decrease cholesterol levels. However, it is not associated with myopathy. Overall, although statins continue to be the gold standard, non-statin therapies are set to play an increasingly important role in managing dyslipidemia., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.)

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.

Importance: Studies have demonstrated an association between single measures of high-sensitivity troponin (hsTn) and future cardiovascular events in patients with chronic coronary syndromes. However, limited data exist regarding the association between changes in serial values of hsTn and subsequent cardiovascular events in this patient population., Objective: To evaluate the association between changes in high-sensitivity troponin T (hsTnT) and subsequent cardiovascular events in patients stabilized after acute coronary syndrome (ACS)., Design, Setting, and Participants: This is a secondary analysis from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), a randomized clinical trial of ezetimibe vs placebo on a background of simvastatin in 18 144 patients hospitalized for an ACS across 1147 sites in 39 countries. The current biomarker substudy includes the 6035 participants consenting to the biomarker substudy with available hsTnT at months 1 and 4. Data were collected from October 26, 2005, through July 8, 2010, with the database locked October 21, 2014. Data were analyzed from February 28, 2021, through August 14, 2022., Main Outcomes and Measures: The outcomes of interest were cardiovascular death, myocardial infarction (MI), stroke, or hospitalization for heart failure (HHF). Associations of absolute and relative changes in hsTnT between month 1 and month 4 as a function of the starting month 1 hsTnT and the composite outcome were examined using landmark analyses., Results: Of 6035 patients in this analysis (median [IQR] age, 64 [57-71]), 1486 (24.6%) were female; 361 (6.0%) were Asian; 121 were (2.0%) Black; 252 (4.2%) were Spanish descent; 4959 were (82.2%) White; and 342 (5.7%) reported another race (consolidated owing to small numbers), declined to respond, or were not asked to report race owing to regulatory prohibitions. Most patients (4114 [68.2%]) had stable hsTnT values (change <3 ng/L), with 1158 (19.2%) and 763 (12.6%) having changes of 3 to less than 7 ng/L and 7 ng/L or more, respectively. After adjustment for clinical risk factors and stratification by the starting month 1 hsTnT level, an absolute increase in hsTnT of 7 ng/L or more was associated with a more than 3-fold greater risk of the composite outcome (adjusted hazard ratio [aHR], 3.33; 95% CI, 1.99-5.57; P < .001), whereas decreases of 7 ng/L or more were associated with similar to lower risk (aHR, 0.51; 95% CI, 0.26-1.03; P = .06) compared with stable values. There was a stepwise association moving from larger absolute decreases (aHR, 0.51; 95% CI, 0.26-1.03) to larger absolute increases (aHR, 3.33; 95% CI, 1.99-5.57) in hsTnT with future risk of the composite outcome (P trend <.001). A similar association was observed when analyzed on the basis of relative percent and continuous change., Conclusions and Relevance: Among stable patients post-ACS, changes in hsTnT were associated with a gradient of risk of subsequent cardiovascular events across the range of starting hsTnT values. Serial assessment of hsTnT may refine risk stratification with the potential to guide therapy decisions in this patient population., Trial Registration: ClinicalTrials.gov Identifier: NCT00202878.

It remains unknown whether statin therapy in combination with ezetimibe is a beneficial and equivalent alternative to statin monotherapy in reducing proinflammatory cytokines. In the present systematic review and meta-analysis, we aimed to assess the effect of combination therapy with statins and ezetimibe on some proinflammatory cytokines. Databases, including MEDLINE, SciVerse, Scopus, and Clarivate Analytics Web of Science databases, were searched up to February 2022, for terms related to combination therapy with statins and ezetimibe and proinflammatory cytokines. The quality of the included studies was evaluated with Cochrane risk of bias tool 1, and weighted mean difference [WMD] and SD of changes were used for meta-analysis. The results were expressed as differences in means and 95 % CIs with an inverse variance and a random-effects model. Finally, 12 studies [13 arms] were included in the qualitative and quantitative synthesis. The average patient's age ranged from 49.3 to 71 years, and the duration of intervention lasted seven days to 12 months. Overall, our result did not show any significant reduction in interleukin-1beta (IL-1β) (3 randomized controlled trial studies (RCTs), 292 participants, WMD: -0.4 pg/ml; 95 % CI: -1.3, 0.4, P = 0.3, I 2  = 93.1 %, P < 0.001), tumor necrosis factor-alpha (TNF-α) (4 RCTs, 199 participants, WMD: -0.3 pg/ml; 95 % CI: -0.8, 0.1, P = 0.1, I 2  = 13.8 %, P = 0.3) and monocyte chemoattractant protein-1 (MCP-1) (4 RCTs, 216 participants, WMD: -7.8 pg/ml; 95 % CI: -18.5, 2.8, P = 0.1, I 2  = 30.8 %, P = 0.2). However, there was a significant reduction in interleukin-6 (IL-6) (9 RCTs, 514 participants, WMD: -1.4 pg/ml; 95 % CI: -2.4, -0.3, P < 0.007, I 2  = 97.1 %, P < 0.001) and interferon-gamma (IFN-γ) (2 RCTs, 78 participants, WMD: -0.2 pg/ml; 95 % CI: -0.4, -0.1, P < 0.001, I 2  = 0 %, P = 0.7). Following subgroup analysis, there was a significant reduction in IL-6 in the age group ≥ 60 years and the Asian population. Statin therapy in combination with ezetimibe causes a significant decrease in IL-6 and IFN-γ, and the reduction in IL-6 is significant in ≥ 60 years and the Asian population., 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 © 2022 Elsevier B.V. All rights reserved.)

Background: A decade ago, systemic inflammation became widely recognized as an etiology of type 2 diabetes mellitus (T2DM) and complications thereof. Senescent CD8 + T cells of T2DM patients exhibit increased secretion of pro-inflammatory cytokines and enhanced expression of cytotoxic molecules, contributing to systemic inflammation. Recently, many anti-inflammatory roles played by statins and ezetimibe (cholesterol-lowering drugs) have been reported. We will explore the effects of statin/ezetimibe therapy on CD8 + T cell senescence in patients with T2DM and hypercholesterolemia., Methods: This 2-group, parallel, randomized, controlled clinical trial will recruit 108 subjects with T2DM and low-density lipoprotein-cholesterol (LDL-C) levels ≥100 mg/dL and randomly assign them to rosuvastatin/ezetimibe and rosuvastatin groups at a 1:1 ratio. Blood samples will be drawn at baseline and after 12 weeks of medication. The primary outcomes will be the LDL-C-lowering effects after 12 weeks. The secondary outcomes will be changes in the senescent (CD28 - CD57+) CD8 + T cell proportions; the levels of circulating pro-inflammatory cytokines, cytotoxic molecules, interleukin-1, transforming growth factor-β, fasting glucose, and HbA1c; and biochemical indices of kidney, liver, and muscle function. Symptoms and signs of predictable adverse events (myopathy and hepatitis) will be routinely monitored., Discussion: We will evaluate the effects of statin/ezetimibe on CD8 + T cell senescence. Statin/ezetimibe may exert a beneficial immunomodulatory effect., Competing Interests: The authors have no conflicts of interest to disclose, (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver., Methods: We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed., Results: Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P&lt;0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain., Conclusions: Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.)., (Copyright © 2022 Massachusetts Medical Society.)

We aim to estimate the number and proportion of very-high risk patients with atherosclerotic cardiovascular disease (ASCVD) who would be able to achieve low-density lipoprotein cholesterol (LDL-C) <70 mg/dL with various lipid-lowering therapies (LLTs), including statins, ezetimibe, bempedoic acid, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and evinacumab, using a Monte Carlo simulation model described previously. With current treatment options for LDL-C lowering, including statin, ezetimibe, bempedoic acid, and PCSK9 inhibitors, it was estimated that most very-high risk patients with ASCVD (99.1%) were able to achieve the LDL-C goal of <70 mg/dL. Nevertheless, approximately 88,715 patients in the USA were estimated to not be able to achieve the LDL-C goal after current available LLTs, thus remaining at elevated risk for recurrent cardiovascular events. Evinacumab may be useful to address such unmet needs effectively, as the majority of those not at goal after PCSK9 inhibitors could achieve the goal of <70 mg/dL after taking evinacumab., Competing Interests: Conflicts of interest J.G., R.J.S., and S.F. are employees of and stockholders in Regeneron Pharmaceuticals, Inc. A.C. is an employee of Axtria. R.S.R. reports grants and/or personal fees for scientific advisory board participation from Regeneron Pharmaceuticals, Inc., Amgen, Arrowhead, CRISPER Therapeutics, Lilly, Novartis, and Precision BioSciences; honoraria for non-promotional speaking from Amgen and Kowa; royalties from UpToDate; and stock holdings in MediMergent, LLC., (Copyright © 2022. Published by Elsevier Inc.)

Source Citation: Kim BK, Hong SJ, Lee YJ, et al. Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open-label, non-inferiority trial. Lancet. 202;400:380-90. 35863366.

Background: In atherosclerotic stroke, lipid-lowering treatment with a target LDL (low-density lipoprotein) cholesterol of <70 compared with 100±10 mg/dL reduced the risk of subsequent cardiovascular events. This post hoc analysis explored the relative effects of the combination of statin and ezetimibe (dual therapy) and statin monotherapy in achieving the lower LDL cholesterol target and in reducing the risk of major vascular events, as compared with the higher target group., Methods: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned to a target LDL cholesterol of <70 or 100±10 mg/dL, using statin and/or ezetimibe as needed. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and vascular death. Cox regression model including lipid-lowering therapy as a time varying variable, after adjustment for randomization strategy, age, sex, index event (stroke or transient ischemic attack), and time since the index event., Results: Among 2860 patients enrolled, patients who were on dual therapy during the trial in the lower target group had a higher baseline LDL cholesterol as compared to patients on statin monotherapy (141±38 versus 131±36, respectively, P <0.001). In patients on dual therapy and on statin monotherapy, the achieved LDL cholesterol was 66.2 and 64.1 mg/dL respectively, and the primary outcome was reduced during dual therapy as compared with the higher target group (HR, 0.60 [95% CI, 0.39-0.91]; P =0.016) but not during statin monotherapy (HR, 0.92 [95% CI, 0.70-1.20]; P =0.52), with no significant increase in intracranial bleeding., Conclusions: In the TST trial (Treat Stroke to Target), targeting an LDL cholesterol of < 70 mg/dL with a combination of statin and ezetimibe compared with 100±10 mg/dL consistently reduced the risk of subsequent stroke., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01252875. URL: clinicaltrialsregister.eu; Unique identifier: EUDRACT2009-A01280-57.

Competing Interests: Conflict of interest: D.P. received speaker’s fees from Daiichi-Sankyo, outside the submitted work. M.V. reports personal fees for speaker bureau and/or consulting in Advisory Board from Amgen, Astra Zeneca, Daiichi-Sankyo, Menarini Int, MSD, Novartis Pharma, and Novo Nordisk, outside the submitted work.

Background and Aims: Blood cholesterol levels are regulated by competing mechanisms of cholesterol synthesis, absorption and excretion. Plant sterols are natural constituents of plants, are not synthesized in humans, and serve as markers for cholesterol absorption. Ezetimibe lowers the intestinal absorption of cholesterol and plant sterols. We analyzed the associations of differences in cholesterol metabolism, in particular increased cholesterol absorption, and the occurrence of in-stent restenosis (ISR) in patients with stable coronary artery disease., Methods: Elective stent implantation of de novo stenosis was conducted in 59 patients (74.6 % males, 67.2 ± 9.6 years). Cholesterol and non-cholesterol sterols were quantified in serum samples by gas chromatography or mass spectrometry. ISR was assessed by optical coherence tomography (OCT) and quantitative angiography (QCA) after six months., Results: Markers for cholesterol absorption (e.g. campesterol-to-cholesterol) were positively associated with ISR measured by QCA (%diameter stenosis, late lumen loss) and OCT (proliferation volume, %area stenosis), whereas markers for cholesterol synthesis (e.g. lathosterol-to-cholesterol) were negatively associated with ISR (%area stenosis: r = -0.271, p = 0.043). There was no association between ISR and total cholesterol, LDL, HDL, triglycerides. Markers for cholesterol absorption (e.g. campesterol-to-cholesterol) were significantly lower in ezetimibe-treated patients compared to patients on a statin only (1.29 ± 0.69 vs. 2.22 ± 1.23; p = 0.007). Combined lipid-lowering with ezetimibe plus statin reduced ISR compared to statin only (13.7 ± 10.4 vs. 22.5 ± 12.1 %diameter stenosis, p = 0.015)., Conclusions: Differences in cholesterol metabolism, more specifically increased cholesterol absorption, are associated with ISR., 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 © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aims: The LDL cholesterol (LDL-C) treatment goals recommended by the 2019 ESC/EAS guidelines are only achieved in a minority of patients. The study objective was to estimate the impact of bempedoic acid treatment on LDL-C target attainment, drug costs, and atherosclerotic cardiovascular disease (ASCVD) events. The simulation used a Monte Carlo approach in a representative cohort of German outpatients at high or very-high cardiovascular risk. Additionally to statins, consecutive treatment with ezetimibe, bempedoic acid, and a PCSK9 inhibitor was simulated in patients not achieving their LDL-C goal. Considered were scenarios without and with bempedoic acid (where bempedoic acid was replaced by a PCSK9 inhibitor when LDL-C was not controlled)., Results: The simulation cohort consisted of 105,577 patients, of whom 76,900 had very-high and 28,677 high cardiovascular risk. At baseline, 11.2% of patients achieved their risk-based LDL-C target. Sequential addition of ezetimibe and bempedoic acid resulted in target LDL-C in 33.1% and 61.9%, respectively. Treatment with bempedoic acid reduced the need for a PCSK9 inhibitor from 66.6% to 37.8% and reduced drug costs by 35.9% per year on stable lipid-lowering medication. Compared to using only statins and ezetimibe, this approach is projected to prevent additional 6,148 ASCVD events annually per 1 million patients, whereas PCSK9 inhibition alone would prevent 7,939 additional ASCVD events annually., Conclusions: A considerably larger proportion of cardiovascular high- and very-high-risk patients can achieve guideline-recommended LDL-C goals with escalated lipid-lowering medication. Bempedoic acid is projected to substantially decrease the need for PCSK9 inhibitor treatment to achieve LDL-C targets, associated with reduced drug costs albeit with fewer prevented events., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JLK has received consulting fees and travel grants from Daiichi Sankyo. CB and AB are employees of Daiichi Sankyo. UL has received speaker honoraria from Amgen, Daiichi Sankyo, Novartis, and Sanofi. The company Daiichi Sankyo Europe GmbH is marketing authorisation holder of Nilemdo® and Nustendi® in the UK, European Economic Area, and Switzerland. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The company IQVIA Germany (https://www.iqvia.com/de-de/locations/germany) provided and analysed the data which are presented in this analysis. The data can be obtained from IQVIA on request.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to improve cardiovascular outcomes when added to conventional statin therapy. This study aims to investigate the efficacy and safety of in-hospital initiation of PCSK9 inhibitors among patients with acute myocardial infarction (AMI) based on real-world experience., Methods and Results: Data were collected from the Biobank of the First Affiliated Hospital of Xi'an Jiaotong University between January 2016 and December 2020. A total of 7556 AMI patients were screened for eligibility. Propensity Score Match (PSM) was employed, and covariates were age, sex, admission blood pressure and lipid profiles. Eligible participants were (1) propensity-matched 1:2:2 of statin plus evolocumab (dual therapy) vs. statin vs. statin plus ezetimibe. Ninety-five statin plus evolocumab users achieved significantly decreased low density lipoprotein (LDL) levels (0.92 ± 0.62 mmol/L in the 1st month and 1.17 ± 0.73 in the 3rd month) and a promising attainment rate of LDL (79.5% in the 1st month and 80.0% in the 3rd month) compared to the other two groups. (2) Propensity-matched 1:2:2 of statin plus ezetimibe evolocumab (triple therapy) vs. statin vs. statin plus ezetimibe. Similarly, 75 triple medication users achieved significantly decreased LDL levels and a promising attainment rate of LDL compared to the other two groups. In-hospital mortality and readmission rates within 3 months were then analyzed, and a decreased readmission rate was observed with PCSK9i therapy., Conclusions: Based on the present single-center real-world PSM-adjusted study, PCSK9i has been effective in short-term lipid control among AMI patients. The long-term effectiveness for reducing major cardiovascular events among AMI patients based on real-world experience remains to be explored., Trial Registration: The study was registered at ClinicalTrials.gov, ClinicalTrials.gov ID: NCT05184530., (© 2022. The Author(s).)

Aims: European guidelines set low-density lipoprotein cholesterol (LDL-C) treatment goals &lt;1.4 mmol/L after acute coronary syndrome (ACS), and &lt;1.0 mmol/L for patients with recurrent cardiovascular events ≤2 years. Many ACS patients do not achieve these goals on statin alone. We examined actual goal achievement with alirocumab and projected achievement with ezetimibe, either added to optimized statin therapy., Methods and Results: The ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18 924 patients with recent ACS and hyperlipidaemia despite high-intensity or maximum-tolerated statin therapy. This subanalysis comprised 17 589 patients with LDL-C ≥1.4 mmol/L at baseline who did not receive ezetimibe treatment. High-intensity statin treatment was used in 88.8%. Median (interquartile range) baseline LDL-C was 2.3 (1.9-2.7) mmol/L. With alirocumab, 94.6% of patients achieved LDL-C &lt;1.4 mmol/L at ≥1 post-baseline measurement vs. 17.3% with placebo. Among 2236 patients with a previous cardiovascular event within 2 years (before the qualifying ACS), 85.2% vs. 3.5%, respectively, achieved LDL-C &lt;1.0 mmol/L. Among patients not treated with ezetimibe, we projected that its use would have achieved LDL-C &lt;1.4 and &lt;1.0 mmol/L in 10.6 and 0%, respectively, at baseline (assuming 18 ± 3% reduction of LDL-C)., Conclusion: Among patients with recent ACS and LDL-C ≥1.4 mmol/L despite optimized statin therapy, the addition of alirocumab allowed 94.6% to achieve the 2019 European guideline LDL-C goal &lt;1.4 mmol/L, and 85.2% of those with recurrent cardiovascular events to achieve &lt;1.0 mmol/L. In contrast, the addition of ezetimibe to optimized statin therapy was projected to achieve LDL-C &lt;1.4 mmol/L in only 10.6% of patients at baseline., Competing Interests: Conflict of interest: U.L. reports grants and personal fees from Bayer, Novartis, and Amgen and personal fees from Sanofi, Abbott, Astra Zeneca, Boehringer Ingelheim. J.M. is an employee of Regeneron Pharmaceuticals; P.G.S. reports grants, personal fees, and non-financial support from Sanofi; grants and personal fees from Amarin, Servier, and Bayer; personal fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Idorsia, Pfizer, and Novartis. In addition, P.G.S. has a patent use of alirocumab to reduce risk after ACS (royalties to Sanofi) pending. D.L.B. discloses the following relationships—Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company, 89Bio; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Philips, Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Takeda. V.A.B. reports grant support from Sanofi, Regeneron Pharmaceuticals, Astra Zeneca, DalCor, Esperion, and Novartis; consulting fees from Pfizer; honoraria from Medscape; and fees for participating on a Data Safety Monitoring Board or Advisory Board from the National Institutes of Health. R.D. reports research grants from Sanofi, DalCor Pharmaceuticals, Population Health Research Institute, Duke Clinical Research Institute, the TIMI group, Amgen, Cirius, Montreal Health Innovations Coordinating Center, and Lepetit; and personal fees, as a member of the Executive Steering Committee, from Amgen and Cirius. M.D. reports uncompensated; National Coordinator and Principal Investigator in EORP surveys EUROSPIRE IV and EUROASPIRE V, serving as National Coordinator for Bosnia & Herzegovina CVD Prevention, serving as National Coordinator for Bosnia & Herzegovina version of HeartScore Programme, serving on Board of Bosnia & Herzegovina Association of Cardiology, serving as Editor-in-Chief of Medical Journal CCUS; reports research grant from Sanofi, and lectures fees from Bayer, Sanofi, Boehringer Ingelheim, Novartis, Pfizer, GlaxoSmithKline, Bosnalijek, Berlin-Chemie Menarini, Abbott, Krka, and report fee for Chair of PhD Study on Medical Faculty University of Sarajevo. S.G.G. reports research grant support (e.g. steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (e.g. advisory boards) from: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, JAMP Pharma, Janssen/Johnson & Johnson, Merck, Novartis, Novo Nordisk A/C, Pendopharm, Pfizer, Regeneron, Sanofi, Servier, Valeo Pharma; and salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, and PERFUSE Research Institute. J.W.J. reports research grants from the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Commission Seventh Framework Programme; and research support from Amgen, Astellas, AstraZeneca, Daiichi-Sankyo, Lilly, Merck-Schering-Plough, Pfizer, Roche, and Sanofi. M.L. is an employee of Sanofi. I.P. reports receiving honoraria for lectures from Novartis, Amgen, Sanofi and Sandoz. R.P. is an employee of Regeneron Pharmaceuticals, Inc. S.H.P. reports participating in an Advisory Board meeting arranged by Sanofi. M.S. reports serving as a consultant or on advisory boards (or both) for CiVi, Resverlogix, Baxter, Esperion, Sanofi, and Regeneron Pharmaceuticals, Inc. H.D.W. reports receiving grant support paid to the institution and fees for serving on a steering committee for the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) from Sanofi-Aventis and Regeneron Pharmaceuticals, for the ACCELERATE study (A Study of Evacetrapib in High-Risk Vascular Disease) from Eli Lilly, for the STRENGTH trial (Outcomes Study to Assess Statin Residual Risk Reduction With EpaNova in High CV Risk Patients With Hypertriglyceridemia) from Omthera Pharmaceuticals, for the SPIRE trial (The Evaluation of Bococizumab [PF-04950615; RN 316] in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects) from Pfizer USA, for the HEART-FID study (Randomized Placebo-Controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency) from American Regent; for the CAMELLIA-TIMI study (A Study to Evaluate the Effect of Long-term Treatment With BELVIQ [Lorcaserin HC] on the Incidence of Major Adverse Cardiovascular Events and Conversion to Type 2 Diabetes Mellitus in Obese and Overweight Subjects With Cardiovascular Disease or Multiple Cardiovascular Risk Factors) from Eisai Inc, for the dal-GenE study (Effect of Dalcetrapib vs. Placebo on CV Risk in a Genetically Defined Population With a Recent ACS) from DalCor Pharma UK Inc, for the AEGIS-II study from CSL Behring, for the SCORED trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) and the SOLOIST-WHF trial (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type2 Diabetes Post-Worsening Heart Failure) from Sanofi-Aventis Australia Pty Ltd, and for the CLEAR Outcomes Study (Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid [ETC-1002] or Placebo) from Esperion Therapeutics Inc. H.D.W. was on the Advisory Boards for Acetelion, Sirtex and Genentech, Inc. (an affiliate of F. Hoffmann-La Roche Ltd, ‘Roche’; Lytics Post-PCI Advisory Board at European Society of Cardiology), and received lecture fees from AstraZeneca. G.G.S. reports research grants to the University of Colorado from Resverlogix, Sanofi, The Medicines Company, and Roche; and is coinventor of pending US patent 62/806 313 (‘Methods for Reducing Cardiovascular Risk’) assigned in full to the University of Colorado., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The additive effects of ezetimibe, evolocumab or alirocumab on lipid level, plaque volume, and plaque composition using intravascular ultrasound (IVUS) remain unclear., Methods: According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement, we performed a systematic review and meta-analysis of trials assessing the effects of ezetimibe, evolocumab, and alirocumab on coronary atherosclerosis using IVUS. The primary outcome was change in total atheroma volume (TAV), and the secondary outcomes were changes and differences in plaque composition and lipid content., Results: Data were collected from 9 trials, involving 917 patients who received ezetimibe, evolocumab or alirocumab in addition to a statin and 919 patients who received statins alone. The pooled estimate demonstrated a significant reduction in TAV with the addition of ezetimibe and favorable effects of evolocumab and alirocumab on TAV. Subgroup analysis also supported favorable effects of evolocumab and alirocumab on TAV, according to baseline TAV, gender, type 2 diabetes mellitus, and prior stain use. Addition of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to statin therapy resulted in significant reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG), but not in high-density lipoprotein cholesterol (HDL-C). The pooled estimate also showed significant favorable effects of ezetimibe on LDL-C, TC, and TG, but an insignificant effect on HDL-C. Patients who received ezetimibe showed similar changes in the necrotic core, fibro-fatty plaque, fibrous plaque, and dense calcification compared with patients not treated with ezetimibe., Conclusions: The addition of ezetimibe to statin therapy may further reduce plaque and lipid burdens but may not modify plaque composition. Although current evidence supports a similar impact from the addition of PCSK9 inhibitors to statin therapy, more evidence is needed to confirm such an effect., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)