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Background: Previous studies have reported that statin or ezetimibe therapy has an anti-inflammatory effect. However, the results of individual studies on the effect of statin therapy in combination with ezetimibe on C-reactive protein (CRP) and high-sensitivity CRP (hs-CRP) levels have not been clear. Therefore, the present systematic review and meta-analysis were conducted on randomized clinical trials (RCTs) to evaluate the effect of statin therapy in combination with ezetimibe on CRP and hs-CRP levels., Methods: A literature search was carried out on the MEDLINE, SciVerse Scopus, and Clarivate Analytics Web of Science databases up to February 2022 to find eligible studies. The pooled effect sizes were considered for weighted mean difference (WMD) and 95% confidence intervals (CI) for CRP and hs-CRP, and it was also determined as standardized weighted mean difference (SMD) for overall CRP. For all variables, a random-effects model was used., Results: Of the 57 studies included in the systematic review, 53 were used for meta-analysis. Statin therapy in combination with ezetimibe significantly reduced the serum levels of hs-CRP (WMD - 0.2 mg/l; 95% CI - 0.4, - 0.1, P ˂ 0.001) and overall CRP (SMD - 0.16 mg/l; 95% CI - 0.2, - 0.07, P ˂ 0.001). Nevertheless, CRP levels were not significantly changed by combination therapy. A significant association was observed between the serum low-density lipoprotein cholesterol (LDL-C) changes and hs-CRP levels, which can justify the source of heterogeneity., Conclusions: The current study showed that statin therapy in combination with ezetimibe could be effective in reducing the levels of hs-CRP and overall CRP., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The HAUSER-RCT study showed that 24 weeks of evolocumab (a proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor) in paediatric patients with heterozygous familial hypercholesterolaemia was safe and improved lipid parameters compared to placebo. Here, we aimed to evaluate the safety and efficacy of evolocumab in this population for an additional 80 weeks., Methods: HAUSER-OLE was an 80-week, single-arm, open-label extension of HAUSER-RCT, a randomised controlled trial, and was conducted at 46 centres in 23 countries. Paediatric patients aged 10-17 years with heterozygous familial hypercholesterolaemia who completed 24 weeks of monthly treatment with subcutaneously administered placebo or 420 mg evolocumab in HAUSER-RCT with no serious treatment-emergent adverse events were eligible to enrol in HAUSER-OLE. All patients received open-label subcutaneous evolocumab 420 mg monthly with background statins with or without ezetimibe for 80 additional weeks. The primary endpoint was treatment-emergent adverse events. Efficacy was evaluated by changes in lipids from the baseline of HAUSER-RCT to the end of HAUSER-OLE (104 weeks). This study is registered with ClinicalTrials.gov (NCT02624869) and is now completed., Findings: Between Sept 10, 2016, and Nov 25, 2019, 157 patients were enrolled in HAUSER-RCT and received randomised treatment; 150 continued to HAUSER-OLE, received evolocumab treatment, and were included in the full analysis set, presented here. 146 (97%) of 150 patients completed the open-label extension. The incidence of treatment-emergent adverse events in HAUSER-OLE was 70% (105 of 150). Overall, the most common treatment-emergent adverse events were nasopharyngitis (22 [15%] of 150), headache (14 [9%]), and influenza-like illness (13 [9%]). Serious treatment-emergent adverse events occurred in four (3%) of 150 patients (perforated appendicitis and peritonitis, wrist fracture, anorexia nervosa, and headache); none was considered related to evolocumab. No treatment-emergent adverse events led to treatment discontinuation. At week 80, the mean percentage change from baseline in LDL cholesterol was -35·3% (SD 28·0)., Interpretation: After 80 weeks of treatment, evolocumab was safe, well tolerated, and led to sustained reductions in LDL cholesterol in paediatric patients with heterozygous familial hypercholesterolaemia. When lipid goals cannot be achieved with conventional treatments, evolocumab is an effective add-on therapy in paediatric patients., Funding: Amgen., Translations: For the French, Spanish, Spanish, Portuguese, Italian and Dutch translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests RDS reports receiving consulting fees and lecture fees from AstraZeneca, Aché, Amryt, Libbs, Hoffmann-La Roche, and Novo Nordisk; grant support, consulting fees, and lecture fees from Amgen and Sanofi-Regeneron Pharmaceuticals; lecture fees from Getz Pharma, Eli Lilly, Hypera, PTC Therapeutics, and Pfizer; fees for coordinating a research protocol from Esperion; grant support from Kowa; and consulting fees from Abbott, Novartis, and Hypera. AR is a former employee and a stockholder of Amgen and is an inventor on the pending patent application 63/032451 on PCSK9 inhibitors and methods of use thereof to treat cholesterol-related disorders. GKH reports study funding from Amgen and grants or contracts from Vidi Grant (zonMW) and Klinkerpad Fonds. GKH also reports being employed by Novo Nordisk. OSD reports receiving grants or contracts from Amgen, Daiichi Sankyo, Novartis, Novo Nordisk, and Viatris; consulting fees from Amgen, Daiichi Sankyo, Merck Sharp & Dohme, and Sanofi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, Daiichi Sankyo, Merck Sharp & Dohme, Mylan, Sanofi, and Viatris; support for attending meetings from Sanofi and Daiichi Sankyo; and participation on a data safety monitoring board or advisory board from Sanofi and Daiichi Sankyo. JB reports receiving advisory board fees or lecture fees from Amgen, HLS Therapeutics, Medison, and Novartis; and grant or contract support from Amgen, Arrowhead, LIB Therapeutics, Novartis, Regeneron Pharmaceuticals, Sanofi, and The Medicines Company. BW and AKB are employees and stockholders of Amgen. SG-P reports receiving study funding from Amgen. FJR reports grants or contracts from Regeneron, Novartis, and LIB Therapeutics; fees for advisory board presentations and lectures from Amgen, Sanofi-Aventis, Regeneron, and Novartis; and travel support to attend the 2022 European Atherosclerosis Society (EAS) Congress from EAS. JJPK reports grants or contracts from NewAmsterdam Pharma; a leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from NewAmsterdam Pharma; stock or stock options from NewAmsterdam Pharma; and patents planned, issued, or pending from NewAmsterdam Pharma. JJPK also reports consulting fees from CSL Behring, Esperion, Madrigal Pharmaceuticals, Novartis, and Pfizer; and participation on a data safety monitoring board or advisory board for CSL Behring, North Sea Therapeutics, Silence Therapeutics, and Scribe Therapeutics. DG reports receiving grants or contracts from Amgen, Aegerion (Amryt), Eli Lilly, Esperion, Ionis, Pfizer, Regeneron, Sanofi, and The Medicines Company; payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, Aegerion (Amryt), and Regeneron; and participation on a data safety monitoring board or advisory board for Amgen, Aegerion (Amryt), Arrowhead, Eli Lilly, Pfizer, Regeneron, Sanofi, and Verve Therapeutics. AW reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Novartis and Algorithm; participation on a data safety monitoring board or advisory board for Amryt; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for Novartis; and research support for pharmaceutical trials from Amgen, Regeneron, Novartis, and Silence Therapeutics. CS, FM, AB, PSB, and IL declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Coronary CT angiography (CTA) derived fractional flow reserve (FFR CT ) shows high diagnostic performance when compared to invasively measured FFR. Presence and extent of low attenuation plaque density have been shown to be associated with abnormal physiology by measured FFR. Moreover, it is well established that statin therapy reduces the rate of plaque progression and results in morphology alterations underlying atherosclerosis. However, the interplay between lipid lowering treatment, plaque regression, and the coronary physiology has not previously been investigated., Aim: To test whether lipid lowering therapy is associated with significant improvement in FFR CT , and whether there is a dose-response relationship between lipid lowering intensity, plaque regression, and coronary flow recovery., Methods: Investigator driven, prospective, multicenter, randomized study of patients with stable angina, coronary stenosis ≥50% determined by clinically indicated first-line CTA, and FFR CT  ≤ 0.80 in whom coronary revascularization was deferred. Patients are randomized to standard (atorvastatin 40 mg daily) or intensive (rosuvastatin 40 mg + ezetimibe 10 mg daily) lipid lowering therapy for 18 months. Coronary CTA scans with blinded coronary plaque and FFR CT analyses will be repeated after 9 and 18 months. The primary endpoint is the 18-month difference in FFR CT using (1) the FFR CT value 2 cm distal to stenosis and (2) the lowest distal value in the vessel of interest. A total of 104 patients will be included in the study., Conclusion: The results of this study will provide novel insights into the interplay between lipid lowering, and the pathophysiology in coronary artery disease., (© 2022 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

Background The emergence of PCSK9i (proprotein convertase subtilisin kexin type 9 inhibitor) and icosapent ethyl (IPE) has expanded the role of lipid-lowering therapies beyond statins. Despite recommendations by clinical practice guidelines, their national eligibility and use rates remain unclear. Methods and Results In the National Health and Nutrition Examination Survey data from 2017 to 2020, we assessed eligibility and the use of statins, PCSK9i, and IPE among US adults according to American College of Cardiology/American Heart Association guideline recommendations. Eligibility for PCSK9i and IPE were determined in the following 2 scenarios: (1) assuming existing lipid-lowering therapy as the maximum tolerated before assessing eligibility for novel therapies and (2) assessing eligibility after assuming initiation and maximal escalation of preexisting lipid-lowering therapies and accounting for expected lipid improvements. Of 2729 sampled individuals, representing 149.3 million adults, 1376 had indications for statins, representing 65.8 million or 44.0% (95% CI, 40.9%-47.2%) of adults. Current statin use was 45% of those eligible and was low across demographic groups. A total of 9.7 and 11.6 million adults would benefit from PCSK9i and IPE, respectively, based on lipid profiles and existing therapies. Assuming maximal escalation of statins and addition of ezetimibe, 4.1% (95% CI, 2.8%-5.4%) of adults or 6.1 million would benefit from PCSK9i and 6.8% (95% CI, 5.4%-8.3%) or 10.2 million from IPE. Conclusions Six and 10 million individuals have clinical profiles whereby PCSK9i and IPE, respectively, would be expected to improve cardiovascular outcomes even after maximum escalation of statins and ezetimibe use, but remain undertreated with lipid-lowering therapies. Optimal use of lipid-targeted agents that include these novel agents is needed to improve population health outcomes.

Background: To evaluate the reductions of C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDL-C) in different lipid-lowering drugs, and to assess the relationships between the reductions of CRP, LDL-C, and cardiovascular (CV) events., Methods: We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to September 1, 2021. Randomized controlled trials (RCTs) comparing statins, proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9-mAbs), or ezetimibe against placebo with a treatment duration of at least 4 weeks and data on the effects of cholesterol-lowering interventions on LDL-C and CRP were included in this meta-analysis. The weighted mean difference (WMD) and 95% confidence interval (CI) were calculated., Results: Compared with placebo treatment, statins and ezetimibe treatments resulted in a significant decrease in LDL-C level (statins: WMD -47.94 mg/dL, 95% CI -51.21 to -44.67 mg/dL; ezetimibe: WMD -22.84 mg/dL, 95% CI -26.76 to -18.92 mg/dL) and CRP level (statins: WMD -0.67 mg/L, 95% CI -0.90 to -0.45 mg/dL; ezetimibe: -0.64 mg/L, 95% CI -1.07 to -0.21 mg/dL). Compared with placebo treatment, treatment with PCSK9-mAbs resulted in significant decrease in LDL-C level (WMD -54.24 mg/dL, 95% CI -59.77 to -48.70 mg/dL), while the concentration of CRP did not decrease significantly. Meta-regression analysis showed no significant association between change in CRP level and change in LDL-C level. Subgroup comparisons suggested that treatment with PCSK9-mAbs showed a greater reduction in LDL-C level when compared with the statins group and ezetimibe group, while the risks of CV death, myocardial infarction (MI), and stroke showed no significant differences., Conclusion: Based on the current study, our results suggested that statins, ezetimibe, and PCSK9-mAbs are effective in reducing LDL-C levels. Treatment with statins and ezetimibe also demonstrated a significant effect on CRP. The traditional lipid-lowering strategy including statin and ezetimibe showed similar benefit on CV outcomes compared with the PCSK9-mAbs treatment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Conventional lipid-lowering agents, including statins, ezetimibe, fibrates, bile acid sequestrants, nicotinic acid, bempedoic acid and Omega-3, are essential to the management of dyslipidaemia. However, these agents have been shown to increase the level of plasma proprotein convertase subtilisin/kexin 9 (PCSK9), a serine protease associated with increased cardiovascular risk. This review aims to investigate the impact of commonly available conventional lipid-lowering agents on circulating PCSK9 levels and lipid profiles., Methods and Analysis: This protocol is conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. A systematic search will be conducted in the following databases: MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Web of Science, SCOPUS and ScienceDirect. Additional information will be retrieved from clinical trial registries or from reference list searches. Published and peer-reviewed randomised controlled trials with adults receiving statin, ezetimibe, fibrate, bile acid sequestrant, nicotinic acid, bempedoic acid or Omega-3 monotherapy or in combination for at least 2 weeks, with availability of plasma PCSK9 at the beginning and end of treatment or the net changes in values, will be included. Study selection, data extraction and assessment of the risk of bias will be independently conducted by two investigators. Continuous data will be presented as a standardised mean difference with 95% confidence interval (CI) and dichotomous data as risk ratios with 95% CI. Subgroup analysis and sensitivity analysis will be performed when sufficient studies are included. Publication bias will be assessed with a funnel plot and Egger's test., Ethics and Dissemination: Ethics approval is not required as this review will only include data from published sources. The results will be published in a peer-reviewed journal., Patient and Public Involvement: No patient or members of the general public are involved., Prospero Registration Number: CRD42022297942., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: The European Society of Cardiology (ESC) has released three consecutive guidelines within 5 years addressing cardiovascular prevention, risk scores, and cholesterol treatment. This study aims to evaluate whether the 2021 ESC guidelines improved the eligibility of individuals for primary prevention statin therapy before their first ST-segment elevation myocardial infarction (STEMI), and for intensive lipid-lowering treatments in secondary prevention., Methods and Results: The cardiovascular risk category of 2757 consecutive individuals admitted for a first STEMI was evaluated to assess whether they would have been eligible for primary prevention statins according to 2021 vs. 2019 and 2016 ESC guidelines. Eligibility for intensive lipid-lowering therapy in secondary prevention was assessed according to the real-life follow-up low-density lipoprotein cholesterol (LDL-C) and the expected follow-up LDL-C. More individuals would have been eligible for primary prevention statins according to 2021 and 2019 vs. 2016 guidelines (61.8% vs. 38.7% vs. 23.6%, P < 0.01), a finding observed in both men (62.3% vs. 35.0% vs. 24.9%, P < 0.01) and women (60.2% vs. 50.7% vs. 19.3%, P = 0.18). Only 27% of individuals reached the LDL-C objective of 55 mg/L in secondary prevention: using the ESC stepwise approach, 61.7% were eligible for higher doses of statins, 26.2% for ezetimibe, and 12.1% for a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (PCSK9i). Based on expected LDL-C reductions, eligibility for a PCSK9i in secondary prevention was greater with 2021 vs. 2016 guidelines (44.5% vs. 22.5%, P < 0.01)., Conclusion: The 2021 ESC guidelines improved the detection and treatment of individuals at risk for a first myocardial infarction. In secondary prevention, 70% of patients kept LDL-C levels above 55 mg/dL: increasing the statin dose and adding ezetimibe were the most frequently recommended therapeutic actions., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Individuals with familial hypercholesterolemia (FH) undergo an aggressive treatment with cholesterol-lowering drugs to prevent coronary heart disease. Recent evidence suggests an interplay between the gut microbiota, blood lipid levels and lipid-lowering drugs, but this has yet to be studied in individuals with FH. The objective of the study was to characterize the gut microbiota of individuals with familial hypercholesterolemia and examine if effects of omega-3 polyunsaturated fatty acids (PUFAs) on blood lipids act through modification of the gut microbiome. The gut microbiota composition of individuals with FH ( N  = 21) and healthy controls ( N  = 144) was analyzed by extracting DNA from stool samples and sequencing of the V3-V4 region of the 16S rRNA gene. A subgroup ( n  = 15) of the participants received omega-3 polyunsaturated fatty acids (PUFAs) supplementation or placebo in a crossover manner, and the effect of PUFAs on the gut microbiota was also investigated. Individuals with FH had a different gut microbiota composition compared to healthy controls, characterized by reduced richness ( p  = .001) and reduction of several genera belonging to Clostridia and Coriobacteriia. Patients using ezetimibe in addition to statins appeared to have lower richness compared to those only using statins ( p  = .01). Intervention with omega-3 PUFAs had negligible impact on the microbiota composition. Positive effects on blood lipids after intervention with omega-3 PUFA were not associated with baseline gut microbiota composition or gut microbial changes during treatment. Further, patients with FH have an altered gut microbiota compared to healthy controls, possibly driven by the use of ezetimibe.

Familial hypercholesterolemia (FH) is the most common monogenic disorder. Due to the marked elevation of cardiovascular risk, the early detection, diagnosis, and proper management of this disorder are critical. Herein, the 2022 Korean guidance on this disease is presented. Clinical features include severely elevated low-density lipoprotein cholesterol (LDL-C) levels, tendon xanthomas, and premature coronary artery disease. Clinical diagnostic criteria include clinical findings, family history, or pathogenic mutations in the LDLR, APOB, or PCSK9. Proper suspicion of individuals with typical characteristics is essential for screening. Cascade screening is known to be the most efficient diagnostic approach. Early initiation of lipid-lowering therapy and the control of other risk factors are important. The first-line pharmacological treatment is statins, followed by ezetimibe, and PCSK9 inhibitors as required. The ideal treatment targets are 50% reduction and < 70 or < 55 mg/dL (in the presence of vascular disease) of LDL-C, although less strict targets are frequently used. Homozygous FH is characterized by untreated LDL-C > 500 mg/dL, xanthoma since childhood, and family history. In children, the diagnosis is made with criteria, including items largely similar to those of adults. In women, lipid-lowering agents need to be discontinued before conception.

Lipid-lowering therapy plays a crucial role in reducing adverse cardiovascular (CV) events in patients with established atherosclerotic cardiovascular disease (ASCVD) and familial hypercholesterolemia. Lifestyle interventions along with high-intensity statin therapy are the first-line management strategy followed by ezetimibe. Only about 20-30% of patients who are on maximally tolerated statins reach recommended low-density lipoprotein cholesterol (LDL-C) goals. Several factors contribute to the problem, including adherence issues, prescription of less than high-intensity statin therapy, and de-escalation of statin dosages, but in patients with very high baseline LDL-C levels, including those with familial hypercholesterolemia and those who are intolerant to statins, it is critical to expand our arsenal of LDL-C-lowering medications. Moreover, in the extreme risk group of patients with an LDL-C goal of ≤30 mg/dL according to the Lipid Association of India (LAI) risk stratification algorithm, there is a significant residual risk requiring the addition of non-statin drugs to achieve LAI recommended targets. This makes bempedoic acid a welcome addition to the existing non-statin therapies such as ezetimibe, bile acid sequestrants, and PCSK9 inhibitors. A low frequency of muscle-related side effects, minimal drug interactions, a significant reduction in high-sensitivity C-reactive protein (hsCRP), and a lower incidence of new-onset or worsening diabetes make it a useful adjunct for LDL-C lowering. However, the CV outcomes trial results are still pending. In this LAI consensus document, we discuss the pharmacology, indications, contraindications, advantages, and evidence-based recommendations for the use of bempedoic acid in clinical practice., (© Journal of the Association of Physicians of India 2011.)

Stroke is the second most common cause of mortality worldwide and the third most common cause of disability. Arterial hypertension is the most prevalent risk factor for stroke. A precise management of arterial hypertension prevents the first episode of stroke and the recurrence. Blood pressure must be decreased carefully and not very vigorously in the acute phase of the stroke. Recommended blood pressure goals in chronic tratment are at least 140 / 90 mm Hg and lower if tolerated. ACE inhibitors or angiotensin receptor blockers in combination with calcium channel blockers or indapamide are favorable antihypertensive drugs. Dyslipidemia is also a strong risk factor for ischaemic stroke and has no relatioship to the other etiologies of stroke. The cardiovascular risk in patients after a stroke is very high. An intensive hypolipidemic treatment by statins, ezetimibe and PCSK9i to LDL-cholesterol goals < 1,4 mmol/l and a 50% decrease was proved to decrease the incidence of recurrent stroke.

Background: Despite lipid-lowering and antiplatelet therapy, the pattern of residual lipoproteins seems relevant to long-term cardiovascular outcomes. This study aims to evaluate the effects of combined therapies, commonly used in subjects with acute myocardial infarction, in the quality of low-density lipoprotein (LDL) particles., Methods: Prospective, open-label trial, included patients with acute myocardial infarction. Patients were randomized to antiplatelet treatment (ticagrelor or clopidogrel) and subsequently to lipid-lowering therapy (rosuvastatin or simvastatin/ezetimibe) and were followed up for six months. Nonlinear optical properties of LDL samples were examined by Gaussian laser beam (Z-scan) to verify the oxidative state of these lipoproteins, small angle X-ray scattering (SAXS) to analyze structural changes on these particles, dynamic light scattering (DLS) to estimate the particle size distribution, ultra violet (UV)-visible spectroscopy to evaluate the absorbance at wavelength 484 nm (typical from carotenoids), and polyacrylamide gel electrophoresis (Lipoprint) to analyze the LDL subfractions., Results: Simvastatin/ezetimibe with either clopidogrel or ticagrelor was associated with less oxidized LDL, and simvastatin/ezetimibe with ticagrelor to lower cholesterol content in the atherogenic subfractions of LDL, while rosuvastatin with ticagrelor was the only combination associated with increase in LDL size., Conclusions: The quality of LDL particles was influenced by the antiplatelet/lipid-lowering strategy, with ticagrelor being associated with the best performance with both lipid-lowering therapies. Trial registration: NCT02428374., Competing Interests: I confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials. The study design, data collection, statistical analysis, or publications were not influenced by the sponsors and are the exclusive responsibility of the investigators.

Soluble epidermal growth factor receptor (sEGFR) levels are elevated in patients with type 2 diabetes mellitus (T2DM) and positively correlate with blood glucose and cholesterol levels. However, how cholesterol-lowering treatment in patients with T2DM affects the sEGFR level is unknown. Therefore, we investigated the change of serum sEGFR after cholesterol-lowering treatment in type 2 diabetic patients with hypercholesterolemia. This study is a non-randomized, prospective observational study. A total of 115 patients were treated in either the rosuvastatin monotherapy group (R group, 5 mg/day, n = 59) or the rosuvastatin/ezetimibe combination therapy group (RE group, 5 mg/10 mg/day, n = 56) for 12 weeks. We measured serum levels of lipids and sEGFR using an ELISA kit before and after 12 weeks of treatment in each group. The low-density lipoprotein cholesterol (LDL-C) level was significantly reduced (from 130.27 ± 27.09 to 76.24 ± 26.82 mg/dL; P < .001) after 12 weeks of treatment and more so in the RE group than in the R group (from 131.68 ± 28.72 to 87.13 ± 27.04 mg/dL, P < .001 in the R group; from 128.78 ± 25.58 to 64.75 ± 21.52 mg/dL, P < .001 in the RE group; R vs RE group, P < .001). The sEGFR level was significantly decreased after 12 weeks of treatment (from 50.34 ± 13.31 to 45.75 ± 11.54 ng/mL; P = .007). The RE group only showed a significant reduction in the sEGFR level after treatment (from 50.94 ± 12.10 to 44.80 ± 11.36 ng/mL; P = .007). Moreover, the sEGFR level was significantly reduced only when the LDL-C level was significantly reduced (from 50.46 ± 10.66 to 46.24 ± 11.86 ng/mL; P = .043). The serum sEGFR level was significantly reduced by cholesterol-lowering treatment with rosuvastatin alone or rosuvastatin/ezetimibe. We suggested that sEGFR may play a significant role in insulin resistance (IR) and inflammation, which are central pathophysiological mechanisms. We confirmed the possibility of using sEGFR as a biomarker to predict a good response to lipid-lowering treatment in type 2 diabetes patients with hypercholesterolemia., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: Conflict of interest: G.L. received grant support (to the Institution) for investigator-initiated research from American Heart Association, Italian National Health Service and Italian Minister of Education, University and Research. She is currently involved in the Research Programs of the Italian Cardiovascular Network. She received personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi and Novartis. C.P. received consultant and speaker fees from Acticor Biotech, Amgen, Bayer, GlaxoSmithKline, Tremeau, Zambon, and grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission; he chairs the Scientific Advisory Board of the International Aspirin Foundation.

Ankylosing spondylitis (AS) is a chronic inflammatory disease that causes spinal inflammation and fusion. Although the cause of AS is unknown, genetic factors (e.g., HLA-B27) and environmental factors (e.g., sex, age, and infection) increase the risk of AS. Current treatments for AS are to improve symptoms and suppress disease progression. There is no way to completely cure it. High blood cholesterol and lipid levels aggravate the symptoms of autoimmune diseases. We applied hyperlipidemia drugs ezetimibe and rosuvastatin to AS mice and to PBMCs from AS patients. Ezetimibe and rosuvastatin was administered for 11 weeks to AS model mice on the SKG background. Then, the tissues and cells of mice were performed using flow cytometry, computed tomography, immunohistochemistry, and immunofluorescence. Also, the normal mouse splenocytes were cultured in Th17 differentiation conditions for in vitro analysis such as flow cytometry, ELISA and RNA sequencing. The 10 AS patients' PBMCs were treated with ezetimibe and rosuvastatin. The patients' PBMC were analyzed by flow cytometry and ELISA for investigation of immune cell type modification. Ezetimibe caused substantial inhibition for AS. The present study showed that ezetimibe inhibits Th17 cell function, thereby slowing the progression of AS. It is well known that statins are more effective in reducing blood lipid concentrations than ezetimibe, however, our results that ezetimibe had a better anti-inflammatory effect than rosuvastatin in AS. This data suggests that ezetimibe has an independent anti-inflammatory effect independent of blood lipid reduction. To investigate whether ezetimibe has its anti-inflammatory effect through which signaling pathway, various in vitro experiments and RNA sequencing have proceeded. Here, this study suggests that ezetimibe can be an effective treatment for AS patients by inhibiting Th17 differentiation-related genes such as IL-23R and IL-1R. Thus, this study suggests that ezetimibe has therapeutic potential for AS through inhibition of Th17 differentiation and the production of pro-inflammatory cytokines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Moon, Lee, Na, Lee, Cho, Choi, Park and Cho.)

Background Bempedoic acid (BA) inhibits ATP-citrate lyase in the cholesterol synthesis pathway and lowers low-density lipoprotein cholesterol (LDL-C). As with other lipid-lowering therapies, interindividual variation in response to BA was observed in clinical trials. We characterized LDL-C response to BA using guideline-defined statin intensity categories and identified clinical factors associated with enhanced LDL-C lowering with BA. Methods and Results This post hoc analysis used pooled data from 4 phase 3 studies. Patients were randomized 2:1 to once-daily BA 180 mg (n=2321) or placebo (n=1167) for 12 to 52 weeks and grouped based on percent change in LDL-C from baseline to week 12 according to guideline-established statin intensity categories. Factors associated with ≥30% reduction in LDL-C were identified using logistic regression analyses. From baseline to week 12, BA lowered LDL-C levels comparable to a moderate- or high-intensity statin (≥30%) in 28.9% of patients; this degree of LDL-C lowering was observed in 50.9% of patients not receiving background statin therapy. In a multivariable analysis, the absence of statins, female sex, a history of diabetes, ezetimibe use, and higher high-sensitivity C-reactive protein level were associated with increased rates of achieving ≥30% LDL-C reduction with BA ( P <0.01 for each). Conclusions A large percentage of patients receiving BA achieved LDL-C reductions comparable to a moderate- or high-intensity statin. Factors including statin absence, female sex, diabetes history, ezetimibe use, and a higher high-sensitivity C-reactive protein level may be useful to identify patients who may have a greater LDL-C reduction with BA. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02666664, NCT02991118, NCT02988115, NCT03001076.

Background: Despite treatment with statins, dyslipidaemia patients with elevated cholesterol- and triglyceride-levels remain at high residual risk for major adverse cardiovascular events (MACE). New lipid-lowering drugs must prevent the occurrence of MACE and exhibit cost-effectiveness for their successful adoption to clinical practice., Objective: To assess the cost effectiveness of icosapent ethyl, fenofibrate, ezetimibe, evolocumab, and alirocumab in combination with statins compared to statin monotherapy for cardiovascular prevention from the perspective of UK's National Health Service., Methods: A Markov model simulated the progression of cardiovascular disease and MACE, including myocardial infarction, stroke, angina pectoris, and coronary revascularisation, in dyslipidaemia patients. The model was populated with cardiovascular outcome trial data for each drug. Cost and utility data were extracted from peer-reviewed literature. The incremental cost-effectiveness ratio (ICER) is reported per quality-adjusted life years (QALY) gained in 2021 Great Britain Pounds (£)., Results: For primary cardiovascular prevention, icosapent ethyl increased QALYs by 0.79 and costs by £15,421 compared to statin monotherapy (ICER = £19,485/QALY). Fenofibrate yielded 0.62 additional QALYs at cost-savings of - £6127 (ICER = - £9932/QALY). For secondary prevention, the omega-3 fatty acid icosapent ethyl extended QALYs by 0.98 at costs of £12,981 compared to statin monotherapy (ICER = £13,285/QALY). Fenofibrate added 0.85 QALYs whilst saving - £637 (ICER = - £7472/QALY). Ezetimibe increased QALYs by 0.60 at cost reductions of - £2529 (ICER = - £4231/QALY). PCSK9 inhibitors provided QALYs of 0.53 and 0.86 at costs of £45,279 and £46,375 for evolocumab (ICER = £85,193/QALY) and alirocumab (ICER = £54,211/QALY), respectively. At a willingness-to-pay threshold of £25,000/QALY, there is a probability of 100% for icosapent ethyl (98% in primary prevention) and 0% for PCSK9 inhibitors to be cost effective in secondary prevention., Conclusions: Icosapent ethyl is cost effective for primary and secondary cardiovascular prevention at an annual price of £2064 in the UK. For PCSK9 inhibitors, price discounts or prescription restrictions are necessary to achieve cost effectiveness., (© 2022. The Author(s).)

Current dyslipidemia guidelines emphasize statins as the cornerstone of pharmacological lipid-lowering therapy. The cholesterol absorption inhibitor ezetimibe, PCSK9-antibodies, as well as bempedoic acid and inclisiran are newly available options to further reduce LDL-cholesterol. Since modern lipid-lowering therapy is characterized by an individual, "treat-to-target" approach the aim of this review is to provide a better understanding of cholesterol metabolism to guide decision-making and the rational for using early individualized combination therapies., Competing Interests: OW: Honorare für Vorträge und Advisory Boards von: AMGEN, Berlin-Chemie, Novo-Nordisk, Novartis, Amarin, Sanofi-Aventis, Fresenius, Hexal, AkceaTherapeutics, Pfizer.GK: Vortragshonorare von Akcea, Amgen, BMS, Daiichi Sankyo, esanum, Novartis, Sanofi, Sobi und Synlab.NM hat Vorträge gehalten für Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Lilly, NovoNordisk; NM hat Forschungsprojekte durchgeführt, die von Boehringer Ingelheim unterstützt wurden, und als Berater für Amgen, Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, NovoNordisk fungiert.UL: Vortragshonorere von AMGEN, Daiichi-Sankyo, Novartis, Sanofi., (Thieme. All rights reserved.)

Source Citation: Hao Q, Aertgeerts B, Guyatt G, et al. PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations. BMJ. 2022;377:e069066. 35508320.

Aim      To study the prevalence of hyperlipidemia in patients with myocardial infarction (MI) in the Russian Federation; to assess the compliance with clinical practice guidelines of the lipid-lowering therapy prescribed upon discharge from the hospital; and to determine the number of patients who are indicated for the combination lipid-lowering therapy to achieve the low-density lipoprotein cholesterol (LDL-C) goal.Material and methods  REGION-MI is Russian rEGIstry Of acute myocardial iNfarction, a multicenter, retrospective and prospective observational study. The observation period was divided into 3 stages: observation during the stay in the hospital and at 6 and 12 months after the inclusion in the registry. Plasma total cholesterol (TC) and LDL-C were measured in all patients on admission. Evaluation of the prescribed lipid-lowering therapy included the intensity of the treatment.Results The study included 3 620 patients; 62.4 of them had hyperlipidemia on admission. Mean TC on admission was 5.29 mmol/l and LDl-C level was 3.35 mmol/l. Upon discharge, 95.4% of patients after myocardial infarction continued on or were prescribed statin therapy; ezetimibe was prescribed to 1.22% of patients. Patients with an extremely high level of LDL-C &gt;5 mmol/l accounted for 10.7% of patients with hyperlipidemia. The target level of LDL-C ≤1.4 mmol/l cannot be achieved with the statin and ezetimibe combination therapy in these patients; drugs from the group of PCSK9 inhibitors are indicated for them.Conclusion      According to the data of the Russian registry of acute myocardial infarction, REGION-MI, a high incidence of hyperlipidemia is observed in patients with acute MI. Despite multiple studies that have proven the importance of achieving a low LDL-C level and good tolerance and safety of ezetimibe and PCSK9 inhibitors, the prescription frequency of combination therapy remains unreasonably low. Results of a simulation study that was conducted in Sweden and the data of the REGION-MI registry showed that PCSK9 inhibitors as a part of the combination therapy are indicated for many patients. The combination therapy is presently the most powerful type of lipid-lowering treatment that allows, in most cases, achievement of the LDL-C goal.

Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors significantly reduce low-density lipoprotein cholesterol (LDL-C) and improve the prognosis of patients with acute coronary syndrome (ACS). However, the feasibility and safety of early application of PCSK9 inhibitors on the basis of statins combined with ezetimibe to strengthen lipid lowering in extremely high-risk coronary heart disease populations are still unknown.This study was a prospective, randomized controlled study. A total of 136 patients with extremely high-risk ACS with LDL-C ≥ 3.0 mmol/L after percutaneous coronary intervention (PCI) treatment were randomly assigned 1:1 to the control group (atorvastatin 40 mg/day and ezetimibe 10 mg/day) or the evolocumab group (evolocumab 140 mg every 2 weeks combined with atorvastatin 40 mg/day and ezetimibe 10 mg/day). We compared the blood lipid profiles, major adverse cardiovascular events (MACEs), and adverse reactions. MACEs included cardiogenic death, nonfatal myocardial infarction, nonfatal stroke, and readmission due to angina. Adverse reactions included allergies, myalgia, poor blood glucose control, and liver damage.Within 1 month, the average level of LDL-C in the evolocumab group decreased from 3.54 to 0.57 mmol/L and that in the control group decreased from 3.52 to 1.26 mmol/L. The LDL-C compliance (< 1.0 mmol/L) rate was significantly increased in the evolocumab group compared with the control group (82.35% versus 22.06%, P < 0.01). The average level of lipoprotein (a) (Lp (a) ) in the control group increased by 9.94 ± 51.93% from baseline after treatment, but evolocumab reduced the Lp (a) level (-38.84 ± 32.40%). Additionally, evolocumab further reduced the levels of apolipoprotein B/A1 (-70.56 ± 22.38% versus -51.29 ± 18.14%), cholesterol (-54.76 ± 18.10% versus -41.16 ± 18.14%), and apolipoprotein B (-66.47 ± 26.89% versus -46.78 ± 24.12%) compared with those in the control group, all P < 0.01. The blood lipid levels of both control and evolocumab groups stabilized after 1 month. During the 3-month follow-up, the incidence of MACEs after PCI was lower in the evolocumab group than in the control group (8.82% versus 24.59%, P = 0.015), and evolocumab combined with statins and ezetimibe did not increase the occurrence of adverse reactions (13.24% versus 11.48%, P = 0.762).In patients with extremely high-risk ACS with high levels of LDL-C, adding evolocumab to their treatment regimen as early as possible may enhance lipid lowering, increase the patient's LDL-C compliance rate in the short term, and improve cardiovascular prognosis but will not increase adverse reactions.

Objective: To analyze the significance of ezetimibe in combination with low- to moderate-intensity atorvastatin adjuvant aspirin therapy for cerebrovascular disease., Methods: 110 patients with cerebrovascular disease treated in our hospital from June 2020 to June 2021 were selected and divided into 55 patients in the control group and 55 patients in the study group according to the lottery method. After a comprehensive examination, patients in the two groups should be given aspirin for treatment; the control group was treated with conventional dose of atorvastatin on top of the above, and the study group was given ezetimibe and medium-low-dose atorvastatin on top of aspirin treatment, activities of daily living (ADL) score, carotid artery intima-media thickness, lipid level, coagulation level, clinical effect, and adverse rate of the two groups which were tested and compared., Results: After treatment, ADL score, high-density leptin cholesterol (HDL-C), and ATIII levels increased, while carotid artery media thickness, triglyceride (TG), total cholesterol (TC), low-density leptin cholesterol (LDL-C), DD, PC, and hs-CRP levels decreased ( P < 0.05). After treatment, ADL score, HDL-C, and ATIII levels were higher in the study group. The levels of carotid media thickness, TG, TC, LDL-C, DD, PC, and hs-CRP were significantly lower ( P < 0.05). The clinical effect of the study group was outstanding ( P < 0.05). The defect rate of the study group was lower than that of the control group, but there was no difference ( P < 0.05)., Conclusion: Ezetimibe combined with medium- and low-intensity atorvastatin with aspirin in the treatment of cerebrovascular diseases can effectively improve the coagulation function of patients, reduce the level of inflammatory factors in patients, and improve the level of blood lipids in patients, with high safety and worthy of clinical application., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Lijie Wang and Xiaoqin Tang.)

Cardiovascular disease is one of the leading causes of death around the world with various efforts being made to reduce risk in patients through preventive measures. One major method for prevention has been managing cholesterol, particularly low-density lipoprotein to decrease atherosclerotic plaque burden, potentially decreasing future cardiac complications. Statins have been the gold standard therapy for hypercholesterolemia treatment due to their ease of dosing, limited drug interactions, and favorable safety profile. Unfortunately, statin therapy alone is not always effective enough to adequately control a patient's elevated lipid levels and combination therapy may be warranted. Ezetimibe is commonly added to regimens to help augment cholesterol lowering by inhibiting the absorption of cholesterol. The recent approval of a combination tablet of high-intensity rosuvastatin and ezetimibe has introduced a potentially more beneficial option for cholesterol management in addition to the only available combination of moderate intensity simvastatin and ezetimibe. We aimed to identify potential beneficial effects of ezetimibe by comparing its use in combination with high-intensity rosuvastatin compared to a statin therapy alone or in combination with moderate intensity simvastatin through a literature review. The current evidence indicated that combination therapy outperformed statin monotherapy in reduction of low-density lipoprotein cholesterol and patients were more likely to achieve their target low-density lipoprotein cholesterol goal level. This suggests rosuvastatin/ezetimibe combination holds a potential place in therapy for patients requiring a more aggressive reduction in cholesterol to help prevent atherosclerotic disease., Competing Interests: Dr Qing Ma reports grants from Gilead Science CO-US-380-5529, outside the submitted work. The author reports no conflicts of interest in this work., (© 2022 Chilbert et al.)

Purpose of Review: We reviewed lipid-modifying therapies and the risk of stroke and other cerebrovascular outcomes, with a focus on newer therapies., Recent Findings: Statins and ezetimibe reduce ischemic stroke risk without increasing hemorrhagic stroke risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors similarly reduce ischemic stroke risk in statin-treated patients with atherosclerosis without increasing hemorrhagic stroke, even with very low achieved low-density lipoprotein cholesterol levels. Icosapent ethyl reduces the risk of total and first ischemic stroke in patients with established cardiovascular disease or diabetes mellitus. Clinical outcome trials are underway for newer lipid-modifying agents, including inclisiran, bempedoic acid, and pemafibrate. New biologic agents including evinacumab, pelacarsen, olpasiran, and SLN360 are also discussed. In addition to statins and ezetimibe, PCSK9 inhibitors and icosapent ethyl reduce the risk of ischemic stroke without increasing the risk of hemorrhagic stroke. These therapies dramatically expand options for reducing stroke in high-risk settings., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The last 50 years have experienced a rapid evolution in the development of lipid-lowering agents to reduce low-density lipoprotein cholesterol levels. This significant advance in medicine has not occurred without debate. Whether lowering blood cholesterol levels was beneficial has remained one of the most controversial issues during the past 50 years. The discovery of statins was the revolution that made it possible to delay and stop the progression of the atherosclerotic process resulting in improved health and longevity for millions of people. To date, statins remain the drugs of choice for the treatment of hypercholesterolemia. Despite their use, the risk of cardiovascular events persists. Therefore, the use of non-statin drugs, such as ezetimibe or PCSK9 inhibitors, in combination with statins has been shown to further reduce the risk of cardiovascular events. This review aims to summarize the advances in the field of lipid-lowering therapies over the past 50 years, focusing on advances in the development of drug therapies up to and including gene silencing or gene editing treatments that are expected in the near future.

Background: Despite the availability of effective lipid-lowering drugs, only few high-risk patients attain their LDL cholesterol (LDL-C) guideline-recommended risk-based goal because of underprescription of combination therapy. We present an 18-month experience with variation of prescription protocols after publication of the 2019 ESC/EAS guidelines for the management of dyslipidemias., Methods: Overall, 621 consecutive patients hospitalized for acute coronary syndrome at Mauriziano Hospital in Turin, Italy, between January 2020 and June 2021 were enrolled. Lipid-lowering therapy recommended at discharge was registered to evaluate how many patients received statin monotherapy, statin plus ezetimibe combination or triple therapy with high-intensity statin plus ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i). At 6-month follow-up, the reduction in LDL-C, adverse events, compliance and cardiovascular recurrences was analyzed., Results: Of 621 patients enrolled, 7 died during hospitalization. During the entire study period, 33% of patients received statin monotherapy, 50% were discharged on statin-ezetimibe combination, and PCSK9i (evolocumab) was prescribed to 17% of patients. Between April 2020 and June 2021, when new recommendations were introduced into clinical practice, 20% of patients received evolocumab, 56% combination therapy and only 24% were discharged on statin monotherapy. At the beginning of observation, evolocumab was prescribed to 3% of patients hospitalized for acute coronary syndrome, while at the end of the study period 27% of patients were discharged on PCSK9i, with an increase of the prescription rate by 759%; in the same period, prescription of statin monotherapy decreased by 75%. At 6-month follow-up, LDL-C reduction was 77% in patients treated with PCSK9i vs 48% in patients taking statin-ezetimibe combination therapy (p<0.001). All patients on evolocumab reached the guideline-directed goals and a low rate of adverse events was reported, mainly represented by local injection site reactions. Six patients experienced acute coronary syndrome recurrence; only one of them was treated with evolocumab., Conclusion: Prescription of intensive lipid-lowering therapy after acute coronary syndrome, eventually with introduction of PCSK9i during hospitalization or at discharge, leads to attainment of guideline-recommended goals for all patients, with a low incidence of adverse events and optimal compliance.

Lipid-lowering medications comprise standard of care in the prevention of cardiovascular disease. This study examined the trends in the utilization of statin and non-statin medications in the Australian general population between 2013 and 2019. Pharmacoepidemiological analyses were performed using pharmacy dispensing data from Australian Pharmaceutical Benefits Scheme. One-year prevalence and incidence of statin and non-statin prescribing patterns were reported, and relative variations in prescribing examined via Poisson regression modelling. The one-year prevalence of statins' prescriptions decreased between 2013-2019 by 5.5% (from 25.0%-19.5%). Females were less likely than males to be prescribed statins (rate ratio [RR]=0.90, 95% confidence interval [CI] 0.89-0.91). The one-year prevalence of ezetimibe alone, and in combination with statins, increased consistently from 2013-2019 from 1.5%-3.6% (P<0.01) and 0.1%-1.1% (P<0.01), respectively. The prevalence was higher among those aged 61-80 years (RR=1.20, 95%CI 1.10-1.21) and those aged older than 80 years (RR=1.34, 95%CI 1.22-1.47), when compared to people aged <60 years. The incidence of ezetimibe prescriptions was highest in people aged 61-80 years (RR=1.36, 95%CI 1.31-1.41) compared to those aged <60 years. The one-year prevalence of proprotein convertase subtilisin/kexin type 9 inhibitor prescriptions was highest among those aged 46-60 years (RR=1.24, 95%CI 0.97-4.97) compared to people aged <46 and >60 years. Females were less likely than males to be prescribed a proprotein convertase subtilisin/kexin type 9 inhibitor (RR=0.87, 95%CI 0.75-0.98). Statins remain the most prevalent lipid-lowering medication prescribed in Australia. The prescribing of non-statin medications remains low, but is increasing., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose of Review: Despite the elevation of lipid values during pregnancy is mostly physiological, evidence suggest that it may be associated with adverse events. This article reviews the characteristics of lipid disorders and the possible management with dyslipidemia in pregnant women., Recent Findings: Among many available groups of lipid-lowering drugs, only bile acid sequestrants are approved for the treatment of dyslipidemia during pregnancy. Ezetimibe and fenofibrate might be considered if benefits outweigh the potential risk. Statins are still contraindicated due to the results mainly from animal studies and series of human cases. However, recent systematic reviews and meta-analyses showed that their use may not be detrimental, and in some selected cases may be beneficial. Especially, in some groups of pregnant patients with very high cardiovascular risk-those already after an event, or with established cardiovascular disease, with homozygous familial hypercholesterolemia; in such cases the final decision should weight the potential risk of discontinuation of therapy. Finally, we need to wait for the data with new drugs, including PCSK9 inhibitors and especially inclisiran, which (still hypothetically) might be a very interesting option as it may be used just before the pregnancy and immediately after with the duration of about 9 months between injections. The decisions on lipid-lowering therapy in pregnant patients should be individualized. Despite design and ethical difficulties with such studies, further investigations on dyslipidemia treatment during pregnancy are highly awaited., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Peripheral artery disease (PAD) is the occlusion or narrowing of the arteries supplying the lower extremities. Peripheral artery disease has been estimated to affect approximately 240 million people worldwide, approximately 70% of whom are within low- or middle-income countries. Due to the ageing population and diabetes epidemic, the prevalence of PAD is rapidly rising. The symptoms of PAD are heterogeneous and thus a high index of suspicion is needed to prevent delays in diagnosis and treatment. Measurement of ankle brachial pressure index or arterial duplex ultrasound are traditionally used to diagnose PAD. Patients with PAD have a high risk of major adverse cardiovascular events. Early diagnosis and implementation of secondary cardiovascular prevention is therefore critical. This includes therapies to reduce low-density lipoprotein cholesterol, such as statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, blood-pressure reducing medications and anti-thrombotic drugs. Treatments to facilitate smoking cessation and control blood sugar if relevant and an exercise programme are also critical in reducing cardiovascular risk. Currently, these treatments are not well implemented. This review summarises the clinical presentation, risk factors and medical management of PAD. Global efforts are needed to reduce the burden from the growing PAD epidemic by implementing best practices and improving outcomes through further research., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In addition to statin therapy, Ezetimibe, a non-statin lipid-modifying agent, is increasingly used to reduce low-density lipoprotein cholesterol and atherosclerotic cardiovascular disease risk. Literature suggests the clinical effectiveness of Ezetimibe plus statin (EPS) therapy; however, primary evidence on its economic effectiveness is inconsistent. Hence, we pooled incremental net benefit to synthesise the cost-effectiveness of EPS therapy. We identified economic evaluation studies reporting outcomes of EPS therapy compared with other lipid-lowering therapeutic agents or placebo by searching PubMed, Embase, Scopus, and Tufts Cost-Effective Analysis registry. Using random-effects meta-analysis, we pooled Incremental Net Benefit (INB) in the US $ with a 95% confidence interval (CI). We used the modified economic evaluations bias checklist and GRADE quality assessment for quality appraisal. The pooled INB from twenty-one eligible studies showed that EPS therapy was significantly cost-effective compared to other lipid-lowering therapeutic agents or placebo. The pooled INB (95% CI) was $4,274 (621 to 7,927), but there was considerable heterogeneity (I2 = 84.21). On subgroup analysis EPS therapy is significantly cost-effective in high-income countries [$4,356 (621 to 8,092)], for primary prevention [$4,814 (2,523 to 7,106)], and for payers' perspective [$3,255 (571 to 5,939)], and from lifetime horizon [$4,571 (746 to 8,395)]. EPS therapy is cost-effective compared to other lipid-lowering therapeutic agents or placebo in high-income countries and for primary prevention. However, there is a dearth of evidence from lower-middle-income countries and the societal perspective., Competing Interests: The authors have declared that no competing interests exist.

To assess the potential therapeutic role of antilipidemic ezetimibe on endometriosis in an experimental rat model. A standard experimental endometriosis model was created with 18 Whistar-Albino rats, and after 1 month, the sizes of the endometriotic explants were measured. The rats were randomized as study and control groups. A total of 1 mg/kg/day ezetimibe and 1 ml/kg/day saline were administered orally to the study and control groups respectively for 28 days. At the end of 28 days, the explants were measured again, excised, and sent for histopathologic assessment for expression of tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF) and number of mast cells. At the end of the study period, the size of the endometriotic explants decreased significantly in the study group; but not in the control group (from 145.3 ± 120.5 to 89.8 ± 60.1 vs 174.72 ± 88.3 to 87.65 ± 27.1 cm 3 respectively); however, the amount of post- and pretreatment differences in explant sizes was similar in the groups. The median TNF-α and VEGF levels were significantly lower in the ezetimibe group when compared to the control group (4 [3-4] vs 2 [1-3], p 0.029; 4 [3-4] vs 2 [2-3], p 0.002; respectively). And numbers of mast cells in all uterine layers were also lower in the ezetimibe group. Ezetimibe decreased the size of the endometriotic explants with its anti-inflammatory and anti-angiogenic properties. This agent alone or with combination of other agents may have a potential role in the treatment of endometriosis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Lowering of low-density lipoprotein (LDL) cholesterol represents one of the most effective interventions in cardiovascular prevention. Besides the oral treatment with statins, ezetimibe and bempedoic acid, subcutaneously administered inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) have been established as further cornerstones of lipid-lowering treatment. The antibodies evolocumab and alirocumab are administered subcutaneously every 2-4 weeks and lower LDL cholesterol by around 60%, independent of pre-treatment with very good tolerability. Both drugs successfully reduced cardiovascular endpoints in large outcome trials. A novel principle of PCSK9 inhibition is RNA interference, which is exploited by the novel compound inclisiran. Inclisiran is a double-stranded modified RNA molecule, which neutralizes the mRNA of PCSK9 and thus inhibits PCSK9 protein synthesis intracellularly. Inclisiran only needs to be administered every 6 months. The cardiovascular outcome trial ORION‑4 is currently ongoing. In Germany, prescription of PCSK9 inhibitors is regulated by the decision of the Federal Joint Committee. Novel strategies to inhibit PCSK9 function are under development and include orally available drugs and animal experiment concepts on gene editing, which are in different states of evaluation., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Clinical Question: In adults with low density lipoprotein (LDL) cholesterol levels >1.8 mmol/L (>70 mg/dL) who are already taking the maximum dose of statins or are intolerant to statins, should another lipid-lowering drug be added, either a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor or ezetimibe, to reduce the risk of major cardiovascular events? If so, which drug is preferred? Having decided to use one, should we add the other lipid-lowering drug?, Current Practice: Most guidelines emphasise LDL cholesterol targets in their recommendations for prescribing PCSK9 inhibitors and/or ezetimibe in adults at high risk of experiencing a major adverse cardiovascular event. However, to achieve these goals in very high risk patients with statins alone is almost impossible, so physicians are increasingly considering other lipid-lowering drugs solely for achieving LDL cholesterol treatment goals rather than for achieving important absolute cardiovascular risk reduction. Most guidelines do not systematically assess the cardiovascular benefits of adding PCSK9 inhibitors and/or ezetimibe for all risk groups across primary and secondary prevention, nor do they report, in accordance with explicit judgments of assumed patients' values and preferences, absolute benefits and harms and potential treatment burdens., Recommendations: The guideline panel provided mostly weak recommendations, which means we rely on shared decision making when applying these recommendations. For adults already using statins, the panel suggests adding a second lipid-lowering drug in people at very high and high cardiovascular risk but recommends against adding it in people at low cardiovascular risk. For adults who are intolerant to statins, the panel recommends using a lipid-lowering drug in people at very high and high cardiovascular risk but against adding it in those at low cardiovascular risk. When choosing to add another lipid-lowering drug, the panel suggests ezetimibe in preference to PCSK9 inhibitors. The panel suggests further adding a PCSK9 inhibitor to ezetimibe for adults already taking statins at very high risk and those at very high and high risk who are intolerant to statins., How This Guideline Was Created: An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified four risk groups of patients (low, moderate, high, and very high cardiovascular risk) and primarily applied an individual patient perspective in moving from evidence to recommendations, though societal issues were a secondary consideration. The panel considered the balance of benefits and harms and burdens of starting a PCSK9 inhibitor and/or ezetimibe, making assumptions of adults' average values and preferences. Interactive evidence summaries and decision aids accompany multi-layered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that also allows re-use and adaptation., The Evidence: A linked systematic review and network meta-analysis (14 trials including 83 660 participants) of benefits found that PCSK9 inhibitors or ezetimibe probably reduce myocardial infarctions and stroke in patients with very high and high cardiovascular risk, with no impact on mortality (moderate to high certainty evidence), but not in those with moderate and low cardiovascular risk. PCSK9 inhibitors may have similar effects to ezetimibe on reducing non-fatal myocardial infarction or stroke (low certainty evidence). These relative benefits were consistent, but their absolute magnitude varied based on cardiovascular risk in individual patients (for example, for 1000 people treated with PCSK9 inhibitors in addition to statins over five years, benefits ranged from 2 fewer strokes in the lowest risk to 21 fewer in the highest risk). Two systematic reviews on harms found no important adverse events for these drugs (moderate to high certainty evidence). PCSK9 inhibitors require injections that sometimes result in injection site reactions (best estimate 15 more per 1000 in a 5 year timeframe), representing a burden and harm that may matter to patients. The MATCH-IT decision support tool allows you to interact with the evidence and your patients across the alternative options: https://magicevidence.org/match-it/220504dist-lipid-lowering-drugs/., Understanding the Recommendations: The stratification into four cardiovascular risk groups means that, to use the recommendations, physicians need to identify their patient's risk first. We therefore suggest, specific to various geographical regions, using some reliable risk calculators that estimate patients' cardiovascular risk based on a mix of known risk factors. The largely weak recommendations concerning the addition of ezetimibe or PCSK9 inhibitors reflect what the panel considered to be a close balance between small reductions in stroke and myocardial infarctions weighed against the burdens and limited harms.Because of the anticipated large variability of patients' values and preferences, well informed choices warrant shared decision making. Interactive evidence summaries and decision aids linked to the recommendations can facilitate such shared decisions. The strong recommendations against adding another drug in people at low cardiovascular risk reflect what the panel considered to be a burden without important benefits. The strong recommendation for adding either ezetimibe or PCSK9 inhibitors in people at high and very high cardiovascular risk reflect a clear benefit.The panel recognised the key uncertainty in the evidence concerning patient values and preferences, namely that what most people consider important reductions in cardiovascular risks, weighed against burdens and harms, remains unclear. Finally, availability and costs will influence decisions when healthcare systems, clinicians, or people consider adding ezetimibe or PCSK9 inhibitors., Competing Interests: Competing interests: All authors have completed the BMJ Rapid Recommendations interest disclosure form and a detailed, contextualised description of all disclosures is reported in web appendix 1. As with all BMJ Rapid Recommendations, the executive team and The BMJ judged that no panel member had any financial conflict of interest. Professional and academic interests were minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Network meta-analysis was used to derive estimates of the relative efficacy of inclisiran, evolocumab, alirocumab, bempedoic acid, and ezetimibe in patients with hypercholesterolemia and/or at increased cardiovascular risk due to elevated low-density lipoprotein cholesterol taking maximum tolerated dose statins., Methods: Clinical trials published through February 2021 comparing percent change from baseline in low-density lipoprotein cholesterol were identified via a systematic review. Bayesian network meta-analyses were performed for patients with atherosclerotic cardiovascular disease and/or high cardiovascular risk on maximally tolerated statins in the base case, which included 23 trials., Results: Results from the base-case analyses demonstrated that inclisiran, evolocumab, and alirocumab provide superior efficacy over placebo, bempedoic acid, and ezetimibe in terms of reduction in low-density lipoprotein cholesterol. Inclisiran was also comparable to alirocumab (mean difference: 0.78% [95% CrI: -8.35, 9.88]) and evolocumab (8.16%, [95% CrI: -1.82, 18.49]). Findings of a scenario which also included trials conducted in patients with heterozygous familial hypercholesterolemia were consistent with the base case. There was evidence of statistical heterogeneity across the included trials, roughly equivalent to variation of 5-10% change in low-density lipoprotein cholesterol, suggesting that any differences between treatments that were greater than 5-10% are generalizable., Conclusions: This study provides insight regarding the comparative efficacy of drugs for which no head-to-head trials exist and suggests that inclisiran, alirocumab, and evolocumab are expected to provide similar clinically meaningful improvements in low-density lipoprotein cholesterol in patients with hypercholesterolemia on maximally tolerated statins who are at increased cardiovascular risk.

Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high serum levels of low-density lipoprotein (LDL)-cholesterol (LDL-C), tendon and skin xanthomas, and premature coronary artery disease (CAD). In Japan, detailed information on the current status of drug therapies for patients with FH has not been reported so far, and their efficacy and safety have not been clarified. After the introduction of ezetimibe, which can further reduce serum LDL-C levels on top of statins, the changes of management for FH patients with these drugs are of particular interest. The current study aimed to evaluate the clinical status of FH heterozygotes and homozygotes, especially focusing on the real-world lipid-lowering drug therapy, attained serum LDL-C levels, and cardiovascular events at registration and during the follow-up., Methods: The FAME Study enrolled 762 heterozygous (including 17 newly diagnosed cases) and 7 homozygous FH patients from hospitals and clinics nationwide. Diagnosis of FH was based upon the criteria defined in the Study Report in 2008 of the Research Committee on Primary Hyperlipidemia supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Health, Labor and Welfare. Data analysis was primarily carried on heterozygous FH patients., Results: Xanthoma or thickening of the Achilles tendon was observed in more than 80% of the patients. CAD was recorded in 23% of patients. Patients with parental and sibling CAD accounted for 47% and 24%, respectively. At baseline, patients without CAD who had LDL-C ＜100 mg/dL accounted for 12.3% and those with CAD who had attained the target (LDL-C ＜70 mg/dL) in the secondary prevention accounted for only 1.8%. In the multiple logistic analysis, male sex, age ＞40, heterozygous FH score ＞20, hypertension, and sibling CAD were significantly and positively associated with prevalent CAD, whereas serum HDL-cholesterol levels showed a significant inverse association with CAD. Patients treated with statin alone, statin＋ezetimibe, statin＋resin, or statin＋probucol accounted for 31.1%, 26.3%, 4.0%, and 3.7%, respectively. Patients treated with three-drug combination (statin＋ezetimibe＋resin or statin＋ezetimibe＋probucol) accounted for 7.5%. Statins and ezetimibe were used in 88.0% and 48.0% at the baseline, respectively. Although high-intensity statins were mainly prescribed, statin doses were much lower than those reported in Western countries. The addition of ezetimibe resulted in ~20% reduction in serum LDL-C. CAD was diagnosed in 17 patients with 21 episodes during follow-up. The Cox hazard model analysis demonstrated that male sex, CAD at the baseline, and parental CAD were related to the development of atherosclerotic cardiovascular disease (ASCVD) events. Furthermore, an increase in serum HDL-C was associated with a significant reduction of ASCVD events, while serum LDL-C and triglyceride levels were not related to ASCVD events., Conclusion: The prevalence of CAD in Japanese patients with heterozygous FH is still very high. In most of the cases, the target level of serum LDL-C was not achieved for primary and secondary prevention of CAD, suggesting that a more aggressive LDL-C lowering and appropriate management of residual risks are necessary.

Background and Objective: To describe the clinical characteristics, the reasons for initiating therapy and the effects of treatment in the initial phase of evolocumab availability in the Nephrology Units of Spain., Material and Methods: Retrospective, observational and multicentric study that included patients initiating treatment with evolocumab (from February 2016 to August 2018), in 15 Nephrology Units in Spain. The demographic and clinical characteristics of the patients, the lipid lowering treatment and the evolution of the lipid profiles between 24 weeks pre-initiation and 12±4 weeks post-initiation of evolocumab were reviewed., Results: 60 patients were enrolled: 53.3% women; mean (SD) age, 56.9 (12.8) years, 45.0% with familial hypercholesterolemia (FH) (5.0% homozygous and 40.0% heterozygous) and 65.0% with atherosclerotic cardiovascular disease. The mean (SD) eGFR was 62.6 (30.0) ml/min/1.73m 2 (51.7% of patients had eGFR <60ml/min/1.73m 2 [CKD stage>2]), 50.0% had proteinuria (>300mg/g) and 10.0% had nephrotic syndrome. Other CV risk factors were hypertension (75.0%), diabetes (25.0%), and smoking (21.7%). A 40.0% of patients were statin intolerant. At evolocumab initiation, 41.7% of patients were on a high intensity statin, 18.3% on moderate intensity statin and 50.0% were receiving ezetimibe. Mean (SD) LDL-c at evolocumab initiation was 179.7 (62.9) mg/dL (53.4% of patients with LDL-c ≥160mg/dL and 29.3% ≥190mg/dL). After 12 weeks, evolocumab resulted in LDL-c reductions of 60.1%. At week 12, 90.0% of patients reached LDL-c levels <100mg/dL, 70.0% <70mg/dL, and 55.0% <55mg/dL, while mean eGFR levels and statin use remained stable., Conclusion: In Nephrology Units of Spain, evolocumab was predominantly prescribed in patients with FH, chronic renal disease (CRD>2) and secondary prevention, with LDL-c levels above those recommended by the guidelines. Evolocumab used in clinical practice significantly reduced the LDL-c levels in all patients included in the study., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Mutations in the LDL receptor gene LDLR cause familial hypercholesterolemia (FH); however, the pharmacogenomics of specific LDLR mutations remains poorly understood. The goals of this study were to identify the genetic cause of a three-generation Chinese family affected with autosomal dominant FH, and to investigate the response of FH patients in the family to statin and evolocumab. Whole exome sequencing of the FH family with four patients and six unaffected members identified a heterozygous splicing mutation (c.1187-2A>G) in LDLR. The mutation co-segregated with FH in the family, providing strong genetic evidence to support its pathogenicity. The proband was a 48-year-old male FH patient who had an acute myocardial infarction (MI) and ventricular fibrillation (VF), and showed LDL-C of 5.23 mmol/L. A combination of life style modifications on food and exercise and treatment with rosuvastatin reduced his LDL-C to 2.05-2.80 mmol/L. Addition of ezetimibe did not improve rosuvastatin therapy, but addition of evolocumab further reduced LDL-C by 70% to 0.7 mmol/L at the first time and by 67% to 1.31 mmol/L at the second time. Rosuvastatin also reduced LDL-C for proband's father and sister by 40% and 43-63%, respectively. Lovastatin alone or addition to rosuvastatin treatment did not have any effect on LDL-C for the proband and his son. Both patients carry ApoE 3/4 genotype and SLCO1B1 rs4149056 TT genotype. These results suggest that combined treatment with rosuvastatin (but not lovastatin or ezetimibe) and evolocumab can control LDL-C to meet the LDL-C treatment goal for patients with LDLR splicing mutation c.1187-2A>G., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: Proprotein convertase subtilisin-kexin type 9(PCSK9) monoclonal antibody (Mab; Evolocumab) has been reported to inhibit low-density lipoprotein cholesterol (LDL-C) and Lipoprotein(a) [LP(a)] in coronary heart diseases (CHD) patients in America, Europe and Japan. However, little is known about the effect of Evolocumab in Chinese population. This retrospective study in Chinese CHD patients compared the efficacy without or with Evolocumab therapy added to the conventional treatment with a statin (Rosuvastatin) and a gut cholesterol absorption inhibitor (Ezetimibe)., Methods: CHD patients from our hospital were divided into three therapeutic groups, A) the statin monotherapy group (10 mg Rosuvastatin every night); B) the statin/cholesterol absorption inhibitor group (10 mg Rosuvastatin and 10 mg Ezetimibe daily); and C) the triple therapy with PCSK9 Mab group (10 mg Rosuvastatin daily, 10 mg Ezetimibe daily, and 140 mg Evolocumab once 2 weeks). The plasma lipid data were collected at 0, 4, 12, and 24 Week(s). The Graphpad Prism 7 program was used to perform all the statistical analysis., Results: Out of 103 patients 91 were eligible for further evaluation with 31 in group A, 31 in group B, and 29 in group C. The plasma LDL-C levels were reduced only by 33.82% in the Rosuvastatin monotherapy group, 52.13% in the Rosuvastatin/Ezetimibe group, and 73.59% in the Evolocumab/Rosuvastatin/Ezetimibe group (P < 0.0001) at 24 weeks compared to the prior therapy levels. Neither the statin therapy alone (5.95%; P = 0.6), nor the double therapy (5.27%; P = 0.7) affected LP(a) levels. In contrast, addition of Evolocumab to the double therapy significantly decreased LP(a) level by 37.2% (P < 0.0001)., Conclusion: Addition of Evolocumab to the standard double therapy in Chinese CHD patients improved the efficacy in LDL-C reduction when compared to Rosuvastatin alone or in Rosuvastatin/Ezetimibe double therapy. Furthermore, the addition of Evolocumab lowered LP(a) level in Chinese CHD patients., (Copyright © 2021. Published by Elsevier B.V.)

Background: Cardiovascular disease (CVD) is the most frequent cause of death in Austria. The European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines recommend intensive lipid lowering therapy (LLT) in patients at high or very high CV risk. Lipid management and achievement of low-density lipoprotein cholesterol (LDL-C) goals in Austria have not recently been assessed., Methods: Subgroup analysis for Austria of a European 18 country, cross-sectional, observational study. Patients received LLT for primary (PP) or secondary prevention (SP). Data including LLT in the preceding 12 months and most recent LDL‑C were collected during a single visit between June 2017 and November 2018. Achievement of the risk-based 2016 and 2019 ESC/EAS LDL‑C goal while receiving stabilized LLT was assessed., Results: A total of 293 patients were enrolled from 8 Austrian sites, of which 200 (PP = 104, SP = 96) received stabilized LLT at the LDL‑C measurement date. Overall, 58% (71% PP, 43% SP) and 38% (52% PP, 23% SP) achieved the risk-based 2016 and 2019 goals, respectively. Most patients received moderate-intensity statin monotherapy (46%), while 34% used high-intensity statin monotherapy. Combination therapy of moderate/high-intensity statin with ezetimibe (12%), or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors with statin ± ezetimibe (1%), was used infrequently., Conclusion: The current Austrian routine lipid management using mainly moderate-intensity or high-intensity statin monotherapy is insufficient to attain ESC/EAS guideline goals, in particular the more stringent 2019 recommendations, a situation comparable to other participating European countries. In addition to switching to and optimizing doses of high-intensity statins, a combination with ezetimibe or PCSK9 inhibitors will be needed in many cases., (© 2021. The Author(s).)

Purpose: Clinical trials have demonstrated efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in reducing risk of cardiovascular disease events, but effectiveness in routine clinical care has not been well-studied. We used negative control outcomes to assess potential confounding in an observational study of PCSK9i versus ezetimibe or high-intensity statin., Methods: Using commercial claims, we identified U.S. adults initiating PCSK9i, ezetimibe, or high-intensity statin in 2015-2018, with other lipid-lowering therapy (LLT) use in the year prior (LLT cohort) or atherosclerotic cardiovascular disease (ASCVD) in the past 90 days (ASCVD cohort). We compared initiators of PCSK9i to ezetimibe and high-intensity statin by estimating one-year risks of negative control outcomes influenced by frailty or health-seeking behaviors. Inverse probability of treatment and censoring weighted estimators of risk differences (RDs) were used to evaluate residual confounding after controlling for covariates., Results: PCSK9i initiators had lower one-year risks of negative control outcomes associated with frailty, such as decubitus ulcer in the ASCVD cohort (PCSK9i vs. high-intensity statin RD = -3.5%, 95% confidence interval (CI): -4.6%, -2.5%; PCSK9i vs. ezetimibe RD = -1.3%, 95% CI: -2.1%, -0.6%), with similar but attenuated associations in the LLT cohort. Lower risks of accidents and fractures were also observed for PCSK9i, varying by cohort. Risks were similar for outcomes associated with health-seeking behaviors, although trended higher for PCSK9i in the ASCVD cohort., Conclusions: Observed associations suggest lower frailty and potentially greater health-seeking behaviors among PCSK9i initiators, particularly those with a recent ASCVD diagnosis, with the potential to bias real-world analyses of treatment effectiveness., (© 2021 John Wiley & Sons Ltd.)

Background: The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies., Methods: To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1. We measured bile acid composition, cholesterol absorption, and plasma cholesterol. In parallel, we measured markers of cholesterol absorption and synthesis in humans with type 1 diabetes treated with ezetimibe and simvastatin in a double-blind crossover study., Results: Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of FoxO1 . FoxO1 is inhibited by insulin and required for the production of 12α-hydroxylated bile acids, which promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis. Knockdown of Cyp8b1 normalized 12α-hydroxylated bile acid levels and completely prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor (n=5-30), as well as mouse models of type 1 diabetes (n=5-22). In parallel, the cholesterol absorption inhibitor, ezetimibe, normalized cholesterol absorption and low-density lipoprotein cholesterol in patients with type 1 diabetes as well as, or better than, the cholesterol synthesis inhibitor, simvastatin (n=20)., Conclusions: Insulin, by inhibiting FoxO1 in the liver, reduces 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol levels. Thus, type 1 diabetes leads to a unique set of derangements in cholesterol metabolism, with increased absorption rather than synthesis. These derangements are reversed by ezetimibe, but not statins, which are currently the first line of lipid-lowering treatment in type 1 diabetes. Taken together, these data suggest that a personalized approach to lipid lowering in type 1 diabetes may be more effective and highlight the need for further studies specifically in this group of patients.

Several randomized, double blind, placebo-controlled trials (RCTs) have demonstrated that low-density lipoprotein cholesterol (LDL-C) lowering by using statins, including high-doses of strong statins, reduced the development of cardiovascular disease (CVD). However, among the eight RCTs which investigated the effect of statins vs. placebos on the development of CVD, 56-79% of patients had the residual CVD risk after the trials. In three RCTs which investigated the effect of a high dose vs. a usual dose of statins on the development of CVD, 78-87% of patients in the high-dose statin arms still had the CVD residual risk after the trials. An analysis of the characteristics of patients in the RCTs suggests that elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C), the existence of obesity/insulin resistance, and diabetes may be important metabolic factors which determine the statin residual CVD risk. To understand the association between lipid abnormalities and the development of atherosclerosis, we show the profile of lipoproteins and their normal metabolism, and the molecular and biological mechanisms for the development of atherosclerosis by high TG and/or low HDL-C in insulin resistance. The molecular biological mechanisms for the statin residual CVD risk include an increase of atherogenic lipoproteins such as small dense LDL and remnants, vascular injury and remodeling by inflammatory cytokines, and disturbed reverse cholesterol transport. Peroxisome proliferator-activated receptor alpha (PPARα) agonists improve atherogenic lipoproteins, reverse the cholesterol transport system, and also have vascular protective effects, such as an anti-inflammatory effect and the reduction of the oxidative state. Ezetimibe, an inhibitor of intestinal cholesterol absorption, also improves TG and HDL-C, and reduces intestinal cholesterol absorption and serum plant sterols, which are increased by statins and are atherogenic, possibly contributing to reduce the statin residual CVD risk.

Background: The effect of ezetimibe, Niemann-Pick C1-like 1 inhibitor, on liver fat is not clearly elucidated. Our primary objective was to evaluate the efficacy of ezetimibe plus rosuvastatin versus rosuvastatin monotherapy to reduce liver fat using magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) in patients with non-alcoholic fatty liver disease (NAFLD)., Methods: A randomized controlled, open-label trial of 70 participants with NAFLD confirmed by ultrasound who were assigned to receive either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks. The liver fat change was measured as average values in each of nine liver segments by MRI-PDFF. Magnetic resonance elastography (MRE) was used to measure liver fibrosis change., Results: Combination therapy significantly reduced liver fat compared with monotherapy by MRI-PDFF (mean difference: 3.2%; p = 0.020). There were significant reductions from baseline to study completion by MRI-PDFF for both the combination and monotherapy groups, respectively (18.1 to 12.3%; p < 0.001 and 15.0 to 12.4%; p = 0.003). Individuals with higher body mass index, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to treatment with ezetimibe. MRE-derived change in liver fibrosis was not significantly different (both groups, p > 0.05). Controlled attenuation parameter (CAP) by transient elastography was significantly reduced in the combination group (321 to 287 dB/m; p = 0.018), but not in the monotherapy group (323 to 311 dB/m; p = 0.104)., Conclusions: Ezetimibe and rosuvastatin were found to be safe to treat participants with NAFLD. Furthermore, ezetimibe combined with rosuvastatin significantly reduced liver fat in this population., Trial Registration: The trial was registered at ClinicalTrials.gov (registration number: NCT03434613 )., (© 2022. The Author(s).)

Background and Aims: The achievement of a target low-density lipoprotein cholesterol (LDL-C) level in clinical settings is often insufficient. A hospital lipid-lowering protocol (HLP) could be effective for providing the optimal lipid-lowering therapy. Herein we determined the effectiveness of a HLP for acute coronary syndrome (ACS) patients., Methods: We retrospectively analyzed 1,497 patients who underwent successful percutaneous coronary intervention for ACS at our hospital (November 2011 to May 2020). In December 2018, we introduced a HLP that included the prescription of the maximum tolerated dose of statin, ezetimibe, and eicosapentaenoic acid. We compared the lipid profile and clinical outcomes at 12 months between before (Control group: 1,219 patients) and after the HLP's introduction (HLP group: 278 patients). The primary outcome was the achievement rate of LDL-C < 1.8 mmol/L (70 mg/dL). The key secondary outcomes were the change value and ratio of LDL-C plus the major adverse cardiac events (MACE), defined as a composite of cardiac death, myocardial infarction, target vessel revascularization, and stent thrombosis., Results: The achievement rate of LDL-C < 1.8 mmol/L was significantly higher in the HLP group than in the Control group (58% vs. 27%, p < 0.01). The HLP group's change ratio and LDL-C values were significantly lower than those of the Control group (-39.5 [-55.1, -13.2]% vs. -20.4 [-38.4, 0]%, p < 0.001; -41 [-69, -11] mg/dL vs. -21 [-38, 0] mg/dL, p < 0.001). MACE was similar between the groups (16.9 vs. 15.5%, p = 0.66)., Conclusion: Implementing a HLP for ACS patients improved the achievement of target LDL-C at 12 months., Competing Interests: Declaration of Competing Interest O. Iida received remuneration from Boston Scientific Japan, W. L. Gore & Associates G.K., BD and TERUMO. T. Mano received a research grant from Abbott Vascular Japan. The other authors have no disclosures to report., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: The protein encoded by mitogen-inducible gene 6 (MIG6) plays an essential role in the regulation of cholesterol homeostasis and bile acid synthesis in mice. However, the physiological functions of MIG6 remain poorly understood in humans. Therefore, we aimed to evaluate the relationship between the serum MIG6 concentration and low-density lipoprotein (LDL)-cholesterol in patients undergoing cholesterol-lowering treatment., Methods: We performed a non-randomized, prospective controlled trial. In total, 63 patients with type 2 diabetes and hypercholesterolemia were treated using either rosuvastatin monotherapy or rosuvastatin/ezetimibe combination therapy for 12 weeks. We then compared their serum lipid and MIG6 concentrations before and after treatment., Results: The serum LDL-cholesterol concentration of the participants significantly decreased and the concentration of MIG6 significantly increased during treatment. In addition, higher pre-treatment serum concentrations of MIG6 were associated with larger reductions in LDL-cholesterol, regardless of the therapeutic agent used., Conclusions: Serum MIG6 concentration significantly increases alongside the reduction in LDL-cholesterol achieved using cholesterol-lowering therapies in patients with diabetes and hypercholesterolemia. This is the first study to provide evidence that MIG6 may be involved in human cholesterol metabolism. CRIS registration number : KCT0003477. https://cris.nih.go.kr.

Cholesterol is an important component of cell membrane. However, elevated level of serum cholesterol is a key risk factor for heart disease. Niemann-Pick C1-Like 1 (NPC1L1) is the crucial target involving in cholesterol cellar uptake. Ezetimibe is the first, and only, NPC1L1 inhibitor approved for the treatment of hypercholesterolemia through decreasing cholesterol absorption for nearly two decades. That means that the development of NPC1L1 inhibitors encounters much challenge, as well as offers exciting therapeutic opportunities. Substantial efforts have been undertaken to develop NPC1L1 inhibitors. The present review describes the mechanism of cholesterol transport by NPC1L1, highlights the development of NPC1L1 inhibitors, and discusses the current challenges., 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 Masson SAS. All rights reserved.)

Aim: The 2018 American Heart Association/American College of Cardiology/Multi-Society Cholesterol Guidelines recommended the addition of non-statins to statin therapy for high-risk secondary prevention patients above a low-density lipoprotein cholesterol (LDL-C) threshold of ≥70 mg/dL (1.8 mmol/L). We compared effectiveness and safety of treatment to achieve lower (<70) vs. higher (≥70 mg/dL) LDL-C among patients receiving intensive lipid-lowering therapy (statins alone or plus ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors)., Methods and Results: Eleven randomized controlled trials (130 070 patients), comparing intensive vs. less-intensive lipid-lowering therapy, with follow-up ≥6 months and sample size ≥1000 patients were selected. Meta-analysis was reported as random effects risk ratios (RRs) [95% confidence intervals] and absolute risk differences (ARDs) as incident cases per 1000 person-years. The median LDL-C levels achieved in lower LDL-C vs. higher LDL-C groups were 62 and 103 mg/dL, respectively. At median follow-up of 2 years, the lower LDL-C vs. higher LDL-C group was associated with significant reduction in all-cause mortality [ARD -1.56; RR 0.94 (0.89-1.00)], cardiovascular mortality [ARD -1.49; RR 0.90 (0.81-1.00)], and reduced risk of myocardial infarction, cerebrovascular events, revascularization, and major adverse cardiovascular events (MACE). These benefits were achieved without increasing the risk of incident cancer, diabetes mellitus, or haemorrhagic stroke. All-cause mortality benefit in lower LDL-C group was limited to statin therapy and those with higher baseline LDL-C (≥100 mg/dL). However, the RR reduction in ischaemic and safety endpoints was independent of baseline LDL-C or drug therapy., Conclusion: This meta-analysis showed that treatment to achieve LDL-C levels below 70 mg/dL using intensive lipid-lowering therapy can safely reduce the risk of mortality and MACE., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Objective: Systematic review and meta-analysis of lipid outcomes for human immunodeficiency virus (HIV)-positive or HIV-infected patients treated with ezetimibe., Methods: We conducted a literature search from 1946 to 2021 for trials studying the effectiveness of ezetimibe in hyperlipidaemic HIV patients. We included trials of all designs in which HIV patients on highly active antiretroviral therapy (HAART)/non-nucleoside reverse transcriptase inhibitor (NNRTI) therapy had hyperlipidaemia, were treated with ezetimibe, and reported lipid outcomes., Results: Of thirteen eligible trials, five were randomized controlled trials (RCTs) and eight were single-arm trials. Two of the eligible RCTs were placebo-controlled; we performed a meta-analysis across those two trials for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG). LDL-C was significantly lower in the ezetimibe arm (net change: -23.56 mg/dL, 95% CI: -40.22, -6.90 mg/dL). We then performed meta-analysis of the single-arm trials examining lipid outcomes after ezetimibe treatment which, like in the RCTs, revealed significant reductions of LDL-C (-23.89 mg/dL, 95% CI -29.94 to -17.83 mg/dL). In addition, significant reductions were seen for total cholesterol (TC) (-26.17 mg/dL, 95% CI -32.81 to -19.54 mg/dL) and TG (-18.57 mg/dL, 95% CI -34.01 to -3.14 mg/dL) but HDL-C did not show a change., Conclusions: Evidence for LDL-C reduction is limited in RCTs; single-arm trial LDL-C reductions are consistent with the RCTs. In addition, significant reductions in TC and TG were also seen in the meta-analysis of the single arm trials. The single-arm trials' meta-analysis corroborates evidence from RCTs to suggest that ezetimibe can be an option for hyperlipidaemia among HIV patients with mildly elevated TC and LDL-C levels, especially in cases where statins are contra-indicated due to drug-drug interactions with concomitant anti-retroviral therapy.