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      Simulation study on LDL cholesterol target attainment, treatment costs, and ASCVD events with bempedoic acid in patients at high and very-high cardiovascular risk

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          Abstract

          Background and aims

          The LDL cholesterol (LDL-C) treatment goals recommended by the 2019 ESC/EAS guidelines are only achieved in a minority of patients. The study objective was to estimate the impact of bempedoic acid treatment on LDL-C target attainment, drug costs, and atherosclerotic cardiovascular disease (ASCVD) events.

          The simulation used a Monte Carlo approach in a representative cohort of German outpatients at high or very-high cardiovascular risk. Additionally to statins, consecutive treatment with ezetimibe, bempedoic acid, and a PCSK9 inhibitor was simulated in patients not achieving their LDL-C goal. Considered were scenarios without and with bempedoic acid (where bempedoic acid was replaced by a PCSK9 inhibitor when LDL-C was not controlled).

          Results

          The simulation cohort consisted of 105,577 patients, of whom 76,900 had very-high and 28,677 high cardiovascular risk. At baseline, 11.2% of patients achieved their risk-based LDL-C target. Sequential addition of ezetimibe and bempedoic acid resulted in target LDL-C in 33.1% and 61.9%, respectively. Treatment with bempedoic acid reduced the need for a PCSK9 inhibitor from 66.6% to 37.8% and reduced drug costs by 35.9% per year on stable lipid-lowering medication. Compared to using only statins and ezetimibe, this approach is projected to prevent additional 6,148 ASCVD events annually per 1 million patients, whereas PCSK9 inhibition alone would prevent 7,939 additional ASCVD events annually.

          Conclusions

          A considerably larger proportion of cardiovascular high- and very-high-risk patients can achieve guideline-recommended LDL-C goals with escalated lipid-lowering medication. Bempedoic acid is projected to substantially decrease the need for PCSK9 inhibitor treatment to achieve LDL-C targets, associated with reduced drug costs albeit with fewer prevented events.

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          Most cited references32

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          2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk

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            Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease

            Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.
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              Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials

              Summary Background Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy. Methods We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years' treatment duration of more versus less intensive statin regimens (five trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation. Findings In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11–18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7–19; p<0·0001), in coronary revascularisation of 19% (95% CI 15–24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5–26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76–0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87–0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74–0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81–0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84–1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81–1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92–1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96–1·04; p=0·9), even at low LDL cholesterol concentrations. Interpretation Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2–3 mmol/L would reduce risk by about 40–50%. Funding UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLOS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                27 October 2022
                2022
                : 17
                : 10
                : e0276898
                Affiliations
                [1 ] Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig, Germany
                [2 ] Daiichi Sankyo Deutschland GmbH, München, Germany
                [3 ] Daiichi Sankyo Europe GmbH, München, Germany
                Medizinische Hochschule Hannover, GERMANY
                Author notes

                Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JLK has received consulting fees and travel grants from Daiichi Sankyo. CB and AB are employees of Daiichi Sankyo. UL has received speaker honoraria from Amgen, Daiichi Sankyo, Novartis, and Sanofi. The company Daiichi Sankyo Europe GmbH is marketing authorisation holder of Nilemdo® and Nustendi® in the UK, European Economic Area, and Switzerland. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The company IQVIA Germany ( https://www.iqvia.com/de-de/locations/germany) provided and analysed the data which are presented in this analysis. The data can be obtained from IQVIA on request.

                Author information
                https://orcid.org/0000-0002-2457-1129
                https://orcid.org/0000-0002-8212-1433
                Article
                PONE-D-22-24031
                10.1371/journal.pone.0276898
                9612573
                36301892
                4545adf5-00fd-4f3e-8fbb-50a6700656b8
                © 2022 Katzmann et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 28 August 2022
                : 15 October 2022
                Page count
                Figures: 3, Tables: 2, Pages: 13
                Funding
                Funded by: Daiichi-Sankyo Europe GmbH
                Funded by: Daiichi Sankyo Deutschland GmbH
                This study was co-funded by Daiichi Sankyo Europe and Daiichi Sankyo Deutschland GmbH.
                Categories
                Research Article
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Statins
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Cardiovascular Therapy
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Medicine and Health Sciences
                Medical Conditions
                Cardiovascular Diseases
                Cardiovascular Disease Risk
                Medicine and Health Sciences
                Cardiology
                Cardiovascular Medicine
                Cardiovascular Diseases
                Cardiovascular Disease Risk
                Research and analysis methods
                Mathematical and statistical techniques
                Statistical methods
                Monte Carlo method
                Physical sciences
                Mathematics
                Statistics
                Statistical methods
                Monte Carlo method
                Biology and Life Sciences
                Biochemistry
                Lipids
                Biology and Life Sciences
                Biochemistry
                Lipids
                Cholesterol
                Medicine and Health Sciences
                Vascular Medicine
                Atherosclerosis
                Custom metadata
                The company IQVIA Germany ( https://www.iqvia.com/de-de/locations/germany) provided and analyzed the data which are presented in this analysis. The authors did not have access to the full database (which is administered by the company) and are not allowed to share the data retrieved. The data can be obtained from IQVIA on request. Importantly, no statistical testing per se was performed in our analysis. Every calculation presented can be replicated using the numbers provided in the respective tables.

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