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Background: Despite widespread use of high-intensity statin monotherapy, achieving target LDL-C levels and reducing cardiovascular events in patients with or at high risk of developing ASCVD remains challenging. Our study measured the effects of low/moderate-intensity statins and ezetimibe combination therapy compared to high-dose statin monotherapy on major adverse cardiovascular events (MACEs) and coronary atherosclerotic plaque reduction., Methods: We searched PubMed, Scopus, Web of Science, and Cochrane CENTRAL register of trials for studies comparing the combination therapy to high-intensity statin monotherapy in terms of MACEs and coronary atherosclerotic plaque reduction. The primary outcome was a composite of cardiovascular death or major cardiovascular events (MI, HF, Revascularization, or non-fatal stroke). Other outcomes included other MACEs, lipid-lowering efficacy, and safety outcomes. A protocol was registered to PROSPERO under registration number [CRD42024545807]., Results: 15 studies encompassing 251,450 participants were included in our meta-analysis. In our pooled analysis of observational studies, combination therapy was associated with lower rates of the primary composite outcome (HR = 0.76, CI 95% [0.73, 0.80]), cardiovascular death (HR = 0.80, CI 95% [0.74, 0.88]), all-cause death (HR = 0.84, CI 95% [0.78, 0.91]), and non-fatal stroke (HR = 0.81, CI 95% [0.75, 0.87]). However, the pooled analysis of RCTs did not demonstrate a statistically significant difference between both arms concerning clinical endpoints. Combination therapy had a higher number of patients with LDL-C < 70 mg/dL (RR = 1.27, CI 95% [1.21, 1.34]), significantly lowered LDL-C (MD = -7.95, CI 95% [-10.02, -5.89]) and TC (MD = -26.77, CI 95% [-27.64, -25.89]) in the pooled analysis of RCTs. In terms of safety, the combination therapy lowered muscle-related adverse events (RR = 0.52, CI 95% [0.32, 0.85]) and number of patients with liver enzyme elevation (RR = 0.51, CI 95% [0.29, 0.89]) in the pooled analysis of RCTs and was associated with lower rates of new-onset diabetes (HR = 0.80, CI 95% [0.74, 0.87]) in the pooled analysis of observational studies., Conclusion: Evidence from RCTs indicates that low/moderate statin therapy in combination with ezetimibe has a superior lipid-lowering effect and reduces side effects compared to high-dose statins. Observational studies suggest improved clinical outcomes but need to be corroborated by large, outcomes-powered RCTs over longer follow-up periods., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Statins are the gold standard in the treatment of dyslipidemia, significantly reducing the risk of cardiovascular disease., Objective: To systematically review the efficacy and safety of Moderate-intensity Rosuvastatin Plus Ezetimibe compared with High-intensity Rosuvastatin in treating Composite Cardiovascular Events., Methods: PubMed, Embase, Cochrane Library, CINAHL, Web of Science, China Knowledge Network, China Biological Literature Database, Wan Fang Database, and Weipu Database were searched to retrieve randomized controlled trials assessing the safety and efficacy of the two therapies from the time of construction to December 2023. The Jadad scale assessment tool was used to evaluate the quality of the included literature, and Review Manager 5.4 software was used for meta-analysis. The heterogeneity of outcomes was estimated by the I2 test, where we applied risk ratios (RR) and 95% confidence intervals (CI) to assess dichotomous outcomes and mean difference (MD) and 95% CI to present continuous outcomes. We used funnel plots to assess study publication bias and sensitivity analysis was used to address significant clinical heterogeneity., Results: The meta-analysis described 21 RCTs involving 24592 participants. The findings indicated that moderate-intensity statin combination therapy improved low-density lipoprotein cholesterol (LDL-C) (MD -8.06, 95% CI [-9.48, -6.64] p < 0.05), total cholesterol (TG) (MD -5.66, 95% CI [-8.51, -2.82] p < 0.05), and non-high-density lipoprotein cholesterol (non-HDL-C) (MD -17.04, 95% CI [-29.55, -4.54] p < 0.05) to a greater extent and superior in achieving LDL-C <70 (RR1.26, 95% CI [1.22, 1.29] p < 0.05) and LDL-C <55 (RR1.66, 95% CI [1.56, 1.77] p < 0.05) ratios and in the incidence of adverse events than the high-intensity Rosuvastatin monotherapy group. However, there was no statistical difference between the two in improving HDL-C, total cholesterol (TC), and preventing long-term composite adverse cardiovascular events (ACE). Funnel plots indicated publication bias. Sensitivity analysis suggested instability in long-term composite cardiovascular events, HDL-C, and TC results., Conclusions: Moderate-intensity statin plus ezetimibe with combination therapy had better efficacy and safety than high-intensity statins. Future validation is needed with more long-term high-quality large samples., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Liu 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.)

Aims: No data are available on early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients with acute coronary syndrome (ACS) in the real world. This study investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major cardiovascular (CV) events in the real world., Methods and Results: The lipid control outcome was the percentage of patients reaching the LDL-C target of <55 mg/dL at first lipid control. The clinical outcome was the incidence of composite major CV events (all-cause death, non-fatal MI, non-fatal stroke, and ischaemia-driven revascularization) during a follow-up in relation to quartiles of LDL-C at first lipid control. We included 771 patients with ACS from the AT-TARGET-IT registry, receiving PCSK9i prescription during hospitalization or at discharge. Median LDL-C was 137 mg/dL and decreased to 43 mg/dL at first lipid control. 527 (68.3%) patients achieved LDL-C target at the first lipid control at a median time of 37 days from hospitalization; of them, 404 (76.8%) were discharged on statin plus ezetimibe background therapy. Event curves through a median follow-up of 11 months across quartiles of LDL-C showed a stepwise lower risk of 4P-MACE, 3P-MACE, all-cause mortality, and ischaemia-driven revascularization in lower quartile of LDL-C values at first lipid control (<23 mg/dL) and in patients reaching LDL-C < 55 mg/dL., Conclusion: Intensive and early lipid-lowering therapy using PCSK9i in patients with ACS (strike early-strike strong strategy) is safe and effective in clinical practice and associated with a reduction of residual CV risk., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Inclisiran, an siRNA targeting hepatic PCSK9 mRNA, administered twice-yearly (after initial and 3-month doses), substantially and sustainably reduced LDL-cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a reduced risk of major adverse cardiovascular events (MACE) is not yet established. In-silico trials applying a disease computational model to virtual patients receiving new treatments allow to emulate large scale long-term clinical trials. The SIRIUS in-silico trial programme aims to predict the efficacy of inclisiran on CV events in individuals with established atherosclerotic cardiovascular disease (ASCVD)., Methods and Results: A knowledge-based mechanistic model of ASCVD was built, calibrated, and validated to conduct the SIRIUS programme (NCT05974345) aiming to predict the effect of inclisiran on CV outcomes. The SIRIUS Virtual Population included patients with established ASCVD (previous myocardial infarction (MI), previous ischemic stroke (IS), previous symptomatic lower limb peripheral arterial disease (PAD) defined as either intermittent claudication with ankle-brachial index <0.85, prior peripheral arterial revascularization procedure, or vascular amputation) and fasting LDL-C ≥ 70 mg/dL, despite stable (≥4 weeks) well-tolerated lipid-lowering therapies.SIRIUS is an in-silico multi-arm trial programme. It follows an idealized crossover design where each virtual patient is its own control, comparing inclisiran to (i) placebo as adjunct to high-intensity statin therapy with or without ezetimibe, (ii) ezetimibe as adjunct to high-intensity statin therapy, (iii) evolocumab as adjunct to high-intensity statin therapy and ezetimibe.The co-primary efficacy outcomes are based on the time to the first occurrence of any component of 3P-MACE (composite of CV death, nonfatal MI, or nonfatal IS) and time to occurrence of CV death over 5 years., Perspectives/conclusion: The SIRIUS in-silico trial programme will provide early insights regarding potential effect of inclisiran on MACE in ASCVD patients, several years before the availability of the results from ongoing CV outcomes trials (ORION-4 and VICTORION-2-P)., Clinical Trial Registration: Clinicaltrials.gov identifier: NCT05974345., Competing Interests: Conflict of interest: Denis Angoulvant reports having received payment or honoraria for lectures, presentations, speakers bureaus or educational events from Amgen, Alnylam, Amarin, Astra Zeneca, Boehringer, BMS, Bouchara Recordati, Pfizer, Novartis, Novo Nordisk, Organon, Sanofi, Servier, Vifor. Gabriel Steg reports the following: research grants from Amarin and Sanofi. Consulting or speaking for Amarin, Amgen, BMS and Novo-Nordisk. Clinical Trials (Steering committee, CEC, DSMB) for Amarin, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Idorsia, Janssen, Novartis, Novo-Nordisk, Pfizer, Sanofi. Senior Associate Editor at Circulation and Chief Scientific Officer of Bioquantis Guillaume Mahé reports having received payments for consulting, speaking, or educational events from Amgen, Amarin, Bayer Healthcare, BMS, Leo Pharma, Novartis, Novo Nordisk, Pfizer and Sanofi. Bertrand Cariou reports having received payments for consulting, speaking, or educational events from Amgen, Astra Zeneca, BMS, Eli Lilly, Novartis, Novo Nordisk, Sanofi, Ultragenyx. Franck Boccara reports having received payments for consulting, speaking, or educational events from Amgen, Amarin, Novartis, Novo Nordisk, Boehringer, Servier, ViiV healthcare, Gilead and Sanofi. Pierre Amarenco reports the following: grants from the French government (PHRC: RIISC-THETIS, TST-40, SPICAF trials), Pfizer and AstraZeneca (TST trial). Speaker fee from Novartis, Viatris and Sanofi. Advisory board for Novartis and Neuraltide. Steering committee for Bayer., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: Hyperlipidemia plays a crucial role in increasing the risk of cardiovascular diseases such as atherosclerosis. Recent studies have established that inclisiran positively influences lipid regulation. Nevertheless, its effectiveness in comparison to conventional treatments is still questionable. Hence, a methodical assessment of its effectiveness and safety is required. This research evaluates the efficacy and safety of inclisiran, PCSK9 inhibitors, and the combination of statins with ezetimibe in the treatment of hyperlipidemia via a network meta-analysis of randomized controlled trials (RCTs)., Methods: We performed an extensive search of English-language publications in the PubMed, Medline, Embase, and Cochrane Library databases until April 2024. We conducted a web-based meta-analysis and reported in accordance with the guidelines. We selected the percentage change in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) as efficacy evaluation metrics and the incidence of adverse events as safety evaluation metrics for analysis and comparison., Result: We incorporated 33 studies involving 23,375 patients, evaluating three interventions regarding their effects on LDL-C, TC, TG, HDL-C, and adverse events. All treatments improved metrics over placebo. Inclisiran significantly reduced LDL-C compared to statins (mean - 15.21, 95% CI [-25.19, -5.23]) but showed no significant difference from statin + ezetimibe. Surface under the cumulative ranking curve (SUCRA) rankings placed inclisiran highest for LDL-C reduction (26.2%). The combination of statin and ezetimibe was the most efficacious for triglyceride reduction (mean 17.2, 95% CI [10.22, 24.19]; mean 15.61, 95% CI [16.87, 24.35]). The safety profiles were comparable across treatments., Conclusion: Inclisiran with its superior LDL-C reduction and low frequency of administration, appears promising for hyperlipidemia treatment, particularly for patients with adherence issues or side effects from other medications., Systematic Review Registration: CRD42024550852., (© 2024. The Author(s).)

Backgrounds: High-intensity statin is recommended for patients undergoing percutaneous coronary intervention (PCI), and ezetimibe is recommended to be added in patients not achieving low-density lipoprotein cholesterol (LDL-C) targets. Moderate-intensity statin plus ezetimibe can reduce LDL-C levels similar to high-intensity statin. The aim of this study is to examine the long-term efficacy and safety of moderate-intensity statin plus ezetimibe as the first-line strategy compared to high-intensity statin in patients undergoing PCI., Method: Data was obtained from the Health Insurance Review and Assessment Service database of South Korea. Patients who underwent PCI from 2012 to 2017 were included. The primary efficacy endpoint was major adverse cardiac cerebrovascular events (MACCEs), a composite of all-cause death, revascularization, or ischemic stroke. The safety endpoint was new-onset diabetes mellitus (DM)., Results: A total of 45,501 patients received high-intensity statin (n = 38,340) or moderate-intensity statin plus ezetimibe (n = 7,161). Among propensity-score-matched 7,161 pairs, MACCEs occurred in 1,460 patients with high-intensity statin and 1,406 patients with moderate-intensity statin plus ezetimibe (33.8% vs. 31.9%, hazard ratio 0.96, 95% confidence interval 0.89-1.03, P = 0.27) at a median follow-up of 2.7 years. DM was newly diagnosed in 398 patients with high-intensity statin and 342 patients with moderate-intensity statin plus ezetimibe (12.5% vs. 10.7%; hazard ratio 0.84, 95% confidence interval 0.73-0.97, P = 0.02)., Conclusion: In patients undergoing PCI, moderate-intensity statin plus ezetimibe demonstrated a similar risk of MACCEs but a lower risk of new-onset DM than high-intensity statin. Early combination treatment of moderate-intensity statin and ezetimibe may be a useful and safe lipid-lowering strategy after PCI., (© 2024. The Author(s).)

Background: Evolocumab is the first monoclonal antibody against proprotein convertase subtilisin/kexin type 9 approved in Japan for familial hypercholesterolemia (FH) and hypercholesterolemia; however, data on its safety and effectiveness in the real-world setting in Japan are limited., Methods and Results: This real-world, postmarketing, single-arm study assessed the safety and effectiveness of low-density lipoprotein cholesterol lowering with evolocumab in patients with homozygous/heterozygous familial hypercholesterolemia and hypercholesterolemia with high risk in Japan (668 sites). The primary safety end point was the incidence (percentage) and number of patients with adverse drug reactions and serious adverse events during the 104-week follow-up. Primary effectiveness end points included the percentage change in low-density lipoprotein cholesterol levels from baseline to week 12, assessed using 2-sided paired t tests. The safety and effectiveness sets comprised 3724 (homozygous FH, n=108; heterozygous FH, n=2009; hypercholesterolemia with high risk, n=1607) and 2797 (homozygous FH, n=91; heterozygous FH, n=1615; hypercholesterolemia with high risk, n=1091) patients, respectively. Overall, mean age and disease duration were 63.2 and 12.3 years, respectively. Serious adverse drug reactions and serious adverse events were experienced by 0.5% and 10.3% of patients; the incidence rates of myocardial infarction and stroke were 0.7% and 0.3%, respectively. A significant mean±SD percentage change in low-density lipoprotein cholesterol levels was observed at week 12 among patients with homozygous FH (-45.7%±28.2; P <0.001), heterozygous FH (-55.9%±28.8; P <0.001), and hypercholesterolemia with high risk (-63.3%±23.7; P <0.001)., Conclusions: Evolocumab was well tolerated, and real-world patients with familial hypercholesterolemia and hypercholesterolemia with high risk in Japan had sustained low-density lipoprotein cholesterol reduction., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02808403.

Background: Elevated Lp(a) (lipoprotein[a]) is a risk marker for atherosclerotic disease, but the underlying mechanisms remain elusive. We examined the association of Lp(a) with changes in coronary atherosclerosis following intensive lipid-lowering therapy., Methods: In the PACMAN-AMI trial (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction), 300 patients with acute myocardial infarction were randomized to receive biweekly alirocumab 150 mg or placebo in addition to high-intensity statins. Patients underwent serial 2-vessel intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy in the non-infarct-related arteries at baseline and after 52 weeks. The main end points were percent atheroma volume by intravascular ultrasound, minimum fibrous cap thickness by optical coherence tomography, and maximum lipid core burden index within 4 mm (maxLCBI 4mm ) by near-infrared spectroscopy., Results: A total of 265 patients had serial intravascular ultrasound data (mean age, 58±9 years; 16% women). Alirocumab resulted in greater reductions in percent atheroma volume and maxLCBI 4mm , as well as a greater increase in minimum fibrous cap thickness, compared with placebo. In the alirocumab group, the reduction in maxLCBI 4mm was smaller in patients with higher baseline Lp(a), defined by the highest quartile (Q4, ≥98 nmol/L; n=30), than in those with lower baseline Lp(a) (Q1-Q3, <98 nmol/L; n=99; -40.2 [-91.1 to 10.7] versus -91.4 [-113.9 to -68.9], respectively; P =0.01 after adjustment for clinically relevant baseline variables), and was comparable to the maxLBI 4mm reduction in the placebo group (-37.60 [-57.40 to -17.80]; n=134). These findings were consistent when higher baseline Lp(a) was defined by cut-off values of ≥75 versus <75 nmol/L (n=35 versus 94, respectively, in the alirocumab group) and ≥125 versus <125 nmol/L (n=23 versus 106, respectively). Changes in percent atheroma volume and minimum fibrous cap thickness did not differ in relation to baseline Lp(a)., Conclusions: In patients with acute myocardial infarction, elevated Lp(a) at baseline is associated with attenuation of plaque lipid regression despite intensive treatment with alirocumab plus high-intensity statin. This finding may explain the residual cardiovascular risk associated with high Lp(a) despite optimal control of lipid levels., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03067844., Competing Interests: Dr Koskinas has received speaker fees from Amgen, Sanofi, and Daiichi Sankyo. Dr Kakizaki has received speaker fees from Abbott Medical, Boston Scientific, Philips, OrbusNeich Medical, Terumo, Eli Lilly, Mochida Pharmaceutical, Novartis, Kowa, Takeda Pharmaceuticals, Ono Pharmaceutical, Boehringer Ingelheim, Daiichi Sankyo, Mitsubishi Tanabe Pharma, AstraZeneca, and consulting fees from Infraredx. Dr van Geuns reported grants and personal fees from Boston Scientific, Abbott Vascular, Astra Zeneca, Amgen, and grants from InfraRedx. Dr Praz has received travel expenses from Abbott Vascular, Edwards Lifesciences, Polares Medical, Medira, and Siemens Healthineers. Dr Spirk reports personal fees from Sanofi-Aventis (Switzerland), outside the submitted work. Dr Lanz has received speaker fees to the institution from Abbott and Edwards Lifesciences. Drs Heg and Losdat are employed by CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees; however, CTU Bern is involved in the design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organizations. Dr Windecker has received research and educational grants to the institution from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi-Sankyo, Edwards Lifesciences, Guerbet, Infraredx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohme, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Swiss, Pfizer, Polares, Regeneron, Sanofi, Servier, Sinomed, Terumo, Vifor, and V-Wave. He serves as an unpaid advisory board member and unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave, and Xeltis but has not received personal payments from pharmaceutical companies or device manufacturers. Dr Engstrøm has received speaker fees from Abbott Vascular. Dr Lang has received consultancy fees and research grants from AOP Health, Johnson & Johnson, MSD, United Therapeutics, Sanofi, Medtronic, Novo Nordisk, Neutrolis, and Pulnovo. Dr Räber has received grants from Sanofi, Regeneron, and Infraredx to the institution, speaker fees from Sanofi, and grants from Abbott, HeartFlow, Boston Scientific, and Biotronik to the institution, as well as grants from Abbott, Amgen, AstraZeneca, Occlutech, Sanofi, Canon, and Medtronic for speaker and consultation fees outside the submitted work. The other authors report no conflicts.

Background: This study investigated whether intensive lipid-lowering therapy with pitavastatin and ezetimibe lowers the incidence of heart failure (HF) events in patients with acute coronary syndrome (ACS)., Methods and Results: In the HIJ-PROPER study, 1,734 patients with ACS were randomly assigned to either pitavastatin plus ezetimibe therapy (n=864) or pitavastatin monotherapy (n=857). We examined the incidence of HF between these 2 groups over a 3.9-year period after ACS. The primary endpoint of the study was hospitalization for HF. The mean low-density lipoprotein cholesterol levels during the follow-up period were 65.1 mg/dL in the pitavastatin plus ezetimibe group and 84.6 mg/dL in the pitavastatin monotherapy group. The incidence of HF hospitalization was significantly lower in the pitavastatin plus ezetimibe group than in the pitavastatin monotherapy group (19 [2.2%] vs. 40 [4.7%] patients; hazard ratio 0.47, 95% confidence interval 0.27-0.81; P<0.005). This trend was consistent after multivariable analysis using multiple models., Conclusions: Intensive lipid-lowering therapy with pitavastatin and ezetimibe is associated with a lower incidence of hospitalization for HF in patients with ACS.

Background: Although the relation between statin use and liver cancer risk has been extensively examined, few studies have examined other cholesterol-lowering medications in relation to liver cancer risk. The authors examined five classes of nonstatin medications and liver cancer risk., Methods: A nested case-control including 3719 cases and 14,876 matched controls was conducted within the Clinical Practice Research Datalink. Additional matches on type 2 diabetes and chronic liver disease were also implemented. The medications examined included cholesterol absorption inhibitors, bile acid sequestrants, fibrates, niacin, and omega-3 fatty acids. Conditional logistic regression estimated odds ratios and 95% confidence intervals., Results: Cholesterol absorption inhibitor use was associated with reduced liver cancer risk in the overall analysis (odds ratio, 0.69; 95% confidence interval, 0.50-0.96) and in analyses based on type 2 diabetes and chronic liver disease status. Although bile acid sequestrant use was associated with increased liver cancer risk in the overall analysis (odds ratio, 5.31; 95% confidence interval, 3.53-7.97), the results of the analyses based on type 2 diabetes and chronic liver disease status were inconsistent. [Correction added on 19 August 2024, after first online publication: In the preceding sentence, the value '3.534' has been changed to '3.54'.]. No associations were observed for the other medications., Conclusions: Cholesterol absorption inhibitors may be associated with reduced liver cancer risk. Whether bile acid sequestrant use was associated with increased risk was only partially supported in the current study., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Aims: Data describing the long-term efficacy and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials., Methods and Results: Following completion of the parent trial, adult patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent, or heterozygous familial hypercholesterolaemia received open-label inclisiran twice yearly (after initial and 3-month doses) until Day 990, followed by an end-of-study visit at Day 1080 or ≥ 90 days after the last dose. The study endpoints included the proportion of patients achieving pre-specified low-density lipoprotein cholesterol (LDL-C) goals [ASCVD: < 1.8 mmol/L (< 70 mg/dL); ASCVD risk equivalent: < 2.6 mmol/L (< 100 mg/dL)], percentage and absolute changes in LDL-C at end-of-study, and safety of inclisiran. Of 3274 patients, 2446 (74.7%) were followed until end-of-study. Mean age was 64.9 ± 9.9 years, 82.7% (n = 2709) had ASCVD, and mean baseline LDL-C was 2.9 ± 1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% [95% confidence interval (CI): 76.8, 80.0] of patients achieved pre-specified LDL-C goals and mean percentage change in LDL-C was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at injection site (all mild/moderate) occurred in 5.9% of the patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified., Conclusion: In the largest and longest follow-up to date with >12 000 patient-years exposure, inclisiran demonstrated consistent and effective LDL-C lowering with a favourable long-term safety and tolerability profile., Trial Registration Number: ClinicalTrials.gov identifier: NCT03814187., Competing Interests: Conflict of interest: R.S.W. reports receiving advisory board fees from Boehringer Ingelheim and past fees for consulting on lipid issues with The Medicines Company; F.J.R. reports receiving advisory board fees and lecture fees from Amgen, Sanofi-Aventis, Regeneron Pharmaceuticals, Novartis, and LIB Therapeutics; W.K. reports receiving consulting fees and lecture fees from AstraZeneca, Novartis, and Amgen; consulting fees from Pfizer, The Medicines Company, Novartis, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, Esperion, Genentech, OMEICOS, Novo Nordisk, LIB Therapeutics, Daiichi Sankyo, New Amsterdam Pharma, and TenSixteen Bio; lecture fees from Berlin-Chemie, Bristol-Myers Squibb, and Sanofi; and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr Beckmann Pharma; U.L. reports receiving grant support from Amgen, Bayer, and Novartis and advisory board fee from Novartis; L.A.L. reports grant support paid to his institution and advisory board fees and fees for CME from Amgen and Novartis; grant support paid to his institution and fees for serving on a steering committee from Kowa, The Medicines Company and Novartis; and advisory board fees and fees for CME from Amarin, AstraZeneca, HLS, Merck, New Amsterdam, Pfizer, and Sanofi; G.G.S. reports receiving research support paid to his institution from AstraZeneca, Sanofi, Silence Therapeutics, and The Medicines Company and a patent (62/806313) on a method for reducing cardiovascular risk assigned in full to the University of Colorado; K.K.R. reports receiving support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre; his institution (Imperial College London) receives support from the NIHR Applied Research Collaboration Northwest London. K.K.R. also reports receiving lecture fees from Aegerion Pharmaceuticals, Kowa, Cipla, Algorithm, and Zuelling Pharma; grant support paid to his institution; lecture fees and advisory board fees from Amgen, Regeneron Pharmaceuticals/Sanofi, and Pfizer; lecture fees and fees for serving on steering committees for trials from AstraZeneca and Eli Lilly; fees for serving on steering committees for trials from Cerenis Therapeutics, The Medicines Company, and Esperion; advisory board fees from Akcea Therapeutics, Novartis, Silence Therapeutics, Bayer, and Daiichi Sankyo; lecture fees and advisory board fees from Takeda, Boehringer Ingelheim, and Dr Reddy’s Laboratories; grant support and advisory board fees from Merck Sharp & Dohme; fees for serving on a clinical events adjudication committee from AbbVie; and fees for serving as principal investigator for a trial from Resverlogix; Z.T., S.V., and X.Z. are all employees of Novartis Pharmaceuticals Corp, East Hanover, New Jersey, USA and hold shares in Novartis; A.L. is employee of Novartis Pharma AG, Basel, Switzerland; P.M. was an employee of Novartis Pharma AG, Basel, Switzerland, at the time of conducting this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Amiodarone is an antiarrhythmic drug which may be associated with thyroid dysfunction. Type I amiodarone-induced thyrotoxicosis (AIT) is treated with thionamides and type II AIT is treated with glucocorticoids. Combined therapy is used in mixed or indeterminate forms. When medical treatment is unsuccessful, radioiodine ablation or thyroidectomy is considered. This report reviews a case of AIT refractory to conventional treatment. Despite high doses of methimazole and prednisone, the patient remained clinically and biochemically thyrotoxic. Cholestyramine, a bile salt sequestrant, was used as an off-label adjunctive treatment resulting in significant improvement and achievement of euthyroidism that may also be in part due to the expected natural timeline of recovery from AIT after several months. The patient subsequently trended towards hypothyroidism with symptomatic weight gain and cold intolerance for which he was initiated on levothyroxine., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: Limited evidence exist regarding the association between ongericimab, a novel recombinant humanized anti-PCSK9 monoclonal antibody, and primary hypercholesterolemia and mixed dyslipidemia. This study aimed to evaluate the efficacy and safety of ongericimab administered by prefilled syringe (PFS) or autoinjector (AI) in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia on stable optimized lipid-lowering therapy., Methods and Results: A total of 255 patients on stable optimized lipid-lowering therapy were randomized in a 2:1:2:1 ratio to receive PFS for the subcutaneous injection of ongericimab 150 mg every 2 weeks (Q2W) or a matching placebo, or AI for the subcutaneous injection of ongericimab 150 mg Q2W or a matching placebo. The primary efficacy endpoint was the percent change in low-density lipoprotein cholesterol (LDL-C) levels from baseline to week 12. Safety was also evaluated. At week 12, the least squares mean percent changes were -72.7% (3.9%) for PFS and -71.1% (3.8%) for AI (all P < 0.001) compared to respective matching placebo groups. Beneficial effects were also seen for all secondary lipid parameters, notably with robust reduction in Lp (a). Treatment-emergent adverse events (TEAEs) and serious AEs with ongericimab were reported in 46.2% and 2.4% of patients, compared to 44.2% and 3.5% with placebo., Conclusion: In Chinese patients with primary hypercholesterolemia and mixed dyslipidemia, a 12-week treatment regimen with ongericimab administered by PFS or AI significantly reduced LDL-C and other lipid parameters, proving to be safe and well tolerated. Patients experienced consistent effects from PFS or AI devices., Clinical Trial Registration: CTR20220027; January 11, 2022; http://www.chinadrugtrials.org.cn/index.html., Competing Interests: Declaration of competing interest Minghui Wang, Yi Zhao, and Xuelian Bai are employees of Shanghai Junshi Biosciences Co., Ltd. The remaining authors declare that they have not received support from any organization for the submitted work, do not have any financial relationships with organizations that might have an interest in the submitted work over the past three years, and have not engaged in any activities that may have influenced the submitted work., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Randomized clinical trials (RCTs) of PCSK9 monoclonal antibody(mAb) specifically for Chinese patients have been limited. This multi-center RCT is to clarify the efficacy and safety of a novel mAb, Ebronucimab, in Chinese patients. Patients diagnosed with primary hypercholesterolemia, including Heterozygous Familial Hypercholesterolemia, or mixed dyslipidemia, were categorized by ASCVD risk and randomly assigned at a ratio of 2:1:2:1 to receive Ebronucimab 450 mg or matching placebo every 4 weeks (Q4W), or Ebronucimab 150 mg or matching placebo every 2 weeks (Q2W). The primary outcome was the percentage change of LDL-C from baseline to week 12 for all groups. The least squares mean reduction difference (95 %CI) in LDL-C from baseline to week 12 of Ebronucimab 450 mg Q4W and Ebronucimab 150 mg Q2W groups versus the placebo group was -59.13 (-64.103, -54.153) (Adjusted p<0.0001) and -60.43 (-65.450, -55.416) (Adjusted p<0.0001), respectively. Meanwhile, the Ebronucimab group exhibited notably high rates in reaching LDL-C goals of each cardiovascular risk stratification. In addition, Ebronucimab effectively improved other lipid panel. During the double-blind treatment period, relatively frequently reported adverse events (AEs) were injection site reactions (ISR), urinary tract infection, and hyperuricemia (Incidence rate are 6.9 %, 4.8 % and 3.5 %). Among treatment-associated AEs, only injection site reactions (ISR) occurred more in the dose groups. In conclusion, Ebronucimab, with either 450 mg Q4W or 150 mg Q2W doses, demonstrated significant efficacy in lowering serum LDL-C level with a favorable safety and immunogenicity profile among hypercholesterolemic patients., Competing Interests: Declaration of Competing Interest Binge Yu, Guoqin Wang, Fang Xu, Dongmei Lu, Zhimei He, Benchao Chen, Lei Ma, Max Wang, Baiyong Li, and Michelle Xia are employees of Akeso Pharmaceutical (Guangzhou) Co., Ltd. The remaining co-authors have nothing to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Background/aims: Achieving rapid reduction of low-density lipoprotein cholesterol (LDL-C) levels below 55 mg/dL in patients with acute myocardial infarction (AMI) can be challenging with statins alone. This single-center, retrospective study aimed to assess the impact of single-dose injection of evolocumab 140 mg on LDL-C levels during the peri-percutaneous coronary intervention (PCI) period in patients with AMI., Methods: A total of 95 patients with AMI who underwent PCI were divided into the evolocumab (n = 50) and non-evolocumab (n = 45) groups., Results: The percentage change of LDL-C level at 1-3 weeks from baseline was 78.4 ± 13.4% reduction in the evolocumab group versus 45.6 ± 22.6% in the non-evolocumab group, with a mean difference of -33.5% between the groups (95% CI: -42.6 to -24.5%; p < 0.001). The achievement rate of LDL-C levels below 55 mg/dL at 1-3 weeks was significantly higher in the evolocumab group than in the non-evolocumab group (97.7% vs. 60.0%, p < 0.001)., Conclusion: Patients with AMI who received single-dose injection of evolocumab 140 mg during the peri-PCI period had a significantly greater LDL-C reduction and higher proportion of patients achieved the target LDL-C level in the early phase AMI than those who did not receive evolocumab.

Competing Interests: Conflict of interest: M.S. reports serving as a consultant or research support (or both) from CiVi, Resverlogix, Lexicon, Baxter, Esperion, Amarin, New Amsterdam, Tourmaline, Sanofi, and Regeneron Pharmaceuticals, Inc. E.R.: No disclosures. P.G.S. reports grants, personal fees, and non-financial support from Sanofi; grants and personal fees from Amarin, Servier, and Bayer; personal fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Idorsia, Pfizer, and Novartis. J.W.J. receives research grants from The Netherlands Heart Foundation, the Interuniversity Cardiology Institute of The Netherlands, and the European Commission Seventh Framework Programme; and research support from Amgen, Astellas, AstraZeneca, Daiichi Sankyo, Lilly, Merck-Schering-Plough, Novartis, Pfizer, Roche, and Sanofi. M.Sc. is an employee of Roche and may hold shares in the company. D.L.B. discloses the following relationships: Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; Board of Directors: Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures, Hims; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co-Investigator: Author contributions Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solut.

Aim: People with chronic kidney disease experience high rates of cardiovascular disease. Cholesterol-lowering therapy is a mainstay in the management but there is uncertainty in the treatment effects on patient-important outcomes, such as fatigue and rhabdomyolysis. Here, we summarise the updated CARI Australian and New Zealand Living Guidelines on cholesterol-lowering therapy in chronic kidney disease., Methods: We updated a Cochrane review and monitored newly published studies weekly to inform guideline development according to international standards. The Working Group included expertise from nephrology, cardiology, Indigenous Health, guideline development and people with lived experience of chronic kidney disease., Results: The guideline recommends people with chronic kidney disease (eGFR ≥15 mL/min/1.73 m 2 ) and an absolute cardiovascular risk of 10% or higher should receive statin therapy (with or without ezetimibe) to reduce the risk of cardiovascular events and death (strong recommendation, moderate certainty evidence). The guidelines also recommends a lower absolute cardiovascular risk threshold (≥5%) for Aboriginal and Torres Strait Islander Peoples and Māori with chronic kidney disease to receive statin therapy (with or without ezetimibe) (strong recommendation, low certainty evidence). The evidence was actively surveyed from 2020-2023 and updated as required. No changes to guideline recommendations were made, with no new data on the balance and benefits of harms., Conclusions: The development of living guidelines was feasible and provided the opportunity to update recommendations to improve clinical decision-making in real-time. Living guidelines provide the opportunity to transform chronic kidney disease guidelines., (© 2024 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Abstract: In vitro investigations have established metformin's capacity to downregulate proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, suggesting a potential beneficial effect on atherogenic lipoprotein particles when combined with metformin therapy. Our objective was to assess whether metformin could mitigate statin-induced adverse effects on PCSK9, thereby improving lipid profiles in patients with coronary artery disease (CAD) but without diabetes. Employing an open-label, placebo-controlled, randomized trial, we randomized patients with CAD but without diabetes into CLA (cholesterol-lowering agents alone: atorvastatin ± ezetimibe, n = 38) and Met + CLA groups (metformin plus CLA, n = 33) in a 1:1 ratio. The primary end point was the therapeutic impact of 1-month metformin combination treatment on low-density lipoprotein cholesterol (LDL-C) and PCSK9 levels. Baseline LDL-C and PCSK9 levels were 76.18 mg·dL -1 and 80.54 ng·mL -1 , respectively. After 1 month, metformin significantly reduced LDL-C (-20.81%, P < 0.001), enabling 72% of patients to attain guideline-recommended LDL-C goals. Noteworthy reductions in PCSK9 levels (-15.03%, P < 0.001) were observed. Moreover, Met + CLA markedly reduced LDL particle number more than CLA alone (-10.65% vs. 1.45%, P = 0.009), primarily due to diminished small-dense LDL particle count. Mechanistically, our study demonstrated metformin's inhibition of statin-induced PCSK9 expression in human hepatocellular cells. In summary, a 1-month metformin combination regimen reduced LDL-C levels in patients with CAD but without diabetes by inhibiting PCSK9 expression., Trial Registration: Chinese Clinical Trial Registry identifier: ChiCTR1900026925 (26/10/2019)., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Monoclonal antibodies (mAb) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have been established in cardiovascular risk prevention. The purpose of this review is to summarize the effects of PCSK9 inhibitors across different patient populations., Recent Findings: Long-term data on the use of evolocumab and alirocumab shows persisting low- density lipoprotein cholesterol (LDL-C) lowering and good tolerability. PCSK9 inhibitors are effective and safe in both sexes, in pediatric patients as well as in the elderly. Initiation of PCSK9 mAb during acute myocardial infarction is safe and leads to beneficial morphological plaque changes. The PCSK9 inhibitors evolocumab, alirocumab and inclisiran lower LDL-C in patients with heterozygous familial hypercholesterolemia (FH), while the response of patients with homozygous FH is heterogeneous. New areas of application beyond lipid lowering are currently investigated., Summary: PCSK9 inhibitors are safe, well tolerated, and effective in primary and secondary prevention in a wide range of patient populations., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: It remains controversial whether adding ezetimibe to low/moderate-intensity statins has a more beneficial impact on the treatment efficacy and safety of patients with existing atherosclerotic cardiovascular disease (ASCVD) compared to high-intensity statin regimens., Hypothesis: A combination of low/moderate-intensity statins plus ezetimibe might be more effective and safer than high-intensity statin monotherapy., Methods: We searched databases for randomized controlled trials comparing lipid profile alterations, drug-related adverse events, and MACE components between high-intensity statin monotherapy and low/moderate-intensity statin plus ezetimibe combination therapy. Pooled risk ratios (RR), mean differences (MD), and 95% confidence intervals (95% CI) were estimated using a random-effects model., Results: Our comprehensive search resulted in 32 studies comprising 6162 patients treated with monotherapy against 5880 patients on combination therapy. Combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels compared to monotherapy (MD = -6.6, 95% CI: -10.6 to -2.5); however, no significant differences were observed in other lipid parameters. Furthermore, the combination therapy group experienced a lower risk of myalgia (RR = 0.27, 95% CI: 0.13-0.57) and discontinuation due to adverse events (RR = 0.61, 95% CI: 0.51-0.74). The occurrence of MACE was similar between the two treatment groups., Conclusions: Adding ezetimibe to low/moderate-intensity statins resulted in a greater reduction in LDL-C levels, a lower rate of myalgia, and less drug discontinuation compared to high-intensity statin monotherapy in patients with existing cardiovascular disease. However, according to our meta-analysis, the observed reduction in LDL-C levels in the combination group did not correlate with a reduction in MACE compared to the high-intensity statin group., (© 2024 The Author(s). Clinical Cardiology published by Wiley Periodicals, LLC.)

Underutilization of lipid-lowering therapy (LLT) and failure to attain guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals are important quality gaps in cardiovascular risk optimization, especially among patients with atherosclerotic cardiovascular disease (ASCVD). Large database analyses demonstrate an unmet need for improved LDL-C measurement, and that nearly 75% of patients with ASCVD have an LDL-C level above guideline-recommended levels, and greater than 50% are not treated with statins or ezetimibe. Proposed solutions for overcoming these obstacles to optimal lipid management include provider- and patient-facing educational interventions, health information technology strategies, implementation of incentive-based care, advocacy efforts, and systems-based process innovations. While individual interventions may not be enough to overcome the totality of barriers to optimal LLT, comprehensive multifaceted approaches that address barriers at the provider, patient, and healthcare delivery level are likely to offer the greatest likelihood of success and improved patient outcomes., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Safety data on the use of monoclonal antibodies inhibiting proprotein convertase subtilisin/kexin type 9 in pregnancy are scarce. This study queried VigiBase®, the World Health Organization global pharmacovigilance database, to search for signals of disproportionate reporting for pregnancy outcomes with alirocumab and evolocumab. As of November 22, 2023, there were 45 safety reports of exposure to evolocumab (N = 31) and alirocumab (N = 14) in pregnancy. Most of them originated from Europe (N = 25, 55.6%) and were more frequently reported by healthcare professionals (N = 35, 77.8%). Median patient age was 37 years (25th-75th percentiles; 32-41 years). Drug exposure occurred during pregnancy in 36 (80.0%) safety reports, via paternal exposure during pregnancy in four (8.9%), during lactation in three (6.7%), and in two safety reports the time of drug exposure remained unknown. Twenty safety reports (57.8%) merely reported drug exposure, while 19 (42.2%) also reported pregnancy outcomes, however, without specific maternal toxicities or patterns of birth defects. Spontaneous abortion was reported in eight safety reports without representing a signal of disproportionate reporting compared with either the full database (reporting odds ratio, ROR, 0.06 95% confidence interval, CI 0.03-0.12) or statins (ROR 0.16, 95% CI 0.08-0.32). In conclusion, this study showed that, currently, there are no signals of increased reporting of spontaneous abortion with alirocumab and evolocumab compared with the full database and statins in VigiBase®. Notwithstanding, lack of disproportionality is not synonymous with safety and, as disproportionality analyses depend on the number of safety reports that progressively accumulate in VigiBase®, they should be repeated at regular intervals to confirm the results of the present study., (© 2024 The Authors. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Background: High-intensity statin therapy is currently recommended initial guideline therapy in ACS treatment. However, only a minority of patients are achieving LDL-C attainment goal at 6 months. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are on recommended guideline therapy post-ACS if LDL-C goal attainment is not achieved after high-intensity statin (4-6 weeks) and after the addition of ezetimibe if guideline goal attainment is not achieved after an additional 4-6 weeks. Thus, it has been recommended that PCSK9 inhibitors be considered earlier post-ACS. However, the efficacy of early PCSK9 inhibitors initiation in ACS patients remains uncertain., Methods: This systematic review and meta-analysis was conducted following PRISMA guidelines. Randomized controlled trials (RCTs) and observational studies involving ACS patients who received PCSK9 inhibitors within 48 h of hospitalization were included. Common and random effects models were used to evaluate the pooled effect of early PCSK9 inhibitor administration. Nine RCTs and three cohort studies were included., Results: Early PCSK9 inhibitor administration reduced the incidence of MI, ACS hospitalization, and revascularization at 6-18 months post-ACS. Although there was a drift towards reduced stroke, all-cause mortality, and cardiovascular death, no statistically significant reduction was observed. Additionally, PCSK9 inhibitors significantly enhanced lipid control at 4-12 weeks after index hospitalization., Conclusion: Early PCSK9 inhibitors initiation in ACS patients reduces MACE and improves lipid profiles. While the results propose promising benefits in terms of stroke and mortality, further research with longer follow-up is required for more decisive evidence., (© 2024. The Author(s).)

The ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) and concomitant multivessel coronary artery disease (CAD) are considered patients with extremely high-risk atherosclerotic cardiovascular disease (ASCVD), and current guidelines specify a lower low-density lipoprotein cholesterol (LDL-C) target for this population. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to effectively reduce LDL-C levels on a statin background. Additionally, several studies have confirmed the role of PCSK9 inhibitors in plaque regression and reducing residual cardiovascular risk in patients with ACS. However, those studies included coronary lesions with a degree of stenosis <50%. Whether the application of PCSK9 inhibitors in patients with NSTE-ACS with non-culprit artery critical lesions (stenosis degree between 50% and 75%) has a similar effect on plaque regression and improvement of cardiovascular outcomes remains unknown, with a lack of relevant research. This study aims to further investigate the safety and efficacy of evolocumab in patients with NSTE-ACS and concomitant multivessel CAD (non-culprit artery stenosis between 50% and 75%)., Methods and Analysis: In this single-centre clinical randomised controlled trial, 122 patients with NSTE-ACS and concomitant multivessel CAD (non-culprit artery stenosis between 50% and 75%) will be randomly assigned to either the evolocumab treatment group or the standard treatment group after completing culprit vessel revascularisation. The evolocumab treatment group will receive evolocumab in addition to statin therapy, while the standard treatment group will receive standard statin therapy. At baseline and week 50, patients in the evolocumab treatment group will undergo coronary angiography and OCT imaging to visualise pre-existing non-lesional vessels. The primary end point is the absolute change in average minimum fibrous cap thickness (FCT) from baseline to week 50. Secondary end points include changes in plaque lipid arc, lipid length, macrophage grading, lipid levels and major adverse cardiovascular events during the 1-year follow-up period., Ethics and Dissemination: Ethics: this study will adhere to the principles outlined in the Helsinki Declaration and other applicable ethical guidelines. This study protocol has received approval from the Medical Research Ethics Committee of the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital), with approval number 2022-ky214., Dissemination: we plan to disseminate the findings of this study through various channels. This includes publication in peer-reviewed academic journals, presentation at relevant academic conferences and communication to the public, policymakers and healthcare professionals. We will also share updates on the research progress through social media and other online platforms to facilitate the exchange and application of scientific knowledge. Efforts will be made to ensure widespread dissemination of the research results and to have a positive impact on society., Trial Registration Number: ChiCTR2200066675., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by severely elevated LDL cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. In the pivotal Phase 3 HoFH trial (NCT03399786), evinacumab significantly decreased LDL-C in patients with HoFH. This study assesses the long-term safety and efficacy of evinacumab in adult and adolescent patients with HoFH., Methods: In this open-label, single-arm, Phase 3 trial (NCT03409744), patients aged ≥12 years with HoFH who were evinacumab-naïve or had previously received evinacumab in other trials (evinacumab-continue) received intravenous evinacumab 15 mg/kg every 4 weeks with stable lipid-lowering therapy., Results: A total of 116 patients (adults: n = 102; adolescents: n = 14) were enrolled, of whom 57 (49.1%) were female. Patients were treated for a median (range) duration of 104.3 (28.3-196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 93 (80.2%) and 27 (23.3%) patients, respectively. Two (1.7%) deaths were reported (neither was considered related to evinacumab). Three (2.6%) patients discontinued due to TEAEs (none were considered related to evinacumab). From baseline to Week 24, evinacumab decreased mean LDL-C by 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] in the overall population; mean LDL-C reduction in adults and adolescents was 41.7% [mean (SD), 3.2 (3.3) mmol/L] and 55.4% [mean (SD), 4.7 (2.5) mmol/L], respectively., Conclusions: In this large cohort of patients with HoFH, evinacumab was generally well tolerated and markedly decreased LDL-C irrespective of age and sex. Moreover, the efficacy and safety of evinacumab was sustained over the long term., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: The objective of this investigation is to examine the benefits and potential risks of these drugs in individuals by varying baseline low-density lipoprotein cholesterol (LDL-C) values, utilizing the concept of the number needed to treat (NNT)., Methods: We extensively searched electronic databases, such as PubMed, EMBASE, Cochrane, and Web of Science, up to 6 August 2023. Baseline LDL-C values were stratified into four categories: < 100, 100-129, 130-159, and ≥ 160 mg/dL. Risk ratios (RRs) and NNT values were computed., Results: This analysis incorporated data from 46 randomized controlled trials (RCTs), encompassing a total of 237,870 participants. The meta-regression analysis demonstrated an incremental diminishing risk of major adverse cardiovascular events (MACE) with increasing baseline LDL-C values. Statins exhibited a significant reduction in MACE [number needed to treat to benefit (NNTB) 31, 95% confidence interval (CI) 25-37], but this effect was observed only in individuals with baseline LDL-C values of 100 mg/dL or higher. Ezetimibe and PCSK9 inhibitors also were effective in reducing MACE (NNTB 18, 95% CI 11-41, and NNTB 18, 95% CI 16-24). Notably, the safety outcomes of statins and ezetimibe did not reach statistical significance, while the incidence of injection-site reactions with PCSK9 inhibitors was statistically significant [number needed to treat to harm (NNTH) 41, 95% CI 80-26]., Conclusion: Statins, ezetimibe, and PCSK9 inhibitors demonstrated a substantial capacity to reduce MACE, particularly among individuals whose baseline LDL-C values were relatively higher. The NNT visually demonstrates the gradient between baseline LDL-C and cardiovascular disease (CVD) risk., Systematic Review Registration: Registration: PROSPERO identifier number: CRD42023458630., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The use of alirocumab and evolocumab is generally safe and well-tolerated. However, concerns remain about their long-term safety, especially with regard to new-onset or worsening diabetes mellitus (DM). We aim to assess the safety profile of alirocumab and evolocumab compared to comparator., Methods: Studies were retrieved comparing the safety of PCSK9i vs. comparator (placebo or statin with or without ezetimibe). The primary outcome was adverse events leading to death. Secondary outcomes included serious adverse events, new onset diabetes mellitus (DM), worsening of DM, neurocognitive dysfunction, creatine kinase (CK) elevation, elevation of liver enzymes and local injection site reaction. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on PCSK9i type and treatment duration., Results: We identified 56 studies with 85,123 adults (29.14% females). PCSK9i was not associated with adverse events that lead to death (OR 0.94, 95% CI 0.84 to 1.04, p  = 0.22). Between the two PCSK9i, alirocumab decreased adverse events leading to death (OR 0.79, 95% CI, 0.67 to 0.94, p  = 0.008). PCSK9i was associated with less serious events compared to the comparator (OR 0.93, 95% CI 0.89 to 0.98, p  < 0.001). This reduction was driven mainly by alirocumab (OR 0.89, 95% CI, 0.85 to 0.93, p  < 0.001). Evolocumab worsened DM (OR 2.3, 95% CI 1.26 to 4.2, p  = 0.041). Subgroup analysis showed worsening of DM in the first 24 weeks of treatment with odds being highest in the first 12 weeks of treatment (<12 weeks: OR 3.82, 95% CI 1.13 to 12.99, p  = 0.03; 12-24 weeks OR 2.12, 95% CI 1.20 to 3.73, p  = 0.01. On the other hand, therapy >24 weeks reduced the odds of worsening DM (OR 0.89, 95% CI 0.79 to 0.99, p  = 0.04). PCSK9i did not increase cognitive dysfunction, (OR 1.02, 95% CI 0.88 to 1.18, p  = 0.76), or cause elevations in liver enzyme (OR 0.91, 95% CI 0.81 to 1.03, p  = 0.14), or CK (OR 0.82, 95% CI 0.65 to 1.04, p  = 0.10). However, PCSK9i was associated with local injection site reaction (OR 1.54, 95% CI 1.37 to 1.73, p  < 0.01)., Conclusion: Alirocumab decreased adverse events leading to death. Alirocumab and Evolocumab both decreased serious adverse events. PCSK9i did not increase new onset DM however evolocumab worsened DM in the first 24 weeks of treatment. PCSK9i did not increase neurologic dysfunction, and did not elevate liver enzymes and CK, however it was associated with local injection site reaction.

Background: Evolocumab and alirocumab are self-injected proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors indicated for low-density lipoprotein cholesterol reduction. Complications in the use or functionality of self-injection devices may precipitate incomplete dosing., Objective: This study sought to characterize postmarketing dosing failure reports involving self-injected PCSK9 inhibitors., Methods: US Food and Drug Administration Adverse Event Reporting System (FAERS) [2016-second quarter of 2023] data were utilized for a disproportionality analysis. Eight self-injected comparator medications served as referents. Medical Dictionary for Regulatory Activities preferred terms indicating explicit or probable failure to administer a complete dose classified cases. Proportional reporting ratios (PRRs) > 2.0 and lower 95% confidence intervals (CIs) > 1.0 indicated disproportionality signals. US FDA Manufacturer and User Facility Device Experience (MAUDE) [2013-2023] data underwent a narrative review., Results: During the study period, 194,781 (evolocumab, n = 152,831; alirocumab, n = 41,950) drug-event pairs and 43,725 (evolocumab, n = 38,489; alirocumab, n = 5236) cases reported to FAERS identified PCSK9 inhibitors. MAUDE contained six evolocumab reports, half describing dose omission, and no alirocumab reports. A potential dosing failure signal was detected for evolocumab (PRR 2.01; 95% CI 1.98-2.03), but not alirocumab (PRR 0.99; 95% CI 0.97-1.02), relative to pooled comparator reports. Across three case term subcategories, incomplete dosing disproportionality signals were further identified for evolocumab patient usage complication terms (PRR 3.44; 95% CI 3.38-3.50) and alirocumab device malfunction terms (PRR 2.09; 95% CI 1.98-2.22)., Conclusions: Proprotein convertase subtilisin kexin type 9 inhibitor incomplete dosing-related complications are frequently reported in the postmarketing setting. Systematic efforts to understand the incidence and mechanisms of dosing failure and associated patient burdens are needed., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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

Background: Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline differences, and (2) the relationship of baseline differences with effects on low-density lipoprotein-cholesterol (LDL-c) and clinical outcomes in the trials., Methods: We performed a meta-epidemiological study. PubMed, Embase, regulatory reports, ClinicalTrials.gov and company websites were searched for trials. Seven baseline characteristics (mean age, LDL-c, BMI, percentage males, diabetics, smokers, and hypertensives) and five outcomes (LDL-c, major adverse cardiac events, serious adverse events, any adverse events, all-cause mortality) were extracted. We calculated (1) range and distribution of baseline imbalances (sign-test), (2) pooled baseline differences and heterogeneity (meta-analysis), (3) differences in SDs around continuous variables (sign-test and pooling), and (4) the relationship of baseline differences with outcomes (meta-regression). The comparisons of PCSK9-inhibitor groups with either placebo or ezetimibe were analysed separately and combined., Results: We identified 43 trials with 63,193 participants. Baseline characteristics were frequently missing. Many trials showed small baseline imbalances, but some large imbalances. Only baseline BMI showed a statistically significant lower pooled mean for the drug versus placebo groups (MD -0.16; 95% CI -0.24 to -0.09). Heterogeneity in baseline imbalances was present in six placebo- and five ezetimibe-comparisons. Heterogeneity was statistically significant for BMI, males, diabetics and hypertensives in the combined comparisons. There was a statistically significant preponderance for larger SDs in the PCSK9-inhibitor versus control groups (sign-test age 0.014; LDL-c 0.014; BMI 0.049). Meta-regression showed clinically relevant relationships of baseline imbalances in age, BMI and diabetics with the risk of any adverse events and the risk of mortality. Two relationships were statistically significant: A higher mean BMI in the drug versus control group with a decreased risk of mortality (beta - 0.56; 95% CI -1.10 to -0.02), and a higher proportion of diabetics with an increased risk of any adverse events (beta 0.02; 95% 0.01 to 0.04)., Conclusions: Heterogeneous baseline imbalances and systematically different SDs were present in evolocumab and alirocumab trials, so study groups cannot be assumed to be comparable. These findings raise concerns about the design and conduct of the randomization procedures., (© 2024. The Author(s).)

This is a case report of a 70-year-old woman with possible cholestyramine-induced bowel perforation. She had a prior history of pancreaticoduodenectomy for pancreatic cancer with a daily intake of cholestyramine. She underwent emergency laparotomy for small bowel perforation twice. Subsequent pathology reports showed crystal depositions in the small bowel wall. Leasions spread out on the small bowel and the omentum during the second surgery were thought to be carcinomatosis. However, the pathology report showed no malignant cells but plenty of crystal depositions as seen with cholestyramine intake., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

In this case report, a 31-year-old woman with heterozygous familial hypercholesterolaemia (FH) underwent treatment with statins and PCSK9 inhibitor but had to discontinue due to elevated creatine kinase levels and neurological and muscular side effects. In 2021, the patient received inclisiran therapy, the first known instance of its application in Denmark. No side effects were reported, and LDL cholesterol levels were significantly reduced. This case report highlights the potential of inclisiran as an effective and well-tolerated treatment for individuals with heterozygous FH., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Background: A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9, as an add-on treatment to optimized lipid-lowering therapy in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia., Methods and Results: A total of 806 patients who were receiving stable and optimized lipid-lowering therapy but did not achieve their low-density lipoprotein cholesterol (LDL-C) targets were enrolled and randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or matching placebo every 2 weeks, or ongericimab 300 mg or matching placebo every 4 weeks for 52 weeks. Efficacy and safety were evaluated in 802 patients who received at least 1 dose of ongericimab or placebo. The primary end point was the percentage change in LDL-C from baseline to week 24. Our findings demonstrated that the least-squares mean difference of percentage change in LDL-C from baseline to week 24 was -67.7% (95% CI, -72.5% to -63.0%; P <0.0001) in the ongericimab 150 mg every 2 weeks group compared with the placebo every 2 weeks group, and -61.2% (95% CI, -67.1% to -55.2%; P <0.0001) in the ongericimab 300 mg every 4 weeks group compared with the placebo every 4 weeks group. These reductions were sustained up to week 52. Furthermore, treatment with ongericimab favorably altered other lipid parameters. A similar incidence of adverse events was observed in the ongericimab and placebo groups., Conclusions: Ongericimab, as an add-on treatment to optimized lipid-lowering therapy, significantly reduced LDL-C and was well-tolerated in Chinese patients with primary hyperlipidemia and mixed dyslipidemia who did not achieve their LDL-C targets., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04781114.

Aims: Current guidelines advise against the use of lipid-lowering drugs during pregnancy. This is based only on previous observational evidence demonstrating an association between statin use and congenital malformations, which is increasingly controversial. In the absence of clinical trial data, we aimed to use drug-target Mendelian randomization to model the potential impact of fetal LDL-lowering, overall and through PCSK9 drug targets, on congenital malformations., Methods and Results: Instrumental variants influencing LDL levels overall and through PCSK9-inhibitor drug targets were extracted from genome-wide association study (GWAS) summary data for LDL on 1 320 016 individuals. Instrumental variants influencing circulating PCSK9 levels (pQTLs) and liver PCSK9 gene expression levels (eQTLs) were extracted, respectively, from a GWAS on 10 186 individuals and from the genotype-tissue expression project. Gene-outcome association data was extracted from the 7th release of GWAS summary data on the FinnGen cohort (n = 342 499) for eight categories of congenital malformations affecting multiple systems. Genetically proxied LDL-lowering through PCSK9 was associated with higher odds of malformations affecting multiple systems [OR 2.70, 95% confidence interval (CI) 1.30-5.63, P = 0.018], the skin (OR 2.23, 95% CI 1.33-3.75, P = 0.007), and the vertebral, anorectal, cardiovascular, tracheo-esophageal, renal, and limb association (VACTERL) (OR 1.51, 95% CI 1.16-1.96, P = 0.007). An association was also found with obstructive defects of the renal pelvis and ureter, but this association was suggestive of horizontal pleiotropy. Lower PCSK9 pQTLs were associated with the same congenital malformations., Conclusion: These data provide genetic evidence supporting current manufacturer advice to avoid the use of PCSK9 inhibitors during pregnancy., Competing Interests: Conflict of interest: C.W. is a consultant for Mirum Pharmaceuticals and GlaxoSmithKline. M.C.H. has received consulting fees from CRISPR Therapeutics, reports advisory board service for Miga Health, and receives research support from Genentech, all unrelated to this work. All authors have no conflicts of interest to report., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Patients with homozygous familial hypercholesterolemia (HoFH) remain at very high cardiovascular risk despite the best standard of care lipid-lowering treatment. The addition of evinacumab, an angiopoietin-like protein 3 monoclonal antibody, more than halves low-density lipoprotein cholesterol in short-term studies. This study evaluated whether the evinacumab response was durable in the long term and improved cardiovascular outcome., Methods: The OLE ELIPSE HoFH (Open-Label Extension to Evinacumab Lipid Studies in Patients With HoFH) study included newly diagnosed patients and those completing the ELIPSE HoFH trial, on stable lipid-lowering therapy including lipoprotein apheresis but not lomitapide. All patients received evinacumab (15 mg/kg intravenously) every 4 weeks, with no change in concomitant lipid-lowering treatment during the first 6 months. The primary efficacy end points were the mean absolute and percentage changes in low-density lipoprotein cholesterol from baseline to 6 months. A key secondary end point was cardiovascular event-free survival, which was compared with a control HoFH cohort not treated with evinacumab or lomitapide and matched for age, sex, and lipoprotein apheresis, derived from French Registry of Familial hypercholesterolemia., Results: Twelve patients, 5 women and 7 men (12-57 years), were enrolled in 3 centers in France. At 6 months, the mean low-density lipoprotein cholesterol reduction with evinacumab was 3.7 mmol/L or 56% (from 6.5 mmol/L at baseline to 2.8 mmol/L; P <0.0001) and was sustained over the median 3.5-year follow-up. No patients on evinacumab experienced cardiovascular events versus 13 events for 5/21 (24%) over 4 years in the control cohort (likelihood P =0.0267)., Conclusions: Real-life, long-term evinacumab adjunctive to lipid-lowering therapy including lipoprotein apheresis led to sustained low-density lipoprotein cholesterol lowering and improved cardiovascular event-free survival of patients with HoFH., Competing Interests: Disclosures S. Béliard reports grants/honoraria from Ultragenyx for clinical trials and consultancy and from Amarin, Amgen, Amryt Novartis, Sanofi for clinical trials, conferences and consultancy. R. Valero reports personal or institutional honoraria for speakers’ bureaux, consultancy, clinical trials and travel/accommodation for professional purposes from Adelia Médical, Akcea, Amarin, Amgen, AstraZeneca, Boehringer-Ingelheim, Dinno Santé, Ionis, Janssen, Lilly, Merck and Co., Nestlé, Novartis, Novo Nordisk, Orkyn, Pfizer, Sanofi-Regeneron, Servier. E. Bruckert reports grants/honoraria for clinical trials/consultancy from MSD, Astra Zeneca, Genfit, Amgen, Sanofi-Aventis, Aegerion/Amryt, Lilly, Mylan/Viatris, Novartis, Pfizer, Servier, Organon, Akcea Therapeutics, and Ultragenyx. M. Farnier reports consultancy honoraria from Abbott, Amarin, Amgen, AstraZeneca, Austell, Kowa, Merck and Co., Organon, Pfizer, Recordati, Sanofi/Regeneron, Servier, SMB, Ultragenyx, and Viatris. A. Gallo reports research grants and honoraria from Amgen, Sanofi and Regeneron, Mylan Viatris, Merck and Co., Akcea Therapeutics, Amryt, Novartis, Servier, Ultragenyx, Amarin, and Eli Lilly. The other authors report no conflicts.

Objectives: Although the clinical role of protein convertase subtilisin kexin type 9 (PCSK9) inhibitors for cholesterol management is increasing, the post-marketing period of use is short compared to other lipid-lowering drugs, so there is still insufficient evidence for their efficacy and safety. In this meta-analysis, we evaluated preventive effects of stroke and cardiovascular (CV) events using evolocumab and alirocumab., Materials and Methods: We assessed the relative risk of stroke and CV events after alirocumab or evolocumab treatment in individuals with or without clinical CV diseases compared with that in controls. In addition, we evaluated the relative risk of hemorrhagic stroke., Results: A total of 25 articles were included (median of study duration = 52 weeks). The risk of stroke was significantly decreased after treatment with alirocumab or evolocumab (primary prevention in patients without CV diseases: RR = 0.733; 95% CI, 0.618 - 0.870; secondary prevention in patients with CV diseases: RR = 0.703; 95% CI, 0.562 - 0.880). The risk of CV events also significantly decreased in patients treated with alirocumab or evolocumab (primary prevention: RR = 0.818; 95% CI, 0.777 - 0.861; secondary prevention: RR = 0.725; 95% CI, 0.578 - 0.910). The relative risk of hemorrhagic stroke was not significantly different between PCSK9 inhibitor-treated patients and controls (RR = 1.041; 95% CI, 0.690 - 1.573)., Conclusion: Our findings indicate that evolocumab and alirocumab are significantly effective without increasing the risk of hemorrhagic stroke. Based on this, the PCSK9 inhibitors can be highly recommended for cholesterol management.

Background: The effect of proprotein convertase subtilisin kexin type (PCSK9) inhibitors on blood lipids and major adverse cardiovascular events (MACEs) is still controversial for acute coronary syndrome (ACS) patients. This study aimed to evaluate the efficacy and safety of PCSK9 inhibitors for ACS patients., Methods: We searched the following databases until March 2023: PubMed, Embase, Cochrane, Web of Science, CNKI, Chongqing VIP Database and Wan Fang Database. Finally, all randomized controlled trials, retrospective studies and prospective studies were included in the analysis., Results: A total of 20 studies involving 48,621 patients were included in this meta-analysis. The results demonstrated that PCSK9 inhibitors group was more beneficial for ACS patients compared to control group (receiving statins alone or placebo). The meta-analysis showed: there was no significant difference in high density lipoprotein cholesterol between PCSK9 inhibitors group and control group (standard mean difference = 0.17, 95% confidence interval [CI]: -0.02 to 0.36, P = .08), while the level of low density lipoprotein cholesterol in PCSK9 inhibitors group was lower than that in control group (standard mean difference = -2.32, 95% CI: -2.81 to -1.83, P < .00001). Compared with the control group, the PCSK9 inhibitors group also decreased the levels of total cholesterol and triglycerides (mean difference = -1.24, 95% CI: -1.40 to -1.09, P < .00001, mean difference = -0.36, 95% CI: -0.56 to -0.16, P = .0004). Moreover, compared with the control group, PCSK9 inhibitors group could reduce the incidence of MACEs (relative risk [RR] = 0.87, 95% CI: 0.83-0.91; P < .00001). However, this study showed that the incidence of drug-induced adverse events in PCSK9 inhibitors group was higher than that in the control group (RR = 1.15, 95% CI: 1.05-1.25, P < .0001)., Conclusion: Although this study demonstrates that PCSK9 inhibitors have higher drug-induced adverse events, they can not only reduce low-density lipoprotein cholesterol levels but also reduce the incidence of MACEs simultaneously. However, these findings needed to be further verified through large sample, multicenter, double-blind randomized controlled trials., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Hypertension and hypercholesterolemia are important risk factors for cardiovascular disease, and treatment with fixed-dose combination (FDC) regimens is recommended by current guidelines. However, the clinical outcomes of different FDC dosages remain unknown. This study aimed to examine the clinical outcomes of FDC regimens and the free combination of amlodipine and atorvastatin at different dosages., Methods and Results: Patients with concurrent hypertension and hypercholesterolemia treated daily with an FDC of 5 mg amlodipine and 10 mg atorvastatin (5/10 fixed group), and FDC of 5 mg amlodipine and 20 mg atorvastatin (5/20 fixed group), or free combination of 5 mg amlodipine and 20 mg atorvastatin (5/20 free group) were identified from the National Health Insurance Research Database of Taiwan. The primary outcome was the composite cardiovascular outcomes, including cardiovascular death, acute myocardial infarction, stroke, and coronary intervention. A total of 9095 patients were eligible for inclusion. The incidence of primary outcome per 1000 person-years was 16.6 in the 5/10 fixed group, 12.6 in the 5/20 fixed group, and 16.5 in the 5/20 free group (5/20 fixed versus 5/20 free: hazard ratio [HR], 0.76 [95% CI, 0.64-0.91]; 5/20 fixed versus 5/10 fixed: HR, 0.76 [95% CI, 0.63-0.90])., Conclusions: Among patients with concomitant hypertension and hypercholesterolemia, treatment with an FDC of amlodipine and high-dose atorvastatin led to a lower risk of a composite of cardiovascular outcomes than treatment with the free combination or a similar FDC with a lower dose of atorvastatin.

Monacolin K is the major active component in red yeast rice (RYR) which is structurally identical to lovastatin and has the most powerful effect, in terms of reducing blood cholesterol levels. This review aimed to examine the effect and safety of different doses of monacolin K on blood cholesterol levels. PubMed and Cochrane were searched for articles published between 2012 and 2023 for clinical-trials and randomized-controlled-trials. Eligible studies included participants>18-years-old, of any gender and ethnicity. The intervention/exposure of interest was monacolin K. Hypercholesterolemia was considered the outcome of interest defined as the elevated total or low-density-lipoprotein (LDL) cholesterol levels. 12 randomized-controlled-trials were eligible for inclusion in the analysis including 769 participants>18-years-old. 11 out of 12 studies were assessed with high methodological quality and one study with low methodological quality. Monacolin K supplementation varied between 2mg and 10mg per day and the maximum period of supplementation was 12 weeks. All studies indicated a beneficial effect of monacolin supplementation on LDL and total cholesterol levels (p<0.05) regardless the dose and period of supplementation. Also, 3 of the included studies reported adverse side effects after treatment with monacolin K. Low doses of monacolin K equal to 3mg/day exert potential cholesterol-lowering effects although the number of relative studies is limited. Regarding the safety of monacolin K supplementation, findings seem to be more controversial and therefore, it is suggested for all patients treated with monacolin K to be routinely monitored regardless the dose of supplementation., (Copyright © 2023 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.)

Aim: Statin therapy is considered the gold standard for treating hypercholesterolemia. This updated meta-analysis aims to compare the efficacy and safety of a low/moderate-intensity statin in combination with ezetimibe compared with high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (ASCVD)., Methods: A systematic search of two databases (PubMed and Cochrane CENTRAL) was conducted from inception to January 2023 and a total of 21 randomized clinical trials (RCTs) were identified and included in the analysis. Data were pooled using Hedges's g and a Mantel-Haenszel random-effects model to derive standard mean differences (SMDs) and 95% confidence intervals (Cis). The primary outcome studied was the effect of these treatments on lipid parameters and safety events., Results: The results revealed that combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels (SMD= - 0.41; CI - 0.63 to - 0.19; P = 0.0002). There was no significant change in the levels of high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglyceride (TG), high-sensitivity C-reactive protein (hs-CRP), Apo A1, or Apo B. The safety of these treatments was assessed by the following markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine phosphokinase (CK), and a significant difference was only observed in CK (SMD: - 0.81; CI - 1.52 to - 0.10; P = 0.02)., Conclusion: This meta-analysis demonstrated that the use of low/moderate-intensity statin combination therapy significantly reduced LDL-C levels compared with high-intensity statin monotherapy, making it preferable for patients with related risks. However, further trials are encouraged to evaluate potential adverse effects associated with combined therapy., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab., Methods: Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9., Results: Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C., Conclusions: In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869., Competing Interests: Disclosures F.J. Raal has received research grants, honoraria, or consulting fees for professional input and lectures from Sanofi, Regeneron, Amgen, and Novartis; and travel support to attend the 2023 European Atherosclerosis Society (EAS) Congress from EAS. R.A. Hegele reports receiving consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, Boston Heart, HLS Therapeutics, Novartis, Pfizer, Regeneron, Sanofi, and Ultragenyx; and lecture fees from Amgen, HLS Therapeutics, and Novartis. A. Ruzza is a former employee and a stockholder of Amgen. He is a current employee and a stockholder of GlaxoSmithKline. He holds a pending patent application PCT/US2021/034489 on PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors and methods of use thereof to treat cholesterol-related disorders. J.A.G. López, A.K. Bhatia, H. Wang, and J. Wu are employees and stockholders of Amgen. D. Gaudet reports receiving research grants, honoraria, or consulting fees for professional input and lectures from Alnylam, Amgen, Applied Therapeutics, Arrowhead, Boehringer Ingelhein, Chiesi (Amryt), CRISPR Therapeutics, Eli Lilly, Esperion, Ionis, Kowa, New Amsterdam Pharma, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, Ultragenyx, Uniqure, and Verve Therapeutics. A. Wiegman reports research support for pharmaceutical trials of lipid-lowering agents from Amgen, Sanofi-Regeneron Pharmaceuticals, Novartis, Silence Therapeutics, Esperion, and Ultragenyx; and is member of a safety board for Amryt. R.D. Santos reports receiving consulting fees and lecture fees from Abbott, Amgen, Amryt, AstraZeneca, Aché, Biolab, Getz Pharma, Eli Lilly, Libbs, Merck, PTC Therapeutics, Novo Nordisk, Novartis, and Sanofi-Regeneron Pharmaceuticals; and grant support from Amgen, Kowa, Esperion, Novartis, and Sanofi-Regeneron Pharmaceuticals. The other author reports no conflicts.

Background: High-risk stroke patients are recommended to receive high-intensity statin therapy to reduce the risk of stroke recurrence. However, doubling the dosage of statin drugs did not increase the achievement rate of LDL-C target or provide additional clinical benefits, but significantly increased the risk of adverse reactions. Statins and ezetimibe work through different mechanisms and the combined use of statins and ezetimibe significantly improves outcomes with comparable safety profiles. We tested the hypothesis that moderate-intensity statin with ezetimibe may offer advantages over the conventional high-intensity statin regimen in terms of efficacy and safety., Methods: We conducted a randomized controlled trial. Eligible participants were aged 18 years or older with acute ischemic cerebrovascular disease. We randomly assigned (1:1) participants within the acute phase of ischemic stroke, i.e., within 1 week after the onset of mild ischemic stroke (NIHSS score ≤ 5), within 1 month for severe cases (NIHSS score ≥ 16), and within 2 weeks for the rest, as well as patients with TIA within 1 week of symptom onset, to receive either moderate-intensity statin with ezetimibe (either 10-20 mg atorvastatin calcium tablets plus a 10 mg ezetimibe tablet, or 5-10 mg rosuvastatin calcium tablets once per day plus a 10 mg ezetimibe tablet once per day) or high-intensity statin (40 mg atorvastatin calcium tablets or 20 mg rosuvastatin calcium tablets once per day) for 3 months. Randomization was performed using a random number table method. The primary efficacy outcome was the level and achievement rate of LDL-C after 3 months of treatment, specifically LDL-C ≤ 1.8 mmol/L or a reduction in LDL-C ≥ 50 %. The secondary outcome was the incidence of new stroke or transient ischemic attack (TIA) within 3 months. The safety outcome was liver and renal function tests, and the occurrence of statin-related muscle events within 3 months., Findings: This trial took place between March 15, 2022, and March 7, 2023. Among 382 patients screened, 150 patients were randomly assigned to receive either medium-intensity statins with ezetimibe (n = 75) or high-intensity statins (n = 75). Median age was 60.0 years (IQR 52.75-70.25); 49 (36.6 %) were women and 85 (63.4 %) were men. The target achievement of LDL-C at 3 months occurred in 62 (89.86 %) of 69 patients in the medium-intensity statin with ezetimibe group and 46 (70.77 %) of 65 patients in the high-intensity statin group (P=0.005, OR=0.273, 95 % CI: 0.106, 0.705). The reduction magnitude of LDL-C in moderate-intensity statin with ezetimibe group was significantly higher (-56.540 % vs -47.995 %, P=0.001). Moderate-intensity statin with ezetimibe group showing a trend of a greater reduction in LDL-C absolute value than high-intensity statin group but without statistical significance (-1.77±0.90 vs -1.50±0.89, P=0.077). New AIS or TIA within 3 months, liver and renal function tests, and the occurrence of statin-related muscle events within 3 months were also statistically insignificant. Multivariate logistic regression analysis showed that both gender and lipid-lowering regimen as independent risk factors influencing the rate of LDL-C achievement in individuals diagnosed with acute ischemic cerebrovascular disease, but only lipid-lowering regimen had predictive value., Interpretation: Compared to guideline-recommended high-intensity statin therapy, moderate-intensity statin with ezetimibe further improved the achievement rate of LDL-C in patients with acute ischemic cerebrovascular disease, with a higher reduction magnitude in LDL-C. In terms of safety, there was no significant difference between the two regimens, suggesting that moderate-intensity statin with ezetimibe can also be considered as an initial treatment option for patients with acute ischemic cerebrovascular disease., Competing Interests: Declaration of competing interest None, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Lipid-lowering therapy (LLT) is underutilized for very high-risk atherosclerotic cardiovascular disease. PROMPT-LIPID (PRagmatic Trial of Messaging to Providers about Treatment of HyperLIPIDemia) sought to determine whether electronic health record (EHR) alerts improve 90-day LLT intensification in patients with very high-risk atherosclerotic cardiovascular disease., Methods: PROMPT-LIPID was a pragmatic trial in which cardiovascular and internal medicine clinicians within Yale New Haven Health (New Haven, CT) were cluster-randomized to receive an EHR alert with individualized LLT recommendations or no alert for outpatients with very high-risk atherosclerotic cardiovascular disease and LDL-C (low-density lipoprotein cholesterol), ≥70 mg/dL. The primary outcome was 90-day LLT intensification (change to high-intensity statin and addition of ezetimibe or PCSK9i [proprotein subtilisin/kexin type 9 inhibitors]). Secondary outcomes included LDL-C level, proportion of patients with LDL-C of <70 or < 55 mg/dL, rate of major adverse cardiovascular events, ED visit incidence, and 6-month mortality. Results were analyzed using logistic and linear regression clustered at the provider level., Results: The no-alert group included 47 clinicians and 1370 patients (median age, 71 years; 50.1% female, median LDL-C, 93 mg/dL); the alert group included 49 clinicians and 1130 patients (median age, 72 years; 47% female, median LDL-C 91, mg/dL). The primary outcome was observed in 14.1% of patients in the alert group as compared with 10.4% in the no-alert group. There were no differences in any secondary outcomes at 6 months. Among 542 patients whose clinicians (n=46) did not dismiss the EHR alert recommendations, LLT intensification was significantly greater (21.2% versus 10.4%, odds ratio, 2.33 [95% CI, 1.48-3.66])., Conclusions: With a real-time, targeted, individualized EHR alert as compared with usual care, the proportion of patients with atherosclerotic cardiovascular disease with LLT intensification was numerically higher but not statistically significant. Among clinicians who did not dismiss the alert, there was a > 2-fold increase in LLT intensification. EHR alerts, coupled with strategies to reduce clinician dismissal, may help address persistent gaps in LDL-C management., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04394715, https://www.clinicaltrials.gov/ct2/show/study/NCT04394715., Competing Interests: Disclosures Dr Desai receives support from the Centers for Medicare and Medicaid Services to develop and maintain performance measures that are used for public reporting and payment programs; receives research support from and provides consulting for Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Novartis, SC Pharmaceuticals, and Vifor; and serves on the medical review committee for Anthem. R.J. Riello is a consultant for Alexion, Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Johnson & Johnson, PhaseBio, and Portola. The other authors report no conflicts.

Objective: Investigate the efficacy and safety of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on stroke prevention., Background: PCSK9i reduce low-density lipoprotein cholesterol (LDL-C) and lipoprotein a (LpA) levels. Their efficacy in reducing the risk of major cardiovascular events has been shown in multiple randomized clinical trials (RCT). However, clinical equipoise remains on the magnitude and mechanisms by which PCSK9i decrease the risk of stroke., Methods: We performed a systematic search of biomedical databases from inception to January 15, 2024, to identify RCTs that investigated the efficacy of PCSK9i versus placebo for major cardiovascular event prevention. The primary outcome was total stroke. The safety outcome was the risk of adverse neurological events, as defined by each trial. Effect size was represented by risk ratio (RR), and analysis was done using random-effects meta-analysis. Heterogeneity was assessed by I 2 and Cochrane Q statistics. Meta-regression analyses were performed to assess the association between LDL-C and LpA reduction and stroke risk., Results: Overall, 20 studies with 93,093 patients were included. The quality of the evidence was moderate and heterogeneity for all comparisons was low (I 2 < 25 %). The mean age was 60.1 years for the PCSK9i group and 59.6 years for the placebo group, with a mean follow-up time of 60.1 weeks. PCSK9i reduced the LDL-C levels by 11 % and LpA levels by 8 %. PCSK9i were associated with a significant reduction in stroke risk (RR 0.75, 95 % CI 0.66-0.86, I 2 = 0 %), without an increase in mortality (RR 0.97, 95 % CI 0.87-1.08, I 2 = 0 %). The risk of adverse neurological events was similar between groups (RR 0.99, 95 % CI 0.84-1.18, I 2 = 11 %). In meta-regression analyses, the stroke risk was not associated with the magnitude of the effect of PCSK9i on LDL-C (LDL C β = -0.01, 95 % CI = -0.03-0.02) and LpA (β = -0.01, 95 % CI = -0.06-0.04) levels., Conclusions: PCSK9i significantly reduced the stroke risk, without increasing mortality or the risk of adverse neurological events. Our findings also suggest that the beneficial effect of PCSK9i on stroke risk is mediated by LDL-C- and LpA-independent mechanisms., 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 © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: We aimed to explore the effect of PCSK9 inhibitor based on the background of statin on carotid intraplaque neovascularization (IPN) assessed by serial contrast-enhanced ultrasound (CEUS) analysis in Chinese patients with premature coronary artery disease (PCAD)., Methods: 41 patients were included to receive treatments with biweekly evolocumab (n = 22) or placebo (n = 19) in addition to statin therapy for 52 weeks. All patients were newly diagnosed with PCAD and treatments were initiated at baseline of the observations. Baseline and 52-week CEUS were acquired to measure the max plaque height (MPH) and IPN. The primary outcome was the 52-week IPN changes, the secondary endpoints included the 52-week MPH changes and major adverse cardiovascular events., Results: The mean ± SD age of the participants was 46.76 ± 8.56 years, and 61% (25/41) of patients were on statins before the start of the study. There was no statistically significant difference in the history of statins treatment and the initiated lipid-lowering therapy of atorvastatin and rosuvastatin between groups (p > 0.05). At 52 weeks, the evolocumab group showed a lower LDL level (0.84 ± 0.45 mmol/L vs. 1.58 ± 0.51 mmol/L, p < 0.001) and a greater decrease in percent reduction of LDL-C level (-65% vs. -32%) and a higher percent of achieving lipid-lowering target (95% vs. 53%, p < 0.05) compared with the placebo group. At 52 weeks, IPN (evolocumab group: 0.50 ± 0.60 vs. 1.50 ± 0.80, p < 0.001; placebo group: 0.79 ± 0.54 vs. 1.26 ± 0.65, p < 0.05) and MPH (evolocumab group: 2.01 ± 0.44 mm vs. 2.57 ± 0.90 mm, p < 0.05, placebo group: 2.21 ± 0.58 mm vs. 2.92 ± 0.86 mm, p < 0.05) reduced significantly in both groups from baseline to 52-week follow-up. IPN and MPH were decreased by both treatments. Still, there was no significant difference in delta (52 weeks - baseline) MPH by an ANOVA analysis between the two groups [evolocumab group: -0.56 mm (2.01 mm-2.57 mm); placebo group: -0.71 mm (2.21 mm-2.92 mm), p > 0.05]. In the evolocumab group, the change in the mean reduction of IPN from baseline [-1.00 (0.50-1.50) vs. -0.47 (0.79-1.26), p < 0.05] and the incidence of patients with carotid IPN decrease were significantly greater reduction (90% vs. 58%, p < 0.05)., Conclusions: If compared to placebo, the PCSK9 inhibitor evolocumab combined with statins resulted in a greater decrease in LDL-C and plaque neovascularization in Chinese patients with PCAD., Competing Interests: Declaration of competing interest 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder caused by pathogenic variants in the LDL-C metabolism. Lifelong exposure to elevated LDL-C levels leads to a high risk of premature cardiovascular disease. To reduce that risk, children with HeFH should be identified and treated with lipid-lowering therapy. The cornerstone consists of statins and ezetimibe, but not in all patients this lowers the LDL-C levels to treatment targets. For these patients, more intensive lipid-lowering therapy is needed., Areas Covered: In this review, we provide an overview of the monoclonal antibodies which are currently available or being tested for treating HeFH in childhood., Expert Opinion: Monoclonal antibodies that inhibit PCSK9 are first in line lipid-lowering treatment options if oral statin and ezetimibe therapy are insufficient, due to intolerance or very high baseline LDL-C levels. Both evolocumab and alirocumab have been shown to be safe and effective in children with HeFH. For children, evolocumab has been registered from the age of 10 years old and alirocumab from the age of 8 years old. The costs of these new agents are much higher than oral therapy, which makes it important to only use them in a selected patient population.

Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone of reducing risk for atherosclerotic cardiovascular disease. Despite the approval of nonstatin therapies for LDL-C lowering over the past 2 decades, these medications are underused, and most patients are still not at guideline-recommended LDL-C goals. Barriers include poor adherence, clinical inertia, concern for side effects, cost, and complex prior authorization processes. With atherosclerotic cardiovascular disease-related mortality increasing globally, there remains a need for additional therapeutic options for lowering LDL-C as part of an atherosclerotic cardiovascular disease prevention strategy. Following the identification of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a promising therapeutic target, inclisiran was developed using the natural process of RNA interference for robust, sustained prevention of hepatic PCSK9 synthesis. Twice-yearly maintenance subcutaneous inclisiran (following initial loading doses at Day 1 and Day 90) reduces circulating LDL-C levels by ≈50% versus placebo when added to maximally tolerated statins. Long-term safety and tolerability of inclisiran have been assessed, with studies underway to evaluate the effects of inclisiran on cardiovascular outcomes and to provide additional safety and effectiveness data. In 2021, <20 years after the discovery of PCSK9, inclisiran became the first RNA interference therapeutic approved in the United States for LDL-C lowering in patients with established atherosclerotic cardiovascular disease or familial hypercholesterolemia and has since been approved for use in patients with primary hyperlipidemia. This article reviews the journey of inclisiran from bench to bedside, including early development, the clinical trial program, key characteristics of inclisiran, and practical points for its use in the clinic.