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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: Lipoprotein(a) (Lp(a)) is an inherited risk factor for atherosclerotic cardiovascular disease (ASCVD). Limited data exist on Lp(a) values in children. We aimed to evaluate whether Lp(a) concentrations in youth are influenced by BMI., Methods: 756 blood samples of 248 children with obesity and 264 matched healthy children aged 5 and 18 years, enrolled in the population-based LIFE Child (German civilization diseases cohort) study, were analyzed. Repeat measurements were available in 154 children (1-4 follow ups, ~1 year apart)., Results: The median Lp(a) concentration in the total cohort (n = 512) at first visit was 9.7 mg/dL (IQR 4.0-28.3). Lp(a) concentrations between 30-50 mg/dL were observed in 11.5%, while 12.5% exhibited Lp(a) ≧50 mg/dL. There was no association of Lp(a) with body mass index (BMI) (ß = 0.004, P = 0.49). Lp(a) levels did not correlate with age or sex, while Lp(a) was associated positively with low-density lipoprotein cholesterol (ß = 0.05, P < 0.0001). The Lp(a) risk category remained stable in 94% of all children in repeated measurements., Conclusions: The data showed no association of Lp(a) levels in children with BMI, age or sex. Measurement of Lp(a) in youth may be useful to identify children at increased lifetime risk for ASCVD., Impact: In youth, Lp(a) levels are not affected by age, sex and BMI. Lp(a) risk categories remain stable over time in repeated measurements in children. Measurement of Lp(a) in children may be useful as an additional factor to identify children at increased lifetime risk for ASCVD and for reverse family screening., (© 2024. The Author(s).)

Background: Statin intolerance is associated with increased cardiovascular risk. Symptoms and patients' characteristics are incompletely known. We aimed to analyse the health-related quality of life (QOL) associated with statin intolerance., Methods: The Statin Intolerance Registry (SIR) is an observational, prospective, multicentre study that included 1111 patients, with intolerance to at least two different statins, between 2021 and 2023 in Germany. SIR baseline data were compared to individuals with and without statin therapy of the population-based LIFE-Adult Study (n = 9983)., Findings: The mean age in SIR was 66.1 years (standard deviation (SD) 9.9). The cohort was characterized by a higher proportion of women compared to patients on statins in LIFE-Adult (57.7% vs. 38.2%). SIR patients had impaired QOL (mean EQ VAS score of 64.9 (SD 18.1)) as measured by EuroQol (EQ-5D-5L)), which further deteriorated with age. Muscle symptoms were frequent (95.8%) and were associated with severe pain in 43.2% and intake of pain medication in 32.3% of statin intolerant patients. 10.3% had a diagnosis of depression. Women reported more pronounced symptoms than men. A data-driven k-means analysis, based on variables predicting severity of pain while on statin therapy, identified five clusters of SIR patients. The clusters differed in sex, prevalence of depression, QOL, comorbidities, and expectations to tolerate statin therapy., Interpretation: Statin intolerance is associated with impaired QOL. Women are more frequently and severely affected. The identified clusters may help to identify patients at risk and to develop individualized strategies to improve patient trajectories and outcomes., Funding: Leipzig University, research grants from Daiichi Sankyo, Novartis, and Amgen to Leipzig University., Competing Interests: PES has received honoraria from Daiichi Sankyo, Amgen, Novartis, Synlab and from Novartis for an advisory board. IGB has received honoraria from Amgen, Regeneron, Sanofi, Aegereon, Akcea Therapeutics, Novartis, Daiichi-Sankyo, Synlab, Ultragenyx, and Amarin. MS received funding from Pfizer Inc., and Owkin for projects not related to this research. US has received honoraria from Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Sanofi, Synlab, Novartis, NovoNordisk. OW reports honoraria for lectures from AMGEN, Berlin-Chemie, Daiichi-Sankyo, Novo Nordisk, Novartis, Sanofi-Aventis, Fresenius, Hexal, Akcea Therapeutics, and honoraria for advisory board activities from AMGEN, Sanofi-Aventis, Berlin-Chemie, Novartis, Hexal, Akcea Therapeutics, Daiichi-Sankyo, Pfizer, and Sobi. UK has received honoraria from Daiichi Sankyo, Amgen, MSD, Synlab. UL has received honoraria from Amgen, AstraZeneca, Bayer, Boehringer, Daiichi-Sankyo, Lilly, MSD, Novartis, NovoNordisk, Pfizer, Sanofi, Synlab. CM, OF, SE, JNB have nothing to declare., (© 2024 The Author(s).)

The inability to tolerate sufficient doses of statins, statin intolerance (SI), contributes to the non-achievement of guideline-recommended low-density lipoprotein cholesterol (LDL-C) treatment targets. Patients with SI require alternative lipid-lowering therapies (LLT). We conducted a simulation study on LDL-C target achievement with oral LLT (ezetimibe, bempedoic acid) in patients with SI, using representative data of 2.06 million German outpatients. SI was defined using literature-informed definitions based on electronic medical records (EMR). Among n = 130,778 patients with hypercholesterolaemia, available LDL-C measurement, and high or very-high cardiovascular risk, 8.6% met the definition of SI. Among patients with SI, 7.7% achieved the LDL-C target at baseline. After simulation of the stepwise addition of treatment with ezetimibe and bempedoic acid, 22.6 and 52.0% achieved the LDL-C target, respectively. The median achieved LDL-C was 80 and 62 mg/dL, the corresponding reductions from baseline were 20.0 and 38.0%, respectively. A higher proportion of patients classified as high risk achieved the target compared to those at very-high risk (58.1 vs. 49.9%). In conclusion, in patients with increased cardiovascular risk meeting the definition of SI based on EMR, combination LLT with ezetimibe and bempedoic acid has the potential to substantially increase the proportion of patients achieving clinically relevant LDL-C reductions., (© 2024. The Author(s).)

Introduction: Current 2019 ESC/EAS guidelines for the management of dyslipidemia recommend LDL cholesterol (LDL-C) goals according to the patients' cardiovascular (CV) risk. SANTORINI is the first large European observational study since the 2019 guidelines to assess whether lipid management in patients at high and very high CV risk has improved., Methods: SANTORINI is a multinational, prospective, non-interventional, observational study in 9602 patients ≥ 18 years at high and very high CV risk requiring lipid-lowering therapy. Individual CV risk was assessed by the investigator. The primary study objective is to document, in a real-world setting, the effectiveness of current lipid management regarding LDL-C levels., Results: For this analysis, complete recruitment data was available for 2086 patients in Germany and 6958 patients Europe. Investigators used the 2019 ESC/EAS guidelines as a basis for CV risk classification in > 50 % of the patients and classified 15.6 % (173/1112) of patients in Germany as high and 84.4 % (939/1112) as very high-risk (Europe: 20.7 % [743/3594] high, 79.3 % [2851/3594] very high CV risk). An independent re-calculation of the CV risk based on these guidelines classified 4.1 % (46/1112) of patients in Germany as high and 94.5 % (1051/1112) as very high-risk. Also in Europe, CV risk was underestimated in around 10 % of patients.At baseline, 59.5 % (1241/2086) patients in Germany and 52.6 % (3661/6958) patients in Europe received lipid-lowering monotherapy; 19.9 % (416/2086) and 25.2 % (1753/6958) of patients in Germany and Europe received combination therapy. 78.6 % (1640/2086) of patients in Germany missed the 2019 ESC/EAS guideline recommended LDL-C treatment goals (Europe: 71.1 % [4989/6958])., Discussion: The 2019 ESC/EAS guideline recommendations are only implemented in a minority of patients. The study identifies opportunities for improvements in the prevention of CV diseases in Germany., Competing Interests: K. T. ist Mitarbeiterin von Daiichi Sankyo. U. L. hat persönliche Honorare von Amgen, Daiichi Sankyo, Novartis und Sanofi erhalten., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background and Aims: Lipoprotein(a) (Lp(a)) is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Our goal was to characterize patients undergoing Lp(a) testing and to assess the impact of Lp(a) testing on treatment changes and subsequent ASCVD events., Methods: A cross-sectional and a longitudinal claims data analysis were performed on 4 million patient records in Germany. Patients were followed up for a maximum of 4 years., Results: In 2015 and 2018, 0.25% and 0.34% of patients were tested, respectively. Testing was more frequent in younger women in the overall population, and in men in the ASCVD population. Patients tested for Lp(a) had more comorbidities and higher ASCVD risk compared to matched control patients. ASCVD hospitalizations were more frequent prior to the first Lp(a) test (5.55 vs 1.42 per 100/person-years). The mortality rate of the Lp(a)-tested cohort and the control group was similar. Mortality was lower in patients with prior ASCVD and Lp(a) testing compared to matched controls with prior ASCVD and no Lp(a) test (2.30 vs 3.64 per 100/person-years, p <0.001). Patients with Lp(a) test received more laboratory examinations and cardiovascular medications and had more visits with specialized physicians., Conclusions: Lp(a) testing is rarely performed even in patients with very high cardiovascular risk. Patients tested for Lp(a) have more comorbidities and a higher ASCVD risk. Lp(a) testing is associated with more intensive preventive treatment and with positive effects on clinical outcomes and survival. The data support the value of Lp(a) measurements to characterize ASCVD risk and to improve ASCVD prevention., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.S. and S.K. are employees of Novartis Pharma GmbH, Nuernberg, Germany. U.L. has received personal fees from Amgen, DaiichiSankyo, Novartis, Sanofi. P.S. has nothing to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Lipodystrophy syndromes (LDs) are characterized by loss of adipose tissue, metabolic complications such as dyslipidemia, insulin resistance, and fatty liver disease, as well as accelerated atherosclerosis. As a result of adipose tissue deficiency, the systemic concentration of the adipokine leptin is reduced. A current promising therapeutic option for patients with LD is treatment with recombinant leptin (metreleptin), resulting in reduced risk of mortality. Here, we investigate the effects of leptin on endothelial to mesenchymal transition (EndMT), which impair the functional properties of endothelial cells and promotes atherogenesis in LD. Leptin treatment reduced inflammation and TGF-β2-induced expression of mesenchymal genes and prevented impairment of endothelial barrier function. Treatment of lipodystrophic- and atherosclerosis-prone animals (Ldlr -/- ; aP2-nSrebp1c-Tg) with leptin reduced macrophage accumulation in atherosclerotic lesions, vascular plaque protrusion, and the number of endothelial cells with mesenchymal gene expression, confirming a reduction in EndMT in LD after leptin treatment. Treatment with leptin inhibited LD-mediated induction of the proatherosclerotic cytokine growth/differentiation factor 15 ( GDF15 ). Inhibition of GDF15 reduced EndMT induction triggered by plasma from patients with LD. Our study reveals that in addition to the effects on adipose tissue function, leptin treatment exerts beneficial effects protecting endothelial function and identity in LD by reducing GDF15 .

Statins are among the best studied drugs. Due to the extensive evidence regarding efficacy and safety, they are the cornerstone of lipid-lowering therapy. While the tolerability of statins in large blinded studies is at the placebo level, so-called statin intolerance (SI) is a frequent and complex problem in everyday clinical practice. Statin-associated muscular pain (SAMS) is most commonly reported. In many cases SI is associated with inadequate lowering of low-density lipoprotein (LDL) cholesterol (LDL-C), thereby increasing the cardiovascular risk. The diagnosis of SAMS is based on the exclusion of possible alternative causes of muscular symptoms and the exclusion of nocebo effects through a diagnostic strategy of discontinuation of statin treatment, observation and assessment of symptoms, followed by renewed administration of a different statin initially at a low dose with subsequent dose increase. A large proportion of patients with SI and SAMS can take statins permanently and without discomfort by this approach. If LDL‑C lowering is insufficient, combination therapies are used. It is an important task of the prescribing physicians and all those involved in the treatment to increase the adherence to statins through appropriate communication. Numerous questions on SI remain open and are being addressed by an ongoing register., (© 2022. The Author(s).)