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Pharmacological reduction of LDL-cholesterol (LDL-C) is a major treatment strategy in limiting atherosclerotic cardiovascular (ASCVD) risk. Statins remain the primary therapeutic cornerstone in ASCVD prevention. Furthermore, ezetimibe, bempedoic acid, and PCSK9 inhibition have recently also shown to reduce cardiovascular risk. Unfortunately, a treatment gap remains between guideline-recommended LDL-C goals and what is achieved in real-world practice. An important reason for this is the limited use of novel and effective non-statin lipid-lowering therapies. In order to achieve LDL-C treatment goals and, ultimately, reduction of cardiovascular events, a combination lipid-lowering therapy needs to be considered as the standard of care for patients at very high cardiovascular risk., Competing Interests: D. Sinning hat Vortrags- bzw. Beratungshonorare von Amgen, Sanofi-Aventis, Daiichi-Sankyo, Novartis und Berlin-Chemie Menarini erhalten. U. Landmesser hat Vortrags- bzw. Beratungshonorare von Amgen, Sanofi-Aventis, Daiichi-Sankyo, Novartis, Medicines Company, Bayer, NovoNordisc und Berlin-Chemie Menarini erhalten., (Thieme. All rights reserved.)

Background: An elevated low-density lipoproteincholesterol (LDL-C) level is one of the most important modifiable cardiovascular risk factors. Despite potent combination treatment, the LDL‑C target values are not achieved in many high-risk patients., Objective: Presentation of the rationale for lowering LDL‑C, the current status of lipid-lowering treatment and established and novel approaches to lower LDL‑C., Current Data: Based on the large outcome trials with ezetimibe and antibodies against proprotein convertase subtilisin-kexin type 9 (PCSK9), the professional societies recommend LDL‑C target values depending on the individual cardiovascular risk. For patients with manifest atherosclerosis, the LDL‑C target value is < 55 mg/dL (1.4 mmol/L). The LDL‑C target values are only achieved in the minority of patients. The reasons for this include a lack of awareness among treating physicians, low medication adherence, restrictions in prescriptions and intolerance. On the basis of a healthy lifestyle, statins are the cornerstone of LDL-C-lowering treatment. If LDL‑C targets are not achieved, the cholesterol absorption inhibitor ezetimibe is additionally recommended. As a third step, PCSK9 antibodies are added. A novel drug to lower LDL‑C is the orally available bempedoic acid, which acts on the same metabolic pathway as statins but is specifically activated in the liver and not in the skeletal muscle. Another novel drug is inclisiran, which acts as an intracellular PCSK9 inhibitor through RNA interference. Inclisiran is administered subcutaneously only every 6 months and has potential advantages regarding adherence. According to the new recommendations, active substances should be combined and fixed-dose combinations should be used early for lowering of LDL‑C., Conclusion: Using established and novel LDL-C-lowering drugs, the recommended LDL‑C target values can be achieved in the majority of patients with a high cardiovascular risk., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

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

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

Diagnosis and Treatment of Familial Hypercholesterolemia Abstract. Familial hypercholesterolemia secondary to heterozygous mutations in the LDL receptor, Apolipoprotein B or PCSK9 gene is characterized by 2- to 3-fold elevated LDL cholesterol levels, premature atherosclerosis and extravascular cholesterol deposits (tendon xanthomata, corneal arcus). The same phenotype may occur if a person carries several LDL cholesterol rising polymorphisms (polygenic FH). Primary prevention with statins has been shown to dramatically reduce the cardiovascular burden in patients with the disease. However, it is estimated that less than 10 % of affected subjects in Switzerland have received the diagnosis, and undertreatment is frequent. Thus, clinical cardiovascular events are still the first manifestation of the disease in many cases. A correct diagnosis in index patients and cascade screening of families are mandatory to identify and treat patients before they suffer the sequelae of untreated severe hypercholesterolemia. In patients with clinical cardiovascular disease combination lipid lowering treatment with potent statins, ezetimibe and the newly available PCSK9 inhibitors will successfully lower LDL cholesterol to normal or even target levels.

Homozygous hypercholesterolemia is an extremely rare genetic disorder caused by mutations in the LDL receptor gene or occasionally by mutations in other genes like proprotein convertase subtilisin / kexin 9 (PCSK9). Gold standard of homozygous hypercholesterolemia therapy is apheresis, accompanied by high-dose statin and ezetimibe therapy. The cholesterol-lowering effect can be supported by new agents like inhibitors of microsomal triglyceride transfer protein (lomitapide), or by enhancing LDL catabolism through inhibition of the PCSK9 activity. We present the case of a young woman with homozygous hyperlipidemia due to a mutation c.1200 C> A(p.Tyr400*) in the LDLR gene that introduces a stop-codon at amino acid position 400. This truncated LDLR cannot mediate a membrane-bound uptake of LDL cholesterol. A combined therapy including simvastatin, ezetimibe and apheresis did not lead to satisfactory LDL levels. By adding lomitapide, a dramatic receptor-independent reduction of LDL was achieved., (© Georg Thieme Verlag KG Stuttgart · New York.)