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Effects of Drugs on Low-Density Lipoprotein (LDL) and Lipoprotein (a) Level

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 48855

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Prof. Dr. Ioanna Gouni-Berthold

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Center for Endocrinology, Diabetes and Preventive Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
Interests: medications modulating lipid metabolism; hyperlipoproteinemias; dyslipidemias; rare disorders of lipid metabolism; familial hypercholesterolemia; familial chylomicronemia

Special Issue Information

Dear Colleagues,

Atherosclerotic cardiovascular diseases (ASCVD) remain the number one cause of death in the industrialized world. The main culprit for their development is low-density lipoprotein cholesterol (LDL-C) which accumulates in the arterial wall and initiates the chronic inflammatory process of atherosclerosis with plaque development and progression. A plethora of evidence has established that LDL-C is causal for the development of ASCVD, such as data from monogenic disorders; Mendelian randomization; and genome-wide association studies (GWAS); and observational, epidemiological, clinical, and interventional trials. The degree and duration of exposure to LDL-C determine atherosclerotic risk, thus early and aggressive LDL-C lowering is associated with greater protection from ASCVD.

LPL-C is the most studied lipoprotein and represents the major treatment target in clinical practice. LDL-C lowering decreases cardiovascular events as studies with statins and non-statin therapies [ezetimibe,

proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies] have shown. New promising treatments include the ATP citrate lyase inhibitor bempedoic acid, the small interfering (siRNA) targeting PCSK9 inclisiran, and the monoclonal antibody against angiopoetin-like 3 (ANGPTL3) evinacumab.

Lipoprotein(a) [Lp(a)] is a special form of LDL with an apolipoprotein(a) [apo(a)] bound covalently to the apolipoprotein B of the LDL particle. Lp(a) can also become trapped in the artery wall and thus initiate the atherosclerotic process. Multiple evidence from observational epidemiologic studies, Mendelian randomization studies, as well as GWAS have established the causality of increased Lp(a) levels and ASCVD. Although, currently, there are no pharmacologic treatments to decrease Lp(a) there are promising substances in various phases of development such as the antisense oligonucleotide (ASO) targeting apo(a) pelacarsen, and two siRNAs targeting APOA, olpasiran and SLN360 which have been shown to decrease Lp(a) up to 98%. Cardiovascular outcome trials are needed to establish the clinical relevance of both the new LDL-C- and Lp(a)-lowering therapies.

This Special Issue has the aim to summarize the state-of-the-art, and the latest developments regarding LDL-C and Lp(a) lowering pharmacotherapies.

Prof. Dr. Ioanna Gouni-Berthold
Guest Editor

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Keywords

LDL-C
Lipoprotein(a)
statins
fibrates
ezetimibe
PCSK9 antibodies
inclisiran
evinacumab
bempedocic acid
lomitapide, pelacarsen

Published Papers (10 papers)

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Research

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14 pages, 794 KiB

Open AccessArticle

Prevalence of Diabetes and Its Association with Atherosclerotic Cardiovascular Disease Risk in Patients with Familial Hypercholesterolemia: An Analysis from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH)

by Chrysoula Boutari, Christos V. Rizos, Michalis Doumas, George Liamis, Ioannis Skoumas, Loukianos Rallidis, Anastasia Garoufi, Genovefa Kolovou, Konstantinos Tziomalos, Emmanouil Skalidis, Vasileios Kotsis, George Sfikas, Vaia Lambadiari, Panagiotis Anagnostis, Eleni Bilianou, Georgia Anastasiou, Iosif Koutagiar, Estela Kiouri, Achilleas Attilakos, Vana Kolovou, Evangelos Zacharis, Christina Antza and Evangelos Liberopoulos Show full author list Hide full author list

Pharmaceuticals 2023, 16(1), 44; https://doi.org/10.3390/ph16010044 - 28 Dec 2022

Cited by 3 | Viewed by 10646

Abstract

Familial hypercholesterolemia (FH) and type 2 diabetes mellitus (T2DM) are both associated with a high risk of atherosclerotic cardiovascular disease (ASCVD). Little is known about the prevalence of T2DM and its association with ASCVD risk in FH patients. This was a cross-sectional analysis from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH) including adults with FH (n = 1719, mean age 51.3 ± 14.6 years). Of FH patients, 7.2% had a diagnosis of T2DM. The prevalence of ASCVD, coronary artery disease (CAD), and stroke was higher among subjects with T2DM compared with those without (55.3% vs. 23.3%, 48.8% vs. 20.7%, 8.3% vs. 2.7%, respectively, p < 0.001). When adjusted for age, systolic blood pressure, smoking, body mass index, hypertension, waist circumference, triglyceride levels, high-density lipoprotein cholesterol levels, and gender, T2DM was significantly associated with prevalent ASCVD [OR 2.0 (95% CI 1.2–3.3), p = 0.004]. FH patients with T2DM were more likely to have undergone coronary revascularization than those without (14.2% vs. 4.5% for coronary artery bypass graft, and 23.9% vs. 11.5% for percutaneous coronary intervention, p < 0.001). T2DM is associated with an increased risk for prevalent ASCVD in subjects with FH. This may have implications for risk stratification and treatment intensity in these patients. Full article

(This article belongs to the Special Issue Effects of Drugs on Low-Density Lipoprotein (LDL) and Lipoprotein (a) Level)

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17 pages, 2659 KiB

Open AccessArticle

Post-Marketing Surveillance of Statins—A Descriptive Analysis of Psychiatric Adverse Reactions in EudraVigilance

by Gabriela Pop, Andreea Farcaș, Anca Butucă, Claudiu Morgovan, Anca Maria Arseniu, Manuela Pumnea, Minodora Teodoru and Felicia Gabriela Gligor

Pharmaceuticals 2022, 15(12), 1536; https://doi.org/10.3390/ph15121536 - 10 Dec 2022

Cited by 9 | Viewed by 4368

Abstract

Statins are included in the category of high-frequency prescription drugs, and their use is on an upward trend worldwide. In 2012, the FDA issued a warning about possible cognitive adverse drug reactions (ADRs) related to statins, some of which are listed in the Summary of Product Characteristics, but there are still concerns about their potential risk of psychiatric events. The aim of this research was to investigate spontaneous reports containing psychiatric ADRs associated with statins by analyzing the EudraVigilance (EV) database. From January 2004 to July 2021, a total of 8965 ADRs were reported for the Systems Organ Class (SOC) “psychiatric disorders”, of which 88.64% were registered for atorvastatin (3659), simvastatin (2326) and rosuvastatin (1962). Out of a total of 7947 individual case safety reports (ICSRs) of the 3 statins mentioned above, in 36.3% (2885) of them, statins were considered the only suspected drug, and in 42% (3338), no other co-administered drugs were mentioned. Moreover, insomnia has been reported in 19.3% (1536) of cases, being the most frequent adverse reaction. A disproportionality analysis of psychiatric ADRs was performed. The Reporting Odds Ratio (ROR) and 95% confidence interval (95% CI) were calculated for simvastatin, atorvastatin and rosuvastatin compared with antiplatelets and antihypertensive drugs. The reporting probability for most ADRs of these statins compared to antiplatelets was higher. The reporting probability for insomnia, nightmares and depression produced by statins compared to antihypertensive drugs was also higher. The results of this analysis augment the existing data about a possible correlation between the administration of statins and the occurrence of psychiatric side effects. Full article

(This article belongs to the Special Issue Effects of Drugs on Low-Density Lipoprotein (LDL) and Lipoprotein (a) Level)

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13 pages, 3015 KiB

Open AccessArticle

Long-Term Efficacy and Safety of Evinacumab in Patients with Homozygous Familial Hypercholesterolemia: Real-World Clinical Experience

by Claudia Stefanutti, Dick C. Chan, Serafina Di Giacomo, Claudia Morozzi and Gerald F. Watts

Pharmaceuticals 2022, 15(11), 1389; https://doi.org/10.3390/ph15111389 - 11 Nov 2022

Cited by 9 | Viewed by 2315

Abstract

Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic condition characterized by markedly elevated plasma low-density lipoprotein cholesterol (LDL-C) concentrations from birth and increased risk of premature atherosclerotic cardiovascular disease. Evinacumab is an inhibitor of angiopoietin-like 3 protein that offers a new approach for correcting high LDL-C in HoFH. Evinacumab was administered intravenously (15 mg/kg Q4W) for 24 months in 7 patients with genetically confirmed HoFH, receiving background lipoprotein apheresis (LA) and/or lipid-lowering treatment (LLT). Assessment of efficacy and safety were carried out before and after 24 months of evinacumab treatment. The LDL-C lowering effect of evinacumab without LA were also investigated in the 7 HoFH patients after a subsequent compassionate extension period. Twenty-four months of treatment with evinacumab against background LA and LLT resulted in a significant reduction in LDL-C (−46.8%; p < 0.001). LDL-C reduction with evinacumab was maintained during the compassionate extensions period in the absence of treatment with LA (−43.4%; mean follow-up of 208 ± 90 days). Evinacumab was well-tolerated, with no major adverse event reported or significant changes in liver and muscle enzyme concentrations. Our findings suggest that evinacumab is a safe and effective treatment for patients with HoFH receiving best standard of care in a routine setting. Full article

(This article belongs to the Special Issue Effects of Drugs on Low-Density Lipoprotein (LDL) and Lipoprotein (a) Level)

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Review

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19 pages, 1523 KiB

Open AccessReview

High-Density Lipoprotein in Metabolic Disorders and Beyond: An Exciting New World Full of Challenges and Opportunities

by Evangelia Zvintzou, Eva Xepapadaki, George Skroubis, Victoria Mparnia, Katerina Giannatou, Karim Benabdellah and Kyriakos E. Kypreos

Pharmaceuticals 2023, 16(6), 855; https://doi.org/10.3390/ph16060855 - 8 Jun 2023

Cited by 1 | Viewed by 1949

Abstract

High-density lipoprotein (HDL) is an enigmatic member of the plasma lipid and lipoprotein transport system, best known for its ability to promote the reverse cholesterol efflux and the unloading of excess cholesterol from peripheral tissues. More recently, data in experimental mice and humans suggest that HDL may play important novel roles in other physiological processes associated with various metabolic disorders. Important parameters in the HDL functions are its apolipoprotein and lipid content, further reinforcing the principle that HDL structure defines its functionality. Thus, based on current evidence, low levels of HDL-cholesterol (HDL-C) or dysfunctional HDL particles contribute to the development of metabolic diseases such as morbid obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. Interestingly, low levels of HDL-C and dysfunctional HDL particles are observed in patients with multiple myeloma and other types of cancer. Therefore, adjusting HDL-C levels within the optimal range and improving HDL particle functionality is expected to benefit such pathological conditions. The failure of previous clinical trials testing various HDL-C-raising pharmaceuticals does not preclude a significant role for HDL in the treatment of atherosclerosis and related metabolic disorders. Those trials were designed on the principle of “the more the better”, ignoring the U-shape relationship between HDL-C levels and morbidity and mortality. Thus, many of these pharmaceuticals should be retested in appropriately designed clinical trials. Novel gene-editing-based pharmaceuticals aiming at altering the apolipoprotein composition of HDL are expected to revolutionize the treatment strategies, improving the functionality of dysfunctional HDL. Full article

(This article belongs to the Special Issue Effects of Drugs on Low-Density Lipoprotein (LDL) and Lipoprotein (a) Level)

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16 pages, 1376 KiB

Open AccessReview

Effects of Lipid-Modifying and Other Drugs on Lipoprotein(a) Levels—Potent Clinical Implications

by Amalia Despoina Koutsogianni, George Liamis, Evangelos Liberopoulos, Petros Spyridonas Adamidis and Matilda Florentin

Pharmaceuticals 2023, 16(5), 750; https://doi.org/10.3390/ph16050750 - 16 May 2023

Cited by 6 | Viewed by 3058

Abstract

The past few years have shown an ongoing interest in lipoprotein(a) (Lp(a)), a lipid molecule that has been proven to have atherogenic, thrombogenic, and inflammatory properties. Several lines of evidence, indeed, have demonstrated an increased risk of cardiovascular disease as well as calcific aortic valve stenosis in patients with elevated Lp(a) levels. Statins, the mainstay of lipid-lowering therapy, slightly increase Lp(a) levels, while most other lipid-modifying agents do not significantly alter Lp(a) concentrations, except for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The latter have been shown to reduce Lp(a) levels; however, the clinical significance of this effect has not been clearly elucidated. Of note, the pharmaceutical lowering of Lp(a) may be achieved with novel treatments specifically designed for this purpose (i.e., antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs)). Large clinical trials with cardiovascular outcomes with these agents are ongoing, and their results are eagerly awaited. Furthermore, several non-lipid-modifying drugs of various classes may influence Lp(a) concentrations. We have searched MEDLINE, EMBASE, and CENTRAL databases up to 28 January 2023 and summarized the effects of established and emerging lipid-modifying drugs and other medications on Lp(a) levels. We also discuss the potent clinical implications of these alterations. Full article

(This article belongs to the Special Issue Effects of Drugs on Low-Density Lipoprotein (LDL) and Lipoprotein (a) Level)

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15 pages, 573 KiB

Open AccessReview

Inclisiran, Low-Density Lipoprotein Cholesterol and Lipoprotein (a)

by Niki Katsiki, Michal Vrablik, Maciej Banach and Ioanna Gouni-Berthold

Pharmaceuticals 2023, 16(4), 577; https://doi.org/10.3390/ph16040577 - 12 Apr 2023

Cited by 22 | Viewed by 4977

Abstract

Dyslipidemia treatment is of major importance in reducing the risk of atherosclerotic cardiovascular disease (ASCVD), which is still the most common cause of death worldwide. During the last decade, a novel lipid-lowering drug category has emerged, i.e., proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Apart from the two available anti-PCSK9 monoclonal antibodies (alirocumab and evolocumab), other nucleic acid-based therapies that inhibit or “silence” the expression of PCSK9 are being developed. Among them, inclisiran is the first-in-class small interfering RNA (siRNA) against PCSK9 that has been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of hypercholesterolemia. Importantly, inclisiran therapy may improve low-density lipoprotein cholesterol (LDL-C) target achievement by offering a prolonged and significant LDL-C-lowering effect with the administration of only two doses per year. The present narrative review discusses the ORION/VICTORION clinical trial program that has been designed to investigate the impact of inclisiran on atherogenic lipoproteins and major adverse cardiac events in different patient populations. The results of the completed clinical trials are presented, focusing on the effects of inclisiran on LDL-C and lipoprotein (a) (Lp(a)) levels as well as on other lipid parameters such as apolipoprotein B and non-high-density lipoprotein cholesterol (non-HDL-C). Ongoing clinical trials with inclisiran are also discussed. Full article

(This article belongs to the Special Issue Effects of Drugs on Low-Density Lipoprotein (LDL) and Lipoprotein (a) Level)

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17 pages, 703 KiB

Open AccessReview

Atherogenic Dyslipidemias: Unmet Needs and the Therapeutic Potential of Emerging and Novel Approaches and Drugs

by Alessandra Romandini, Damiano Baldassarre, Stefano Genovese, Stefano Capri, Giulio Pompilio, Marco Scatigna and José Pablo Werba

Pharmaceuticals 2023, 16(2), 176; https://doi.org/10.3390/ph16020176 - 24 Jan 2023

Viewed by 2541

Abstract

Innovative lipid-modifying agents are valuable resources to improve the control of atherogenic dyslipidemias and reduce the lipid-related residual cardiovascular risk of patients with intolerance or who are not fully responsive to a consolidated standard of care (statins plus ezetimibe). Moreover, some of the upcoming compounds potently affect lipid targets that are thus far considered “unmodifiable”. The present paper is a viewpoint aimed at presenting the incremental metabolic and cardiovascular benefits of the emerging lipid-modulating agents and real-life barriers, hindering their prescription by physicians and their assumption by patients, which need to be worked out for a more diffuse and appropriate drug utilization. Full article

(This article belongs to the Special Issue Effects of Drugs on Low-Density Lipoprotein (LDL) and Lipoprotein (a) Level)

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14 pages, 16970 KiB

Open AccessReview

Current Treatment Options in Homozygous Familial Hypercholesterolemia

by Meral Kayikcioglu and Lale Tokgozoglu

Pharmaceuticals 2023, 16(1), 64; https://doi.org/10.3390/ph16010064 - 31 Dec 2022

Cited by 3 | Viewed by 5057

Abstract

Homozygous familial hypercholesterolemia (HoFH) is the rare form of familial hypercholesterolemia causing extremely high low-density lipoprotein cholesterol (LDL-C) levels, leading to atherosclerotic cardiovascular disease (ASCVD) in the first decades of life, if left untreated. Early diagnosis and effective lipid lowering therapy (LLT) are crucial for the prevention of early ASCVD in patients with HoFH. On-treatment LDL-C levels are the best predictor of survival. However, due to the absent or defective LDL-receptor activity, most individuals with HoFH are resistant to conventional LLT, that leads to LDL-C clearance by upregulating LDL-receptors. We are at the dawn of a new era of effective pharmacotherapies for HoFH patients, with new agents providing an LDL-receptor independent cholesterol reduction. In this context, the present review provides a summary of the currently available therapies and emerging therapeutic agents for the management of patients with HoFH, in light of recent evidence and guideline recommendations. Full article

(This article belongs to the Special Issue Effects of Drugs on Low-Density Lipoprotein (LDL) and Lipoprotein (a) Level)

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18 pages, 1398 KiB

Open AccessReview

Targeted Treatment against Lipoprotein (a): The Coming Breakthrough in Lipid Lowering Therapy

by Bożena Sosnowska, Stanisław Surma and Maciej Banach

Pharmaceuticals 2022, 15(12), 1573; https://doi.org/10.3390/ph15121573 - 16 Dec 2022

Cited by 16 | Viewed by 8871

Abstract

Atherosclerotic cardiovascular diseases (ASCVD) are a very important cause of premature death. The most important risk factor for ASCVD is lipid disorders. The incidence of lipid disorders and ASCVD is constantly increasing, which means that new methods of prevention and treatment of these diseases are still being searched for. In the management of patients with lipid disorders, the primary goal of therapy is to lower the serum LDL-C concentration. Despite the available effective lipid-lowering therapies, the risk of ASCVD is still increased in some patients. A high level of serum lipoprotein (a) (Lp(a)) is a risk factor for ASCVD independent of serum LDL-C concentration. About 20% of Europeans have elevated serum Lp(a) levels, requiring treatment to reduce serum Lp(a) concentrations in addition to LDL-C. Currently available lipid lowering drugs do not sufficiently reduce serum Lp(a) levels. Hence, drugs based on RNA technology, such as pelacarsen, olpasiran, SLN360 and LY3819469, are undergoing clinical trials. These drugs are very effective in lowering the serum Lp(a) concentration and have a satisfactory safety profile, which means that in the near future they will fill an important gap in the armamentarium of lipid-lowering drugs. Full article

(This article belongs to the Special Issue Effects of Drugs on Low-Density Lipoprotein (LDL) and Lipoprotein (a) Level)

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13 pages, 298 KiB

Open AccessReview

New Therapeutic Approaches in Treatment of Dyslipidaemia—A Narrative Review

by Iveta Merćep, Dominik Strikić, Ana Marija Slišković and Željko Reiner

Pharmaceuticals 2022, 15(7), 839; https://doi.org/10.3390/ph15070839 - 7 Jul 2022

Cited by 19 | Viewed by 4008

Abstract

Dyslipidaemia is a well-known risk factor for the development of cardiovascular disease, a leading cause of morbidity and mortality in developed countries. As a consequence, the medical community has been dealing with this problem for decades, and traditional statin therapy remains the cornerstone therapeutic approach. However, clinical trials have observed remarkable results for a few agents effective in the treatment of elevated serum lipid levels. Ezetimibe showed good but limited results when used in combination with statins. Bempedoic acid has been thoroughly studied in multiple clinical trials, with a reduction in LDL cholesterol by approximately 15%. The first approved monoclonal antibodies for the treatment of dyslipidaemia, PCSK9 inhibitors, are currently used as second-line treatment for patients with unregulated lipid levels on statin or statin combination therapy. A new siRNA molecule, inclisiran, demonstrates great potential, particularly concerning compliance, as it is administered twice yearly and pelacarsen, an antisense oligonucleotide that targets lipoprotein(a) and lowers its levels. Volanesorsen is the first drug that was designed to target chylomicrons and lower triglyceride levels, and olezarsen, the next in-line chylomicron lowering agent, is currently being researched. The newest possibilities for the treatment of dyslipidaemia are ANGPTL3 inhibitors with evinacumab, already approved by the FDA, and EMA for the treatment of familial hypercholesterolemia. This article provides a short summary of new agents currently used or being developed for lipid lowering treatment. Full article

(This article belongs to the Special Issue Effects of Drugs on Low-Density Lipoprotein (LDL) and Lipoprotein (a) Level)

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