Small dense low-density lipoprotein-lowering agents

AbstractMetabolic disorders, including obesity, diabetes, and hyperlipidemia, as well as cardiovascular diseases (CVD), particularly atherosclerosis, are still leading causes of death worldwide. Plasma levels of low-density lipoprotein (LDL) are currently being considered as a critical risk factor for the diseases mentioned above, especially atherosclerosis. Because of the heterogeneous nature of LDL, many studies have already been conducted on its subclasses, especially small dense LDL (sdLDL). According to available evidence, sdLDL levels can be considered as an ideal alternative to LDL levels for monitoring CVD and early diagnosis of atherosclerosis. Recently, several researchers have focused on factors that are able to decrease sdLDL levels and improve health quality. Therefore, the purpose of this study is to describe the production process of sdLDL particles and review the effects of pharmaceutical and dietary agents as well as lifestyle on sdLDL plasma levels. In brief, their mechanisms of action are discussed. Apparently, cholesterol and LDL-lowering compounds are also effective in the reduction of sdLDL levels. In addition, improving lipid profile, especially the reduction of triglyceride levels, appropriate regimen, and lifestyle can decrease sdLDL levels. Therefore, all the aforementioned parameters should be taken into consideration simultaneously in sdLDL levels reducing strategies.

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Monoclonal Antibodies in the Management of Familial Hypercholesterolemia: Focus on PCSK9 and ANGPTL3 Inhibitors

Current Atherosclerosis Reports ◽

10.1007/s11883-021-00972-x ◽

2021 ◽

Vol 23 (12) ◽

Author(s):

Angela Pirillo ◽

Alberico L. Catapano ◽

Giuseppe D. Norata

Keyword(s):

Monoclonal Antibodies ◽

High Risk ◽

Familial Hypercholesterolemia ◽

Plasma Levels ◽

Low Density Lipoprotein ◽

Genetic Defect ◽

Density Lipoprotein ◽

Lipid Lowering ◽

Low Density ◽

Premature Cardiovascular Disease

Abstract Purpose of Review Familial hypercholesterolemia (FH) is a monogenic disorder characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C) since birth and a high risk of premature cardiovascular disease. The genetic defect is carried in only one allele in heterozygous FH (HeFH) or in both in the most severe homozygous FH (HoFH). Current guidelines recommend to reduce substantially LDL-C levels in these high-risk patients, with the need to use association therapy combining agents with different mechanisms of action. As most cases of FH are attributable to mutations in the gene encoding the low-density lipoprotein receptor (LDLR), statins, even in combination with ezetimibe, are less effective in reducing LDL-C plasma levels in FH patients, who require a more intensive approach with additional lipid-lowering agents. Additional targets playing key roles in regulating LDL-C levels are represented by PCSK9 and ANGPTL3. Recent Findings Two monoclonal antibodies (mAbs) targeting PCSK9, evolocumab and alirocumab, significantly reduce LDL-C levels in HeFH patients. In patients with HoFH, the efficacy of mAbs to PCSK9 is strictly related to the presence of a residual LDLR activity; thus, patients carrying null mutations do not respond to the therapy with these mAbs, whereas some effects can be appreciated in HoFH bearing defective mutations. Conversely, evinacumab, the mAb targeting ANGPTL3, is highly effective in reducing LDL-C levels even in HoFH patients carrying null LDLR mutations, thanks to its LDLR-independent mechanism of action. Summary Monoclonal antibodies inhibiting PCSK9 have shown a robust effect in FH patients presenting a residual LDLR activity, while ANGPTL3 inhibitors appear to be promising even in patients carrying null LDLR mutations.

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Anagliptin Monotherapy for Six Months in Patients With Type 2 Diabetes Mellitus and Hyper-Low-Density Lipoprotein Cholesterolemia Reduces Plasma Levels of Fasting Low-Density Lipoprotein Cholesterol and Lathosterol: A Single-Arm Intervention Trial

Journal of Clinical Medicine Research ◽

10.14740/jocmr4623 ◽

2021 ◽

Vol 13 (10-11) ◽

pp. 502-509

Author(s):

Yuichi Ikegami ◽

Yasuhiro Takenaka ◽

Daigo Saito ◽

Akira Shimada ◽

Ikuo Inoue

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Plasma Levels ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density ◽

Intervention Trial ◽

Low Density Lipoprotein Cholesterol

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Changes in Bradykinin and Prostaglandins Plasma Levels during Dextran-sulfate Low-density-lipoprotein Apheresis

The International Journal of Artificial Organs ◽

10.1177/039139889702000310 ◽

1997 ◽

Vol 20 (3) ◽

pp. 178-183 ◽

Cited By ~ 30

Author(s):

S. Kojima ◽

M. Ogi ◽

Y. Yoshitomi ◽

M. Kuramochi ◽

J. Ikeda ◽

...

Keyword(s):

Plasma Levels ◽

Dextran Sulfate ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Guanosine Monophosphate ◽

Prostaglandin E ◽

Plasma Kallikrein ◽

Low Density ◽

Ldl Apheresis

The negative charges of dextran-sulfate (DS) used for low-density-lipoprotein (LDL) apheresis initiate the intrinsic coagulation pathway in which plasma kallikrein acts on the high-molecular-weight kininogen to produce large amounts of bradykinin. This study was undertaken to assess whether bradykinin generated during DS LDL apheresis has any physiologic effects in vivo. The plasma levels of bradykinin, prostaglandins and cyclic guanosine monophosphate (cGMP) were compared, when either of two anticoagulants, heparin or nafamostat mesilate (NM), was used during DS LDL apheresis. Although anticoagulative action by NM depends on the inhibition of thrombin activity, this substance also inhibits the activity of plasma kallikrein. During apheresis using heparin, the plasma levels of prostaglandin E2 (PGE2) increased significantly (5.6 ± 1.2 (mean ± SE, n=4) pg/ml before apheresis and 33.4 ± 13.2 after apheresis, p < 0.05) in association with an increase in bradykinin levels (17.9 ± 2.6 pg/ml before apheresis and 470 ± 135 after apheresis, p < 0.01). Interestingly, these changes were suppressed during apheresis using NM. There were no appreciable changes in cGMP during DS LDL apheresis with either of the anticoagulants. This finding suggests that bradykinin generated during apheresis has some pathophysiological effects via activation of the prostaglandin system. Our results support the view that in patients taking angiotensin-convertingenzyme inhibitors, the anaphylactoid reaction occurring during apheresis may be caused by an excessive rise in the bradykinin levels.

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