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Generalized and Metabolic Disease
Published in Wilmer W Nichols, Michael F O'Rourke, Elazer R Edelman, Charalambos Vlachopoulos, McDonald's Blood Flow in Arteries, 2022
The latest breakthrough in cardiovascular prevention is considered by many to be the development of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for the treatment of hypercholesterolemia. Their impressive reductions in lipids (about 60 percent) seems to be accompanied by a 15 percent reduction in cardiovascular events over a period of 2 to 3 years (Evolocumab, FOURIER: Sabatine et al., 2017; alirocumab, ODYSSEY outcomes: Schwartz et al., 2018). We, among others, have shown a strong, positive association of PCSK9 levels with vascular function indices identifying a new pathophysiological link for the associations of dyslipidemia and vascular dysfunction (Vlachopoulos et al., 2018; Ruscica et al., 2017). Whether these monoclonal antibodies will show an effect on arterial function and structure indices is awaited with anticipation.
Dyslipidemia
Published in Jahangir Moini, Matthew Adams, Anthony LoGalbo, Complications of Diabetes Mellitus, 2022
Jahangir Moini, Matthew Adams, Anthony LoGalbo
PCSK9 monoclonal antibodies are formulated for subcutaneous injection, once to twice per month. They stop proprotein convertase subtilisin/kexin type 9 from attaching to LDL receptors, improving their function. The LDL is lowered by 40%–70%. Trials with alirocumab and evolocumab revealed less cardiovascular events when previous atherosclerotic cardiovascular disease was present. The cholesterol absorption inhibitors, including ezetimibe, inhibit absorption of cholesterol and phytosterol in the intestines. The LDL is usually lowered by ezetimibe by 15%–20%, with small increases in HDL and a slight decrease in total triglycerides. Ezetimibe can be used alone if the patient cannot tolerate statins, or it can be added to statins if the patient is on maximum statin dosage, with LDL remaining chronically elevated. Adverse effects of cholesterol absorption inhibitors are rare.
Familial hypercholesterolemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
FH is heterogeneous genetically. It is caused by mutations in at least three different genes. The most common variant, accounting for approximately 93 percent of patients, is caused by mutations in the low-density lipoprotein receptor (LDLR); the resultant disease is currently known as familial hypercholesterolemia (FH). Mutations in apolipoprotein B-100 (APOB) account for approximately 5.5 percent of patients, and this disease is referred to as familial defective APOB (FDB). In approximately 2 percent of patients, the mutation is in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) [3]. Some 1741 mutations have been identified in the gene LDLR. Of these, 108 variants were found in Chinese patients [4].
A comprehensive clinical guide for Pneumocystis jirovecii pneumonia: a missing therapeutic target in HIV-uninfected patients
Published in Expert Review of Respiratory Medicine, 2022
Ahmad R. Alsayed, Abdullah Al-Dulaimi, Mohammad Alkhatib, Mohammed Al Maqbali, Mohammad A. A Al-Najjar, Mamoon M.D. Al-Rshaidat
Asthma, the most often diagnosed respiratory disease, has a complex pathophysiology involving hereditary and environmental variables. Due to decreased levels of protective antibodies, pediatric patients with severe asthma may be at an increased risk of chronic P. jirovecii infections and asthma exacerbation. Plasma P. jirovecii antigen, Kexin (KEX1) IgG titers may be beneficial in determining the clinical course of treatment in pediatric asthma patients. Previous research has established a link between P. jirovecii colonization and severe asthma [188,189]. Patients with severe asthma show a greater enrichment of P. jirovecii in BAL fluid [190] and higher sera titer against whole cell P. jirovecii antigens [188], implying that they are more exposed to P. jirovecii than healthy persons. However, a number of P. jirovecii antigens are highly immunogenic but do not confer protection against infection [191].
Icosapent ethyl: safely reducing cardiovascular risk in adults with elevated triglycerides
Published in Expert Opinion on Drug Safety, 2022
Manan Pareek, R. Preston Mason, Deepak L. Bhatt
The body of evidence supporting icosapent ethyl is rapidly growing, with several mechanistic studies underway. Elegant experiments assessing the differential effects of various omega-3 fatty acids on cell membrane preparations will provide further insights into molecular mechanisms of EPA that produce downstream beneficial effects, such as attenuating inflammation. It is already clear that the benefits of icosapent ethyl are mediated largely through EPA and are independent of baseline triglyceride levels. Thus, while the REDUCE-IT trial used elevated triglycerides to enrich the rate of ischemic events, the results likely apply to patients with lower triglyceride levels than what was studied, assuming such patients are otherwise at high cardiovascular risk. In conclusion, icosapent ethyl will have an increasingly important impact on cardiovascular risk reduction given the growing population of patients with hypertriglyceridemia and other associated risk factors. The evaluations of cost-effectiveness in both primary and secondary prevention have been quite favorable, particularly when compared with more expensive therapies such as the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab, and evolocumab [123,124]. Studies of the generalizability of REDUCE-IT have shown that tens of millions of people worldwide could derive benefit from this medication [125–127]. Implementation of this effective and safe therapy should be a priority in healthcare systems worldwide.
Investigational drugs in phase II clinical trials for acute coronary syndromes
Published in Expert Opinion on Investigational Drugs, 2020
Amit Rout, Ajaypaul Sukhi, Rahul Chaudhary, Kevin P Bliden, Udaya S Tantry, Paul A Gurbel
Low density lipoprotein (LDL) cholesterol binds to LDL receptors (LDLR) on the hepatocytes cell surface which is then sequestered inside by endocytosis leading to clearance of LDL cholesterol from circulation. LDLR is then recycled back to the cell surface. This recycling occurs multiple times before LDLRs are finally metabolized. Proprotein convertase subtilisin-kexin type 9 (PCSK9) is mainly secreted from hepatocytes, and also from intestine and kidneys. PCSK9 binds to LDLR, changes its configuration, and prevents its recycling, ultimately leading to degradation. Individuals with loss of function of PCSK9 gene have a reduced risk of cardiovascular diseases. Currently, two human monoclonal antibodies alirocumab and evolocumab are FDA approved PCSK9 inhibitors as a second-line agent for elevated cholesterol not controlled with diet and maximally tolerated statin therapy to prevent heart attacks, strokes and coronary revascularizations in adults with established cardiovascular disease [55,56].