A Systematic Review on the Safety and Efficacy of PCSK9 Inhibitors in Lowering Cardiovascular Risks in Patients With Chronic Kidney Disease

Abstract

Cardiovascular events caused by dyslipidemia are one of the leading causes of death in patients with Chronic Kidney Disease (CKD). Statins are the first line of treatment for patients with hyperlipidemia and in the treatment regimen for patients with CKD. Therefore, the introduction of Proprotein Convertase Subtilisin-Kexin type 9 inhibitors (PCSK9 inhibitors) is a viable and possibly effective treatment option for patients who, despite high doses of statins, struggle to lower their low-density lipoprotein cholesterol (LDL-C) levels. Our paper's objective is to explore the safety of these biological agents, particularly in patients with varying stages of impaired kidney function, and the correlating effectiveness in lowering their LDL-C levels, thereby reducing cardiovascular risks in these patients.We methodically retrieved relevant articles from PubMed, PubMed Central, Medline, and Google scholar in April 2022. We used the Medical Subject Heading (MeSH) Strategy and used the relevant keyword, then applied our inclusion and exclusion criteria; the initial search gave 10,542 results; with the removal of duplicates, irrelevant articles, and application of quality assessments done, we finally included 15 papers for our review with 37,188 patients. PCSK9 inhibitors are reliable, safe, and efficient therapy in lowering LDL-C levels in patients with CKD. However, its safety and efficacy in severe and end-stage kidney disease are grey, as other factors such as infections lead to morbidity and mortality. Future trials on chronic kidney disease and PCSK9 inhibitors should investigate the inhibitors' ability to improve kidney functions at all stages of kidney disease while lowering lipid levels and finally analyze the safety in patients with end-stage kidney disease.

Targeting Allosteric Site of PCSK9 Enzyme for the Identification of Small Molecule Inhibitors: An In Silico Drug Repurposing Study

“…Therapeutic Target PCSK9 inhibitors for lowering LDL cholesterol [11] Drugs in Focus Evolocumab, Alirocumab, and other monoclonal antibodies [12] Drug Development Refining inhibitors, exploring new delivery mechanisms Genetic Variations Studying PCSK9 mutations and their impact on cholesterol [13] Gene Editing Exploring gene-editing technologies for therapeutic use [14] Safety and Efficacy Investigating long-term safety and efficacy of PCSK9 inhibitors [15] Combinatorial Approaches Studying the use of PCSK9 inhibitors in combination with other medications [16] Patient Populations Exploring efficacy and safety in specific patient groups [17][18][19][20][21][22] Ongoing Clinical Trials Continuous assessment of PCSK9 inhibitors in various stages [23][24][25][26] Furthermore, X-ray crystallographic structure and molecular dynamics studies have provided valuable insights into the interaction between PCSK-9 and the epidermal growth factor-like repeat-A (EGF-A) domain of the LDL receptor (LDL-R) [27,28]. It has been observed that PCSK-9 via its catalytic domain binds strongly to EGF-A, impairing the recycling of LDL-R to the cell surface.…”

Unraveling the Crosstalk between Lipids and NADPH Oxidases in Diabetic Kidney Disease

“…Plasma PCSK9 levels have been shown to be elevated in patients with glomerular filtration barrier disorders such as nephrotic syndrome [ 43 , 44 ]. Moreover, a systematic review concluded that PCSK9 inhibitors are safe, reliable, and effective medications for decreasing LDL cholesterol levels in patients with chronic kidney diseases [ 45 ]. Since diabetes is a leading cause of chronic kidney disease, the effect of PCSK9 inhibitor alirocumab was investigated in patients with T1DM and T2DM.…”

“…Drugs targeting PCSK9 directly (such as the FDA-approved monoclonal antibody evolocumab) or affecting its expression (such as Ginkgolide B) have been shown to be effective in the case of kidney diseases. However, the mechanism by which PCSK9 inhibition might exert its protective effect in kidney disease is not well elucidated [ 45 , 103 ]. A possible mechanism by which PCSK9 inhibition might exert its protective effect is by decreasing oxidative stress [ 104 ].…”

The Contribution of Lipotoxicity to Diabetic Kidney Disease

“…The PCSK9 gene is expressed at very low levels in the kidney, with modest modulation in the loop of Henle and collecting duct with diabetes [ 101 ]. A recent review concludes that PCSK9 inhibitors are safe and effective for cholesterol reduction with modest CKD (including DKD), though similar data are unavailable for patients with eGFR < 30 mL/min/1.73 m 2 [ 157 ]. There are also insufficient data regarding the role of PCSK9 inhibitors in renal lipotoxicity or DKD progression.…”