PCSK9 Inhibitors Research Articles

Sex differences in pathogenesis and treatment of dyslipidemia in patients with type 2 diabetes and steatotic liver disease.

Previously published studies have shown that women with type 2 diabetes have a higher risk of atherosclerotic cardiovascular disease than men with type 2 diabetes. The exact reason for this is not yet known. The association between metabolic dysfunction-associated steatotic liver disease and type 2 diabetes appears to be bidirectional, meaning that the onset of one may increase the risk of the onset and progression of the other. Dyslipidemia is common in both diseases. Our aim was therefore to investigate whether there is a sex difference in the pathogenesis and management of dyslipidemia in patients with type 2 diabetes and steatotic liver disease with metabolic dysfunction. While the majority of published studies to date have found no difference between men and women in statin treatment, some studies have shown reduced effectiveness in women compared to men. Statin treatment is under-prescribed for both type 2 diabetics and patients with dysfunction-associated steatotic liver disease. No sex differences were found for ezetimibe treatment. However, to the best of our knowledge, no such study was found for fibrate treatment. Conflicting results on the efficacy of newer cholesterol-lowering PCSK9 inhibitors have been reported in women and men. Results from two real-world studies suggest that up-titration of statin dose improves the efficacy of PCSK9 inhibitors in women. Bempedoic acid treatment has been shown to be effective and safe in patients with type 2 diabetes and more effective in lipid lowering in women compared to men, based on phase 3 results published to date. Further research is needed to clarify whether the sex difference in dyslipidemia management shown in some studies plays a role in the risk of ASCVD in patients with type 2 diabetes and steatotic liver disease with metabolic dysfunction.

Gene Mutation in Patients with Familial Hypercholesterolemia and Response to Alirocumab Treatment-A Single-Centre Analysis.

Background: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by significantly elevated levels of low-density lipoprotein (LDL) cholesterol, which plays a major role in the progression of atherosclerosis and leads to a heightened risk of premature atherosclerotic cardiovascular disease. Methods: We have carried out an observational study on a group of 17 patients treated at the Outpatient Lipid Clinic from 2019 to 2024. Result: The most frequent mutation observed was found in the LDL receptor (LDLR) gene, which was identified in ten patients (58.8%). Five patients were identified to have a mutation in the apolipoprotein B (APOB) gene, whereas two patients had two points mutations, one in the LDLR, and the other in the APOB gene. The average age of patients with LDLR mutation was 54.8 (12.3); for APOB mutation it was 61.4 (9.3) and for patients with two points mutation it was 61.5 (14.8). The study results showed that at Week 12, individuals with LDLR-defective heterozygotes who were given alirocumab 150 mg every two weeks experienced a 63.0% reduction in LDL cholesterol levels. On the other hand, individuals with APOB heterozygotes experienced a 59% reduction in LDL cholesterol levels. However, in patients with double heterozygous for mutations in LDLR and APOB genes, there was a hyporesponsiveness to alirocumab, and the reduction in LDL-C was only by 23% in two individuals. Conclusions: In patients with a single mutation, there was a greater response to treatment with alirocumab in contrast to patients with double heterozygous mutation, who did not respond to treatment with PCSK9 inhibitors.

A Comparative Analysis of Low-Density Lipoprotein Cholesterol (LDL-C)-Lowering Activities of Bempedoic Acid, Inclisiran, and PCSK9 Inhibitors: A Systematic Review.

Newer drugs, such as bempedoic acid, inclisiran, alirocumab, and evolocumab have recently been introduced for dyslipidemia. This systematic review aims to perform a comparative analysis of these drugs' low-density lipoprotein cholesterol (LDL-C)-lowering activities. The PubMed database was utilized to search for randomized controlled trials. Articles were screened and selected based on specific inclusion and exclusion criteria. The primary outcome of this review is to compare the percentage reduction of LDL-C and apolipoprotein-B, along with the number of reported serious adverse events (SAEs) in trials specific to each drug. A total of 14 studies were included, four for bempedoic acid and alirocumab and three for evolocumab and inclisiran. The maximum percentage reduction in LDL-C and apolipoprotein-B from baseline to 12 weeks was observed with alirocumab, administered at 150 mg subcutaneously twice weekly for 12 weeks, achieving reductions of 72.4% and 57.9%, respectively. Lesser reductions were observed with bempedoic acid, administered at 180 mg once daily orally for 12 weeks. The highest number of SAEs were reported with bempedoic acid (216, 10%) and inclisiran (181, 11%; 175, 11%). This systematic review showed that alirocumab achieved the greatest reductions in LDL-C and apolipoprotein-B and a better safety profile. Newer LDL-C-lowering drugs show promise in improving lipid profiles, patient compliance, and safety. However, these findings are not conclusive, as other factors also influence treatment choice.

Unraveling the rapid progression of non-target lesions: risk factors and the therapeutic potential of PCSK9 inhibitors in post-PCI patients

BackgroundRapid progression of non-target lesions (NTLs) leads to a high incidence of NTL related cardiac events post-PCI, which accounting half of the recurrent cardiac events. It is important to identify the risk factors and establish an accurate clinical prediction model for the rapid progression of NTLs post-PCI. PCSK9 inhibitors lower LDL-c levels significantly, also show the anti-inflammation effect, and may have the potential to reduce the rapid progression of NTLs post-PCI. We tried to test this hypothesis and explore the potential mechanisms.MethodsThis retrospective study included 1250 patients who underwent the first PCI and underwent repeat coronary angiography for recurrence of chest pain within 24 months. General characteristics, laboratory tests and inflammatory factors(IL-10, IL-6, IL-8, IL-1β, sIL-2R, and TNF-α) were collected. Machine learning (LASSO regression) was mainly employed to select the important characteristic risk factors for the rapid progression of NTLs post-PCI and build prediction models. Finally, mediator analysis was employed to explore the potential mechanisms by which PCSK9 inhibitors reduce the rapid progression of NTLs post-PCI.ResultsThere were more diabetes, less beta-blockers and PCSK9 inhibitors application, higher HbA1c, LDL-c, ApoB, TG, TC, uric acid, hs-CRP, TNF-α, IL-6, IL-8, and sIL-2R in NTL progressed group. LDL-c, hs-CRP, IL-8, and sIL-2R were characteristic risk factors for the rapid progression of NTLs post-PCI, combining LDL-c, hs-CRP, IL-8, and sIL-2R builds the optimal model for predicting the rapid progression of NTLs post-PCI (AUC = 0.632). LDL-c had a clear and incomplete mediating effect (95% CI, mediating effect: 51.56%) in the reduction of the progression of NTLs by PCSK9 inhibitors, and there was a possible mediating effect of IL-8 (90% CI), and sIL-2R (90% CI).ConclusionsLDL-c, hs-CRP, IL-8, and sIL-2R may be the key characteristic risk factors for the rapid progression of NTLs post-PCI, and combining these parameters might predict the rapid progression of NTLs post-PCI. The application of PCSK9 inhibitors had a negative correlation with the rapid progression of NTLs. In addition to the significant LDL-c-lowering, PCSK9 inhibitors may reduce the rapid progression of NTLs by reducing local inflammation of plaque.Trial registrationChiCTR2200058529; Date of registration: 2022–04-10.

Functional and morphological improvement of significant non-culprit coronary artery stenosis by LDL-C reduction with a PCSK9 antibody: Rationale and design of the randomized FITTER trial

Non-culprit coronary artery lesions are commonly present in patients presenting with an acute coronary syndrome (ACS). Additional stenting of non-culprit lesions in addition to the culprit lesion intends to prevent secondary events caused by these lesions. At the same time, multiple trials have demonstrated the potential of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in reducing plaque size and changing plaque composition of non-culprit lesions. Whether intensive low-density lipoprotein cholesterol (LDL-C) reduction with PCSK9 inhibitor evolocumab improves non-culprit vessel hemodynamics, reduces the risk of plaque rupture of important non-culprit lesions, and might obviate the need for additional stenting has not been investigated. The “Functional Improvement of non‐infarcT related coronary artery stenosis by Extensive LDL‐C Reduction with a PCSK9 Antibody” (FITTER) trial is a multi-center, randomized, double-blind, placebo-controlled clinical trial for patients presenting with ACS and multivessel disease (MVD). After treatment of the culprit lesion, fractional flow reserve (FFR) is performed in non-culprit vessels amenable for percutaneous coronary intervention (PCI). Coronary intervention in patients with hemodynamically important non-critical lesions (FFR: 0.67–0.85) is staged after baseline imaging using near-infrared spectroscopy (NIRS) and intravascular ultrasound (IVUS). Eligible patients are randomized and treated for 12 weeks with either evolocumab or placebo, in addition to high-intensity statin therapy. Follow-up angiography with repeat FFR and IVUS-NIRS is scheduled at 12 weeks. Staged PCI is performed at the operator's discretion.The FITTER trial is the first study to evaluate the effect of maximal LDL-C reduction by the PCSK9 inhibitor evolocumab on invasively measured FFR, plaque size, and plaque composition in hemodynamically important non-culprit lesions, during a treatment period of just 12 weeks after an ACS. Currently, all patients have been included (August 2023) and data analysis is ongoing. Trial registration numberclinicaltrials.gov NCT04141579.

The therapeutic effect of PCSK9 inhibitors on dyslipidemia: one-year follow up.

Despite the availability of statins and lifestyle modifications, many patients with Dyslipidemia struggle to achieve optimal low-density lipoprotein cholesterol (LDL-C) control. PCSK9 inhibitors offer a promising new therapeutic option with superior LDL-C lowering efficacy compared to statins. However, data on their real-world use, particularly in Iran, is limited. This study aims to address this gap by investigating the one-year effects of evolocumab on lipid profiles and potential cardiovascular outcomes in Iranian patients with Familial Hypercholesterolemia (FH).This single-center, prospective study evaluated evolocumab effectiveness in lowering LDL-C in 50 Iranian adults with FH. Participants with a documented LDL-C > 190 mg/dL on existing cholesterol medications (excluding PCSK9 inhibitors) and a clinical FH diagnosis was included. After baseline assessments (medical history, demographics, lipid profile), evolocumab was administered subcutaneously every two weeks for one year. Follow-up assessments at year one measured changes in LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. The study enrolled 50 participants with an average age of 55 years old (range 35-80 years).Treatment with evolocumab led to significant improvements in lipid profiles at all follow-up points compared to baseline. On average, LDL-C levels decreased by 105.24 mg/dL, triglycerides decreased by 59.20 mg/dL, and HDL-C levels increased by a modest but significant 4.5 mg/dL after one year(p<0.001). Subgroup analysis revealed no statistically significant interactions between baseline demographics (age, sex, BMI) or lifestyle habits (smoking, alcohol) and changes in lipid levels(p>0.05). However, a significant interaction emerged between baseline lipid levels and their corresponding reductions, suggesting greater improvement in patients with higher baseline values(p<0.05). It is noteworthy that no new cardiovascular events were reported during the study period. This study demonstrates the effectiveness of evolocumab in improving lipid profiles in Iranian patients with FH. The observed reductions in LDL-C and triglycerides, along with a modest increase in HDL-C, suggest potential benefits for cardiovascular risk reduction. The absence of new cardiovascular events during the study is encouraging, but further research with larger and longer-term follow-up is needed to confirm these findings and assess the long-term safety and impact on quality of life.

Novel insights into the association between genetically proxied inhibition of proprotein convertase subtilisin/kexin type 9 and risk of sarcopenia.

The effects of lipid-lowering drugs [including statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors] on hyperlipidaemia have been established. Some may have treatment effects beyond their reported properties, offering potential opportunities for drug repurposing. Epidemiological studies have reported conflicting findings on the relationship between lipid-lowering medication use and sarcopenia risk. We performed a two-sample Mendelian randomization (MR) study to investigate the causal association between the use of genetically proxied lipid-lowering drugs (including statins, ezetimibe, and PCSK9 inhibitors, which use low-density lipoprotein as a biomarker), and sarcopenia risk. The inverse-variance weighting method was used with pleiotropy-robust methods (MR-Egger regression and weighted median) and colocalization as sensitivity analyses. According to the positive control analysis, genetically proxied inhibition in lipid-lowering drug targets was associated with a lower risk of coronary heart disease [PCSK9 (OR, 0.67; 95% CI, 0.61 to 0.72; P=7.7E-21); 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR; OR, 0.68; 95% CI, 0.57 to 0.82; P=4.6E-05), and Niemann-Pick C1-like 1 (NPC1L1; OR, 0.53; 95% CI, 0.40 to 0.69; P=3.3E-06)], consistent with drug mechanistic actions and previous trial evidence. Genetically proxied inhibition of PCSK9 (beta, -0.040; 95% CI, -0.068 to -0.012; P=0.005) and circulating PCSK9 levels (beta, -0.019; 95% CI, -0.033 to -0.005; P=0.006) were associated with reduced appendicular lean mass (ALM) with concordant estimates in terms of direction and magnitude. Validation analyses using a second instrument for PCSK9 yielded consistent results in terms of direction and magnitude [(PCSK9 to ALM; beta, -0.052; 95% CI, -0.074 to -0.032; P=7.1E-7); (PCSK9 protein to ALM; beta, -0.060; 95% CI, -0.106 to -0.014; P=0.010)]. Genetically proxied inhibition of PCSK9 gene expression in the liver may be associated with reduced ALM (beta, -0.013; 95% CI, -0.035 to 0.009; P=0.25), consistent with the results of PCSK9 drug-target and PCSK9 protein MR analyses, but the magnitude was less precise. No robust association was found between HMGCR inhibition (beta, 0.048; 95% CI, -0.015 to 0.110; P=0.14) or NPC1L1 (beta, 0.035; 95% CI, -0.074 to 0.144; P=0.53) inhibition and ALM, and validation and sensitivity MR analyses showed consistent estimates. This MR study suggested that PCSK9 is involved in sarcopenia pathogenesis and that its inhibition is associated with reduced ALM. These findings potentially pave the way for future studies that may allow personalized selection of lipid-lowering drugs for those at risk of sarcopenia.

PCSK9 inhibitors on the management of primary and secondary cardiovascular prevention

BackgroundProprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have represented an important change in the management of hypercholesterolemia, although, until now, they have barely been used. Without PCSK9i, many patients with atherosclerotic cardiovascular disease (CVD) or those at very high risk do not reach their therapeutic LDLc objectives.ObjectiveThe analysis aimed to examine the clinical and biochemical characteristics of subjects receiving PCSK9i treatment in the Dyslipidemia Registry of the Spanish Atherosclerosis Society.MethodsAll consecutive subjects aged ≥ 18 years from different Lipid Units included in the Dyslipidemia Registry of the SEA were analyzed. Inclusion criteria consisted of unrelated patients aged ≥ 18 at the time of inclusion with hypercholesterolemia (LDL-C ≥ 130 mg/dL or non-HDL-C ≥ 160 mg/dL after the exclusion of secondary causes) who were studied for at least two years after inclusion. Participants’ baseline and final visit clinical and biochemical characteristics were analyzed based on whether they were on primary or secondary prevention and whether they were taking PCSK9i at the end of follow-up.ResultsEight hundred twenty-nine patients were analyzed, 7014 patients in primary prevention and 1281 in secondary prevention at baseline. 4127 subjects completed the required follow-up for the final analysis. The median follow-up duration was 7 years (IQR 3.0–10.0). Five hundred patients (12.1%) were taking PCSK9i at the end of the follow-up. The percentage of PCSK9i use reached 35.6% (n = 201) and 8.7% (n = 318) in subjects with and without CVD, respectively. Subjects on PCSK9i and oral lipid-lowering agents with and without CVD achieved LDLc reductions of 80.3% and 75.1%, respectively, concerning concentrations without lipid-lowering drugs. Factors associated with PCSK9i use included increasing age, LDLc without lipid-lowering drugs and the Dutch Lipid Clinic Network (DLCN) score. However, hypertension, diabetes, smoking, and LDLc after oral lipid-lowering drugs were not independent factors associated with PCSK9i prescription. In subjects with CVD, the use of PCSK9i was higher in men than in women (an odds ratio of 1.613, P = 0.048).ConclusionsApproximately one-third of CVD patients received PCSK9i at the end of follow-up. The use of PCSK9i was more focused on baseline LDLc concentrations rather than on CVD risk. Women received less PCSK9i in secondary prevention compared to men.

Use and effectiveness of PCSK-9 inhibitors in heart diseases: A review.

Proprotein Convertase Subtilisin/Kexin type-9 (PCSK-9) inhibitors have recently used in the management of different cardiac complications. Several clinical trials demonstrated their effectiveness in patients with hypercholesterolemia. However, the effectiveness of these medications in patients with heart diseases is still controversial. To review and summarize the clinical trials pertaining to the use and effectiveness of PCSK-9 inhibitors in heart diseases and to discuss the pharmacotherapy of these agents. A review was conducted of all clinical trials with PCSK-9 inhibitors for heart diseases registered at ClinicalTrials.gov since inception up to and including January 19th, 2024. These trials were retrieved. Data from these trials were extracted manually, categorized and analyzed. The number of identified clinical trials was 25,371. After screening and excluding irrelevant studies, 12 studies met the search criteria. The majority of these studies were conducted in the US. The total number of patients in these studies was 27,700. Alirocumab and Evolocumab were the most frequently used PCSK-9 inhibitors. This review identified only a few clinical trials on PCSK-9 inhibitors in heart disease patients. Therefore, it is recommended to conduct more randomized controlled clinical trials on PCSK-9 inhibitors in this patient population.

PCSK9 Inhibitors and Anthracyclines: The Future of Cardioprotection in Cardio-Oncology.

The field of cardio-oncology is an expanding frontier within cardiovascular medicine, and the need for evidence-based guidelines is apparent. One of the emerging focuses within cardio-oncology is the concomitant use of medications for cardioprotection in the setting of chemotherapy regimens that have known cardiovascular toxicity. While clinical trials focusing on cardioprotection during chemotherapy are sparse, an inaugural trial exploring the prophylactic potential of Sodium-Glucose Cotransporter-2 inhibitors (SGLT2is) for anthracycline (ANT)-induced cardiotoxicity has recently commenced. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, though less studied in this oncology demographic, have exhibited promise in preclinical studies for conferring cardiac protection during non-ischemic toxic insults. While primarily used to reduce low-density lipoprotein, PCSK9 inhibitors exhibit pleiotropic effects, including the attenuation of inflammation, reactive oxygen species, and endothelial dysfunction. In ANT-induced cardiotoxicity, these same processes are accelerated, resulting in premature termination of treatment, chronic cardiovascular sequelae, heart failure, and/or death. This review serves a dual purpose: firstly, to provide a concise overview of the mechanisms implicated in ANT-induced cardiotoxicity, and, finally, to summarize the existing preclinical data supporting the theoretical possibility of the cardioprotective effects of PCSK9 inhibition in ANT-induced cardiotoxicity.

Apolipoprotein A-I Infusions and Cardiovascular Outcomes in Acute Myocardial Infarction According to Baseline LDL-Cholesterol Levels: The AEGIS-II Trial.

In the AEGIS-II trial (NCT03473223), CSL112, a human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity, did not significantly reduce the risk of the primary endpoint through 90 days versus placebo after acute myocardial infarction (MI). Nevertheless, given the well-established relationship between higher low-density lipoprotein cholesterol (LDL-C) and plaque burden, as well as greater risk reductions seen with PCSK9 inhibitors in patients with baseline LDL-C ≥100 mg/dL on statin therapy, the efficacy of CSL112 may be influenced by baseline LDL-C. Overall, 18,219 patients with acute MI, multivessel coronary artery disease, and additional risk factors were randomized to either four weekly infusions of 6 g CSL112 or placebo. This exploratory post-hoc analysis evaluated cardiovascular outcomes by baseline LDL-C in patients prescribed guideline-directed statin therapy at the time of randomization (n=15,731). As baseline LDL-C increased, risk of the primary endpoint at 90 days lowered in those treated with CSL112 compared with placebo. In patients with LDL-C ≥100 mg/dL at randomization, there was a significant risk reduction of cardiovascular death, MI, or stroke in the CSL112 vs. placebo group at 90, 180, and 365 days (hazard ratio 0.69 [0.53-0.90], 0.71 [0.57-0.88], and 0.78 [0.65-0.93]). In contrast, there was no difference between treatment groups among those with LDL-C <100 mg/dL at baseline. In this population, treatment with CSL112 compared to placebo was associated with a significantly lower risk of recurrent cardiovascular events among patients with a baseline LDL-C ≥100 mg/dL. Further studies need to confirm that CSL112 efficacy is influenced by baseline LDL-C.

Sex specific analysis of patients with and without reported statin intolerance referred to a specialized outpatient lipid clinic

BackgroundLowering LDL-cholesterol is a fundamental goal for both primary and secondary prevention of atherosclerotic cardiovascular diseases. Our study aims to analyse potential sex disparities regarding the tolerability and effectiveness of lipid-lowering therapy in patients with and without reported statin intolerance who are being treated at a lipid-outpatient clinic.MethodsFrom 2017 to 2022, n = 1062 patients (n = 612 men, n = 450 women) at high-risk were referred to our lipid-outpatient clinic because of difficulties in lipid control by primary healthcare providers. The main therapeutic objective was to optimize lipid-lowering therapy according to current treatment guidelines.ResultsPatients presented with high LDL-C baseline levels (4.97 ± 1.81 mmol/l (192 ± 70 mg/dL) in men and 5.46 ± 2.04 mmol/l (211 ± 79 mg/dL) in women). Intolerance towards statins was reported more frequently by women (48.2%) than by men (38.9%, p = 0.004). LDL-C continuously decreased with individual treatment adjustments across follow-up visits. In total, treatment goals (LDL < 1.4 mmol/l (< 55 mg/dl) or < 1.8 mmol/l (< 70 mg/dl)) were accomplished in 75.8% of men and 55.5% of women after the last follow-up visit (p < 0.0001). In men, these data are almost identical in subjects with statin intolerance. In contrast, treatment goals were reached less frequently in women with statin intolerance compared to women tolerant to statin therapy.ConclusionEven if treated in a specialized lipid clinic, women are less likely to reach their target LDL-C than men, particularly when statin intolerant. Nevertheless, many patients with statin intolerance can be successfully treated using oral combination and PCSK9 inhibitor therapy. However, ongoing follow-up care to monitor progress and to adjust treatment plans is necessary to reach this goal.

Very short-term effects of a single dose of a proprotein convertase subtilisin/kexin 9 inhibitor before percutaneous coronary intervention: A single-arm study

Background and aimsThe short-term (within 6 weeks) effects of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors on lipid plaques have not been adequately evaluated. We aimed to investigate whether a single dose of a PCSK9 inhibitor before percutaneous coronary intervention (PCI) could reduce the abundance of lipid-core plaques identified via near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) at target lesions within a very short period. MethodsThis prospective, single-arm, single-center interventional study enrolled 27 consecutive patients with coronary artery disease. These patients underwent NIRS-IVUS during coronary angiography and repeat NIRS-IVUS during PCI performed between 2 and 6 weeks after the single-dose administration of 420 mg evolocumab. Changes in lesion lipid-core burden index (LCBI) and maximal LCBI over any 4-mm segment (max-LCBI4mm) were assessed using NIRS at the target lesions, along with lipid profile. ResultsThe max-LCBI4mm significantly decreased from 387 before PCSK9 inhibitor administration to 315 after its administration (interquartile range [IQR]: 268–572 and 221–488, respectively; p = 0.02) within a very short period. The lesion LCBI also decreased from 161 to 117 (IQR: 105–263 and 65–226, respectively; p = 0.02). No significant changes were observed in the minimum lumen area and diameter. After PCSK9 inhibitor administration, low-density lipoprotein (LDL) cholesterol (p < 0.001), lipoprotein(a) (p = 0.001), and malondialdehyde-modified LDL (p < 0.001) levels decreased compared with those before its administration. ConclusionsA single dose of the PCSK9 inhibitor administered before PCI reduced the abundance of lipid-core plaques identified via NIRS-IVUS at target lesions within a very short period of 2–6 weeks.

Efficacy of Traditional Anti-lipidemic Drugs in Lowering Lipoprotein(a) Levels: A Systematic Review.

Lipoprotein(a), or Lp(a), was identified in the early 1960.Its role as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) became widely recognized by the late 20th century, regardless of other traditional risk markers such as low-density lipoproteins and high-density lipoproteins. This study aimed to systematically review available literature and compare the efficacy of different lipid-lowering drugs, both approved for clinical use and currently undergoing trials, in lowering Lp(a) levels. A comprehensive search of medical databases including PubMed, PubMed Central (PMC), Medline, ScienceDirect, Cochrane Library, and Google Scholar was conducted to identify relevant studies. A total of 29 research papers met the inclusion criteria, focusing on the impact of various lipid-lowering drugs on Lp(a) concentration in patients with significantly elevated baseline Lp(a) levels. Plasma Lp(a) levels exceeding 30 mg/dL are associated with a higher risk of ASCVD, including myocardial infarction, stroke, aortic valve stenosis, heart failure, peripheral arterial disease, and increased all-cause mortality. Most commonly used lipid-lowering agents, such as statins, fibrates, ezetimibe, and nutraceuticals like coenzyme Q10 (CoQ10), showed no significant effect on Lp(a) plasma levels. However, Lp(a) apheresis and proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors were found to effectively reduce plasma Lp(a) concentrations. Emerging therapies targeting apolipoprotein(a) RNA, including anti-sense oligonucleotides (ASO) and small interfering RNA (siRNA), significantly reduced Lp(a) levels in Phase 2 trials. While several lipid-lowering agents have minimal impact on Lp(a) levels, therapies like Lp(a) apheresis, PCSK-9 inhibitors, and novel RNA-targeting drugs show promise in effectively reducing Lp(a) concentrations. However, whether these reductions translate into decreased cardiovascular events remains to be determined.

Atherosclerosis and Cardiovascular Complications in People Living with HIV: A Focused Review.

The intersection of Human Immunodeficiency Virus (HIV) infection and cardiovascular disease (CVD) represents a significant area of concern; advancements in antiretroviral therapy (ART) have notably extended the life expectancy of people living with HIV (PLWH), concurrently elevating the prevalence of chronic conditions such as CVD. This paper explores the multifaceted relationship between HIV infection, ART, and cardiovascular health, focusing on the mechanisms by which HIV and ART contribute to increased cardiovascular risk, including the promotion of endothelial dysfunction, inflammation, immune activation, and metabolic disturbances. We highlight the critical roles of HIV-associated proteins-Tat, Nef, and gp120-in accelerating atherosclerosis through direct and indirect pathways that exacerbate endothelial damage and inflammation. Additionally, we address the persistent challenge of chronic inflammation and immune activation in PLWH, factors that are strongly predictive of non-AIDS-related diseases, including CVD, even in the context of effective viral suppression. The impact of ART on cardiovascular risk is examined, with particular attention to the metabolic implications of specific ART regimens, which can influence lipid profiles and body composition, thereby modifying CVD risk. The therapeutic potential of statins, aspirin, and emerging treatments such as PCSK9 inhibitors in mitigating cardiovascular morbidity and mortality among PLWH is discussed, alongside considerations for their use in conjunction with ART. Our review underscores the necessity for a comprehensive, multidisciplinary approach to cardiovascular care in PLWH, which integrates vigilant cardiovascular risk assessment and management with HIV treatment. As we navigate the evolving landscape of HIV care, the goal remains to optimize treatment outcomes while minimizing cardiovascular risk, ensuring that the gains in longevity afforded by ART translate into improved overall health and quality of life for PLWH.

Ferritin-based disruptor nanoparticles: A novel strategy to enhance LDL cholesterol clearance via multivalent inhibition of PCSK9-LDL receptor interaction.

Hypercholesterolemia, characterized by elevated low-density lipoprotein (LDL) cholesterol levels, is a significant risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol metabolism by regulating LDL receptor degradation, making it a therapeutic target for mitigating hypercholesterolemia-associated risks. In this context, we aimed to engineer human H ferritin as a scaffold to present 24 copies of a PCSK9-targeting domain. The rationale behind this protein nanoparticle design was to disrupt the PCSK9-LDL receptor interaction, thereby attenuating the PCSK9-mediated impairment of LDL cholesterol clearance. The N-terminal sequence of human H ferritin was engineered to incorporate a 13-amino acid linear peptide (Pep2-8), which was previously identified as the smallest PCSK9 inhibitor. Exploiting the quaternary structure of ferritin, engineered nanoparticles were designed to display 24 copies of the targeting peptide on their surface, enabling a multivalent binding effect. Extensive biochemical characterization confirmed precise control over nanoparticle size and morphology, alongside robust PCSK9-binding affinity (KD in the high picomolar range). Subsequent efficacy assessments employing the HepG2 liver cell line demonstrated the ability of engineered ferritin's ability to disrupt PCSK9-LDL receptor interaction, thereby promoting LDL receptor recycling on cell surfaces and consequently enhancing LDL uptake. Our findings highlight the potential of ferritin-based platforms as versatile tools for targeting PCSK9 in the management of hypercholesterolemia. This study not only contributes to the advancement of ferritin-based therapeutics but also offers valuable insights into novel strategies for treating cardiovascular diseases.

Statins, but not proprotein convertase subtilisin-kexin type 9 inhibitors, lower chemerin in hypercholesterolemia via low-density lipoprotein receptor upregulation.

Hypercholesterolemia is characterized by elevated low-density lipoprotein (LDL)-cholesterol levels and an increased risk of cardiovascular disease. The adipokine chemerin is an additional risk factor. Here we investigated whether cholesterol-lowering with statins or proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) affects chemerin. Both statins and PCKS9i lowered plasma LDL-cholesterol, triglycerides and total cholesterol in hypercholesterolemic patients, and increased high-density lipoprotein (HDL)-cholesterol. Yet, only statins additionally reduced chemerin and high-sensitivity C-reactive protein (hsCRP). Applying PCSK9i on top of statins did not further reduce chemerin. Around 20% of chemerin occurred in the HDL2/HDL3 fractions, while>75% was free. Statins lowered both HDL-bound and free chemerin. Pull-down assays revealed that chemerin binds to the HDL-component Apolipoprotein A-I (ApoA-I). The statins, but not PCSK9i, diminished chemerin secretion from HepG2 cells by upregulating LDL receptor mRNA. Furthermore, chemerin inhibited HDL-mediated cholesterol efflux via its chemerin chemokine-like receptor 1 in differentiated macrophages. In conclusion, statins, but not PCSK9i, lower circulating chemerin by directly affecting its release from hepatocytes. Chemerin binds to ApoA-I and inhibits HDL-mediated cholesterol efflux. Statins prevent this by lowering HDL-bound chemerin. Combined with their anti-inflammatory effect evidenced by hsCRP suppression, this represents a novel cardiovascular protective function of statins that distinguishes them from PCSK9i.

Hypercholesterolemia - non-pharmacological treatment, monotherapy or combination therapy. Review of the literature

Introduction: As the number of scientific studies on lipid metabolism disorders increases, awareness among the medical community and the general population about the impact of hypercholesterolemia on the risk of cardiovascular diseases is growing. Elevated cholesterol levels in the blood are a major factor in the development of atherosclerosis, thereby increasing the likelihood of sudden cardiovascular events such as heart attacks or strokes. Maintaining normal cholesterol levels in the blood requires effective collaboration between the doctor and the patient, combining optimal pharmacotherapy with effective non-pharmacological methods based on the introduction of a balanced diet and moderate, regular physical activity. Current guidelines, based on numerous scientific studies, provide a clear framework for lipid-lowering treatment, with statins being an integral part. In cases where monotherapy is ineffective, ezetimibe and monoclonal antibodies, among others, can be used. In our work, we will discuss the possibilities of both non-pharmacological therapy and pharmacotherapy. Aim of the study: The aim of this study is to review current knowledge on non-pharmacological and pharmacological therapy in hypercholesterolemia. Material and method: This article presents the current state of knowledge about non-pharmacological and pharmacological therapy in hypercholesterolemia. Publications reviewed using the PubMed platform contain recent report in field of lipid metabolism disorders. The search included the keywords: ‚Hypercholesterolemia’, ‚LDL-C’, ‚Statin’, ,Ezetimibe’, ,PCSK9 inhibitors’.

Associations of different types of statins with the risk of open-angle glaucoma: a systematic review and network meta-analysis.

Previous studies implied that different types of statins may pose divergent impacts on the risk of glaucoma onset. This study aimed to comprehensively evaluate the effects of various statins on the risk of glaucoma occurrence. PubMed, Cochrane CENTRAL, Embase, and Web of Science were searched from February 1994 to February 2024. We included studies that investigated the effects of various types of statins, fibrates, ezetimibe, cholestyramine, niacin, PCSK9 inhibitors, omega-3 fatty acids, and any cholesterol-lowering medications on glaucoma onset or progression. The revised Cochrane risk-of-bias tool for randomized trials (RoB 2.0) and the Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-1) tool were used to assess the quality of randomized controlled trials (RCTs)and non-RCTs, respectively. The frequentist network meta-analysis framework was utilized to evaluate the comparative effectiveness, with the random effects model applied. This network meta-analysis comprised 12 studies, encompassing 262,217 individuals and including cholesterol-lowering medications such as statins, fibrates, ezetimibe, cholestyramine, niacin, and omega-3 fatty acids. Our findings demonstrate that comparing to the placebo, rosuvastatin (risk ratio [RR], 1.23; 95% confidence interval [CI], 1.03 to 1.46), simvastatin (RR, 1.21; 95% CI, 1.02 to 1.43), and pravastatin (RR, 1.20; 95% CI, 1.01 to 1.43) increased the risk of glaucoma onset with statistical significance. Rosuvastatin, simvastatin, and pravastatin were each associated with a significantly increased risk of glaucoma onset. We advise medical practitioners to exercise caution when prescribing these specific statins for patients who are at risk of developing glaucoma. What is known Previous studies have suggested a link between statins and the risk of developing glaucoma. However, there is still ongoing debate regarding the specific effects of each type of statin on the onset of glaucoma. What is new This network meta-analysis comprehensively evaluated the effects of various statins on the risk of glaucoma onset. Rosuvastatin, simvastatin, and pravastatin were associated with a significantly increased risk of glaucoma onset.

Comparative Efficacy of Colchicine and Intensive Low-density Lipoprotein Cholesterol Lowering in Patients with Atherosclerotic Diseases receiving Statins: A Network Meta-analysis of Randomized Controlled Trials.

Adding intensive low-density lipoprotein cholesterol (LDL-C)-lowering agents or colchicine to statin has been shown to result in additional cardiovascular benefits for patients with atherosclerotic cardiovascular diseases (ASCVD). We aimed to compare the efficacy and safety of these supplementary agents in patients with ASCVD receiving statin. We performed a systematic review and frequentist network meta-analysis of randomized controlled trials. The primary efficacy endpoint was the main adverse cardiovascular event (MACE), and the secondary efficacy endpoints were myocardial infarct, stroke, coronary revascularization, cardiovascular death, and all-cause mortality, respectively. The safety endpoints were treatment discontinuation and non-cardiovascular death. We obtained estimates for efficacy outcomes and safety endpoints and presented these estimates as risk ratio (RR) with 95% confidence intervals. We ranked the comparative efficacy and safety of all drugs with P-scores. Seventeen trials totaling 85,823 participants treated with colchicine (5926 participants), intensive LDL-C lowering (37,854 participants) via proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Niemann-Pick C1-like 1 protein (NPC1L1) inhibitor or ATP citrate lyase (ACL) inhibitor, or statin alone (42,043 participants) were included. Colchicine was associated with a greater reduction in the risk of MACE (RR 0.72, 0.69-0.91), stroke (RR 0.55, 0.33-0.92), and coronary revascularization (RR 0.73, 0.60-0.90) compared with NPC1L1 inhibitor, and it provided a larger reduction in the risk of MACE (RR 0.79, 0.69-0.91) compared to PCSK9 inhibitor. However, colchicine was associated with increased risk of non-cardiovascular death compared with NPC1L1 inhibitor (RR 1.48, 1.04-2.10) and PCSK9 inhibitor (RR 1.57, 1.08-2.27). Although no regimen prolonged survival, colchicine had worse performance on non-cardiovascular death and all-cause mortality. In patients with ASCVD receiving statin, colchicine seems to be more effective than intensive LDL-C-lowering therapy with PCSK9 inhibitor or NPC1L1 inhibitor for cardiovascular prevention. However, using colchicine as an alternative to intensive LDL-C-lowering therapy may need to be weighed against the cardiovascular benefits and the potential harms of higher non-cardiovascular death. PROSPERO Identifier: CRD42023441385.