PCSK9 and Lipid Metabolism: Genetic Variants, Current Therapies, and Cardiovascular Outcomes.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the modulation of lipid metabolism as a critical negative regulator of hepatic low-density lipoprotein receptor (LDLR) levels and circulating low-density lipoprotein (LDL) clearance. Numerous gain-of-function (GOF) mutations in PCSK9 have been identified as causing familial hypercholesterolemia (FH) by reducing LDLR levels, and loss-of-function (LOF) mutations associated with a hypercholesterolemia phenotype protective against atherosclerosis. PCSK9 represents an example of successful translational research resulting in the identification of PCSK9 as a major drug target for a lipid-lowering therapy. To explore the genetic constitution of PCSK9 and its biologic role, in this review, we summarize the current evidence of clinically significant PCSK9 genetic variants involved in lipid metabolism as well as emphasize the importance of PCSK9 inhibition for the improvement of cardiovascular outcomes by conducting a meta-analysis of the available data on the incidence of cardiovascular disease events.

There are those who would like zero LDL cholesterol.

The overwhelming evidence that the reduction of LDL cholesterol (LDLc) levels is associated with a parallel reduction in cardiovascular (CV) risk has led the scientific community to progressively and constantly reduce the optimal therapeutic targets of LDLc, both in patients with known CV disease and in patients undergoing primary prevention. The recent introduction of proprotein convertase subtilisin/kexin type 9 inhibitors has allowed clinicians to observe reductions in LDLc levels that go well beyond the limits set by the main international guidelines; following the 'the lower the better' paradigm, it is natural to ask how low LDLc can be reduced, whether this intervention is associated with a further reduction in CV risk and, above all, whether there are no issues related to safety in the use of polypharmacotherapies that determine an extreme reduction in LDLc levels. The purpose of this article is to summarize the main scientific evidence on the topic, trying to provide an answer to all clinicians who 'would like their LDLc to be-almost-zero'.

PCSK9 inhibitors ameliorate arterial stiffness in ACS patients: evidences from Mendelian randomization, a retrospective study and basic experiments.

Background: Current evidences suggest that Proprotein Convertase Subtilisin/kexin Type 9 inhibitors (PCSK9i) exhibit a protective influence on acute coronary syndrome (ACS). Nevertheless, further investigation is required to comprehend the impact and mechanisms of these pharmaceutical agents on inflammatory factors and arterial stiffness (AS) in patients with ACS. Consequently, the objective of this study is to ascertain the influence of PCSK9i on arterial stiffness in ACS patients and elucidate the underlying mechanisms behind their actions. Methods: This study employed Mendelian randomization (MR) analysis to examine the association between genetic prediction of PCSK9 inhibition and arterial stiffness. Data of 71 patients with ACS were retrospectively collected, including PCSK9i group (n = 36, PCSK9 inhibitors combined with statins) and control group (n = 35, statins only). Blood lipid levels, inflammatory markers and pulse wave velocity (PWV) data were collected before treatment and at 1 and 6 months after treatment for analysis. Additionally, cell experiments were conducted to investigate the impact of PCSK9i on osteogenesis of vascular smooth muscle cells (VSMCs), utilizing western blot (WB), enzyme-linked immunosorbent assay (ELISA), and calcification index measurements. Results: The results of the MR analysis suggest that genetic prediction of PCSK9 inhibition has potential to reduce the PWV. Following treatment of statins combined with PCSK9 inhibitors for 1 and 6 months, the PCSK9i group exhibited significantly lower levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen (FIB) and procalcitonin (PCT) compared to the control group (p < 0.05). Additionally, PWV in the PCSK9i group demonstrated significant reduction after 6 months of treatment and was found to be associated with the circulating CRP level. In cell experiments, PCSK9i pretreatment ameliorated osteogenesis of VSMCs through reducing the deposition of calcium ions, alkaline phosphatase (ALP) activity, and expression of runt-related transcription factor 2 (RUNX2). Conclusion: PCSK9i have potential to enhance arterial stiffness in ACS patients. Specifically, at the clinical level, this impact may be attributed to alterations in circulating CRP levels. At the cellular level, it is associated with the signaling pathway linked to RUNX2.

Lipid lowering for prevention of venous thromboembolism: a network meta-analysis.

BACKGROUND AND AIMS: Studies have suggested that statins may be associated with reduced risk of venous thromboembolism (VTE). The aim of the current study was to assess the evidence regarding the comparative effect of all lipid-lowering therapies (LLT) in primary VTE prevention. METHODS: After a systematic search of PubMed, CENTRAL, and Web of Science up until 2 November 2022, randomized controlled trials (RCT) of statins (high- or low-/moderate-intensity), ezetimibe, or proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) were selected. An additive component network meta-analysis to compare VTE risk during long-term follow-up across different combinations of LLT was performed. RESULTS: Forty-five RCTs (n = 254 933 patients) were identified, reporting a total of 2084 VTE events. Compared with placebo, the combination of PCSK9i with high-intensity statin was associated with the largest reduction in VTE risk (risk ratio [RR] 0.59; 95% confidence interval [CI] 0.43-0.80), while there was a trend towards reduction for high-intensity (0.84; 0.70-1.02) and low-/moderate-intensity (0.89; 0.79-1.00) statin monotherapy. Ezetimibe monotherapy did not affect the VTE risk (1.04; 0.83-1.30). There was a gradual increase in the summary effect of VTE reduction with increasing intensity of the LLT. When compared with low-/moderate-intensity statin monotherapy, the combination of PCSK9i and high-intensity statin was significantly more likely to reduce VTE risk (0.66; 0.49-0.89). CONCLUSIONS: The present meta-analysis of RCTs suggests that LLT may have a potential for VTE prevention, particularly in high-intensity dosing and in combination therapy.

Impact of national drug price negotiation policy on the accessibility and utilization of PCSK9 inhibitors in China: an interrupted time series analysis.

BACKGROUND: PCSK9 inhibitors are a novel class of lipid-lowering drugs that have demonstrated favorable efficacy and safety. Evolocumab and alirocumab have been added to China's National Reimbursement Drug List through the National Drug Price Negotiation (NDPN) policy. This study aims to evaluate the impact of the NDPN policy on the utilization and accessibility of these two PCSK9 inhibitors. METHODS: The procurement data of evolocumab and alirocumab were collected from 1,519 hospitals between January 2021 and December 2022. We determined the monthly availability, utilization, cost per daily defined dose (DDDc), and affordability of the two medicines. Single-group interrupted time series (ITS) analysis was performed to assess the impact of the NDPN policy on each drug, and multiple-group ITS analysis was performed to compare the differences between them. RESULTS: The NDPN policy led to a significant and sudden increase in the availability and utilization of PCSK9 inhibitors, along with a decrease in their DDDc. In the year following the policy implementation, there was an increase in the availability, utilization, and spending, and the DDDc remained stable. The affordability of PCSK9 inhibitors in China have been significantly improved, with a 92.97% reduction in out-of-pocket costs. The availability of both PCSK9 inhibitors was similar, and the DDDc of alirocumab was only $0.23 higher after the intervention. The market share of evolocumab consistently exceeded that of alirocumab. Regional disparities in utilization were observed, with higher utilization in the eastern region and a correlation with per capita disposable income. CONCLUSIONS: The NDPN policy has successfully improved the accessibility and utilization of PCSK9 inhibitors in China. However, regional disparities in utilization indicate the need for further interventions to ensure equitable medicine access.

Safety profile of proprotein convertase subtilisin/kexin type 9 inhibitors alirocumab and evolocumab: an updated meta-analysis and meta-regression.

BACKGROUND: The use of alirocumab and evolocumab is generally safe and well-tolerated. However, concerns remain about their long-term safety, especially with regard to new-onset or worsening diabetes mellitus (DM). We aim to assess the safety profile of alirocumab and evolocumab compared to comparator. METHODS: Studies were retrieved comparing the safety of PCSK9i vs. comparator (placebo or statin with or without ezetimibe). The primary outcome was adverse events leading to death. Secondary outcomes included serious adverse events, new onset diabetes mellitus (DM), worsening of DM, neurocognitive dysfunction, creatine kinase (CK) elevation, elevation of liver enzymes and local injection site reaction. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on PCSK9i type and treatment duration. RESULTS: We identified 56 studies with 85,123 adults (29.14% females). PCSK9i was not associated with adverse events that lead to death (OR 0.94, 95% CI 0.84 to 1.04, p = 0.22). Between the two PCSK9i, alirocumab decreased adverse events leading to death (OR 0.79, 95% CI, 0.67 to 0.94, p = 0.008). PCSK9i was associated with less serious events compared to the comparator (OR 0.93, 95% CI 0.89 to 0.98, p < 0.001). This reduction was driven mainly by alirocumab (OR 0.89, 95% CI, 0.85 to 0.93, p < 0.001). Evolocumab worsened DM (OR 2.3, 95% CI 1.26 to 4.2, p = 0.041). Subgroup analysis showed worsening of DM in the first 24 weeks of treatment with odds being highest in the first 12 weeks of treatment (<12 weeks: OR 3.82, 95% CI 1.13 to 12.99, p = 0.03; 12-24 weeks OR 2.12, 95% CI 1.20 to 3.73, p = 0.01. On the other hand, therapy >24 weeks reduced the odds of worsening DM (OR 0.89, 95% CI 0.79 to 0.99, p = 0.04). PCSK9i did not increase cognitive dysfunction, (OR 1.02, 95% CI 0.88 to 1.18, p = 0.76), or cause elevations in liver enzyme (OR 0.91, 95% CI 0.81 to 1.03, p = 0.14), or CK (OR 0.82, 95% CI 0.65 to 1.04, p = 0.10). However, PCSK9i was associated with local injection site reaction (OR 1.54, 95% CI 1.37 to 1.73, p < 0.01). CONCLUSION: Alirocumab decreased adverse events leading to death. Alirocumab and Evolocumab both decreased serious adverse events. PCSK9i did not increase new onset DM however evolocumab worsened DM in the first 24 weeks of treatment. PCSK9i did not increase neurologic dysfunction, and did not elevate liver enzymes and CK, however it was associated with local injection site reaction.

New Insights Into the Treatment of Hyperlipidemia: Pharmacological Updates and Emerging Treatments.

Cardiovascular diseases are the leading causes of global mortality and morbidity. Hyperlipidemia is a significant risk factor for atherosclerosis and subsequent cardiovascular diseases. Hyperlipidemia is characterized by imbalances in blood cholesterol levels, particularly elevated low-density lipoprotein cholesterol and triglycerides, and is influenced by genetic and environmental factors. Current management consists of lifestyle modifications and pharmacological interventions most commonly consisting of statins. This review paper explores pathophysiology, management strategies, and pharmacotherapies including commonly used well-established medications including statins, fibrates, and ezetimibe, exciting novel therapies including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and RNA interference therapies (inclisiran), lomitapide, and bempedoic acid, highlighting their mechanisms of action, clinical efficacy, and safety profiles. Additionally, emerging therapies under clinical trials including ApoC-III inhibitors, DGAT2 inhibitors, ACAT2 Inhibitors, and LPL gene therapies are examined for their potential to improve lipid homeostasis and cardiovascular outcomes. The evolving landscape of hyperlipidemia management underscores the importance of continued research into both established therapies and promising new candidates, offering hope for more effective treatment strategies in the future.

Quantitative assessment of baseline imbalances in evolocumab and alirocumab trials: a meta-epidemiological study.

BACKGROUND: Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline differences, and (2) the relationship of baseline differences with effects on low-density lipoprotein-cholesterol (LDL-c) and clinical outcomes in the trials. METHODS: We performed a meta-epidemiological study. PubMed, Embase, regulatory reports, ClinicalTrials.gov and company websites were searched for trials. Seven baseline characteristics (mean age, LDL-c, BMI, percentage males, diabetics, smokers, and hypertensives) and five outcomes (LDL-c, major adverse cardiac events, serious adverse events, any adverse events, all-cause mortality) were extracted. We calculated (1) range and distribution of baseline imbalances (sign-test), (2) pooled baseline differences and heterogeneity (meta-analysis), (3) differences in SDs around continuous variables (sign-test and pooling), and (4) the relationship of baseline differences with outcomes (meta-regression). The comparisons of PCSK9-inhibitor groups with either placebo or ezetimibe were analysed separately and combined. RESULTS: We identified 43 trials with 63,193 participants. Baseline characteristics were frequently missing. Many trials showed small baseline imbalances, but some large imbalances. Only baseline BMI showed a statistically significant lower pooled mean for the drug versus placebo groups (MD -0.16; 95% CI -0.24 to -0.09). Heterogeneity in baseline imbalances was present in six placebo- and five ezetimibe-comparisons. Heterogeneity was statistically significant for BMI, males, diabetics and hypertensives in the combined comparisons. There was a statistically significant preponderance for larger SDs in the PCSK9-inhibitor versus control groups (sign-test age 0.014; LDL-c 0.014; BMI 0.049). Meta-regression showed clinically relevant relationships of baseline imbalances in age, BMI and diabetics with the risk of any adverse events and the risk of mortality. Two relationships were statistically significant: A higher mean BMI in the drug versus control group with a decreased risk of mortality (beta - 0.56; 95% CI -1.10 to -0.02), and a higher proportion of diabetics with an increased risk of any adverse events (beta 0.02; 95% 0.01 to 0.04). CONCLUSIONS: Heterogeneous baseline imbalances and systematically different SDs were present in evolocumab and alirocumab trials, so study groups cannot be assumed to be comparable. These findings raise concerns about the design and conduct of the randomization procedures.

The role of PCSK9 in heart failure and other cardiovascular diseases-mechanisms of action beyond its effect on LDL cholesterol.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a protein that regulates low-density lipoprotein (LDL) cholesterol metabolism by binding to the hepatic LDL receptor (LDLR), ultimately leading to its lysosomal degradation and an increase in LDL cholesterol (LDLc) levels. Treatment strategies have been developed based on blocking PCSK9 with specific antibodies (alirocumab, evolocumab) and on blocking its production with small regulatory RNA (siRNA) (inclisiran). Clinical trials evaluating these drugs have confirmed their high efficacy in reducing serum LDLc levels and improving the prognosis in patients with atherosclerotic cardiovascular diseases. Most studies have focused on the action of PCSK9 on LDLRs and the subsequent increase in LDLc concentrations. Increasing evidence suggests that the adverse cardiovascular effects of PCSK9, particularly its atherosclerotic effects on the vascular wall, may also result from mechanisms independent of its effects on lipid metabolism. PCSK9 induces the expression of pro-inflammatory cytokines contributing to inflammation within the vascular wall and promotes apoptosis, pyroptosis, and ferroptosis of cardiomyocytes and is thus involved in the development and progression of heart failure. The elimination of PCSK9 may, therefore, not only be a treatment for hypercholesterolaemia but also for atherosclerosis and other cardiovascular diseases. The mechanisms of action of PCSK9 in the cardiovascular system are not yet fully understood. This article reviews the current understanding of the mechanisms of PCSK9 action in the cardiovascular system and its contribution to cardiovascular diseases. Knowledge of these mechanisms may contribute to the wider use of PCSK9 inhibitors in the treatment of cardiovascular diseases.

Classical and Novel Lipid-Lowering Therapies for Diabetic Patients with Established Coronary Artery Disease or High Risk of Coronary Artery Disease-A Narrative Clinical Review.

Diabetic atherosclerosis is a complex process that is characterized by diffuse and unstable lesions increasing 2-4-fold the risk of adverse cardiovascular (CV) events. Diabetic dyslipidemia has a predominant role in coronary artery disease (CAD) and has been the target of classical and emerging pharmaceutical agents with established or promising CV benefits. The aim of the present narrative review was to summarize the effects of classical and novel lipid-lowering pharmaceutical agents on lipid profile and CV outcomes in diabetic patients with established CAD or high risk of CAD. Statins remain the first-line treatment for all diabetic patients since they considerably ameliorate lipid parameters and non-lipid CV risk factors, leading to reduced CV morbidity and mortality. Complementary to statins, ezetimibe exerts lipid-lowering properties with modest but significant reductions in major adverse cardiovascular events (MACEs) and CV mortality. PCSK9 inhibitors considerably reduce LDL-C levels and lower MACEs in diabetic patients. On the other hand, fibrates may confer a very modest decline in MACE incidence, while the CV impact of omega-3 fatty acids is promising but remains questionable. Bempedoic acid and inclisiran have a potential therapeutic role in the management of diabetic dyslipidemia, but this is still not adequately documented. Given the heightened CV risk among individuals with diabetes, more decisive results would be of great importance in the utility of all these drugs.

Lipid Toxicity in the Cardiovascular-Kidney-Metabolic Syndrome (CKMS).

Recent studies of Cardiovascular-Kidney-Metabolic Syndrome (CKMS) indicate that elevated concentrations of derivatives of phospholipids (ceramide, sphingosine), oxidized LDL, and lipoproteins (a, b) are toxic to kidney and heart function. Energy production for renal proximal tubule resorption of critical fuels and electrolytes is required for homeostasis. Cardiac energy for ventricular contraction/relaxation is preferentially supplied by long chain fatty acids. Metabolism of long chain fatty acids is accomplished within the cardiomyocyte cytoplasm and mitochondria by means of the glycolytic, tricarboxylic acid, and electron transport cycles. Toxic lipids and excessive lipid concentrations may inhibit cardiac function. Cardiac contraction requires calcium movement from the sarcoplasmic reticulum from a high to a low concentration at relatively low energy cost. Cardiac relaxation involves calcium return to the sarcoplasmic reticulum from a lower to a higher concentration and requires more energy consumption. Diastolic cardiac dysfunction occurs when cardiomyocyte energy conversion is inadequate. Diastolic dysfunction from diminished ATP availability occurs in the presence of inadequate blood pressure, glycemia, or lipid control and may lead to heart failure. Similar disruption of renal proximal tubular resorption of fuels/electrolytes has been found to be associated with phospholipid (sphingolipid) accumulation. Elevated concentrations of tissue oxidized low-density lipoprotein cholesterols are associated with loss of filtration efficiency at the level of the renal glomerular podocyte. Macroscopically excessive deposits of epicardial and intra-nephric adipose are associated with vascular pathology, fibrosis, and inhibition of essential functions in both heart and kidney. Chronic triglyceride accumulation is associated with fibrosis of the liver, cardiac and renal structures. Successful liver, kidney, or cardiac allograft of these vital organs does not eliminate the risk of lipid toxicity. Lipid lowering therapy may assist in protecting vital organ function before and after allograft transplantation.

PCSK9 inhibitors as safer therapeutics for atherosclerotic cardiovascular disease (ASCVD): Pharmacophore design and molecular dynamics analysis.

Cardiovascular disorders are still challenging and are among the deadly diseases. As a major risk factor for atherosclerotic cardiovascular disease, dyslipidemia, and high low-density lipoprotein cholesterol in particular, can be prevented primary and secondary by lipid-lowering medications. Therefore, insights are still needed into designing new drugs with minimal side effects. Proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme catalyses protein-protein interactions with low-density lipoprotein, making it a critical target for designing promising inhibitors compared to statins. Therefore, we screened for potential compounds using a redesigned PCSK9 conformational behaviour to search for a significantly extensive chemical library and investigated the inhibitory mechanisms of the final compounds using integrated computational methods, from ligand essential functional group screening to all-atoms MD simulations and MMGBSA-based binding free energy. The inhibitory mechanisms of the screened compounds compared with the standard inhibitor. K31 and K34 molecules showed stronger interactions for PCSK9, having binding energy (kcal/mol) of -33.39 and -63.51, respectively, against -27.97 of control. The final molecules showed suitable drug-likeness, non-mutagenesis, permeability, and high solubility values. The C-α atoms root mean square deviation and root mean square fluctuation of the bound-PCSK9 complexes showed stable and lower fluctuations compared to apo PCSK9. The findings present a model that unravels the mechanism by which the final molecules proposedly inhibit the PCSK9 function and could further improve the design of novel drugs against cardiovascular diseases.

PCSK9 inhibitor in acute ischemic stroke patient receiving mechanical thrombectomy: early outcomes and safety.

Background: Lipid-lowering therapies are mainstays in reducing recurrence after acute ischemic stroke (AIS). Evolocumab, a Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, is a promising lipid-lowering agent known to decrease LDL cholesterol and mitigate vascular events alongside statins. However, its effects on the early functional outcomes post-mechanical thrombectomy (MT) remain unclear. This study aimed to assess the short-term effects and incidence of bleeding events after the early, off-label use of PCSK9 inhibitors in AIS patients undergoing MT. Methods: We retrospectively analyzed patients who had MT at a Regional Stroke Center from December 2018 to April 2023. Our primary outcome was discharge functional outcomes. Secondary outcomes included early neurologic deterioration (END), symptomatic intracerebral hemorrhage (sICH), 3-month functional outcomes, 3-month recurrence rate, and lipid profiles. Results: Of 261 patients (mean age 69.2 ± 11.7, men 42.9%), 42 were administered evolocumab peri-procedurally. While baseline characteristics were similar between the two groups, evolocumab group demonstrated improved discharge outcomes, with a lower mean NIHSS (8.8 ± 6.8 vs. 12.4 ± 9.8, p = 0.02) and a higher percentage of patients with discharge mRS ≤ 3 (52.4% vs. 35.6%, p = 0.041). The 3-month follow-up show a non-significant trend toward an improved outcome in the evolocumab group. Multivariable analysis indicated that evolocumab had a potential impact on favorable discharge outcomes (aOR 1.98[0.94-4.22] for mRS ≤ 3 and 0.47[0.27-0.84] for lower ordinal mRS). Notably, evolocuamb users exhibited fewer instances of END and sICH, although they do not reach statistical significance. Additionally, the evolocumab group demonstrated potential benefits in LDL cholesterol reduction over time. Conclusion: Early use of evolocumab in AIS patients undergoing MT appeared to be safe and associated with better early functional outcomes. The potential benefit of the PCSK9 inhibitor shown here warrants further prospective studies.

Strike early-strike strong lipid-lowering strategy with PCSK9i in ACS patients. Real-world evidence from AT-TARGET-IT registry.

AIMS: No data are available on early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients with acute coronary syndrome (ACS) in real-world. This study investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major CV events in real-world. METHODS: The lipid control outcome was the percentage of patients reaching the LDL-C target of < 55 mg/dL at first lipid control. The clinical outcome was the incidence of composite major CV events (all cause death, non-fatal MI, non-fatal stroke, and ischemia-driven revascularization) during follow-up in relation to quartiles of LDL-C at first lipid control. RESULTS: We included 771 patients with ACS from AT-TARGET-IT registry, receiving PCSK9i prescription during hospitalization or at discharge. Median LDL-C was 137 mg/dL and decreased to 43 mg/dL at first lipid control. 527 (68.3%) patients achieved LDL-C target at the first lipid control at a median time of 37 days from hospitalization; of them, 404 (76.8%) were discharged on statin plus ezetimibe background therapy. Event curves through a median follow-up of 11 months across quartiles of LDL-C showed a stepwise lower risk of 4P-MACE, 3P-MACE, all-cause mortality, and ischemia-driven revascularization in lower quartile of LDL-C values at first lipid control (<23 mg/dL) and in patients reaching LDL-C <55 mg/dL. CONCLUSIONS: Intensive and early lipid-lowering therapy using PCSK9i in patients with ACS (strike early strike strong strategy) is safe and effective in clinical practice and associated with a reduction of residual CV risk.

This study, from AT-TARGET-IT registry, investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major CV events in real-world. Intensive and early PCSK9i therapy reduce composite major cardiovascular (CV) events in patients in reaching LDL-C target values. A strike early-strike strong strategy is safe and effective.

Impact of Lipid-lowering Therapy on Cancer Risk: A Narrative Review.

PURPOSE: There are inconsistent reports of an association between low cholesterol, use of lipid-lowering agents, and carcinogenesis. The purpose of this paper was to examine the relationship between cancer, lipids, statin use, and use of other lipid-lowering therapies. METHODS: This comprehensive literature review incorporated article searches in electronic databases (Embase, PubMed, OVID) and reference lists of relevant articles, with the authors' expertise in lipidology. This review considered seminal and novel research looking at the relationship between cholesterol, lipid-lowering therapies, and cancer. FINDINGS: Statin use has been reported to reduce the risk for incident cancer or progression of cancer; however, it is unknown whether this reduced risk of carcinogenesis is due to the pleotropic properties of statins or the effects of low cholesterol. The effect of ezetimibe on carcinogenesis has been regarded as neutral, despite earlier concerns of increased cancer risk with its use. Proprotein convertase subtilisin/kexin (PCSK)-9 monoclonal antibodies have been shown to have a neutral effect on carcinogenesis. Despite anti-cancer effects of fibrates in vitro, studies in humans have yielded inconsistent outcomes leaning toward protection against the development and progression of cancer. IMPLICATIONS: Statins, fibrates, PCSK9 monoclonal antibodies, and ezetimibe have a neutral effect on cancer risk, and the first three may provide some protection. PSCK9 monoclonal antibodies have the potential to enhance the response to checkpoint inhibitor therapy for cancer. Further research is needed to determine which drugs can be issued in adjuvant therapy to improve outcomes in patients undergoing cancer treatment.

The Causal Relationship between PCSK9 Inhibitors and Osteoporosis Based on Drug-Targeted Mendelian Combined Mediation Analysis.

PCSK9 inhibitors have been shown to lower serum low density lipoprotein cholesterol (LDL-C) levels and are considered integral in the treatment of cardiovascular diseases. However, the potential association between PCSK9 inhibitors and osteoporosis is unclear now. In this study, drug-targeted mendelian randomization (MR) was utilized in conjunction with mediation analysis including bone mineral density (BMD), total 25-hydroxyvitamin D (T25(OH)D) levels and calcium supplementation to investigate the causal relationship between PCSK9 inhibitors and osteoporosis. The LDL-C level was chosen as the exposure variable in a sample size of 173,082 individuals. We conducted a MR analysis on the relationship between PCSK9 inhibitors and osteoporosis, elucidating the mediators involved. Utilizing the inverse variance weighted (IVW) method, we found the risk of osteoporosis was reduced by 0.6% in those who used PCSK9 inhibitors compared with non-users (OR: 0.994, 95%CI: 0.991-0.998, P < 0.001). In people aged 30-45 years, the risk of low BMD was 1.176 times higher among PCSK9 inhibitor users compared to non-users (OR: 1.176, 95%CI: 1.017-1.336, P = 0.045). Conversely, people aged 45-60 years who used PCSK9 inhibitors had a 14.9% lower risk of low BMD compared to non-users (OR: 0.851, 95%CI: 0.732-0.968, P = 0.007). Mediation analysis revealed that 43.33% of the impact of PCSK9 inhibitors on osteoporosis was mediated through BMD levels, with the remaining 56.67% being a direct effect. Effects of PCSK9 inhibitors on BMD levels varied in different ages. In addition, the risk of high serum T25(OH)D levels were 1.091 times among PCSK9 inhibitor users compared to non-users (OR: 1.091, 95%CI: 1.065-1.112, P < 0.001), providing valuable insights for clinicians.

An Update on Dyslipidemia Management and Medications: A Review.

Dyslipidemia, characterized by abnormal lipid levels in the bloodstream, is a very common and underappreciated chronic disease associated with a significant cardiovascular disease burden. The management landscape for dyslipidemia has historically been static, with a sparse selection of therapeutic options. This article presents a comprehensive review of contemporary approaches to dyslipidemia management, focusing on therapeutic strategies and emerging interventions. We delineate the most current American Heart Association/American College of Cardiology & Canadian Cardiovascular Society guidelines and examine pivotal clinical trials that are shaping the contemporary approach to dyslipidemia management.

Real-world data on treatment patterns in at least high cardiovascular risk patients on dual and triple lipid lowering therapy in a Hellenic nationwide e-prescription database.

Background: Despite recent guidelines appropriate lipid-lowering treatment (LLT) remains suboptimal in everyday clinical practice. Aims: We aimed to describe clinical practice of use of LLT for at least high CV risk populations in a Hellenic real-world setting and assess how this relates to the European Society of Cardiology treatment guidelines. Methods: We analyzed data from a retrospective cohort study of the National Registry of patients with dyslipidemia between 1/7/2017 and 30/6/2019 who were at least of high CV risk and filled a dual or triple lipid-lowering treatment (dLLT, tLLT) prescription. The primary outcomes of interest of this analysis were to report on the patterns of LLT use in at least high CV risk patients. Results: A total of 994,255 (45.4% of Greeks on LLT) were of at least high CV risk and 120,490 (5.5%) were on dLLT or tLLT. The percentage of patients with reported statin intolerance ranged from 2 to 10%. While persistence was reported to be satisfactory (>85% for both dLLT or tLLT), adherence was low (ranging between 14 and 34% for dLLT). In 6-month intervals, the percentage of patients achieving a low-density lipoprotein cholesterol (LDL-C) target below 100 md/dL ranged from 20% to 23% for dLLT and 34%-37% for tLLT. Conclusions: The prevalence of at least high CV risk patients among patients receiving LLT in Greece is substantial. Despite the high persistence and probably due to the low adherence to treatment, LDL-C remains above targets in more than two thirds of patients.

Effectiveness and safety of injectable PCSK9 inhibitors in dyslipidaemias’ treatment and cardiovascular disease prevention: An overview of 86 systematic reviews and a network metaanalysis / Eficacia y seguridad de los inyectables inhibidores de la PCSK9 en el tratamiento de dislipidemias y la prevención de enfermedades cardiovasculares: una visión general de 86 revisiones sistemáticas y un metaanálisis en red

Objective Multiple systematic reviews (SR) have been performed on the effects of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), often providing conflicting findings. This overview and network meta-analysis (NMA) aimed to summarize SR findings on the efficacy and safety of PCSK9i and provide an updated NMA. Materials and methods MEDLINE (Pubmed), Scopus, Cochrane, Epistemonikos and Google Scholar were searched from inception to September 21, 2023 for SRs of randomized controlled trials (RCTs) and from January 1, 2020 to September 21, 2023 for additional RCTs. Double-independent study selection, data extraction and quality assessment were performed. Qualitative analysis was performed for SRs and a frequentist random-effects model NMA was performed for RCTs. Results Totally, 86 SRs and 76 RCTs were included. Alirocumab (77/86 [90%]) and evolocumab (73/86 [85%]) were mostly analyzed. Associations from SRs (35/42 [83%]) and the updated NMA indicated PCSK9i benefit on major adverse cardiovascular events (MACEs). Reductions were also noted for cerebrovascular events (47/66 [71%]), coronary revascularization (29/33 [88%]) and myocardial infarction (41/63 [65%]). Alirocumab was associated with reductions on all-cause mortality (RR=0.82, 95%CI [0.72,0.94]). Data on any CV event reduction were conflicting (7/16 [44%]). Inclisiran appeared effective only on MACEs (RR=0.76, 95%CI [0.61,0.94]). No reductions in heart failure were observed (0/16). No increases were identified between PCSK9i and any (0/35) or serious adverse events (0/52). However, PCSK9i were associated with injection-site reactions (20/28 [71%]). Conclusion PCSK9i appeared to be effective in CV outcomes and their clinical application was generally safe. (AU)

Objetivo Las revisiones sistemáticas (RS) sobre los efectos de los inhibidores de la proproteína convertasa subtilisina/kexina tipo 9 (PCSK9i), presentan resultados contradictorios. Esta revisión general y metaanálisis en red (MER) tiene como objetivo resumir los hallazgos sobre la eficacia y seguridad de los PCSK9i. Materiales y métodos Se realizaron búsquedas en MEDLINE (PubMed), Scopus, Cochrane, Epistemonikos y Google Scholar desde sus inicios hasta el 21 de septiembre de 2023 para las RS de ensayos controlados aleatorios (ECA) y desde el 1 de enero de 2020 hasta 21 de septiembre de 2023 para los ECA adicionales. La selección de estudios, extracción de datos y evaluación de calidad se llevaron a cabo de manera doble e independiente. Se realizó un análisis cualitativo de las SR y un modelo de efectos aleatorios frecuentistas MER para los ECA. Resultados En total, se incluyeron 86 SR y 76 RCT. Alirocumab (77/86 [90%]) y evolocumab (73/86 [85%]) fueron los más analizados. Se reconocieron beneficios de los PCSK9i en eventos cardiovasculares adversos mayores (ECVAM), reducción de eventos cerebrovasculares (47/66 [71%]), revascularización coronaria (29/33 [88%]) e infartos de miocardio (41/63 [65%]). Alirocumab redujo la mortalidad por todas las causas (RR: 0,82; IC del 95%: 0,72-0,94). Los resultados sobre la reducción de cualquier evento cardiovascular (CV) fueron contradictorios (7/16 [44%]). Inclisiran pareció ser efectivo solo en la reducción de ECVAM (RR: 0,76; IC del 95%: 0,61-0,94). No se observaron reducciones en insuficiencia cardíaca (0/16) o relación con eventos adversos serios (0/52). Sin embargo, se asociaron con reacciones en el lugar de la inyección (20/28 [71%]). (AU)

Failure of lipid control by PCSK9 inhibitors in compound heterozygous familial hypercholesterolemia complicated with premature myocardial infarction: A case report.

Key Clinical Message: A certain level of low-density lipoprotein receptor activity is crucial for the efficacy of PCSK9i. Therapeutic strategies for familial hypercholesterolemia patients should consider drug efficacy, and genetic testing will be helpful. Abstract: Familial hypercholesterolemia (FH) is a serious autosomal dominant disorder. Managing blood lipids in FH patients poses greater challenges for clinicians. Drug therapy may not always yield satisfactory results, particularly in individuals with low-density lipoprotein receptor (LDLR) negative mutations. Herein, we report a young female harboring an LDLR frameshift mutation. This patient developed xanthomas at 7 months old and underwent several years of treatment involving four classes of lipid-lowering drugs, including PCSK9i. However, the response to drug therapy was limited in this patient and eventually culminated in premature myocardial infarction. The efficacy of PCSK9i depends on the activity of LDLR. The inefficacy of PCSK9i may arise from the extensive mutations which leading to loss of LDLR activity. Therapy plans for these patients should take into account the efficacy of drug therapy. Early genetic testing is crucial for clinicians to make informed decisions regarding therapy options.