Familial hypercholesterolemia (FH) is the most common monogenic disorder in humans. It affects millions of people globally, increasing the risk of developing cardiovascular disease (CVD) at a younger age due to elevated levels of low-density lipoprotein cholesterol (LDL-C) from birth. While effective traditional and novel treatments are available, the most significant challenge with FH is the lack of timely diagnosis. As a result, many patients remain undertreated leading to an increased risk of CVD. To mitigate risk, initiating early and aggressive LDL-C-lowering therapies is recommended. Moreover, given its autosomal dominant inheritance patterns, it is also recommended to perform cascade lipid and/or genetic testing of all first-degree relatives. This review highlights the importance of early FH diagnosis and available treatment options. Greater awareness and improved screening efforts can help diagnose and treat more individuals, ultimately reducing the CVD risk associated with FH.

This review explores the many barriers to accessing lipid-lowering therapies (LLTs) for the prevention and management of atherosclerotic cardiovascular disease (ASCVD). Geographical, knowledge, and regulatory barriers significantly impede access to LLTs, exacerbating disparities in healthcare infrastructure and affordability. We highlight the importance of policy reforms, including pricing regulations and reimbursement policies, for enhancing affordability and streamlining regulatory processes. Innovative funding models, such as value-based pricing and outcome-based payment arrangements, have been recommended to make novel LLTs more accessible. Public health interventions, including community-based programs and telemedicine, can be utilized to reach underserved populations and improve medication adherence. Education and advocacy initiatives led by patient advocacy groups and healthcare providers play a crucial role in raising awareness and empowering patients. Despite the barriers to access, novel LLTs present a big opportunity to reduce the burden of ASCVD, emphasizing the need for collaborative efforts among policymakers, healthcare providers, industry stakeholders, and patient advocacy groups to address these barriers to improve access to LLTs globally.

BACKGROUND: Evinacumab is an inhibitor of angiopoietin-like 3 protein (ANGPTL3) that offers a new approach for correcting high low-density lipoprotein-cholesterol (LDL-C) and may reduce the need or frequency for lipoprotein apheresis (LA) in patients with homozygous familial hypercholesterolemia (HoFH).
OBJECTIVE: We aimed to investigate the long-term efficacy and safety of evinacumab in patients with HoFH aged between 14 and 63 years on and off LA in real-world clinical practice.
METHODS: Evinacumab was administrated intravenously (15 mg /kg Q4W) for the first 24 months in 7 patients with genetically confirmed HoFH, receiving best standard of lipid-lowering treatment and LA, followed by a subsequent compassionate extension period of approximately 12-month treatment with evinacumab without LA. Patient experience of evinacumab and health-related EuroQol (EQ-5D-3L) quality of life questionnaire were also assessed.
RESULTS: Compared with baseline, evinacumab resulted in a sustained reduction in plasma LDL-C concentration of -43.4 % and -54.2 % at 30 and 36 months, respectively. All 7 HoFH patients achieved an LDL-C reduction >30 % with 3 patients having on-treatment LDL-C level < 2.5 mmol/L (96 mg/dL). Evinacumab was well-tolerated, with no major adverse reported or significant changes in liver enzyme concentrations. All FH patients agreed that evinacumab was acceptable and less physically demanding than LA. The mean utility score and EQ- visual analogue scale scores were 0.966 and 78.6, respectively, which are comparable to the Italian general population.
CONCLUSIONS: Our findings suggest that evinacumab is a safe and effective treatment for high LDL-cholesterol that is acceptable to HoFH patients receiving and not receiving LA.

OBJECTIVE: European registries and retrospective cohort studies have highlighted the failure to achieve low-density lipoprotein-cholesterol (LDL-C) targets in many very high-risk patients. Hospitalized patients are often frail, and frailty is associated with all-cause and cardiovascular mortality. The aim of this study is to evaluate LDL-C levels in a real-world inpatient setting, identifying cardiovascular risk categories and highlighting treatment gaps in the implementation of LDL-C management.
METHODS: This retrospective, observational study included all adult patients admitted to an Italian hospital between 2021 and 2022 with available LDL-C values during hospitalization. Disease-related real-world data were collected from Hospital Information System using automated data extraction strategies and through the implementation of a patient-centered data repository (the Dyslipidemia Data Mart). We performed assessment of cardiovascular risk profiles, LDL-C target achievement according to the 2019 ESC/EAS guidelines, and use of lipid-lowering therapies (LLT).
RESULTS: 13,834 patients were included: 17.15%, 13.72%, 16.82% and 49.76% were low (L), moderate (M), high (H) and very high-risk (VH) patients, respectively. The percentage of on-target patients was progressively lower towards the worst categories (78.79% in L, 58.38% in M, 33.3% in H and 21.37% in VH). Among LLT treated patients, 28.48% were on-target in VH category, 47.60% in H, 69.12% in M and 68.47% in L. We also analyzed the impact of monotherapies and combination therapies on target achievement.
CONCLUSIONS: We found relevant gaps in LDL-C management in the population of inpatients, especially in the VH category. Future efforts should be aimed at reducing cardiovascular risk in these subjects.

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves excessive lipid accumulation in hepatocytes, impacting global healthcare due to its high prevalence and risk of progression to severe liver conditions. Its pathogenesis involves genetic, metabolic, and inflammatory factors, with cardiovascular events as the leading cause of mortality. This review examines the role of lipid-lowering therapies in MASLD, with a particular focus on bempedoic acid, a recently approved cholesterol-lowering agent for hypercholesterolemia and high cardiovascular-risk patients. It explores its potential in liver disease by modulating lipid metabolism and inflammatory pathways based on the most recent studies available. Bempedoic acid inhibits ATP-citrate lyase, reducing cholesterol and fatty acid synthesis while activating AMP-activated protein kinase to suppress gluconeogenesis and lipogenesis. Animal studies indicate its efficacy in reducing hepatic steatosis, inflammation, and fibrosis. Bempedoic acid holds promise as a therapeutic for MASLD, offering dual benefits in lipid metabolism and inflammation. Further clinical trials are required to confirm its efficacy and safety in MASLD patients, potentially addressing the multifaceted nature of this disease.

BACKGROUND: Inclisiran, a small-interfering RNA enabling long-term inhibition of PCSK9 synthesis, demonstrates good safety and efficacy profile in clinical trials. Real-world data on the potential to attain lipid-goals and reduce treatment gaps is lacking.
OBJECTIVE: To investigate the implementation of inclisiran in real-world clinical setting.
METHODS: Data from a nationwide healthcare organization on patients initiating inclisiran between 3/2022-11/2023. Patients\' characteristics, lipid-lowering therapies, post-treatment reduction in low-density lipoprotein cholesterol (LDL-C), and attainment of treatment goals, were evaluated.
RESULTS: Inclisiran was initiated by 503 patients (57 % women; mean age 66±11 years). Cardiovascular disease was present in 54 %, and peak LDL-C levels >190 mg/dL documented in 64 %. Prior exposure to PCSK9 monoclonal antibodies was evident in 28 %. Lipid profile >2 months after filling first prescription, was available in 397 patients (347 with ≥2 injections). In patients treated by inclisiran only (n = 254), median LDL-C reduction from peak levels was 57 % (IQR, 48 %-67 %), and from pre-injection levels 40 % (19 %-54 %). In those with concomitant lipid-lowering therapies (n = 143), median LDL-C reduction from peak levels was 66 % (IQR, 55 %-73 %), and from pre-injection levels 46 % (23 %-59 %). LDL-C < 70 mg/dL was attained by 39 % and LDL-C < 55 mg/dL by 21.9 %. Of those treated with concomitant statin therapy, 38 % attained LDL-C < 55 mg/dL. Overall, 6.5 % discontinued inclisiran therapy after initial injection.
CONCLUSIONS: In real-world practice, inclisiran showed good efficacy in reducing LDL-C with high interindividual variability. However, attainment rates of lipid-goals were suboptimal due to limited use of combination lipid-lowering therapy and high-rates of severe hypercholesterolemia in our patient population cohort.

UNASSIGNED: Stroke prevention is a pressing global health priority, with reducing elevated lipids recognized as a key strategy. East Asians, constituting more than 1.6 billion individuals and the largest racial group worldwide, are a key demographic in this effort. Yet, the effectiveness of lipid-lowering therapies for stroke prevention in this population remains uncertain.
UNASSIGNED: We conducted a systematic review and meta-analysis of large-scale randomized controlled trials (RCTs) with at least 3 years of follow-up to evaluate the long-term impact of lipid-lowering therapies on stroke incidence in East Asians. We systematically searched four electronic databases up to 11 January 2024. The association was quantified using relative risk (RR) with a 95% confidence interval (CI), and between-study heterogeneity was evaluated using the I2 statistic. In addition, we utilized the Cochrane Risk of Bias Tool to assess the risk of bias in each included RCT and applied the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to evaluate the certainty of the evidence.
UNASSIGNED: This study incorporated data from nine large-scale RCTs involving 54,354 participants. Our findings of overall analyses revealed that lipid-lowering therapies did not significantly affect the long-term incidence of all strokes (9 RCTs; 54,354 participants; RR = 0.98 (95% CI = 0.87-1.10); P = 0.75), ischemic stroke (7 RCTs; 52,059 participants; RR = 0.91 (95% CI, = 0.79-1.04); P = 0.16), or hemorrhage stroke (7 RCTs; 52,059 participants; RR = 1.24 (95% CI = 0.97-1.59); P = 0.09) in East Asians. Notably, there was no evidence of heterogeneity or publication bias, and the quality of evidence assessed using GRADE methodologies was rated as high. Sensitivity analyses confirmed the robustness of our results, with no single study significantly affecting the overall findings. Furthermore, subgroup analyses consistently supported the conclusions, further bolstering the reliability of our study.
UNASSIGNED: Lipid-lowering therapies did not demonstrate any beneficial effects on long-term stroke prevention among East Asians.

Neutrophil extracellular traps (NETs) have attracted much attention recently, beyond elemental host immunity, due to their fundamental implication in a variety of pathologic conditions and widespread impactful diseases. Atherosclerotic cardiovascular disease (ASCVD) is one of them, and a major cause of mortality and disability worldwide. Consequently, years of basic and clinical research were dedicated to shedding light on every possible pathophysiologic mechanism that could be used as an effective prevention and treatment tool to ameliorate its burden. This led to the development of complex and prevention protocols and regimens that are now widely used, with lipid-lowering treatment being the current cornerstone; however, this is not adequate to alleviate the residual cardiovascular risk, which remains prominent. Despite the demonstrated pathogenic role of NETs in the progression and complications of ASCVD, little is known about their potential as a therapeutic target and the effects hypolipidemics exert on them.

OBJECTIVE: The availability of novel lipid-lowering therapies (LLTs) has remarkably changed the clinical management of homozygous familial hypercholesterolaemia (HoFH). The impact of these advances was evaluated in a cohort of 139 HoFH patients followed in a real-world clinical setting.
RESULTS: The clinical characteristics of 139 HoFH patients, along with information about LLTs and low-density lipoprotein cholesterol (LDL-C) levels at baseline and after a median follow-up of 5 years, were retrospectively retrieved from the records of patients enrolled in the LIPid transport disorders Italian GEnetic Network-Familial Hypercholesterolaemia (LIPIGEN-FH) Registry. The annual rates of major atherosclerotic cardiovascular events (MACE-plus) during follow-up were compared before and after baseline. Additionally, the lifelong survival free from MACE-plus was compared with that of the historical LIPIGEN HoFH cohort. At baseline, LDL-C level was 332 ± 138 mg/dL. During follow-up, the potency of LLTs was enhanced and, at the last visit, 15.8% of patients were taking quadruple therapy. Consistently, LDL-C decreased to an average value of 124 mg/dL corresponding to a 58.3% reduction (Pt < 0.001), with the lowest value (∼90 mg/dL) reached in patients receiving proprotein convertase subtilisin/kexin type 9 inhibitors and lomitapide and/or evinacumab as add-on therapies. The average annual MACE-plus rate in the 5-year follow-up was significantly lower than that observed during the 5 years before baseline visit (21.7 vs. 56.5 per 1000 patients/year; P = 0.0016).
CONCLUSIONS: Our findings indicate that the combination of novel and conventional LLTs significantly improved LDL-C control with a signal of better cardiovascular prognosis in HoFH patients. Overall, these results advocate the use of intensive, multidrug LLTs to effectively manage HoFH.
Contemporary real-world data from the Italian cohort of patients affected by homozygous familial hypercholesterolaemia demonstrated that the addition of novel, low-density lipoprotein receptor (LDLR)-independent medications to conventional therapies allowed the achievement of unprecedented low-density lipoprotein cholesterol (LDL-C) values with a trend towards a reduction of cardiovascular risk.

Chronic low-degree inflammation is a hallmark of atherosclerotic cardiovascular (CV) disease. To assess the effect of lipid-lowering therapies on C-reactive protein (CRP), a biomarker of inflammation, we conducted a meta-analysis according to the PRISMA guidelines. Databases were searched from inception to July 2023. Inclusion criteria were: (i) randomized controlled trials (RCTs) in human, Phase II, III, or IV; (ii) English language; (iii) comparing the effect of lipid-lowering drugs vs. placebo; (iv) reporting the effects on CRP levels; (v) with intervention duration of more than 3 weeks; (vi) and sample size (for both intervention and control group) over than 100 subjects. The between-group (treatment-placebo) CRP absolute mean differences and 95% confidence intervals were calculated for each drug class separately. A total of 171 668 subjects from 53 RCTs were included. CRP levels (mg/L) were significantly decreased by statins [-0.65 (-0.87 to -0.43), bempedoic acid; -0.43 (-0.67 to -0.20), ezetimibe; -0.28 (-0.48 to -0.08)], and omega-3 fatty acids [omega3FAs, -0.27 (-0.52 to -0.01)]. CRP was reduced by -0.40 (-1.17 to 0.38) with fibrates, although not statistically significant. A slight increase of CRP concentration was observed for proprotein convertase subtilisin/kexin type 9 inhibitors [0.11 (0.07-0.14)] and cholesteryl-ester transfer protein inhibitors [0.10 (0.00-0.21)], the latter being not statistically significant. Meta-regression analysis did not show a significant correlation between changes in CRP and LDL cholesterol (LDL-C) or triglycerides. Statins, bempedoic acid, ezetimibe, and omega3FAs significantly reduce serum CRP concentration, independently of LDL-C reductions. The impact of this anti-inflammatory effect in terms of CV prevention needs further investigation.