Familial hypercholesterolemia.

Familial hypercholesterolemia is a common genetic disorder of autosomal inheritance associated with elevated LDL-cholesterol. It is estimated to affect 1:250 individuals in general population roughly estimated to be 5 million in India. The prevalence of FH is higher in young CAD patients (<55 years in men; <60 years in women). FH is underdiagnosed and undertreated. Screening during childhood and Cascade screening of family members of known FH patients is of utmost importance in order to prevent the burden of CAD. Early identification of FH patients and early initiation of the lifelong lipid lowering therapy is the most effective strategy for managing FH. FH management includes pharmaceutical agents (statins and non statin drugs) and lifestyle modification. Inspite of maximum dose of statin with or without Ezetimibe, if target levels of LDL-C are not achieved, Bempedoic acid, proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibitors/Inclisiran can be added.

Treatment of dyslipidemia in acute coronary syndrome.

Despite numerous improvements in the management of acute coronary syndrome(ACS), it is a major cause of mortality in India. Lipids play a critical role in pathogenesis of ACS and reduction of lipid parameters plays a pivotal role in secondary prevention. High total cholesterol and high low-density lipoprotein(LDL) are the major lipid abnormalities globally as well as in Indians. Among all the lipid parameters, LDL is the primary target of lipid-lowering therapies across the globe. High-dose statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bempedoic acid are recommended therapies for LDL reduction in ACS patients. Statins have pleiotropic effects on the modulation of thrombogenesis, endothelial dysfunction, and myocardial protection. Multiple randomised controlled trials and meta-analyses have shown that the use of high-dose statin has significant benefits in ACS. LDL reduction goal is < 55 mg/dl or at least 50 % reduction from the baseline regardless of age or gender. Non-fasting LDL should be measured soon after the ACS as it varies minimally with food intake. The first line of therapy after ACS is to advise lifestyle modifications, combination therapy including high-dose statin with ezetimibe, and evaluation after 4-6 weeks of the index event. If the goal is not achieved then PCSK 9 inhibitors or Bempedoic acid should be used in combination with statins and ezetimibe to reduce recurrent ischaemic events. Despite the proven effect of these lipid-lowering therapies, undertreatment is still a big hurdle across the globe. Prohibitive costs, adverse effects, medication non-adherence, variation in health practice in different countries, and clinical inertia to prescribe this medication by physicians are the main reasons for the undertreatment.

Dyslipidaemia in elderly and stroke patients.

Lowering of cholesterol containing atherogenic particles through lipid lowering therapies is of outmost important in both in the elderly age group and younger age group in reducing the cardiovascular risk. This chapter summarizes the current existing knowledge regarding the factors which affects the key decision-making process in patients with older age, and also in special circumstance where the direct evidence of benefit for cholesterol lowering is lacking. Effort has been made to briefly summarize the recommendations to the patient and his/her family based on risk stratification of atherosclerotic versus non-atherosclerotic cardiovascular disease, comorbidity burden, quality of life, survival prognosis, lifestyle/socioeconomic status and presence of frailty. Here in this chapter, we have collated and presented the available robust clinical trial evidence which is very much necessary for the assessment of risk versus benefit for hypolipidemic drugs in the elderly age group. While plethora of pharmacological interventions has evolved including statins, ezetimibe, bempedoic acid, PCSK9 inhibitors, Inclisiran etc., but it is essential to establish lipid-lowering therapy goals based on the stroke subtype and the presence of comorbidities. Here in this section we have reviewed the collated clinical evidences for optimal drug regimen recommendation for elderly stroke patients for both primary and secondary prevention.

A retrospective nationwide analysis of evolocumab use in Sweden and its effect on low-density lipoprotein cholesterol levels.

Background: Treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduces low-density lipoprotein cholesterol (LDL-C) levels and decreases the incidence of major ischaemic events in clinical trials. However, less is known about the efficacy of PCSK9 inhibition in clinical practice. This study aimed to describe the change in LDL-C levels over time and LDL-C goal achievement in patients with/without atherosclerotic cardiovascular disease (ASCVD), who were prescribed evolocumab in clinical practice, and to describe adherence to and persistence with treatment. Methods: Patients in Sweden with at least one evolocumab prescription filled between July 2015 and May 2020 were included. Medical history and lipid-lowering therapy (LLT) were sourced from national registries. LDL-C levels before and after treatment initiation were assessed using medical records. Persistence with and adherence to evolocumab and oral LLT were assessed up to 12 months after treatment initiation using the refill-gap method and proportion of days covered, respectively. Results: Of the 2,360 patients with at least one prescription for evolocumab, 2,341 were included; 1,858 had ASCVD. Persistence with (76%) and adherence to (86%) evolocumab were high throughout the 12 months following initiation. Mean LDL-C levels decreased by 53% (95% confidence interval [CI]: 51-55%) in patients adherent to evolocumab (n = 567) and 59% (95% CI: 55-63%) in patients adherent to evolocumab and oral LLT (n = 186). Similar reductions in LDL-C were observed in patients with/without ASCVD. Reduced LDL-C levels remained stable during follow-up. Amongst patients adherent to evolocumab and those adherent to evolocumab and oral LLT, 23 and 55% achieved the LDL-C goal of <1.4 mmol/L, respectively. Conclusions: The evolocumab LDL-C-lowering effect observed in clinical trials was confirmed in clinical practice in Sweden, particularly in patients also treated with oral LLT. During follow-up, adherence to and persistence with evolocumab were high, with stable reduced levels of LDL-C during observation.

The Effect of PCSK9 Inhibitors on LDL-C Target Achievement in Patients with Homozygous Familial Hypercholesterolemia: A Retrospective Cohort Analysis.

INTRODUCTION: Achieving target low-density lipoprotein-cholesterol (LDL-C) levels remains challenging when treating homozygous familial hypercholesterolemia (HoFH). Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are prescribed in addition to statins and ezetimibe, but patients' response varies and depends on residual low-density lipoprotein receptor (LDLR) function. METHODS: A multicenter, retrospective observational analysis evaluated LDL-C target achievement in response to PCSK9i treatment in 28 patients with HoFH from the Middle East/North Africa region. Effect of genotype was investigated. Demographic and clinical information was retrospectively obtained from medical records. Patient response to PCSK9i treatment was assessed by calculating percentage changes in lipid levels from pre-PCSK9i treatment baseline to most recent follow-up visit where patients were recorded as receiving PCSK9i on top of standard of care lipid-lowering therapies (LLTs; i.e., statins/ezetimibe) and assessing European Atherosclerosis Society (EAS) target achievement up to January 31, 2022. Lowest LDL-C level while receiving PCSK9i was identified. RESULTS: The cohort (n = 28) had a mean age (standard deviation; SD) of 22.8 (9.8) years (n = 28) and was 51% female (n = 27). Baseline LDL-C data were available in 24/28 (85.7%) patients (mean [SD] 14.0 [3.0] mmol/L). Median (interquartile range) duration of PCSK9i treatment was 12.0 months (4.0-19.1) months and mean (SD) % change in LDL-C after PCSK9i treatment was - 8.6% (12.1). LDL-C reduction from baseline was below 15% in 17/24 patients (70.8%). In the full cohort, mean (SD) minimum LDL-C during PCSK9i treatment was 11.9 (2.8; n = 28) mmol/L. No patient achieved EAS target LDL-C while receiving PCSK9i; genotype analysis suggested LDLR-null/null patients were most refractory to PCSK9i. CONCLUSION: Response to PCSK9i was minimal in this cohort of patients with HoFH. No patients achieved EAS LDL-C targets, and most failed to reach the EAS-recommended 15% LDL-C reduction for PCSK9i therapy continuation. These results suggest additional LLTs are necessary to achieve LDL-C targets in HoFH.

First Report of Inclisiran Utilization for Hypercholesterolemia Treatment in Real-world Clinical Settings in a Middle East Population.

PURPOSE: Inclisiran is the first small interfering RNA-based treatment approved for reducing pro-atherogenic lipoproteins in patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of low-density lipoprotein cholesterol (LDL-C). We report the first evaluation of the effects of inclisiran in a Middle East population. METHODS: We conducted a retrospective review of patients initiating inclisiran treatment at an outpatient diabetology, endocrinology, and cardiology center between May 2021 and December 2022. All patients followed up for 90 days or more, or with at least 1 lipid determination post initiation were included. Participants were categorized into primary prevention (n = 57) and secondary prevention (n = 89) groups according to previous atherosclerotic cardiovascular disease. FINDINGS: Inclisiran was initiated in 146 patients; mean (SD) age was 54.8 (12.12) years, 82 patients (56.2%) were male, 28 patients (19.2%) had received a diagnosis of familial hypercholesterolemia, 89 patients (61%) had received a diagnosis of diabetes mellitus, and 35 patients (23.9%) had a statin intolerance. Median (interquartile range) follow-up was 137 (90 to 193) days. At 90 days, median (interquartile range) reductions in serum LDL-C and triglycerides were -37.9% (-9.5% to -51.2%) and -12.0% (-9.8% to -40.5%), respectively, in primary prevention and -54.1% (-17.1% to -71.4%) and -15.3% (-14% to -38.8%), respectively, in secondary prevention (all, P < 0.001). LDL-C goals were attained in 110 patients (75.3%). Nonattainment of LDL-C goal was attributed to system effect in 26 patients (72.2%), biological effect in 5 patients (13.9%), and discontinuation of treatment in 5 patients (13.9%). Therapy was well tolerated. IMPLICATIONS: This study is the first from the Middle East and North Africa region that reported the real-world efficacy and safety profile of inclisiran in a mixed-risk population of patients with heterozygous familial hypercholesterolemia and other non-familial hypercholesterolemia indications. Clinically meaningful and sustained reductions in pro-atherogenic lipids with good tolerability were observed after inclisiran initiation. Fewer AEs were reported in this predominantly Arabic population, consistent with previous safety reports for inclisiran. It is important to note that no patient stopped inclisiran treatment due to AEs. Strengths of our study included an optimal cohort, patient heterogeneity, and high retention. In addition, we were able to report mean robust effects of inclisiran and good medication tolerability, quite like randomized studies and open-label extension periods. Despite this, our study had some limitations, including selection bias due to the retrospective design and the absence of a comparative group.

Dyslipidemia and peripheral arterial disease.

Peripheral arterial disease (PAD) affects 12 % of adult population and is increasing globally and in India. Peripheral arterial disease when associated with atherosclerosis in two or more other arterial beds such as coronary artery disease (CAD), mesenteric/renal artery and cerebrovascular disease (CVD), is known as polyvascular disease. The Reduction of Atherothrombosis for Continued Health (REACH) registry reported that 1 out of 6 patients had multi-vascular bed involvement. Progression of PAD to critical limb ischaemia (CLI) is seen in 1 % of affected patients per year, but patients who progress to CLI may have a 10- to 15-fold increased risk of cardiovascular death. The 2019 ECS/EAS guidelines for the management of dyslipidaemias have suggested that for primary or secondary prevention in very high risk, patients should follow a therapeutic regimen that achieves >50 % LDL-C reduction from baseline and an LDL-C goal of <55 mg/dl. High Intensity Statin is mainstay of treatment but optimal management is inadequate. Statin treatment reduces all-cause mortality by 39 %, CV death by 41 %, CV outcomes by 34 %, ischaemic stroke by 28 %, acute limb ischaemia by 30 % and amputations by 35 %. Ezetimibe when added to statins in IMPROVE-IT trial, showed significant reduction of MACE. PCSK9 inhibitor (FOURIER TRIAL) showed reduction in primary end point in PAD vs Non PAD patients (3.5 % vs 1.6 %). There is a critical need for an Indian multi-disciplinary task force for research on the direct impact of lipid-lowering agents on limb salvage rates and major limb-related events in PAD patients.

Managing dyslipidaemia in patients with chronic kidney disease.

Patients with CKD are at increased risk for cardiovascular events. Clinical studies suggest statins reduce all-cause mortality and cardiovascular events in patients with CKD. Lipid lowering therapy with statin with or without ezetemibe is recommended for most of the patients in patients with eGFR <60 mL/min and also in those who have an increased urinary albumin-to-creatinine ratio (≥3 mg/mmol) for at least 3 months. Evidence suggests that it should not be started for hemodialysis patients without evidence of ASCVD. Patients who were already taking statins or statin/ezetimibe combination at the time of dialysis should consider continuing these medications, especially if they have ASCVD. Fibrates should not be used in conjunction with statins in patients with CKD, and ezetimibe monotherapy is also not recommended. The role of PCSK9 inhibitors is evolving suggests that it is effective in lowering LDL cholesterol without affecting the renal outcomes.

Evinacumab-dgnb (Evkeeza-REGN1500), A Novel Lipid-Lowering Therapy for Homozygous Familial Hypercholesterolemia.

Chronically elevated low-density lipoprotein (LDL) has harmful effects on the vasculature including increased vasoconstriction and the formation of plaques which may rupture, causing coronary heart disease and stroke. In patients with familial hypercholesterolemia, adequate reduction of LDL is especially challenging. Although HMG-CoA reductase inhibitors (statins) are the mainstays for LDL lowering, other treatments such as proprotein convertase subtilisin/kexin type 9 inhibitors, bempedoic acid, incliseran, lomitapide, and apheresis have been employed in an effort to achieve adequate LDL reduction in these patients. Despite these available therapies, many patients with familial hypercholesterolemia do not meet the LDL targets suggested in current guidelines. Evinacumab is a novel lipid-lowering therapy that exerts its LDL-lowering effect through inhibition of angiopoietin-like protein 3 (ANGPTL3). ANGPTL3 inhibits the breakdown of triglyceride-rich lipoproteins, such as very low-density lipoprotein and chylomicrons. By inhibiting ANGPTL3, evinacumab allows these lipoproteins to be degraded, ultimately leading to reductions in LDL, high-density lipoprotein, and triglycerides. Clinical trials have demonstrated evinacumab to be safe and effective in reducing LDL. However, data are lacking regarding its potential to reduce risk of atherosclerotic cardiovascular disease. Evinacumab is generally well tolerated with the primary adverse effects comprising infusion reactions, nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, and nausea. While evinacumab is an interesting therapy, until it is proven to reduce cardiovascular events, its high cost leaves its anticipated role in therapy somewhat ambiguous. In the meantime, it may be a useful therapy for those with homozygous familial hypercholesterolemia.

PCSK9 inhibitor use during pregnancy in a case of familial hypercholesterolemia complicated with coronary artery disease.

Limited data have been reported on the use of proprotein convertase subtilisin/kexin type 9 (PCSK 9) inhibitors during pregnancy in women with familial hypercholesterolemia (FH). Here, we present the first case of initiating evolocumab (PCSK9 inhibitor) in a compound heterozygous FH mother. The patient was a 34-year-old primipara with severe dyslipidemia and a history of coronary artery bypass surgery. An elevated low-density lipoprotein cholesterol (LDL-C) level of 420 mg/dL was detected in the first trimester and persistently increased throughout pregnancy. Evolocumab was administered at 31 and 35 weeks of gestation, showing a positive effect on stabilizing LDL-C levels. Planned delivery with labor analgesia was performed at 38 + 4 weeks. Both the mother and infant were discharged without any notable complications. Hence, evolocumab, an IgG2 monochromatic antibody with little placental permeability, may be an alternative medication with limited influence on infants. Further studies are needed to assess the safety of evolocumab administration during pregnancy.

Role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in diabetic complications.

Cardiovascular disease (CVD) complications have remained a major cause of death among patients with diabetes. Hence, there is a need for effective therapeutics against diabetes-induced CVD complications. Since its discovery, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been reported to be involved in the pathology of various CVDs, with studies showing a positive association between plasma levels of PCSK9, hyperglycemia, and dyslipidemia. PCSK9 regulates lipid homeostasis by interacting with low-density lipoprotein receptors (LDLRs) present in hepatocytes and subsequently induces LDLR degradation via receptor-mediated endocytosis, thereby reducing LDL uptake from circulation. In addition, PCSK9 also induces pro-inflammatory cytokine expression and apoptotic cell death in diabetic-CVD. Furthermore, therapies designed to inhibit PCSK9 effectively reduces diabetic dyslipidemia with clinical studies reporting reduced cardiovascular events in patients with diabetes and no significant adverse effect on glycemic controls. In this review, we discuss the role of PCSK9 in the pathogenesis of diabetes-induced CVD and the potential mechanisms by which PCSK9 inhibition reduces cardiovascular events in diabetic patients.

PCSK9 ablation attenuates Aß pathology, neuroinflammation and cognitive dysfunctions in 5XFAD mice.

BACKGROUND: Increasing evidence highlights the importance of novel players in Alzheimer's disease (AD) pathophysiology, including alterations of lipid metabolism and neuroinflammation. Indeed, a potential involvement of Proprotein convertase subtilisin/kexin type 9 (PCSK9) in AD has been recently postulated. Here, we first investigated the effects of PCSK9 on neuroinflammation in vitro. Then, we examined the impact of a genetic ablation of PCSK9 on cognitive performance in a severe mouse model of AD. Finally, in the same animals we evaluated the effect of PCSK9 loss on Aß pathology, neuroinflammation, and brain lipids. METHODS: For in vitro studies, U373 human astrocytoma cells were treated with Aß fibrils and human recombinant PCSK9. mRNA expression of the proinflammatory cytokines and inflammasome-related genes were evaluated by q-PCR, while MCP-1 secretion was measured by ELISA. For in vivo studies, the cognitive performance of a newly generated mouse line - obtained by crossing 5XFADHet with PCSK9KO mice - was tested by the Morris water maze test. After sacrifice, immunohistochemical analyses were performed to evaluate Aß plaque deposition, distribution and composition, BACE1 immunoreactivity, as well as microglia and astrocyte reactivity. Cholesterol and hydroxysterols levels in mouse brains were quantified by fluorometric and LC-MS/MS analyses, respectively. Statistical comparisons were performed according to one- or two-way ANOVA, two-way repeated measure ANOVA or Chi-square test. RESULTS: In vitro, PCSK9 significantly increased IL6, IL1B and TNFΑ mRNA levels in Aß fibrils-treated U373 cells, without influencing inflammasome gene expression, except for an increase in NLRC4 mRNA levels. In vivo, PCSK9 ablation in 5XFAD mice significantly improved the performance at the Morris water maze test; these changes were accompanied by a reduced corticohippocampal Aß burden without affecting plaque spatial/regional distribution and composition or global BACE1 expression. Furthermore, PCSK9 loss in 5XFAD mice induced decreased microgliosis and astrocyte reactivity in several brain regions. Conversely, knocking out PCSK9 had minimal impact on brain cholesterol and hydroxysterol levels. CONCLUSIONS: In vitro studies showed a pro-inflammatory effect of PCSK9. Consistently, in vivo data indicated a protective role of PCSK9 ablation against cognitive impairments, associated with improved Aß pathology and attenuated neuroinflammation in a severe mouse model of AD. PCSK9 may thus be considered a novel pharmacological target for the treatment of AD.

Effect of statins combined with PCSK9 inhibitors on the prognosis of patients with acute coronary syndromes after interventional therapy.

Acute coronary syndromes (ACS) are a leading cause of morbidity and mortality worldwide. It has been clinically confirmed percutaneous coronary intervention (PCI) can alleviate the symptoms of ACS, but there are still some patients with slow blood flow or no-reflow after surgery, which has adverse effects on the prognosis of patients. This study aimed to investigate the effect of statins combined with PCSK9 inhibitors on the prognosis of patients with ACS after interventional therapy. A total of 208 ACS patients treated in our hospital from January 2021 to December 2022 were separated into observation and control groups. Patients in the control group received oral rosuvastatin 20 mg/ day. Patients in the observation group received PCSK9 inhibitor elozumab (Repatha) 140 mg, subcutaneously injected twice a week. The levels of inflammatory factors, cardiac function indexes, clinical effectiveness rate, adverse events, and complications were compared before and after treatment. After 1 week of treatment and 4 weeks of follow-up, the levels of inflammatory indicators in the observation group declined relative to the control group (P < 0.05 and P < 0.01). After 4 weeks, LVEF in the observation group was elevated in comparison to the control group, while LVEDD in the observation group declined compared to the control group (P < 0.05). The incidence of adverse events after treatment in the observation group declined relative to the control group (P < 0.05). The incidence of complications in the observation group declined in contrast to the control group (P < 0.05). Statins combined with PCSK9 inhibitors significantly reduce LDL-C levels in ACS patients undergoing PCI without increasing cardiovascular events or major adverse clinical effects.

Familial hypercholesterolemia and its manifestations: Practical considerations for general practitioners.

Familial hypercholesterolemia (FH) is the most common genetic disorder of lipid metabolism, affecting almost 1 in 250 individuals worldwide. It is usually inherited via the autosomal dominant way and is characterized by aberrantly high total and low-density lipoprotein cholesterol (LDL-C) concentrations from early childhood, predisposing to increased risk of premature atherosclerotic cardiovascular disease (ASCVD), mostly coronary heart disease (CHD). Despite its high prevalence in the general population and the high ASCVD risk, FH is often underdiagnosed and undertreated. Genetic diagnosis is not always necessary since specific criteria, taking into account the patient's individual and family history, clinical signs, and untreated LDL-C concentrations, may be used for prompt diagnosis. Except for CHD, which may be already evident at diagnosis, leading to increased mortality, other non-CHD morbidities, such as stroke, peripheral artery disease, carotid artery stenosis, and aortic valve calcification may be also present, substantiating the need for prompt intervention. Statins constitute the mainstay of treatment both in adults and children >8 years old. In cases of statin intolerance or not achieving the LDL-C target despite maximally tolerated statin dose, ezetimibe and/or proprotein convertase subtilisin-kexin type 9 inhibitors may be used. The advent of recently approved medications, such as inclisiran and bempedoic acid, either as monotherapy or as add-on therapy to statins, has further enhanced the therapeutic armamentarium that can be used in FH patients. The purpose of this narrative review is to provide practical considerations regarding the diagnostic and therapeutic approach to FH patients.

Pharmacokinetic/LDL-C and exposure-response analysis of tafolecimab in Chinese hypercholesterolemia patients: Results from phase I, II, and III studies.

Tafolecimab, a novel fully human monoclonal antibody targeting PCSK9, has been assessed in Chinese healthy volunteers and patients with hypercholesterolemia. This analysis is to develop and qualify a population pharmacokinetics (PopPKs)/LDL-C model to characterize tafolecimab PK and LDL-C profiles, evaluate the impact of potential covariates on tafolecimab, estimate individual predicted exposure, and LDL-C decreasing, furthermore, explore exposure-response relationship to support clinical use. Data from six clinical trials in China were used to develop the PopPK/LDL-C model. A Michaelis-Menten approximation of the target-mediated drug disposition (TMDD) model was used to describe PK data and indirect response (IDR) model was developed to estimate the LDL-C profile. A stochastic approximation expectation maximization algorithm was applied to estimate PopPK/LDL-C parameters. The PK/LDL-C time course data for tafolecimab were well described by TMDD/IDR model. Baseline covariates resulting in statistically significant changes in PK/LDL-C parameters included: body weight and sex on absorption rate constant; body weight, sex, and unbound PCSK9 on central volume; body weight and sex on clearance; baseline LDL-C on first-order rate constants for the removal of an effect); and disease and sex on maximum effect. However, the magnitudes of changes associated with these covariates do not necessitate dose adjustment. Exposure-efficacy relationship indicated that the nadir of LDL-C reduction achieved with the steady-state trough plasma concentration (Ctrough ) of tafolecimab at 5 µg/mL, and no further LDL-C decreasing with the increasing Ctrough . There was no exposure dependency observed in exposure-safety exploration. The PopPK/LDL-C model was successfully developed, validated, and predicted tafolecimab/LDL-C concentrations and individual exposures.

New opportunities in the management and treatment of refractory hypercholesterolemia using in vivo CRISPR-mediated genome/base editing.

AIMS: Refractory hypercholesterolemia (RH), caused primarily by the loss-of-function mutation of LDL receptor (LDLR) gene seen in HoFH and HeFH patients, remains a major risk factor for atherosclerotic cardiovascular disease (ASCVD). Statin and ezetimibe combination therapy lower circulating LDL by 30% in HoFH patients. PCSK9 mAB, being an LDLR-dependent therapy, is not effective in HoFH, but lowers LDL by 25% in HeFH patients. A maximum reduction of 50% was noted in HoFH patients treated with ANGPTL3 mAB, which was not enough to achieve therapeutic goal of LDL. Therefore, new approaches are warranted to offer hopes to individuals intolerant to higher dose statins and not able to achieve recommended LDL level. DATA SYNTHESIS: New approaches to lower LDL include gene therapy and gene editing. AAV-based gene therapy has shown encouraging results in animal models. Using CRISPR/Cas9-mediated genome/base editing, gain of function and loss of function have been successfully done in animal models. Recent progress in the refinement of genome/base editing has overcome the issues of off-target mutagenesis with ∼1% mutagenesis in case of PCSK9 and almost no off-target mutagenesis in inactivating ANGPTL3 in animal models showing 50% reduction in cholesterol. Current approaches using CRISPR-Cas9 genome/base editing targeting LDLR-dependent and LDLR-independent pathways are underway. CONCLUSIONS: The new information on gain of LDLR function and inactivation of ANGPTL3 together with developments in genome/base editing technology to overcome off-target insertion and deletion mutagenesis offer hope to refractory hypercholesterolemic individuals who are at a higher risk of developing ASCVD.

Dyslipidemia - the known unknown.

Dyslipidemia (DLP) is the most important risk factor for atherosclerotic cardiovascular disease (ASCVD) and, in the context of severe hypertriglyceridemia (TG > 10 mmol/l), a risk factor for the development of acute pancreatitis. The prevalence of DLP is very high, but their control, especially among the patients at highest risk, is often inadequate. When diagnosing DLP, we should always exclude its possible secondary aetiology (e.g. DLP in the context of hypothyroidism, diabetes, ...). Based on the assessment of the overall CV risk (according to SCORE2/SCORE2-OP or according to the comorbidities of the individual), target values for blood lipids, especially LDL-cholesterol, are determined according to the risk category. The basis of the management of DLP in the prevention of ASCVD is dietary and regimen measures, followed by adequate lipid-lowering therapy in indicated cases. As of April 2023, the portfolio of lipid-lowering medication has been expanded to include inclisiran (small interfering RNA against proprotein convertase subtilisin/kexin type 9 (PCSK9)), which is administered directly in cardiologists' and internists' outpatient clinics, ensuring 100% adherence. In severe hypertriglyceridaemia, fibrate monotherapy may be indicated in addition to dietary and regimen measures; if this treatment fails, some patients may be offered lomitapide, volanesorsen or evinacumab as part of clinical trials or specific treatment programmes if very strict indication criteria are met.

Impact of PCSK9 inhibitors on coronary atheroma phenotype following myocardial infarction: insights from intravascular imaging.

PURPOSE OF REVIEW: The aim of this study was to review the impact of combination lipid lowering with statins and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors on coronary atherosclerosis using serial intravascular imaging. RECENT FINDINGS: Early studies using intravascular ultrasound established the ability of increasingly intensive lipid lowering to both slow progression and ultimately promote regression of coronary disease. More recent clinical trials that have employed serial imaging with optical coherence tomography have permitted the ability to evaluate the impact of intensive lipid lowering on compositional features associated with plaque vulnerability. In particular, the combination of intensive statin and PCSK9 inhibitor therapy promotes plaque stability in patients following an acute coronary syndrome. SUMMARY: More intensive lipid lowering using the combination of statins and PCSK9 inhibitors promote plaque regression in addition to promoting calcification, fibrous cap thickening and reductions in plaque lipid. These plaque-stabilizing effects underscore the benefits of combination therapy on cardiovascular events and highlight the importance of combination lipid-lowering therapy.

Strategies of improving adherence to lipid-lowering therapy in patients with atherosclerotic cardiovascular disease.

PURPOSE OF REVIEW: Lowering LDL-C has been shown to reduce ASCVD events, yet many ASCVD patients do not achieve their guideline-directed LDL-C goals leaving patients at increased risk of another ASCVD event. This review discusses implementation strategies to improve guideline-directed lipid management in patients with ASCVD focusing on the provider, patient, and system level. RECENT FINDINGS: At a provider level, under-prescribing of statin intensity due most often to statin intolerance, clinical inertia, insufficient monitoring of LDL-C levels, and the difficulty and cost of prescribing other lipid-lowering therapies such as the PCSK9 inhibitors leads to suboptimal cholesterol management in ASCVD patients. Patients concerns about medication side effects and lack of understanding of their ASCVD risk are causes of poor adherence to their lipid-lowering therapy as are barriers at a system level. SUMMARY: To improve cholesterol management in ASCVD patients will require an integrated approach targeting the provider, the patient and the system. There is a need for further education of clinicians on the importance of intensive LDL-C lowering in ASCVD patients and greater use of nonstatin LDL-C-lowering therapies for those patients on a maximally tolerated statin who have not achieved their guideline-directed LDL-C goal. This will require shared decision-making with a focus on patient education and patient-clinician communication so that the clinician's goals and aims align with that of the patient.

[Hypercholesterolemia and cardiovascular risk]. / Hypercholesterinämie und kardiovaskuläres Risiko.

Pharmacological reduction of LDL-cholesterol (LDL-C) is a major treatment strategy in limiting atherosclerotic cardiovascular (ASCVD) risk. Statins remain the primary therapeutic cornerstone in ASCVD prevention. Furthermore, ezetimibe, bempedoic acid, and PCSK9 inhibition have recently also shown to reduce cardiovascular risk. Unfortunately, a treatment gap remains between guideline-recommended LDL-C goals and what is achieved in real-world practice. An important reason for this is the limited use of novel and effective non-statin lipid-lowering therapies. In order to achieve LDL-C treatment goals and, ultimately, reduction of cardiovascular events, a combination lipid-lowering therapy needs to be considered as the standard of care for patients at very high cardiovascular risk.