Efficacy and Safety of an Investigational Single-Course CRISPR Base-Editing Therapy Targeting PCSK9 in Nonhuman Primate and Mouse Models.

BACKGROUND: VERVE-101 is an investigational in vivo CRISPR base-editing medicine designed to alter a single DNA base in the PCSK9 gene, permanently turn off hepatic protein production, and thereby durably lower low-density lipoprotein cholesterol. We test the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of nonhuman primates and a murine F1 progeny study. METHODS: Cynomolgus monkeys were given a single intravenous infusion of a vehicle control (n=10) or VERVE-101 at a dose of 0.75 mg/kg (n=4) or 1.5 mg/kg (n=22) with subsequent follow-up up to 476 days. Two studies assessed the potential for germline editing, including sequencing sperm samples from sexually mature male nonhuman primates treated with VERVE-101 and genotyping offspring from female mice treated with the murine surrogate of VERVE-101 (VERVE-101mu). RESULTS: Liver biopsies 14 days after dosing noted mean PCSK9 editing of 46% and 70% in monkeys treated with VERVE-101 at 0.75 and 1.5 mg/kg, respectively. This translated into mean reductions in blood PCSK9 (proprotein convertase subtilisin/kexin type 9) of 67% and 83% and reductions of low-density lipoprotein cholesterol of 49% and 69% at the 0.75 and 1.5 mg/kg doses, respectively, assessed as time-weighted average change from baseline between day 28 and up to 476 days after dosing. Liver safety monitoring noted a transient rise in alanine aminotransferase and aspartate aminotransferase concentrations after infusion that fully resolved by day 14 with no accompanying change in total bilirubin. In a subset of monkeys necropsied 1 year after dosing, no findings related to VERVE-101 were identified on macroscopic and histopathologic assessment of the liver and other organs. In the study to assess potential germline editing of male nonhuman primates, sperm samples collected after VERVE-101 dosing showed no evidence of PCSK9 editing. Among 436 offspring of female mice treated with a saturating dose of VERVE-101mu, the PCSK9 edit was transmitted in 0 of 436 animals. CONCLUSIONS: VERVE-101 was well tolerated in nonhuman primates and led to 83% lower blood PCSK9 protein and 69% lower low-density lipoprotein cholesterol with durable effects up to 476 days after dosing. These results have supported the initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease.

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.

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 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.

Inclisiran: present and future perspectives of a new effective LDL cholesterol-lowering agent.

PURPOSE OF REVIEW: To highlight critical aspects of inclisiran, from preclinical studies to current recommendations in clinical practice and future perspectives. RECENT FINDINGS: Inclisiran use has been recently approved by regulatory agencies. The evidence of its efficacy and safety makes it a promising therapeutical tool for treating dyslipidemias. SUMMARY: The link between LDL-cholesterol and atherosclerotic cardiovascular disease (ASCVD) is well established. Inclisiran, a small interfering RNA, has proven its safety and efficacy in reducing LDL-cholesterol, and FDA and EMA have recently approved its use. This review illustrates the development, structure, and mechanism of action of inclisiran and provides information regarding its efficacy, safety, and current recommendation in clinical practice. Moreover, it provides key information on the most recent/ongoing trials that will help us to implement the use of inclisiran in clinical practice.

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.

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.

Alirocumab and plaque volume, calf muscle blood flow, and walking performance in peripheral artery disease: A randomized clinical trial.

BACKGROUND: The distal superficial femoral artery (SFA) is most commonly affected in peripheral artery disease (PAD). The effects of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab added to statin therapy on SFA atherosclerosis, downstream flow, and walking performance are unknown. METHODS: Thirty-five patients with PAD on maximally tolerated statin therapy were recruited. Patients were randomized to alirocumab 150 mg subcutaneously (n = 18) or matching placebo (n = 17) therapy every 2 weeks for 1 year. The primary outcome was change in SFA plaque volume by black blood magnetic resonance imaging (MRI). Secondary outcomes were changes in calf muscle perfusion by cuff/occlusion hyperemia arterial spin labeling MRI, 6-minute walk distance (6MWD), low-density lipoprotein (LDL) cholesterol, and other biomarkers. RESULTS: Age (mean ± SD) was 64 ± 8 years, 20 (57%) patients were women, 17 (49%) were Black individuals, LDL was 107 ± 36 mg/dL, and the ankle-brachial index 0.71 ± 0.20. The LDL fell more with alirocumab than placebo (mean [95% CI]) (-49.8 [-66.1 to -33.6] vs -7.7 [-19.7 to 4.3] mg/dL; p < 0.0001). Changes in SFA plaque volume and calf perfusion showed no difference between groups when adjusted for baseline (+0.25 [-0.29 to 0.79] vs -0.04 [-0.47 to 0.38] cm3; p = 0.37 and 0.22 [-8.67 to 9.11] vs 3.81 [-1.45 to 9.08] mL/min/100 g; p = 0.46, respectively), nor did 6MWD. CONCLUSION: In this exploratory study, the addition of alirocumab therapy to statins did not alter SFA plaque volume, calf perfusion or 6MWD despite significant LDL lowering. Larger studies with longer follow up that include plaque characterization may improve understanding of the effects of intensive LDL-lowering therapy in PAD (ClinicalTrials.gov Identifier: NCT02959047).

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.

Dendritic cell-derived exosomal miR-3064-5p inhibits SIRT6/PCSK9 to protect the blood-brain barrier after subarachnoid hemorrhage.

The protection of the blood-brain barrier (BBB) is the key direction to improving subarachnoid hemorrhage (SAH). Therefore, developing appropriate targeted drugs and therapies has become an urgent task for SAH patients. In this study, we investigated the role of dendritic cells (DCs) exosomal miR-3064-5p in repairing the BBB, providing a new basis for treating SAH. We detected the expression of miR-3064-5p in exosomes secreted by DCs (DCs-exo). An SAH rat model was constructed by intravascular perforation and characterized by HE and TUNEL-IF staining. We found that overexpression of miR-3064-5p in SAH rats suppressed iNOS expression and promoted the accumulation of tight junction proteins (Occludin, Claudin-3, ZO-1), whereas knockdown of miR-3064-5p exerted the opposite effect. Dual-LUC assay confirmed that miR-3064-5p could target and inhibit SIRT6. Knockdown of SIRT6 inhibited inflammatory cytokine (IL-6, IL-1ß, IFN-γ, and TGF-ß1) levels and apoptosis. The results of the co-IP assay showed that SIRT6 interacted with PCSK9, and knockdown of SIRT6 suppressed the expression of PCSK9. Moreover, DCs-exo reduced brain edema, upregulated miR-3064-5p and downregulated SIRT6 and PCSK9 in SAH rats. DCs-exo reduced inflammatory factors and increased tight junction proteins in SAH rats. Overexpression of miR-3064-5p enhanced the protective effect of DCs-exo, while overexpression of SIRT6 partially counteracted the effect. This study confirmed that DCs could secrete miR-3064-5p to ameliorate BBB damage after SAH. Mechanistically, miR-3064-5p alleviated BBB damage by targeting and inhibiting SIRT6/PCSk9 signaling pathway.

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.

Effect of alirocumab on cataracts in patients with acute coronary syndromes.

BACKGROUND: Some data suggest that low levels of low-density lipoprotein cholesterol (LDL-C) are associated with risk of cataracts. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors reduce LDL-C below levels achieved with statins alone. We determined whether the incidence of cataracts was influenced by treatment with the PCSK9 inhibitor alirocumab versus placebo, and whether that incidence was affected by achieved LDL-C levels. METHODS: The ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving high-intensity or maximum-tolerated statin. Incident cataracts were pre-specified events of interest. In multivariable analysis using propensity score-matching on characteristics including cataract risk factors, incident cataracts were compared in the alirocumab and placebo groups according to LDL-C levels achieved with alirocumab. RESULTS: Over median follow-up of 2.8 years (interquartile range 2.3 - 3.4), the incidence of cataracts was similar with alirocumab (127/9462 [1.3%]) versus placebo (134/9462 [1.4%]); hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74 - 1.20). In patients treated with alirocumab with ≥ 2 LDL-C values < 25 mg/dL (0.65 mmol/L), the incidence of cataracts was 71/4305 (1.6%), versus 60/4305 (1.4%) in propensity score-matched patients from the placebo group (HR 1.10, CI 95% 0.78 - 1.55). In patients treated with alirocumab with ≥ 2 LDL-C values < 15 mg/dL (0.39 mmol/L), the incidence of cataracts was 13/782 (1.7%), versus 36/2346 (1.5%) in matched patients from the placebo group (HR 1.03, CI 95% 0.54 - 1.94). CONCLUSION: Treatment with alirocumab versus placebo, added to statin, did not influence the incidence of cataracts, even when achieved LDL-C levels on alirocumab were very low. Longer follow-up studies might be necessary to exclude the long-term effects on the incidence or progression of cataracts. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01663402 .

Effect of inclisiran on lipids in primary prevention: the ORION-11 trial.

AIMS: Patients often require combination therapies to achieve LDL cholesterol (LDL-C) targets for the primary prevention of atherosclerotic cardiovascular disease. This study investigates the effect of inclisiran, a small interfering ribonucleic acid targeting hepatic proprotein convertase subtilisin/kexin type 9 production, in primary prevention patients with elevated LDL-C despite statins. METHODS AND RESULTS: This pre-specified analysis of the placebo-controlled, randomized ORION-11 trial included 203 individuals at risk of, but without prior, cardiovascular events and LDL-C ≥2.6 mmol/L, despite maximally tolerated statins. Inclisiran 284 mg or placebo was administered on Days 1, 90, and thereafter every 6 months up to 540 days. Co-primary endpoints were percentage LDL-C change from baseline to Day 510 and time-adjusted change from baseline after Day 90 and up to Day 540. Key secondary endpoints included percentage and absolute changes in atherogenic lipoproteins. Safety was assessed over 540 days. The mean baseline (SD) LDL-C was 3.6 (1.5) mmol/L. At Day 510, the placebo-corrected LDL-C change with inclisiran was -43.7% [95% confidence interval (CI): -52.8 to -34.6] with a corresponding time-adjusted change of -41.0% (95% CI: -47.8 to -34.2); (P < 0.0001). The placebo-corrected absolute change in LDL-C at Day 510 with inclisiran was -1.5 mmol/L (95% CI: -1.8 to -1.2), with a respective time-adjusted change of -1.3 mmol/L (95% CI: -1.6 to -1.1). Inclisiran significantly lowered non-HDL cholesterol and apolipoprotein B (apoB) at Day 510 vs. placebo (P < 0.0001 for both), with a greater likelihood of attaining lipoprotein and apoB goals, and was well-tolerated except for mainly mild, treatment-emergent adverse events at the injection site. CONCLUSION: Inclisiran was generally well-tolerated in primary prevention patients with elevated LDL-C, who derived significant reductions in atherogenic lipoprotein levels with twice-yearly maintenance dosing.

Alirocumab after acute coronary syndrome in patients with a history of heart failure.

AIMS: Patients with heart failure (HF) have not been shown to benefit from statins. In a post hoc analysis, we evaluated outcomes in ODYSSEY OUTCOMES in patients with vs. without a history of HF randomized to the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab or placebo. METHODS AND RESULTS: Among 18 924 patients with recent acute coronary syndrome (ACS) receiving intensive or maximum-tolerated statin treatment, the primary outcome of major adverse cardiovascular events (MACE) was compared in patients with or without a history of HF. The pre-specified secondary outcome of hospitalization for HF was also analysed. Overall, 2815 (14.9%) patients had a history of HF. Alirocumab reduced low-density lipoprotein cholesterol and lipoprotein(a) similarly in patients with or without HF. Overall, alirocumab reduced MACE compared with placebo [hazard ratio (HR): 0.85; 95% confidence interval (CI): 0.78-0.93; P = 0.0001]. This effect was observed among patients without a history of HF (HR: 0.78; 95% CI: 0.70-0.86; P < 0.0001), but not in those with a history of HF (HR: 1.17; 95% CI: 0.97-1.40; P = 0.10) (Pinteraction = 0.0001). Alirocumab did not reduce hospitalization for HF, overall or in patients with or without prior HF. CONCLUSION: Alirocumab reduced MACE in patients without a history of HF but not in patients with a history of HF. Alirocumab did not reduce hospitalizations for HF in either group. Patients with a history of HF are a high-risk group that does not appear to benefit from PCSK9 inhibition after ACS.

Management and clinical outcomes of patients with homozygous familial hypercholesteremia in Saudi Arabia.

We report the incidence, patient characteristic with clinical outcomes in patients with homozygous familial hypercholesterolemia (HoFH) in Saudi Arabia. This is a retrospective and prospective, single center study which included 37 patients 14 years and older enrolled and followed up between 2018-2021 for three years. 46% were females, 78% were offspring of consanguineous marriage. LDLR mutation was in 78% and LDL-C/LDLRAP in 3% of patients. Mean LDL-C at the first presentation was 14.2±3.7 mmol/L, average Dutch lipid score was 20.9±6.24. LDL apheresis was performed on 70% of patients. Most patients were on ezetimibe (92%), high-dose statins ( 84%) and  PCSK9 inhibitors (32%). 48.6% had aortic stenosis, out of which 30% had severe aortic stenosis. Ten underwent aortic valve surgery (5 mechanical valve, 3 Ross procedure, 1 aortic valve repair, 1 bioprosthetic valve) and one had transcatheter aortic valve implantation (TAVI). Coronary artery bypass surgery (CABG) was performed on 32% and percutaneous intervention (PCI) on 11% of patients. HoFH patients have complex diseases with high morbidity and mortality, and benefit from a highly specialized multidisciplinary clinic to address their clinical needs. Although there are several therapeutic agents on the horizon, early diagnosis, and treatment of HoFH remain critical to optimize patient outcomes.

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.

Proprotein convertase subtilisin/kexin type 9 inhibition after acute coronary syndrome or prior myocardial infarction.

PURPOSE OF REVIEW: Lowering low-density lipoprotein cholesterol (LDL-C) with statins or ezetimibe reduces major adverse cardiovascular events (MACE) in patients with coronary heart disease. Additional treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may lower LDL-C to levels not achievable with conventional lipid-lowering agents. This review summarizes findings from two large, placebo-controlled trials that evaluated the cardiovascular efficacy of monoclonal antibodies directed against PCSK9, added to background statin therapy, in patients with established atherosclerotic cardiovascular disease (ASCVD) or recent acute coronary syndrome (ACS) and persistent elevation of atherogenic lipoproteins despite statin treatment. RECENT FINDINGS: The FOURIER trial with evolocumab and the ODYSSEY OUTCOMES trial with alirocumab demonstrated 15% overall reductions in MACE compared to placebo, associated with average achieved LDL-C levels as low as 30-40 mg/dl. Alirocumab treatment was associated with fewer deaths after ACS. Subgroups with large absolute treatment benefit included those with baseline LDL-C ≥100 mg/dl, diabetes, polyvascular or peripheral artery disease, prior coronary bypass surgery, statin intolerance, or elevated lipoprotein(a) levels. No safety concerns arose with use of PCSK9 monoclonal antibodies, even in patients who achieved LDL-C levels below 20 mg/dl. SUMMARY: In selected patients with established ASCVD or recent ACS, PCSK9 inhibitors can play an important role in reducing the risk of MACE, and may also reduce the risk of death after ACS.

Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).

BACKGROUND: The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. METHODS: Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. FINDINGS: Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53·6%] women) from 56 countries were included in the study. Of these, 31 798 (75·4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84·2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46·2 years (IQR 34·3-58·0); median age at diagnosis of familial hypercholesterolaemia was 44·4 years (32·5-56·5), with 40·2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17·4% (2·1% for stroke and 5·2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81·1%) were receiving statins and 3691 (21·2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5·43 mmol/L (IQR 4·32-6·72) among patients not taking lipid-lowering medications and 4·23 mmol/L (3·20-5·66) among those taking them. Among patients taking lipid-lowering medications, 2·7% had LDL cholesterol lower than 1·8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1·8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p<0·001). INTERPRETATION: Familial hypercholesterolaemia is diagnosed late. Guideline-recommended LDL cholesterol concentrations are infrequently achieved with single-drug therapy. Cardiovascular risk factors and presence of coronary disease were lower among non-index cases, who were diagnosed earlier. Earlier detection and greater use of combination therapies are required to reduce the global burden of familial hypercholesterolaemia. FUNDING: Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron.

Lipid-Modifying Therapies and Stroke Prevention.

PURPOSE OF REVIEW: We reviewed lipid-modifying therapies and the risk of stroke and other cerebrovascular outcomes, with a focus on newer therapies. RECENT FINDINGS: Statins and ezetimibe reduce ischemic stroke risk without increasing hemorrhagic stroke risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors similarly reduce ischemic stroke risk in statin-treated patients with atherosclerosis without increasing hemorrhagic stroke, even with very low achieved low-density lipoprotein cholesterol levels. Icosapent ethyl reduces the risk of total and first ischemic stroke in patients with established cardiovascular disease or diabetes mellitus. Clinical outcome trials are underway for newer lipid-modifying agents, including inclisiran, bempedoic acid, and pemafibrate. New biologic agents including evinacumab, pelacarsen, olpasiran, and SLN360 are also discussed. In addition to statins and ezetimibe, PCSK9 inhibitors and icosapent ethyl reduce the risk of ischemic stroke without increasing the risk of hemorrhagic stroke. These therapies dramatically expand options for reducing stroke in high-risk settings.

Association between causative mutations and response to PCSK9 inhibitor therapy in subjects with familial hypercholesterolemia: A single center real-world study.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an autosomal dominant disease that leads to cardiovascular (CV) disease. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-I) demonstrated efficacy in low-density lipoprotein cholesterol (LDL-C) reduction and in prevention of CV events. The aim of our study is to evaluate the relationship between LDL receptor (LDLR) mutations and response to PCSK9-I therapy. METHODS AND RESULTS: We evaluated total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in consecutive patients with FH before PCSK9-I treatment and after 12 (T12w) and 36 (T36w) weeks of treatment. We evaluated LDL-C target achievement according to different mutations in LDLR. Eighty FH subjects (mean age:54 ± 13.3 years), 39 heterozygous (He) with defective LDLR gene mutations, 30 He with null mutations and 11 compound-He or homozygous (Ho) were recruited. At baseline, 69 subjects were under maximal lipid lowering therapy (MLLT) and 11 subjects had statin-intolerance. From baseline to T36w we observed an overall 51% reduction in LDL-C. We found no difference in LDL-C changes between subjects with He-defective mutation and He-null mutations both at T12w (p = 1.00) and T36w (p = 0.538). At T36w, LDL-C target was achieved in 59% of He-defective mutations subjects and in 36% of He-null mutations subgroup (p = 0.069), whereas none of compound-He/Ho-FH achieved LDL-C target. CONCLUSIONS: After 36 weeks there were no differences in response to PCSK9-I therapy between different groups of He-FH subjects. Response to PCSK9-I was significantly lower in carriers of compound-He/Ho mutations. Registration number for clinical trials: NCT04313270 extension.