VXX-401, a novel anti-PCSK9 vaccine, reduces LDL-C in cynomolgus monkeys.

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disease burden in the world and is highly correlated with chronic elevations of LDL-C. LDL-C-lowering drugs, such as statins or monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9), are known to reduce the risk of cardiovascular diseases; however, statins are associated with limited efficacy and poor adherence to treatment, whereas PCSK9 inhibitors are only prescribed to a "high-risk" patient population or those who have failed other therapies. Based on the proven efficacy and safety profile of existing monoclonal antibodies, we have developed a peptide-based vaccine against PCSK9, VXX-401, as an alternative option to treat hypercholesterolemia and prevent ASCVD. VXX-401 is designed to trigger a safe humoral immune response against PCSK9, resulting in the production of endogenous antibodies and a subsequent 30-40% reduction in blood LDL-C. In this article, VXX-401 demonstrates robust immunogenicity and sustained serum LDL-C-lowering effects in nonhuman primates. In addition, antibodies induced by VXX-401 bind to human PCSK9 with high affinity and block the inhibitory effect of PCSK9 on LDL-C uptake in a hepatic cell model. A repeat-dose toxicity study conducted in nonhuman primates under good laboratory practices toxicity indicated a suitable safety and tolerability profile, with injection site reactions being the main findings. As a promising safe and effective LDL-C-lowering therapy, VXX-401 may represent a broadly accessible and convenient option to treat hypercholesterolemia and prevent ASCVD.

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.

Real-World Clinical Profile of Patients Prescribed Evolocumab in Japan.

BACKGROUND: Real-world utilization data for evolocumab, the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to be introduced in Japan in 2016, to date are limited. This study aimed to clarify the current real-world patient user profiles of evolocumab based on large-scale health claims data. METHODS AND RESULTS: This retrospective database study examined patients from a health administrative database (MDV database) who initiated evolocumab between April 2016 (baseline) and November 2021. Characteristics and clinical profiles of this patient population are described. In all, 4,022 patients were included in the final analysis. Most evolocumab prescriptions occurred in the outpatient setting (3,170; 78.82%), and 940 patients (23.37%) had a recent diagnosis of familial hypercholesterolemia. Common recent atherosclerotic cardiovascular disease events at baseline included myocardial infarction (1,633; 40.60%), unstable angina (561; 13.95%), and ischemic stroke (408; 10.14%). Comorbidity diseases included hypertension (2,504; 62.26%), heart failure (1,750; 43.51%), diabetes (1,199; 29.81%), and chronic kidney disease (297; 7.38%). Among the lipid-lowering regimens concomitant with evolocumab, ezetimibe+statin was used most frequently (1,281; 31.85%), followed by no concomitant lipid-lowering regimen (1,190; 29.59%), statin (950; 23.62%), and ezetimibe (601; 14.94%). The median evolocumab treatment duration for all patients was 260 days (interquartile range 57-575 days). CONCLUSIONS: This study provides real-world insights into evolocumab utilization in Japan for optimizing patient care and adherence to guideline-based therapies to better address hypercholesterolemia in Japan.

A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 µM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 µM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.

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.

Transiently achieved very low LDL-cholesterol levels by statin and alirocumab after acute coronary syndrome are associated with cardiovascular risk reduction: the ODYSSEY OUTCOMES trial.

AIMS: Long-term, placebo-controlled cholesterol-lowering trials have demonstrated legacy effects (clinical benefits that persist or emerge after trial end). It is unknown whether legacy effects follow a short period of very low low-density lipoprotein cholesterol (LDL-C) levels achieved with statin plus PCSK9 inhibitor. METHODS AND RESULTS: In 18,924 patients post-acute coronary syndrome, the ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab with placebo, each added to high-intensity or maximum-tolerated statin therapy. Patients with two consecutive LDL-C levels <0.39 mmol/L (15 mg/dL) on alirocumab had blinded placebo substitution for the remainder of the trial with continued statin treatment. In post hoc analyses, major adverse cardiovascular events (MACE) in these patients were compared to MACE in propensity score-matched patients from the placebo group with similar baseline characteristics and study medication adherence. In the alirocumab group, 730 patients had blinded placebo substitution at a median 8.3 months from randomization, after a median 6.0 months with LDL-C < 0.39 mmol/L. They were matched to 1460 placebo patients. Both groups had lower baseline LDL-C and lipoprotein(a) and better study medication adherence than the overall cohort. Over a median follow-up of 2.8 years, MACE occurred in 47 (6.4%) alirocumab patients with limited-duration, very low achieved LDL-C versus 122 (8.4%) matched placebo patients (treatment hazard ratio 0.72; 95% confidence interval 0.51, 0.997; P = 0.047). CONCLUSIONS: A short period of LDL-C levels <0.39 mmol/L achieved with statin and alirocumab, followed by statin monotherapy, was associated with lower risk of MACE than statin monotherapy throughout the observation period. Clinical benefit persisted for several years. TRIAL REGISTRATION: ClinicalTrials.gov NCT01663402.

Proprotein convertase subtilisin/kexin type 9 inhibitor ameliorates cerebral ischemia in mice by inhibiting inflammation.

OBJECTIVES: To investigate the potential protective effects of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, on ischemic stroke and its underlying mechanisms. MATERIALS AND METHODS: We established a mouse model with distal middle cerebral artery occlusion. We evaluated the therapeutic effects through neurological function and infarct size, while the underlying mechanisms were elucidated using western blotting and real-time polymerase chain reaction. RESULTS: Evolocumab improved neurological recovery, reduced the infarct volume, suppressed the activation of Toll-like receptor (TLR) 4 and nuclear factor-kappa B (NF-κB), and attenuated the increased levels of IL-1ß and TNF-α after cerebral ischemia. CONCLUSION: Evolocumab protects against cerebral ischemic injury by inhibiting inflammation. Therefore, the TLR4/NF-кB pathway may represent a major mechanism in ischemic stroke.

Chronic PCSK9 inhibitor therapy leads to sustained improvements in endothelial function, arterial stiffness, and microvascular function.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) effectively decrease low-density lipoprotein cholesterol (LDL-C) and reduce cardiovascular events in patients at very high cardiovascular risk. Recent short-term studies suggest a partially LDL-C independent beneficial effect of PCSK9 inhibitor (PCSK9i) therapy on endothelial function and arterial stiffness, whereas it is unknown if this effect persists and what the effect is on microcirculation. OBJECTIVE: To investigate the effects of PCSK9i therapy on vascular parameters beyond its lipid lowering effect. METHODS: In this prospective trial, 32 patients at very high cardiovascular risk and indication for PCSK9i therapy were included. Measurements were performed at baseline and after 6 months of PCSK9i treatment. Endothelial function was assessed as flow-mediated dilation (FMD). Arterial stiffness was measured as pulse wave velocity (PWV) and aortic augmentation index (AIx). Peripheral tissue oxygenation (StO2) as a marker of microvascular function was assessed at the distal extremities using near-infrared spectroscopy camera. RESULTS: Six months of PCSK9i therapy decreased LDL-C levels from 141 ± 54 to 60 ± 30 mg/dl (-56 ± 21 %, p < 0.001), FMD significantly increased from 5.4 ± 1.7 % to 6.4 ± 1.9 % (+19 ± 10 %, p < 0.001), PWV decreased in male patients significantly from 8.9 ± 2.1 to 7.9 ± 1.5 m/s (-12 ± 9 %, p = 0.025). AIx decreased from 27.1 ± 10.4 % to 23.0 ± 9.7 % (-16 ± 14 %, p < 0.001), StO2 significantly increased from 67 ± 12 % to 71 ± 11 % (+7 ± 6 %, p = 0.012). Brachial and aortic blood pressure showed no significant changes after six months. There was no correlation between LDL-C reduction and changes in vascular parameters. CONCLUSIONS: Chronic PCSK9i therapy is associated with sustained improvements in endothelial function, arterial stiffness, and microvascular function independent from lipid lowering.

Early Addition of Evolocumab to Statin Treatment in Patients with Acute Coronary Syndrome and Multivessel Disease Undergoing Percutaneous Coronary Intervention.

Background: Evolocumab has been demonstrated to significantly reduce ischemic cardiovascular events in patients with stable coronary heart disease. However, it is currently unclear whether this benefit extends to patients with acute coronary syndrome (ACS) and multivessel disease (MVD) undergoing percutaneous coronary intervention (PCI). The objective of this study was to assess the safety, efficacy and feasibility of the early addition of evolocumab to statin treatment for ACS patients with MVD undergoing PCI. Methods: The authors conducted a multicenter, retrospective cohort study involving 1199 ACS patients with MVD undergoing PCI and with elevated low-density lipoprotein cholesterol (LDL-C) levels. Patients were divided into an evolocumab group or a standard-of-care group based on evolocumab use or not. The 18-month primary efficacy endpoint was a composite of ischemic stroke, death from cardiac causes, recurrent myocardial infarction (MI), unplanned coronary revascularization or unstable angina requiring hospitalization. The principal secondary efficacy endpoint was a composite of ischemic stroke, death from cardiac causes or recurrent MI. Results: After propensity score matching, the addition of evolocumab to statin treatment lowered LDL-C levels by 42.62% compared with statin therapy alone at 18 months, from a mean baseline level of 3.37-0.75 mmol/L (p < 0.001). Relative to standard therapy, evolocumab added to statins was associated with significant reductions in the primary efficacy endpoint (8.3% vs. 13.3%; adjusted hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.39 to 0.91; p = 0.017) and the principal secondary efficacy endpoint (6.1% vs. 10.2%; adjusted HR, 0.61; 95% CI, 0.37 to 0.99; p = 0.048) after multivariable Cox regression adjustment. The treatment effect of evolocumab was consistent across all prespecified subgroups. There were no significant between-group differences in terms of adverse events. Conclusions: In ACS patients with MVD taken for PCI, early initiation of evolocumab along with statin treatment was associated with a significant reduction in LDL-C levels and a reduced risk of recurrent cardiovascular events. Clinical Trial Registration: Chinese Clinical Trials Registry, identifier ChiCTR2000035165. Date: 2 August 2020. URL: https://www.chictr.org.cn/.

The Effectiveness and Safety of Intensive Lipid-Lowering with Different Rosuvastatin-Based Regimens in Patients at High Cardiovascular Disease Risk: A Nonblind, Randomized, Controlled Trial.

Background: A statin alone or non-statins as add-ons have been introduced to intensive low-density lipoprotein cholesterol (LDL-C) -lowering therapy in patients at risk for high cardiovascular disease (CVD). The purpose of this study was to evaluate the effectiveness and safety of different rosuvastatin-based regimens for patients at high risk. Methods: Three hundred patients at high CVD risk were randomly assigned to the statin group (rosuvastatin, 20 mg/d), statin_EZ group (statin 10 mg/d + ezetimibe 10 mg/d), statin_pcsk group (statin 10 mg/d + alirocumab 75 mg/2 weeks) or combine3 group (statin 10 mg/d + ezetimibe 10 mg/d + alirocumab 75 mg/2 weeks). The primary outcome measure was cholesterol levels after 24 weeks of follow-up. Secondary outcomes included safety markers and the proportion of patients achieving the 70 mg/dL (1.8 mmol/L) target for LDL-C. A logistic regression model was performed to explore the factors affecting lipid target achievement. Results: The total cholesterol (TC) and LDL-C levels in the four groups after treatment were significantly lower than those before treatment. TC and LDL-C levels after treatment were significantly different among the four groups (p < 0.05). The levels in both the combine3 and statin_pcsk9 groups were significantly lower than those in the statin and statin_EZ groups (p < 0.05), but there was no significant difference between the combine3 and statin_pcsk9 groups. Fifty-one participants (69%) in the statin_pcsk9 group and 56 participants (78%) in the combine3 group achieved the target. Body mass index (BMI) and hypertensive status were related to LDL-C target achievement. The incidence of adverse events in the four groups was low. Conclusions: The combination of a statin and a PCSK9 inhibitor was safe and more effective for the treatment of high-risk CVD patients, while the addition of ezetimibe was unable to significantly lower lipid levels any further. The rate of achieving the target was higher in patients with hypertension and a low BMI. Clinical Trial Registration: Chinese Clinical Trial Registry, Identifier: ChiCTR2200058389, Date of Registration: 2022-04-08.

PCSK9 inhibitor attenuates atherosclerosis by regulating SNHG16/EZH2/TRAF5-mediated VSMC proliferation, migration, and foam cell formation.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor has been demonstrated to exert a great cardioprotection in cardiometabolic impairments, including atherosclerosis. However, its underlying mechanism remains not fully understood. This study focuses on uncovering the actions of PCSK9 inhibitor on the connection between atherosclerosis and vascular smooth muscle cell (VSMC) behaviors. qRT-PCR was utilized to detect the expression of SNHG16. Proliferation and migration of VSMC were characterized by Cell Counting Kit-8 and wound healing assays. The intracellular lipids and foam cell formation were assessed by Oil Red O staining, fluorescence image, and cholesterol quantification kit. Atherosclerosis in vivo was evaluated by imaging the atherosclerotic lesions, hematoxylin-eosin staining, Oil Red O staining and Masson staining. The interaction between SNHG16 with EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) were investigated by fluorescence in situ hybridization, RNA immunoprecipitation, and chromatin immunoprecipitation assays. A ApoE-/- mice model was used to validate the role of PCSK9 inhibitor and SNHG16 for atherosclerosis. The protective regulation of PCSK9 inhibitor was observed both in high-fat diet (HFD)-fed mice and oxidized low-density lipoprotein (ox-LDL)-treated VSMC, as manifested in the decreased the atherosclerotic lesions in vivo, as well as the weakened cell proliferation, migration, and formation of foam cells in vitro. SNHG16 was identified to be a downstream effector of PCSK9 inhibitor-mediated biological functions, of which knockdown also significantly ox-LDL-treated VSMC proliferation, migration, and foam cell formation abilities. SNHG16 epigenetically suppressed TRAF5 via recruiting EZH2. Silencing of TRAF5 abolished the protective effects of SNHG16 knockdown on the pathogenesis of atherosclerosis. Collectively, PCSK9 inhibitor attenuated atherosclerosis by regulating SNHG16/EZH2/TRAF5 axis to impair the proliferation, migration, and foam cell formation of VSMC.

Safety and Effectiveness of Alirocumab, a Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitor, in Patients With Familial or Non-Familial Hypercholesterolemia　- A Post-Marketing Survey (J-POSSIBLE).

BACKGROUND: This study evaluated the safety and effectiveness of alirocumab in Japanese patients with familial hypercholesterolemia (FH) or non-FH in a real-world clinical setting.Methods and Results: This post-marketing surveillance study had a 2-year standard observation period. The study included Japanese patients with hypercholesterolemia who were treatment naïve to alirocumab, had a high risk of developing cardiovascular events, and had an insufficient response to, or were unsuitable for, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Alirocumab was administered at a dose of 75 or 150 mg via subcutaneous injection every 2 or 4 weeks. Overall, 1,177 and 1,038 patients were included in the safety and effectiveness analysis populations, respectively. The incidence of adverse drug reactions (ADRs) was 3.4% (40/1,177). The time to ADR occurrence was within 4 weeks in half the patients experiencing ADRs (n=20). There were no meaningful differences in the ADRs experienced in the FH and non-FH groups. The mean (±SE) percentage changes in low-density lipoprotein cholesterol from baseline to last observation carried forward were -46.9±2.1% and -42.7±2.0% in the non-FH and FH groups, respectively. Total cholesterol, triglycerides, apolipoprotein B/E, and lipoprotein(a) concentrations were decreased at Week 4 and maintained until Week 104 in the overall population. CONCLUSIONS: Alirocumab was well tolerated and showed effectiveness in Japanese patients with hypercholesterolemia in a real-world clinical setting.

Screening and verifying the mutations in the LDLR and APOB genes in a Chinese family with familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder. The primary objective of this study was to identify the major pathogenic mutations in a Chinese family with FH. METHODS: Whole-genome sequencing (WGS) was used to identify variants of FH-related genes, including low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9). Bioinformatics software was used to predict signal peptides, transmembrane structures, and spatial construction information of the mutated sequences. Western blotting was performed on the mutant protein to determine the presence of the major structural domains of the LDLR. The PCSK9 and APOB genes were screened and analyzed. Moreover, the proband and his brother were treated with a PCSK9 inhibitor for 1 year, and the effect of the treatment on lipid levels was assessed. RESULTS: WGS revealed two potentially pathogenic mutations in the LDLR gene. One was a novel mutation, c.497delinsGGATCCCCCAGCTGCATCCCCCAG (p. Ala166fs), and the other was a known pathogenic mutation, c.2054C>T (p. Pro685Leu). Bioinformatics prediction and in vitro experiments revealed that the novel mutation could not be expressed on the cell membrane. Numerous gene variants were identified in the APOB gene that may have a significant impact on the family members with FH. Thus, it is suggested that the severe manifestation of FH in the proband primarily resulted from the cumulative genetic effects of variants in both LDLR and APOB. However, a subsequent study indicated that treatment with a PCSK9 inhibitor (Evolocumab) did not significantly reduce the blood lipid levels in the proband or his brother. CONCLUSIONS: The cumulative effect of LDLR and APOB variants was the primary cause of elevated blood lipid levels in this family. However, PCSK9 inhibitor therapy did not appear to be beneficial for the proband. This study emphasizes the importance of genetic testing in determining the most suitable treatment options for patients with FH.

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 .

Barriers to prescribing proprotein convertase subtilisin-kexin type 9 inhibitors after coronary revascularisation.

BACKGROUND: Guidelines advocate for intensive lipid-lowering in patients with atherosclerotic cardiovascular disease (ASCVD). In May 2020, evolocumab, a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, became government subsidised in Australia for patients with ASCVD requiring further low-density lipoprotein cholesterol (LDL-C) lowering. AIM: To identify barriers to prescribing PCSK9 inhibitors in hospitalised patients with ASCVD. METHODS: A retrospective 3-month, single-site, observational analysis was conducted in consecutive patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery. Lipid-lowering therapy prescriptions, including PSCK9 inhibitors, were assessed using electronic medical records, compared against the Australian Pharmaceutical Benefits eligibility criteria, and barriers to PCSK9 inhibitor use identified. RESULTS: Of 331 patients, 244 (73.7%) underwent PCI and 87 (26.3%) underwent CABG surgery. A lipid profile during or within 8 weeks of admission was measured for 202 (82.8%) patients undergoing PCI and 59 (67.8%) undergoing CABG surgery. In patients taking high-intensity statins on admission (n = 109), LDL-C ≥1.4, ≥1.8 and >2.6mmol/L was seen in 64 (58.7%), 44 (40.4%) and 19 (17.4%) patients respectively. High-intensity statin prescribing at discharge was high (>80%); however, ezetimibe was initiated in zero patients with LDL-C ≥1.4 mmol/L. There was variable advice given by clinicians for LDL-C targets. No patients met the criteria for subsidised PSCK9 inhibitor therapy, largely due to lack of qualifying lipid levels following combined statin and ezetimibe therapy. CONCLUSION: Prescribing of non-statin LDL-C-lowering therapies remains low in patients with ASCVD. Underprescribing of ezetimibe and suboptimal lipid testing rates are barriers to accessing subsidised PCSK9i therapy using current Australian eligibility criteria.

Emerging Therapies for the Treatment of Atherosclerotic Cardiovascular Disease: From Bench to Bedside.

Primarily a consequence of sedentary lifestyle, atherosclerosis has already reached pandemic proportions, and with every year the burden of it is only increasing. As low-density lipoprotein cholesterol (LDL-C) represents a crucial factor in atherosclerosis formation and progression, stringent lipid-lowering therapy could conceivably be the key to preventing the unfavorable outcomes that arise as a consequence of atherosclerosis. The use of statins in lipid-lowering is often burdened by adverse events or is insufficient to prevent cardiovascular events as a monotherapy. Therefore, in the present review, the authors aimed to discuss the underlying mechanisms of dyslipidemia and associated atherosclerotic cardiovascular disease (ASCVD) and preclinical and clinical trials of novel therapeutic approaches to its treatment, some of which are still in the early stages of development. Apart from novel therapies, a novel change in perspective is needed. Specifically, the critical objective in the future management of ASCVD is to embrace emerging evidence in the field of atherosclerosis, because clinicians are often burden by common practice and personal experience, both of which have so far been shown to be futile in the setting of atherosclerosis.

Acute effect of proprotein convertase subtilisin/kexin type 9 inhibitor on oxidized low-density lipoprotein and lipid profile in patients at cardiovascular risk.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of potent lipid-lowering drugs. Oxidized low-density lipoprotein (ox-LDL) is the key pathogenic factor leading to atherosclerosis. However, its effect on ox-LDL levels has not been clinically reported. The clinical data of 290 very high-risk atherosclerotic cardiovascular disease (ASCVD) patients diagnosed in the First Affiliated Hospital of Zhengzhou University from May 2022 to October 2022 were collected retrospectively. According to whether evolocumab (a PCSK9 inhibitor) was used after percutaneous coronary intervention (PCI), they were divided into evolocumab group (153 cases) and statin monotherapy group (137 cases). At hospital admission, ox-LDL, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoproteinA1 (apoA1), apolipoprotein B-100 (apoB), lipoprotein (a) [Lp(a)], and high-sensitivity reactive protein (hs-CRP) levels were collected and used as baseline data. After two weeks of treatment, ox-LDL in the evolocumab group and statin monotherapy group were significantly lower than those before treatment (p<0.05). The decrease of ox-LDL in the evolocumab group was more than in the stain monotherapy group (p<0.05). In conclusion, PCSK9 inhibitors reduce ox-LDL levels in very high-risk ASCVD patients in a short time.

Medical Management of Dyslipidemia for Secondary Stroke Prevention: Narrative Review.

Dyslipidemia is a major risk factor for stroke, following hypertension, diabetes, and smoking, and is an important risk factor for the prevention and treatment of coronary artery disease and peripheral vascular disease, including stroke. Recent guidelines recommend considering low-density lipoprotein cholesterol (LDL-C)-lowering therapies, such as statins (preferably), ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to prevent the occurrence or recurrence of stroke, adhering to the "lower is better" approach. In this review, we examined the evidence supporting lipid-lowering medications like statins, ezetimibe, and PCSK9 inhibitors for secondary stroke prevention and dyslipidemia management in different stroke subtypes. Stroke guidelines advocate for administering the maximum tolerable dose of statins as the primary treatment and as soon as possible despite the potential for new-onset diabetes mellitus and possible muscle and liver toxicity due to their demonstrated benefits in secondary prevention of cardiovascular diseases and mortality reduction. When statin use is insufficient for LDL lowering, ezetimibe and PCSK9 inhibitors are recommended as complementary therapies. It is essential to establish lipid-lowering therapy goals based on the stroke subtype and the presence of comorbidities.

Hyperlipidemia patients carrying LDLR splicing mutation c.1187-2A>G respond favorably to rosuvastatin and PCSK9 inhibitor evolocumab.

Mutations in the LDL receptor gene LDLR cause familial hypercholesterolemia (FH); however, the pharmacogenomics of specific LDLR mutations remains poorly understood. The goals of this study were to identify the genetic cause of a three-generation Chinese family affected with autosomal dominant FH, and to investigate the response of FH patients in the family to statin and evolocumab. Whole exome sequencing of the FH family with four patients and six unaffected members identified a heterozygous splicing mutation (c.1187-2A>G) in LDLR. The mutation co-segregated with FH in the family, providing strong genetic evidence to support its pathogenicity. The proband was a 48-year-old male FH patient who had an acute myocardial infarction (MI) and ventricular fibrillation (VF), and showed LDL-C of 5.23 mmol/L. A combination of life style modifications on food and exercise and treatment with rosuvastatin reduced his LDL-C to 2.05-2.80 mmol/L. Addition of ezetimibe did not improve rosuvastatin therapy, but addition of evolocumab further reduced LDL-C by 70% to 0.7 mmol/L at the first time and by 67% to 1.31 mmol/L at the second time. Rosuvastatin also reduced LDL-C for proband's father and sister by 40% and 43-63%, respectively. Lovastatin alone or addition to rosuvastatin treatment did not have any effect on LDL-C for the proband and his son. Both patients carry ApoE 3/4 genotype and SLCO1B1 rs4149056 TT genotype. These results suggest that combined treatment with rosuvastatin (but not lovastatin or ezetimibe) and evolocumab can control LDL-C to meet the LDL-C treatment goal for patients with LDLR splicing mutation c.1187-2A>G.

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2022 European Society of Cardiology Congress.

PURPOSE OF REVIEW: Focused review of select studies presented at the 2022 European Society of Cardiology Congress. RECENT FINDINGS: Included studies assessed the effects of aspirin and omega-3 fatty acid supplements on heart failure (ASCEND study); the impact of icosapent ethyl on ST-elevation MI incidence (REDUCE-IT); air temperature's effect on cardiovascular mortality (EXHAUSTION project); LVEF outcomes after troponin-guided neurohormonal blockade for the prevention of anthracycline toxicity; efficacy of routine stress testing after high-risk PCI (POST-PCI trial); influenza vaccine among patients with acute coronary syndromes (VIP-ACS trial); empagliflozin in patients with acute myocardial infarction (EMMY); effects of comprehensive imaging-based cardiovascular screening on death and cardiovascular events (DANCANVAS); safety of long-term evolocumab in patients with established atherosclerotic cardiovascular disease (FOURIER-OLE); and use of a cardiovascular polypill as a global strategy to improve secondary prevention (SECURE). Research presented at the 2022 ESC Congress highlighted many novel applications of preventative and treatment strategies in cardiology, including the effects of environmental risk factors on the incidence of cardiovascular disease.