on May 16, 2022 At the Eastern Conference on Cardiology (OCC 2022), Professor Lu Guoping from Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine summarized the new progress in the field of blood lipids in 2021-2022.
Biologics target blood cholesterol lowering: a plaque stabilization study
1. Evolumab (HUYGENS study) 1) Study content< The /strong> HUYGENS study is a randomized, double-blind, placebo-controlled, global multicenter clinical trial of 161 patients receiving maximum tolerated doses of statins Treated patients with non-ST-segment elevation myocardial infarction (NSTEMI) were randomly assigned 1:1 to the evolumab group (monthly subcutaneous injection of evolumab 420 mg) and the placebo group (monthly subcutaneous injection phase matching placebo). The study lasted 52 weeks, and the primary endpoint was the change in absolute minimum fibrous cap thickness (FCT) from baseline to week 50 in matched arterial segments. 2) Study Results Baseline OCT Data Display : The lipid-rich plaques (3 consecutive images with FCT≤120μm and lipid arc greater than 90°) accounted for 91% and 90% of the drug group and the control group, respectively. Most subjects had high-risk, vulnerable plaque. In ACS patients, treatment with ivolumab for approximately 1 year significantly increased minimal fibrous cap thickness (FCT) and stabilized vulnerable plaques. In conclusion, the early initiation of statin combined with eloyumab during hospitalization in ACS patients significantly increased the minimum plaque fibrous cap thickness, reduced lipid arc and plaque volume, and effectively stabilized and reversed vulnerable plaques. 2. Alisizumab (PACMAN-AMI study) span>1) Research content PACMAN-AMI double-blind, placebo-controlled, randomized clinical trial included 300 AMI patients in total After primary PCI for culprit vascular lesions, patients were randomly assigned to biweekly alizumab (150 mg, n=148) or placebo (n=152), with rosuvastatin 20 mg daily in both groups. The primary endpoint was change in percent atherosclerosis (PAV) as measured by IVUS. 2) Results of the study 24 after PCI Aliximab should be combined with a high-dose statin as soon as possible. Alisizumab had a significant effect on vulnerable plaque burden, composition and properties, laying the foundation for the benefit of the final key endpoint of ASCVD.
Research on novel targeted lipid-lowering biologics
1. Lower LDL-C (1) Inclisiran (ORION-4 study) 1) Study content ORION-4 is a randomized, double-blind, placebo-controlled study that enrolled 15,000 ASCVD patients aged ≥55 years. Patients were randomized 1:1, and the drug group received subcutaneous injection of Inclisiran 300mg (siRNA molecule that inhibits PCSK-9 transcription), 3 months after the first dose, and every 6 months thereafter. The primary efficacy end point was a clinically relevant composite cardiovascular end point (coronary heart disease-related death, myocardial infarction, fatal or non-fatal ischemic stroke, emergency coronary revascularization). 2) Results of the studyIncisiran once every 6 months can effectively reduce LDL-C, PCSK-9, TC and arteriogenesis Atherosclerotic lipid levels. (2) AZD8233 (ETESIAN study) 1) Study contentETESIAN is a randomized, parallel group, double-blind, placebo-controlled, dose-ranging, phase IIb study in patients with dyslipidemia (70 mg/dL≤LDL- C < 190 mg/dl; TG < 400 mg/dl) 119 cases. Randomly assigned 1:1:1:1 to AZD823 (antisense oligonucleotide drug targeting PCSK9) with different injection dose groups (90mg, 50mg, 15mg, respectively) and placebo group. The primary endpoint of the study was the efficacy of different doses of AZD8233 versus placebo in reducing serum LDL-C levels at 12 weeks. 2) Results AZD8233 significantly reduced PCSK9 and LDL-C levels by 73%-79%. (3) MK-0616 related studies (MK-0616: the first oral PCSK9 mAb) span> 1) Research content A phase I clinical study, divided into two parts: single-dose and multi-dose studies, both Randomized, double-blind, placebo-controlled study. A single-dose escalation study included 60 healthy male subjects aged 18-50, who were randomly assigned to receiveA single dose of MK-0616 (10-300mg) or placebo, designed to evaluate the safety of MK-0616 and its effect on PCSK9 levels. The multi-dose study included 40 subjects aged 18-65 years, baseline LDL-C of 60-160 mg/dL, receiving statin therapy for ≥3 months, and randomly assigned to the MK-0616 treatment group in a 3:1 ratio or placebo, for 14 days, designed to assess the effect of MK-0616 on LDL-C levels. 2) Research results MK-0616 can effectively reduce the level of PCSK9 in a single dose, and after 14 days of multi-dose treatment. Decreases >50% LDL-C. 2. Lower Lp(a) < /span>1) Pelacarcen (TQJ230)Pelacarsen is an antisense oligonucleotide that binds to apolipoprotein (a ) mRNA, inhibiting conversion to protein and reducing Lp(a) by 70-90%. 2) siRNA targeting the apolipoprotein(a) gene of Lp(a) (APOLLO research) Subjects receiving 300 mg and 600 mg of SLN360 had a 96% and 98% reduction in Lp(a) levels, respectively, and a 70% and 81% reduction from baseline at 5 months, while those receiving placebo The patient’s Lp(a) level was unchanged. 3. Lower TG 1 ) Volanesorsen is an antisense oligonucleotide drugthe world’s first approved biologic for the treatment of FCS, targeting apolipoprotein C-III (ApoC-Ill) antisense oligonucleotide drug that modulates plasma TG by inhibiting the production of ApoC-Ill. The approved indication is adjunctive dietary control for the treatment of adult patients with FCS who are poorly controlled by dietary control and triglyceride-lowering therapy, are at high risk for pancreatitis, and have been confirmed by genetic testing. 2) ARO-APOC3ARO-APOC3 is a targeted lipid carrier siRNA of protein C3 mRNA can reduce TG levels by 90%. ARO-APOC3 can significantly reduce AOPC3, TG, non-HDL-C levels and increase HDL-C levels. 4. Lower LDL-C and TG simultaneously Angiopoietin-like protein 3 (ANGPTL3) belongs to the vascular endothelial growth hormone family and is synthesized and secreted by the liver. It is an inhibitor of lipoprotein lipase and endothelial lipase, inhibits the clearance of VLDL and TG, and directly activates the lipolysis of adipocytes. 1) Evinacumab Evinacumab is a Human monoclonal antibody targeting the IgG4 subtype of angiopoietin-like protein 3 (ANGPTL3). On February 11, 2021, the FDA first approved it for the treatment of children 12 years and older or adults with familial homozygous hypercholesterolemia (HoFH). 2) Vupanorsen (TRANSLATE-TIMI 70 study) < span>Vupanorsen is an antisense oligonucleotide drug targeting ANGPTL3 mRNA, which can significantly reduce non-HDL-C levels. Triglycerides decreased in a dose-dependent manner; ANGPTL3 levels decreased in a dose-dependent manner; Vupanorsen had less effect on LDL-C and ApoB and did not show a significant dose response.
EPA (IPE): Update on REDUCE-IT Research< /span>
REDUCE-IT study and its post hoc analysis and subgroup study results show that IPE can benefit patients in the early stage of treatment, and Significant benefit was seen for individual hard endpoints, such as coronary remodeling, fatal and non-fatal stroke, and ischemic stroke. The higher the risk, the greater the benefit, as in previous MI patients. 1.REDUCE-IT study span>1) Research content REDUCE-IT research included 473 studies from 11 countries 8179 statin-treated patients at the center were randomized to IPE 4 g/d or placebo. Patients with cardiovascular disease or diabetes with cardiovascular risk factors, fasting TG level ≥150 mg/dl but ≤500 mg/dl, LDL-C>40 mg/dl but ≤100 mg/dl. The primary end point was the occurrence of the first cardiovascular event (including CV death, non-fatal MI, non-fatal stroke, coronary revascularization, unstable angina requiring hospitalization). 2) Study results Median follow-up for 4.9 years. On the basis of statin therapy, IPE can further significantly reduce the risk of cardiovascular events in patients with elevated TG. 2. Post-hoc analysis of stroke endpoints in the REDUCE-IT study < span> A post hoc analysis of the stroke endpoints of the REDUCE-IT study assessed the incidence of stroke in 8179 patients, with results to be published in 2021 ISC. The study showed that IPE significantly reduced the risk of first fatal and non-fatal stroke events by 28% and 32%, respectively, and reduced the risk of first ischemic stroke events by 36%. 3.REDUCE-IT revascularization post hoc analysisREDUCE-IT study blood A post-hoc analysis of revascularization evaluated 8179 patients for all coronary revascularization, recurrent revascularization, and revascularization subtypes. Coronary revascularization risk decreased by 34% in IPE group; elective, urgent, and emergency coronaryThe incidence of revascularization decreased significantly. The benefit of IPE in reducing the risk of coronary revascularization was evident at 11 months of treatment. 4.REDUCE-IT PRIOR MI subgroup analysis < span> This study included patients with a history of myocardial infarction in REDUCE-IT, 1870 in the IPE group and 1823 in the placebo group. The follow-up results showed that IPE 4g/d made the first and overall (first + relapse) of the previous myocardial infarction patients. The risk of primary endpoint was significantly reduced by 26% and 35% (P<0.001), respectively, and the risk of secondary endpoint was significantly reduced by 32% (P<0.001). 5.REDUCE-IT Subgroup Analysis of Previous PCI < span>3408 (41.7%) of 8179 patients in the REDUCE-IT study had previously undergone PCI, with a median follow-up of 4.8 years. These patients were randomly assigned to IPE or placebo after PCI, and there were no significant differences in baseline characteristics between the two groups. The primary composite endpoint was reduced by 34% in the IPE group compared with the placebo group. In statin-treated patients with elevated TG and prior PCI, IPE significantly reduced the risk of recurrent events during a mean follow-up period of 5 years.
PROMINEBT study terminated
< p>
On April 8, 2022, Kowa announced the termination of the PROMINENT study (Pemafibrat[Pemafibrate< /span>]). The data safety monitoring committee conducted an interim analysis of the PROMINENT study data and believed that the study was difficult to reach the end point of the study, so Kowa announced the early termination of the study. Nevertheless, the results of the PROMINENT trial suggest that pemapet may be useful in new therapeutic areas (non-alcoholic fatty liver disease and non-alcoholic fatty liver disease). hepatitis) showed therapeutic potential. At the same time, the research has also triggered thinking and discussion on fenofibrate. The existing evidence shows that:
1) PROMINENT Early termination cannot negate the previous research and clinical application evidence of fibrates;
2) Fenofibrate and pemafibrate are different compounds and are not completely equivalent;< /span>
3) Fenofibrate can not only significantly reduce TG, but also effectively reduce non-HDL-C levels, VLDL particles and LDL particles;
< p>4) Combined with fenofibrate on the basis of statin, it can more effectively improve the compliance rate of non-HDL-C, reduce VLDL-C and Apo B;
5) Accord, etc. Studies have confirmed that for patients with TG≥2.3mmol/L and low HDL-C, the addition of fenofibrate to statin can significantly reduce the residual cardiovascular risk. Therefore, the analysis of the information after the announcement cannot deny the previous clinical studies of BETTER.