Background: Early neurological deterioration (END) is associated with a poor prognosis in acute ischemic stroke (AIS). Effectively lowering low-density lipoprotein cholesterol (LDL-C) can improve the stability of atherosclerotic plaque and reduce post-stroke inflammation, which may be an effective means to lower the incidence of END. The objective of this study was to determine the preventive effects of evolocumab on END in patients with non-cardiogenic AIS. Methods: This was a multicenter, prospective, open-label, blinded-endpoint clinical trial. Participants with AIS within 24 h were randomly assigned to either the group receiving combination therapy of evolocumab and atorvastatin, which is a 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, i.e., a “statin” (PI group), or the group receiving atorvastatin monotherapy (AT group). The primary outcome was END within 7 days, defined as a 2-point increase in the National Institutes of Health Stroke Scale (NIHSS) score or a 1-point increase in motor function within 24 h–7 days from the onset of AIS. Secondary outcomes included LDL-C target achievement rate on day 7 (≤ 1.8 mmol/L with a reduction exceeding 50% from baseline), inflammatory factors (interleukin [IL]-6, IL-8, and tumor necrosis factor [TNF]-α) before and after 7 days of treatment, and stroke-related death with 7 days. Safety endpoints included any adverse events. Results: Patients with AIS (n = 272) were randomly assigned to the PI (n = 136) or AT (n = 136) groups. Within 7 days, 18 (13.2%) and 33 (24.3%) patients experienced END in the PI and AT groups, respectively (relative risk [RR] −0.90; 95% confidence interval [CI]: −1.59 to −0.22; p = 0.010). On the seventh day, LDL-C target achievement rate in the PI and AT groups was 74.3% and 14.7%, respectively (RR 3.27; 95% CI.: 2.40–4.15; p = 0.001). Changes in IL-6 over 7 days were significantly lower in the PI group compared with the AT group, respectively (median 1.02 [range −1.91, 5.47] versus 2.54 [−0.83, 15.20]; p = 0.033). On the 90th day of follow-up, 83.1% and 65.4% of patients had a modified Rankin Scale score ≤ 2 in the PI and AT groups, respectively (RR 0.51; 95% CI.: 0.66–2.66; p = 0.001). There was no significant difference in stroke recurrence between the two groups within 90 days (RR −1.72; 95% CI.: −4.57 to 1.13; p = 0.237). Regarding adverse events, 15 and 22 patients in the PI and AT groups, respectively, experienced slight abnormalities in liver and kidney function laboratory values during the 7-day treatment period (odds ratio 0.62; 95% CI.: 0.30–1.29; p = 0.203), but no serious adverse events were observed in either group. Conclusion: These results suggest that the combination therapy of evolocumab and atorvastatin within 24 h of AIS onset may effectively reduce the incidence of END compared with atorvastatin monotherapy. Additionally, in the early stages of AIS, this combination therapy can reduce blood LDL-C levels, and inhibit IL-6 elevation, potentially improving the prognosis of patients with AIS within 90 days. Trial Registration: China Clinical Trials Registry (No: ChicTR2200059445, 29 April 2022, https://www.chictr.org.cn/). © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2025.

BACKGROUND:

The prevalence of very high-risk atherosclerotic cardiovascular disease (ASCVD) is significant in China, with suboptimal rates of low-density lipoprotein cholesterol (LDL-C) compliance exacerbating plaque instability and causing a higher incidence of major adverse cardiac events (MACEs). Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are effective in reducing LDL-C levels, increase the stability of vulnerable plaque, and influence the progression of atherosclerosis through multiple mechanisms as demonstrated in animal studies. However, there is currently a lack of in vivo evidence regarding the efficacy and safety of high-intensity statin therapy combined with PCSK9i in the secondary prevention of ASCVD in the Chinese population. This study aims to demonstrate the efficacy of high-intensity statins combined with PCSK9i on vulnerable plaques in very high-risk ASCVD patients through intravascular imaging and non-invasive endothelial function test.

METHODS:

This randomized, open-label, prospective clinical study involves 240 patients with very high-risk ASCVD who meet the criteria outlined in the 2023 Chinese lipid management guidelines. Patients recruitment will be processed in Beijing Anzhen Hospital from January 2021 to December 2024. Patients with thin-cap fibroatheroma (TCFA) detected by optical coherence tomography (OCT) are randomly assigned in a 1:1 ratio to the evolocumab group (evolocumab 140 mg every 2 weeks plus atorvastatin 40 mg nightly) or the standard treatment group (atorvastatin 40 mg nightly). The primary endpoint is the absolute change of the minimum fibrous cap thickness (FCT) at a median follow-up of 1 year. The secondary endpoints are other OCT metrics, assessment of MACE rates, alterations in serum lipid profiles and markers of inflammation, endothelial function, and adverse drug reactions. Logistic regression, analysis of covariance (ANCOVA), Kaplan-Meier curve survival analysis, and Cox regression will be used to investigate the relationship between variables and endpoints.

DISCUSSION:

The purpose of this study is to evaluate the efficacy of high-intensity statin therapy combined to PCSK9i for the secondary prevention of coronary artery disease in Chinese patients with very high-risk ASCVD. The results will provide evidence to optimize the management of this high-risk population.

TRIAL REGISTRATION:

This study was registered on chictr.org.cn (ChiCTR2000032570).

AIM:

The aim of this study was to evaluate the efficacy and safety of evolocumab with background atorvastatin in Chinese patients with type 2 diabetes mellitus (T2DM) and hyperlipidaemia or mixed dyslipidaemia.

MATERIALS AND METHODS:

This is a pre-specified analysis of patients in the BERSON study (ClinicalTrials.gov, NCT02662569) in China. Patients initiated background atorvastatin 20 mg/d, after which they were randomized 2:2:1:1 to evolocumab 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) or to placebo Q2W or QM. Co-primary endpoints were percentage change in LDL cholesterol (LDL-C) from baseline to week 12 and from baseline to the mean of weeks 10 and 12. Additional endpoints included atherogenic lipids, glycaemic measures and adverse events (AEs).

RESULTS:

Among 453 patients randomized in China, 451 received at least one dose of study drug (evolocumab or placebo). Evolocumab significantly reduced LDL-C compared with placebo at week 12 (Q2W, -85.0%; QM, -74.8%) and at the mean of weeks 10 and 12 (Q2W, -80.4%; QM, -81.0%) (adjusted P < 0.0001 for all) when administered with background atorvastatin. Non-HDL-C, ApoB100, total cholesterol, Lp(a), triglycerides, HDL-C and VLDL-C significantly improved with evolocumab vs placebo. No new safety findings were observed with evolocumab. The incidence of diabetes AEs was higher with evolocumab compared with placebo. There were no differences over time between evolocumab and placebo in measures of glycaemic control.

CONCLUSIONS:

In patients in China with T2DM and hyperlipidaemia or mixed dyslipidaemia receiving background atorvastatin, evolocumab significantly reduced LDL-C and other atherogenic lipids, was well tolerated, and had no notable impact on glycaemic measures.

BACKGROUND:

The HAUSER-RCT study showed that 24 weeks of evolocumab (a proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor) in paediatric patients with heterozygous familial hypercholesterolaemia was safe and improved lipid parameters compared to placebo. Here, we aimed to evaluate the safety and efficacy of evolocumab in this population for an additional 80 weeks.

METHODS:

HAUSER-OLE was an 80-week, single-arm, open-label extension of HAUSER-RCT, a randomised controlled trial, and was conducted at 46 centres in 23 countries. Paediatric patients aged 10-17 years with heterozygous familial hypercholesterolaemia who completed 24 weeks of monthly treatment with subcutaneously administered placebo or 420 mg evolocumab in HAUSER-RCT with no serious treatment-emergent adverse events were eligible to enrol in HAUSER-OLE. All patients received open-label subcutaneous evolocumab 420 mg monthly with background statins with or without ezetimibe for 80 additional weeks. The primary endpoint was treatment-emergent adverse events. Efficacy was evaluated by changes in lipids from the baseline of HAUSER-RCT to the end of HAUSER-OLE (104 weeks). This study is registered with ClinicalTrials.gov (NCT02624869) and is now completed.

FINDINGS:

Between Sept 10, 2016, and Nov 25, 2019, 157 patients were enrolled in HAUSER-RCT and received randomised treatment; 150 continued to HAUSER-OLE, received evolocumab treatment, and were included in the full analysis set, presented here. 146 (97%) of 150 patients completed the open-label extension. The incidence of treatment-emergent adverse events in HAUSER-OLE was 70% (105 of 150). Overall, the most common treatment-emergent adverse events were nasopharyngitis (22 [15%] of 150), headache (14 [9%]), and influenza-like illness (13 [9%]). Serious treatment-emergent adverse events occurred in four (3%) of 150 patients (perforated appendicitis and peritonitis, wrist fracture, anorexia nervosa, and headache); none was considered related to evolocumab. No treatment-emergent adverse events led to treatment discontinuation. At week 80, the mean percentage change from baseline in LDL cholesterol was -35·3% (SD 28·0).

INTERPRETATION:

After 80 weeks of treatment, evolocumab was safe, well tolerated, and led to sustained reductions in LDL cholesterol in paediatric patients with heterozygous familial hypercholesterolaemia. When lipid goals cannot be achieved with conventional treatments, evolocumab is an effective add-on therapy in paediatric patients.

FUNDING:

Amgen.

TRANSLATIONS:

For the French, Spanish, Spanish, Portuguese, Italian and Dutch translations of the abstract see Supplementary Materials section.

PURPOSE:

To assess the cost-effectiveness of evolocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, compared with ezetimibe, both added to background statin therapy in patients with recent acute coronary syndrome (ACS) events (in the past 12 months) and low-density lipoprotein cholesterol (LDL-C) levels ≥ 100 mg/dL in China.

METHODS:

A health economic evaluation was performed from a Chinese healthcare perspective, using a Markov model over a lifetime horizon based on a baseline cardiovascular (CV) event rate from claims database data and efficacy from the FOURIER trial. The health benefit was reflected in the decrease of LDL-C level, which led to a decrease of cardiovascular events. The costs of cardiovascular events and the utility value of each health state were derived from the published literature. Sensitivity analyses were conducted to evaluate the effects of uncertainty in parameters and the robustness of the model. The cost-effectiveness of evolocumab was also explored in patients with recent myocardial infarction (MI), at very high risk (VHR) of atherosclerotic cardiovascular disease (ASCVD), and homozygous familiar hypercholesterolemia (HoFH).

RESULTS:

In patients with recent ACS, evolocumab was associated with incremental quality-adjusted life-years (QALYs) of 1.33 and incremental costs of 115,782 yuan versus ezetimibe, both with background statin therapy, resulting in an incremental cost-effectiveness ratio (ICER) of 87,050 yuan per QALY gained. The probability of evolocumab + statins being cost-effective at a threshold of 217,341 yuan (three times per capita GDP, 2020), compared with ezetimibe + statins, was 100% in patients with recent ACS, recent MI, VHR ASCVD, and HoFH.

CONCLUSION:

Compared with ezetimibe + statins, the combination of evolocumab + statins was found to be cost-effective at a threshold of 217,341 yuan (three times per capita GDP, 2020) in patients with recent ACS events in China.

Background: Lerodalcibep, a small binding anti-PCSK9 protein (adnectin), showed effective LDL cholesterol reduction in heterozygous familial hypercholesterolaemia. We aimed to assess the safety and efficacy of lerodalcibep and evolocumab in a globally diverse homozygous familial hypercholesterolaemia population. Methods: This phase 3, randomised, open-label, crossover, non-inferiority study consisted of two 24-week treatment periods separated by an 8-week washout. The study was conducted in 12 lipid clinics in six countries (India, Israel, Norway, South Africa, Türkiye, and the USA). Patients aged 10 years or older with genetically confirmed homozygous familial hypercholesterolaemia were randomly assigned by computer-generated randomisation scheme performed centrally via interactive response technology to either monthly lerodalcibep 300 mg (1·2 mL subcutaneous injection) or monthly evolocumab 420 mg (subcutaneous 9 min infusion of 3·5 mL) for 24 weeks (period A) followed by an 8-week washout and then crossed over to the alternate therapy for the next 24 weeks (period B). The trial was open label, but all efficacy parameters were masked to patients, study staff, and the sponsor from randomisation. The primary efficacy endpoint was the percent change from baseline (day 1 of period A) in LDL cholesterol concentration to week 24 for period A and B. The intention-to-treat (ITT) population, defined as all randomly assigned patients, was used for the primary analysis. The safety population included all patients who received any study medication. The margin used to establish non-inferiority was 6%. The trial is registered with ClinicalTrials.gov (NCT04034485) and EudraCT (2019–003611–62), and has now finished. Findings: Patients were enrolled from Nov 11, 2019, to July 2, 2021, and the final study visit took place on Aug 8, 2022. Of 82 patients screened, 66 entered period A (ITT population). The mean age was 28·7 years (SD 15·2); 20 (30%) of 66 were paediatric patients; 36 (55%) of 66 were female and 30 (45%) of 66 were male; and the mean baseline LDL cholesterol was 10·59 mmol/L (SD 4·37). Mean LDL cholesterol reduction by ITT analysis at week 24 was –4·9% (SE 3·5) on lerodalcibep compared with –10·3% (3·5) on evolocumab; the mean difference between treatments was 5·4% (95% CI –0·2 to 11·1), which did not show non-inferiority at the prespecified 6% margin. LDL cholesterol response varied considerably across the patient population but was generally similar in the same patients with both lerodalcibep and evolocumab. When averaged across all monthly visits, LDL cholesterol response was –9·1% (SE 3·2) on lerodalcibep and –10·8% (3·2) on evolocumab. Importantly, genotyping and free PCSK9 suppression were not predictive of response. Both drugs were well tolerated, with no treatment-related serious adverse events. Injection site reactions were reported in one (2%) of 65 patients on lerodalcibep and 15 (24%) of 62 patients on evolocumab. Interpretation: The LDL cholesterol response was highly variable, but generally similar in patients treated with both lerodalcibep and evolocumab. Importantly, the study showed the inability to predict response based on genotyping, reinforcing the rationale for PCSK9 inhibition in all patients with homozygous familial hypercholesterolemia and continuing its use in responders. Funding: LIB Therapeutics. © 2025 Elsevier Ltd

INTERVENTION:

Product Name: Evolocumab Product Code: Evolocumab Pharmaceutical Form: Solution for injection in pre‐filled pen INN or Proposed

INN:

Evolocumab Current Sponsor code: Evolocumab Other descriptive name: AMG145 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 140‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled pen Route of administration of the placebo: Subcutaneous use Product Name: Evolocumab Product Code: Evolocumab Pharmaceutical Form: Solution for injection in cartridge INN or Proposed

INN:

Evolocumab Current Sponsor code: Evolocumab Other descriptive name: AMG145 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 120‐ Pharmaceutical form of the placebo: Solution for injection in cartridge Route of administration of the placebo: Subcutaneous use

CONDITION:

Hyperlipidemia or mixed dyslipidemia in Diabetic Subjects Therapeutic area: Diseases [C] ‐ Cardiovascular Diseases [C14]

PRIMARY OUTCOME:

Main Objective: To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab every 2 weeks (Q2W) and monthly (QM), in combination with oral (PO) atorvastatin daily (QD), compared with placebo Q2W and QM, in combination with PO atorvastatin QD, on percent change from baseline in low‐density lipoprotein cholesterol (LDL‐C) in diabetic subjects with hyperlipidemia or mixed dyslipidemia. Primary end point(s): Co‐Primary Efficacy Endpoints; a) mean percent change from baseline in LDL‐C at weeks 10 and 12; b) percent change from baseline in LDL‐C at week 12 Secondary Objective: •to evaluate the safety and tolerability of SC evolocumab Q2W and QM in combination with atorvastatin QD, compared with placebo Q2W and QM, in combination with atorvastatin QD, in diabetic subjects with hyperlipidemia or mixed dyslipidemia; • to assess the effects of 12 weeks of SC evolocumab Q2W and QM in combination with atorvastatin QD, compared with placebo Q2W and QM, in combination with atorvastatin QD, on change from baseline in LDL‐C, and percent change from baseline in non‐HDL‐C, ApoB100, total cholesterol, total cholesterol/HDL‐C ratio, ApoB100/ApoA1 ratio, Lp(a), triglycerides, VLDL‐C, and HDL‐C in diabetic subjects with hyperlipidemia or mixed dyslipidemia; • to assess the effects of 12 weeks of SC evolocumab Q2W and QM in combination with atorvastatin QD, compared with placebo Q2W and QM, in combination with atorvastatin QD, on percent of subjects attaining LDL‐C < 70 mg/dL (1.8 mmol/L) in diabetic subjects with hyperlipidemia or mixed dyslipidemia Timepoint(s) of evaluation of this end point: a) Weeks 10 and 12; b) Week 12

SECONDARY OUTCOME:

Secondary end point(s): Co‐secondary efficacy endpoints are (1) the mean of weeks 10 and 12 and (2) week 12 for: ; ; Tier 1 endpoints ; • change from baseline in LDL‐C • percent change from baseline in non‐HDL‐C • percent change from baseline in ApoB100 ; • percent change from baseline in the total cholesterol ; • percent change from baseline in the total cholesterol/HDL‐C ratio ; • percent change from baseline in ApoB100/ApoA1 ratio ; • achievement of target LDL‐C < 70 mg/dL (1.8 mmol/L) ; ; Tier 2 endpoints ; • percent change from baseline in Lp(a) ; • percent change from baseline in triglycerides ; • percent change from baseline in HDL‐C • percent change from baseline in VLDL‐C Timepoint(s) of evaluation of this end point: Weeks 10 and 12

INCLUSION CRITERIA:

1) Subject has provided written informed consent. 2) Male or female, = 18 to = 80 years of age at signing of informed consent. 5) Subjects receiving statin therapy at screening must have a fasting LDL‐C at screening of = 100 mg/dL (2.6 mmol/L) as det 3) Type 2 diabetes, defined as receiving pharmacologic treatment for type 2 diabetes for = 6 months prior to screening, with stable diabetes therapy prior to randomization to IP and not expected to change during the duration of study participation. Stable diabetes therapy is defined as no new agents added, no dose change of any oral antihyperglycemic drug within 2 months, and daily insulin dose not changed by > 25% and > 25 units within 1 month prior to randomization 4) Lipid‐lowering therapy status (eg, not receiving any therapy or receiving any statin, ezetimibe, bile‐acid sequestering resin, stanols, probucol, omega 3 fatty acids or niacin) must be unchanged for = 4 weeks prior to LDL‐C screening.

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INTRODUCTION:

Evolocumab, a fully human proprotein convertase/subtilisin kexin type 9 inhibitor antibody, significantly lowers low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes mellitus and hyperlipidemia and mixed dyslipidemia. This 12-week study evaluated the efficacy and safety of evolocumab in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia at different levels of cardiovascular disease risk.

METHODS:

HUA TUO was a 12-week randomized, double-blind, placebo-controlled study. Chinese patients aged 18 years or older on stable optimized statin therapy were randomized 2:2:1:1 to receive evolocumab 140 mg every 2 weeks (Q2W), evolocumab 420 mg monthly (QM), or a matching placebo. The coprimary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12 and at week 12.

RESULTS:

Overall, 241 randomized patients (mean [standard deviation] age, 60.2 [10.3] years) received evolocumab 140 mg Q2W (n = 79), evolocumab 420 mg QM (n = 80), placebo Q2W (n = 41), or placebo QM (n = 41). At weeks 10 and 12, the placebo-adjusted least-squares mean percent change from baseline in LDL-C for the evolocumab 140 mg Q2W group was - 70.7% (95% CI - 78.0% to - 63.5%); - 69.7% (95% CI - 76.5% to - 63.0%) for the evolocumab 420 mg QM group. Significant improvements in all other lipid parameters were observed with evolocumab. The patient incidence of treatment-emergent adverse events was similar between the treatment groups and across dosing regimens.

CONCLUSION:

In Chinese patients with primary hypercholesterolemia and mixed dyslipidemia, 12-week treatment with evolocumab significantly lowered LDL-C and other lipids, and was safe and well tolerated (NCT03433755).

BACKGROUND:

There are concerns that Asian patients respond differently to some medications. This study evaluated the efficacy and safety of evolocumab among Asian vs. other subjects in the FOURIER trial, which randomized stable atherosclerosis patients to receive either evolocumab or placebo.Methods and Results:Effects of adding evolocumab vs. placebo to background statin therapy on low-density lipoprotein cholesterol (LDL-C) reductions, cardiovascular outcomes, and adverse events were compared among 27,564 participants with atherosclerotic disease, according to self-reported Asian (n=2,723) vs. other (n=24,841) races followed for a median of 2.2 years in the FOURIER trial. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. At randomization, Asians had slightly lower LDL-C (median 89 [IQR 78-104] mg/dL vs. 92 [80-109] mg/dL; P<0.001) and were much less likely to be on a high-intensity statin (33.3% vs. 73.3%; P<0.001). Evolocumab lowered LDL-C more in Asians than in others (66% vs. 58%; P<0.001). The effect of evolocumab on the primary endpoint was similar in Asians (HR, 0.79; 95% CI, 0.61-1.03) and others (HR, 0.86; 95% CI, 0.79-0.93; P interaction=0.55). There was no excess of serious adverse events with evolocumab among Asians over others.

CONCLUSIONS:

Use of evolocumab robustly lowers LDL-C and is equally efficacious in lowering the risk of cardiovascular events and safe in Asians as it is in others.