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Real-World Safety and Effectiveness of Evolocumab in Korean Patients with Atherosclerotic Cardiovascular Disease or Familial Hypercholesterolemia: A Post-Marketing Surveillance Study
Open Access
08.10.2025
Original Research
Verfasst von
Donggyu Moon
Seung-Ho Hur
Sang-Rok Lee
Myung Ho Jeong
Kyung Hoon Cho
Osung Kwon
JinSeon Jeong
Ki Dong Yoo
Evolocumab Post-Marketing Surveillance Research Group
The efficacy and safety of evolocumab have been established in clinical trials. This post-marketing surveillance (PMS) study investigated the real-world safety and effectiveness of evolocumab in patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH) in Korea.
Methods
Patients who received evolocumab for approved indications in Korea between April 2017 and April 2023 across 43 centers were enrolled in this prospective PMS study. Safety (adverse events [AEs] and serious adverse events [SAEs]) and effectiveness (low-density lipoprotein cholesterol [LDL-C] lowering) were assessed up to 52 weeks. AEs and SAEs were categorized by LDL-C levels at 12 weeks: < 20, 20–40, and ≥ 40 mg/dL.
Results
Overall, 539 patients (mean age 58.8 ± 11.1 years, 78.7%/21.3% male/female) were included in the safety analysis set, while 361 patients assessed for LDL-C at least once during follow-up were included in the effectiveness analysis set. The majority of patients had ASCVD (myocardial infarction [55.1%], angina [33.5%], cerebral infarction [13.2%], peripheral artery disease [4.5%]). AEs were reported by 23.9% of patients, with SAEs occurring in 7.1%. When stratified by LDL-C levels, there was no difference in the frequencies of AEs and SAEs. Among all adverse drug reactions (ADRs; 2.4%), the most common were myalgia (0.9%) and headache (0.4%), with no reports of hemorrhagic stroke or nasopharyngitis. Evolocumab significantly reduced LDL-C levels from a baseline median of 100.2 mg/dL by 70.6% at week 12 and 69.0% at 52 weeks, achieving a target LDL-C goal (< 55 mg/dL and > 50% reduction) in 68.1% and 69.2% of patients, respectively.
Conclusions
Evolocumab effectively lowered LDL-C levels and had a favorable safety profile in Korean patients with ASCVD or FH. The incidence of AEs was lower than in clinical trials, and no ADRs were observed among the SAEs. These results support the use of evolocumab as a viable therapeutic option.
Prior Presentation: This study was previously presented as an e-poster at the 2025 Spring Congress on Lipid and Atherosclerosis (SoLA) of the Korean Society of Lipid and Atherosclerosis (KSoLA), held at the Seoul Dragon City Convention Center, Seoul, Republic of Korea on April 5, 2025.
Key Summary Points
Why carry out this study?
The efficacy and safety of evolocumab have been established in clinical trials.
This post-marketing surveillance (PMS) study investigated the real-world safety and effectiveness of evolocumab in patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH) in Korea.
What was learned from the study?
In this PMS study, evolocumab effectively lowered low-density lipoprotein cholesterol levels and had a favorable safety profile in Korean patients with ASCVD or FH.
The incidence of adverse events was lower than in clinical trials, and no adverse drug reactions were observed among the serious adverse events.
These real-world results support the use of evolocumab as a viable therapeutic option.
Introduction
Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide [1]. Among modifiable risk factors for patients with atherosclerotic CVD (ASCVD) and hypercholesterolemia, low-density lipoprotein cholesterol (LDL-C) lowering is a key target in the secondary prevention setting [2, 3], particularly for patients with ASCVD who are at high or very-high risk for recurrent CV events [4]. Emerging evidence supports a “lower is better” paradigm for LDL-C, indicating no threshold below which further LDL-C reduction ceases to provide clinical benefit [5‐8]. Hence, lipid-lowering therapy (LLT) intensification is necessary to further reduce mortality and morbidity in ASCVD. Likewise, residual clinical unmet needs exist in insufficient lipid management, despite statin treatment, leading to the risk of recurrent CV events in the Korean population [9], and necessitating additional therapies to control LDL-C.
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Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) and PCSK9-mediated LDL receptor degradation, resulting in increased LDL receptors and decreased serum LDL-C levels, by about 60% on background statin therapy [10]. The efficacy (LDL-C lowering and CV event reduction) and safety of evolocumab in very high-risk patients with ASCVD were confirmed in the large pivotal evolocumab outcomes trial, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), with 2.2 years of patient follow-up [11]. Even in very high-risk patients with acute coronary syndrome (ACS) in the EVOlocumab for Early Reduction of LDL-cholesterol Levels in Patients With Acute Coronary Syndromes (EVOPACS) trial, evolocumab added to high-intensity statin therapy was well tolerated and significantly reduced LDL-C levels, with most patients achieving recommended targets [12]. Furthermore, evolocumab provided additional and rapid LDL-C lowering in early post-ACS patients in the placebo-controlled Evolocumab in Acute Coronary Syndrome (EVACS) study [13]. For very high-risk patients, cholesterol guidelines recommend the use of a PCSK9 inhibitor with high-intensity statins and ezetimibe, including those in the early post-ACS phase [14, 15].
While evolocumab was well tolerated in clinical trials, concerns regarding potential safety issues due to LDL-C lowering remain unclear [16]. However, this idea was refuted in an analysis of FOURIER-OLE [6], an open-label extension of FOURIER [7]. Long-term (up to 8.6 years) LDL-C lowering—down to levels < 20 mg/dL—was associated with a lower risk of adverse CV events, with no significant safety concerns. There were no statistically significant associations in the primary analyses between lower achieved LDL-C levels and an increased risk of safety outcomes (serious adverse events [SAEs], new or recurrent cancer, cataract-related AEs, hemorrhagic stroke, new-onset diabetes mellitus, neurocognitive AEs, muscle-related events, or non-CV death) [6]. A recent meta-analysis supported the safety of PCSK9 inhibitors compared with control (placebo or ezetimibe); no significant differences were found in any of the comparisons analyzed, including SAEs, diabetes-related AEs, or neurocognitive and neurological AEs [8].
A growing body of clinical evidence suggests the safety and effectiveness of evolocumab across different regions [16]. Although several studies have demonstrated the real-world effectiveness of evolocumab [17‐22], comprehensive evaluation of the safety and long-term effect of LDL-C lowering with evolocumab in the real-world setting is valuable. The aim of this multicenter, post-marketing surveillance (PMS) study was to assess the safety and effectiveness of evolocumab treatment up to 56 weeks in patients with ASCVD or familial hypercholesterolemia (FH) in Korea as part of pharmacovigilance required by the Ministry of Food and Drug Safety, South Korea.
Methods
Study Design
This was a prospective, single-arm, observational, multicenter PMS study conducted between April 2017 and April 2023 in patients with ASCVD or FH (homozygous FH [HoFH] or heterozygous FH [HeFH]) treated with evolocumab at medical centers across Korea. Patients were followed up from the time of administration of the first dose of evolocumab until the end of the 52-week study period, death, or loss to follow-up, whichever occurred first. The duration of follow-up for individual patients was up to 56 weeks (52 ± 4 weeks) from enrollment. This study was approved by the Institutional Review Board at each study site (representatively, no. VC21OSDE0224 of the St Vincent's Hospital Ethics Review Committee), and the study was conducted in accordance with the Declaration of Helsinki. All enrolled patients provided informed consent to participate in the study.
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Patients
Eligible patients were those who received evolocumab as part of routine clinical care according to the therapeutic indications, dosage, and administration in the post-marketing setting in Korea. Any patients who had received evolocumab treatment prior to the baseline visit of this study, or were participating in another interventional study, were excluded. For each patient, follow-up was from their first dose of evolocumab through to the week 52 visit, discontinuation of treatment, withdrawal of consent, death, or lost to follow-up, whichever occurred first. Patients’ participation was terminated if they no longer received evolocumab in accordance with the approved indication and dosing in Korea. Patients who had received at least one dose of evolocumab and were followed up for safety at least once were included in the safety analysis set. Among the safety analysis set, patients who were assessed for LDL-C-lowering effect at least once during follow-up (either at week 12, 24, or 52) were included in the effectiveness analysis set, a subset of the safety analysis set.
Assessments
Patient Characteristics
Data for all enrolled patients were assessed and collected by treating physicians at each participating site in case report forms (CRFs) from baseline and throughout the observation period of up to 56 weeks. Baseline patient data collected included demographic (sex, age, body mass index) and clinical characteristics (history of ASCVD, prior revascularization, FH diagnosis [HoFH or HeFH], and medical history/comorbidities, prior LLT usage). If a patient had both myocardial infarction (MI) and angina recorded, they were counted only in the MI category. LDL-C levels measured as part of routine clinical practice were collected from baseline (the latest time point within 6 months prior to the first evolocumab dose) to the end of follow-up. LDL-C, HDL-C, total cholesterol, and triglyceride test values measured during visits were collected in the CRF at baseline, week 12, week 24, and at week 52 (± 4 weeks for each). For baseline LLT assessment, we used the closest prior measurement to the initial evolocumab administration date for classification: statin only (high-, moderate-, or low-intensity), high- or moderate-intensity statin plus ezetimibe, or ezetimibe only.
Safety
The primary outcome was the incidence (frequency and number) of AEs which were recorded by the investigator in the CRF throughout the follow-up period after the first administration of evolocumab. An AE was characterized as any negative medical incident occurring in a patient receiving evolocumab, regardless of whether it was related to the drug. All AEs were classified using the Medical Dictionary for Regulatory Activities (MedDRA) preferred term (PT). Only AEs reported during the use of evolocumab for approved indications in Korea were included in this analysis. An adverse drug reaction (ADR) was defined as any negative medical incident in a patient receiving evolocumab that was determined by investigators to be causally linked to the treatment. An SAE was defined as any AE that met at least one of the following criteria: is fatal or life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; or is an “other significant medical hazard” that does not meet any of the above criteria.
Additionally, we measured the frequency of AEs when very low LDL-C levels were achieved. We included patients who had their LDL-C levels measured at week 12. Patients were classified into three groups based on their LDL-C values at week 12: less than 20 mg/dL, between 20 and 40 mg/dL, and 40 mg/dL or higher. The occurrence of AEs, SAEs, and ADRs was then measured within each group.
Effectiveness
The secondary outcome was LDL-C lowering following evolocumab treatment in patients within the effectiveness analysis set, which was assessed as the percentage and absolute reduction in LDL-C from baseline to week 12, week 24, and week 52. Additionally, we measured LDL-C goal achievement rates (< 55 mg/dL and > 50% reduction from baseline) after evolocumab administration at week 12, week 24, and week 52, respectively. The target goal achievement rate (%) was calculated as the number of patients who achieved the goal divided by the number of patients who had LDL-C measurements at the given follow-up week.
Subgroup analyses were also conducted. First, we assessed the maintenance of LDL-C-lowering effects at weeks 12, 24, and 52 based on evolocumab treatment status (on-treatment vs. off-treatment). For patients with LDL-C measurements at each time point, we determined whether they were receiving evolocumab treatment, regardless of continuous administration. We applied exposure windows of 14 days for the 140 mg dose and 30 days for the 420 mg dose of evolocumab. Second, to evaluate the effectiveness of evolocumab treatment regardless of baseline LLT use, we measured LDL-C lowering effects at weeks 12, 24, and 52, stratified by baseline LLT use: statin only (moderate or high-intensity) and statin (moderate or high-intensity) plus ezetimibe. Third, we measured LDL-C changes by ASCVD subtype (MI, angina, and cerebral infarction) and by presence of diabetes.
Statistical Analysis
All statistical analyses were descriptive in nature. Summary statistics for continuous variables included the number of patients, mean ± SD or median (first quartile to third quartile). For categorical variables, the frequencies and percentages were calculated. Patient clinical and demographic characteristics were summarized in the safety and effectiveness analysis set. For safety analysis, the frequency (number and percentage of subjects) and number of events are presented for AEs, ADRs, and SAEs. For effectiveness analysis, median percent changes and absolute reductions in LDL-C from baseline were presented at weeks 12, 24, and 52. Nominal two-sided p-values are reported.
Results
Patients
In total, 582 patients who received evolocumab treatment for ASCVD or FH were enrolled at 43 centers across Korea (Fig. 1). Following the exclusion of 43 patients for violations associated with no treatment (n = 5), no follow-up for safety (n = 2), off-label evolocumab treatment at enrollment (n = 4), or administration prior to consent (n = 3), and inclusion/exclusion criteria deviation (n = 29), 539 patients were included in the safety analysis set (Fig. 1). Among the 539 patients in the safety analysis set, 221 were excluded from the effectiveness analysis set, including 178 who had no LDL-C measurement during the follow-up period for effectiveness assessments. Overall, a subset of 361 patients from the safety analysis set comprised the effectiveness analysis set (Fig. 1).
Fig. 1
Flow diagram of patient disposition. Note: The effectiveness analysis set included patients with at least one follow-up low-density lipoprotein cholesterol measurement at week 12, 24, or 52
Patient’s baseline demographic and clinical characteristics are summarized in Table 1 and in Table S1, which shows data for the 178 patients who had no LDL-C measurement during the follow-up period for effectiveness assessments; Table S1 can be found in the electronic Supplementary Material. The mean age of all patients was 58.8 years; 78.7% were male and 21.3% were female. In the safety analysis set, the most common ASCVD conditions in descending order were MI (55.1%), angina pectoris (33.5%), cerebral infarction (13.2%), and peripheral artery disease (4.5%). Percutaneous coronary intervention (PCI) was the most common prior coronary revascularization procedure (81.4%), while 3.9% of patients had required coronary artery bypass grafting. Among the 5.2% of patients classified as having FH, 3.9% had HeFH (3.9%) and 1.3% had FH of unknown type. Most patients (73.8%) had hypertension, a third had diabetes (32.3%), 12.4% had heart failure, and 5% had chronic kidney disease.
Table 1
Baseline patient demographic and clinical characteristics of the safety and effectiveness analysis sets
Characteristicsa
Safety analysis set (N = 539)
Effectiveness analysis set (N = 361)
Sex, male
424 (78.7)
285 (78.9)
Sex, female
115 (21.3)
76 (21.1)
Age (years), mean (SD)
58.8 (11.1)
58.6 (10.7)
BMI, kg/m2
25.9 (3.6)
26 (3.5)
Clinical characteristics
History of ASCVD
Myocardial infarction
297 (55.1)
197 (54.5)
Angina pectoris
181 (33.5)
125 (34.6)
Cerebral infarction
71 (13.2)
44 (12.2)
Peripheral artery disease
24 (4.5)
18 (5)
Prior CABG
21 (3.9)
13 (3.6)
Prior PCI
439 (81.4)
298 (82.5)
Familial hypercholesterolemia
28 (5.2)
20 (5.5)
Heterozygous FH
21 (3.9)
15 (4.2)
Unknown type
7 (1.3)
5 (1.4)
Hypertension
398 (73.8)
257 (71.2)
Diabetes mellitus
174 (32.3)
111 (30.7)
Heart failure
67 (12.4)
40 (11.1)
Chronic kidney disease
27 (5.0)
15 (4.2)
Lipid levels
LDL-C (mg/dL), median (Q1–Q3)
97 (81–131)
100.2 (82–133.2)
HDL-C (mg/dL), median (Q1–Q3)
45 (39–53)
46 (40–54)
Triglycerides (mg/dL), median (Q1–Q3)
145.5 (104–203)
141.5 (103–203)
Baseline LLT
Statin only
High-intensity
142 (26.3)
90 (24.9)
Moderate-intensity
32 (5.9)
23 (6.4)
Low-intensity
5 (0.9)
1 (0.3)
High-intensity statin plus ezetimibe
280 (51.9)
202 (56)
Moderate-intensity statin plus ezetimibe
49 (9.1)
26 (7.2)
Ezetimibe only
7 (1.3)
6 (1.7)
ASCVD atherosclerotic cardiovascular disease, BMI body mass index, CABG coronary artery bypass graft, FH familial hypercholesterolemia, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, LLT lipid-lowering therapy, n number, PAD peripheral arterial disease, PCI percutaneous coronary intervention, Q quarter, SD standard deviation
aUnless otherwise stated, data are presented as n (%)
The baseline median (Q1–Q3) LDL-C level of all patients was 97 (81–131) mg/dL. Median (Q1–Q3) baseline HDL-C and triglyceride levels were 45 (39–53) and 145.5 (104–203) mg/dL. At baseline, just over half of all patients (51.9%) were using high-intensity statin/ezetimibe LLT, while one third were using statin only (33.2%), including high-intensity (26.3%), moderate-intensity (5.9%), and low-intensity (0.9%); 1.3% of patients were using ezetimibe only (Table 1).
Safety
AEs, SAEs, and ADRs in the Safety Analysis Set
The frequency of AEs among the 539 patients in the safety analysis set who received evolocumab during the 52-week study observation period was 23.9% (n = 129) (Table 2). All reported AEs are listed in Table S2 in the electronic Supplementary Material. A total of 184 AEs were reported among the 129 patients; the most frequent were headache (2%), chest pain (1.5%), and myalgia (1.5%). No cases of hemorrhagic stroke were reported. One case of diabetes was reported but an association with evolocumab use was considered unlikely. A total of 44 SAEs were reported among 38 (7.1%) patients (Table 2). None of the SAEs was classified as an ADR, since a relationship with evolocumab treatment was considered unlikely. ADRs were reported in 13 (2.4%) patients; myalgia was the most common (0.9%) followed by headache (0.4%), and asthenia, fatigue, injection-site redness, nausea, ocular discomfort, and abnormal white blood cell count were each observed in 0.2% (n = 1) of patients (Table 2).
Table 2
Incidence of adverse events (with frequency equal or higher than 3), serious adverse events and adverse drug reactions in safety analysis set (n = 539)
AEsa
n (%)
All
129 (23.9)
Headache
11 (2)
Chest pain
8 (1.5)
Myalgia
8 (1.5)
Dizziness
7 (1.3)
Unstable angina
6 (1.1)
Dyspnea
5 (0.9)
ALT increase
4 (0.7)
Angina pectoris
4 (0.7)
AST increase
4 (0.7)
Asymptomatic COVID
4 (0.7)
Fear of injection
4 (0.7)
Hypertension
4 (0.7)
Pruritus
4 (0.7)
Fatigue
3 (0.6)
SARS-CoV-2 test positive
3 (0.6)
SAEs
38 (7.1)
Acute myocardial infarction
1 (0.2)
Adrenal adenoma
1 (0.2)
Angina pectoris
1 (0.2)
Unstable angina
4 (0.7)
Appendicitis
1 (0.2)
Arachnoid cyst
1 (0.2)
Arteriovenous fistula thrombosis
1 (0.2)
COVID-19 pneumonia
1 (0.2)
Cardiac failure
1 (0.2)
Chest pain
2 (0.4)
Colon cancer
1 (0.2)
Coronary artery occlusion
1 (0.2)
Diverticulitis
1 (0.2)
Dyspnea
2 (0.4)
Fracture
1 (0.2)
Gastric adenoma
1 (0.2)
Hematuria
1 (0.2)
Hypertension
1 (0.2)
Hyponatremia
1 (0.2)
Intermittent claudication
1 (0.2)
Ischemic cardiomyopathy
1 (0.2)
Laryngeal cancer
1 (0.2)
Liver abscess
1 (0.2)
Nephrotic syndrome
1 (0.2)
Odontogenic cyst
1 (0.2)
Orthopnea
1 (0.2)
Pancreatitis acute
1 (0.2)
Peripheral arterial occlusive disease
1 (0.2)
Pleural effusion
1 (0.2)
Post-stroke seizure
1 (0.2)
Pyrexia
1 (0.2)
Skin disorder
1 (0.2)
Spinal compression
1 (0.2)
Spinal stenosis
1 (0.2)
Unevaluable event
1 (0.2)
Vasospasm
1 (0.2)
Vertebral artery aneurysm
1 (0.2)
Vitreous hemorrhage
1 (0.2)
ADRsa
13 (2.4)
Myalgia
5 (0.9)
Headache
2 (0.4)
Asthenia
1 (0.2)
Fatigue
1 (0.2)
Injection site redness
1 (0.2)
Nausea
1 (0.2)
Ocular discomfort
1 (0.2)
Low white blood cell count
1 (0.2)
AEs associated with off-label use of evolocumab were excluded. A total of 184 AEs were reported
ADRs adverse drug reactions, AE adverse event, n number of patients, SAEs serious adverse events
aAEs were considered as ADRs when they were likely due to evolocumab use
Safety in Patients with Very Low LDL-C: AEs, SAEs, and ADRs by Achieved LDL-C at Week 12
This analysis included 298 patients who had their LDL-C levels measured at week 12. Patients were classified into three groups based on their LDL-C values at week 12: less than 20 mg/dL (n = 90), between 20 and 40 mg/dL (n = 92), and 40 mg/dL or higher (n = 116). Among these 298 patients, 45 patients reported a total of 63 AEs during the follow-up period after week 12. There was no trend for increasing AE occurrence in the very low LDL-C group, with 12% in the less than 20 mg/dL group, 21% in the 20 to 40 mg/dL group, and 13% in the 40 mg/dL or higher group. Similarly, the very low LDL-C group did not show an increase in SAEs or ADRs (Table S3 in the electronic Supplementary Material).
Effectiveness
LDL-C Reduction: Effectiveness Analysis Set
At week 12 of evolocumab treatment, median LDL-C was reduced from baseline (100.2 mg/dL) by 70.6% (absolute reduction, 69.0 mg/dL; Fig. 2) among 298 patients with available measurements in the effectiveness analysis set. The rate of target LDL-C goal (< 55 mg/dL and ≥ 50% reduction) achievement at week 12 was 68.1%. Median LDL-C reduction from baseline was similar at week 24, 70.5% (absolute reduction 68 mg/dL) and at week 52, 69% (absolute reduction 69 mg/dL). At weeks 24 and 52, 62.8% and 69.2% of patients, respectively, achieved target LDL-C goal (< 55 mg/dL and ≥ 50% reduction).
Fig. 2
Low-density lipoprotein cholesterol (LDL-C) reduction from baseline at weeks 12, 24, and 52 in the effectiveness analysis set. Note: *The target goal achievement rate (%) was calculated as the number of patients who achieved the goal divided by the number of patients who had LDL-C measurements at the given follow-up week
When we determined whether patients were receiving evolocumab treatment at each time point (weeks 12, 24, or 52), regardless of continuous administration, those on treatment maintained their LDL-C levels. In contrast, patients who were off-treatment (≤ 20 patients) at these time points experienced an increase in LDL-C levels, with the week 52 data appearing comparable to the week 12 data (Fig. 3). The LDL-C-lowering effect of evolocumab was consistent irrespective of baseline LLT and intensity (statin only [moderate- or high-intensity], or statin [moderate- or high-intensity] plus ezetimibe) (Fig. 4).
Fig. 3
Low-density lipoprotein cholesterol (LDL-C) reduction by evolocumab treatment status (on-treatment vs. off-treatment) at weeks 12, 24, and 52 from baseline. Note: Evolocumab treatment status (whether the patient was on- or off-treatment) was evaluated at each follow-up measurement at weeks 12, 24, and 52
Low-density lipoprotein cholesterol (LDL-C) reduction with evolocumab from baseline at week 12, 24, and 52 by baseline lipid-lowering therapy subtype (statin only [moderate- or high-intensity] and statin + ezetimibe [moderate- or high-intensity])
In the cohort of 197 patients with previous MI, evolocumab reduced median LDL-C from baseline (92 mg/dL) to week 12 (28 mg/dL) by 70.0% (absolute reduction, 64 mg/dL; Figure S1 in the electronic Supplementary Material). Reductions in LDL-C were maintained through to week 52 assessments (Figure S1). In the cohort of 125 patients with angina, evolocumab reduced median LDL-C from baseline (108 mg/dL) to week 12 (29 mg/dL) by 73.1% (absolute reduction, 79 mg/dL; Figure S2 in the electronic Supplementary Material). In the cohort of 44 patients with previous cerebral infarction, evolocumab reduced median LDL-C from baseline (102 mg/dL) to week 12 (43 mg/dL) by 57.8% (absolute reduction, 59 mg/dL; Figure S3 in the electronic Supplementary Material). In the subgroup of patients with diabetes (n = 111) in the effectiveness analysis set, evolocumab reduced median LDL-C from baseline (100 mg/dL) to week 12 (32 mg/dL) by 68.0% (absolute reduction, 68 mg/dL; Figure S4 in the electronic Supplementary Material).
Discussion
This PMS study reaffirms the safety and effectiveness of evolocumab and adds to the established body of evidence by providing real-world evidence of high-risk patients with ASCVD or FH in Korea, among whom no safety concerns, such as hemorrhagic events, were observed with evolocumab. Importantly, our findings indicate that achieving very low LDL-C levels (< 20 mg/dL) at week 12 did not result in an increased occurrence of AEs, which is consistent with the FOURIER OLE [8] and prior Japanese PMS study [23]. Notably, in our study, median baseline LDL-C was 100.2 mg/dL, despite use of high-intensity statin and ezetimibe in half of all patients and high-intensity statin in a quarter. Nevertheless, following 3 months of evolocumab treatment, median LDL-C was reduced by 70.6% and was maintained at < 30 mg/dL until week 52. Evolocumab on-treatment effectively maintained low LDL-C levels, while off-treatment LDL-C levels increased, regardless of the type of baseline ASCVD (MI, angina, or ischemic stroke [cerebral infarction]).
Our study demonstrated lower AE rates with evolocumab compared to major randomized, controlled trials (RCTs), primarily due to shorter follow-up periods and differences in AE monitoring between RCT and PMS settings. Despite these variations, the safety profile of evolocumab in high-risk Korean patients indicated that it was well tolerated in this PMS study, aligning with findings from RCTs [10, 11, 24]. In our study, the AE rate up to 56 weeks of evolocumab treatment was 23.9%, with the most frequent AEs being headache (2%), chest pain, and myalgia (1.5% each), and no SAEs were ADRs. The rate of ADRs was 2.4%, including a low rate of myalgia (0.9%) and headache (0.4%), while asthenia, fatigue, injection-site redness, nausea, ocular discomfort, and abnormal white blood cell count were reported in 0.2% of patients. In FOURIER, the AE rate did not differ between evolocumab and placebo (77.4%), and in a subanalysis of 2723 Asian patients compared with other patients (n = 24,841), no significant between-group differences in the incidence of AEs, including hemorrhagic stroke, rhabdomyolysis, new-onset diabetes, or cognitive decline, were shown [25]. In other subanalyses of FOURIER, no increased risk of muscle-related events, cataract, new-onset diabetes [26, 27], neurocognitive events [7, 28], or hemorrhagic stroke [11, 29] were shown, even with up to more than 8 years of evolocumab treatment [7].
Prior real-world data also reported a favorable safety profile of evolocumab in populations across Europe [17, 18], North America [19, 20], and in prior Korean studies [21, 22]. Prior Korean studies reported no significant differences in safety outcomes between evolocumab and non-evolocumab treatment in patients with recent acute MI (AMI), including myalgia and fatigue [22]. Another observational study (ZERBINI) of 578 patients with ASCVD and/or FH who initiated evolocumab at sites across Canada, Mexico, Columbia, Kuwait, and Saudi Arabia reported AE rates of 3.3%, with the most common AEs being balance disorder/dizziness (0.9%), myalgia (0.5%), and headache (0.5%); no SAEs were reported [20]. Thus, despite theoretical concerns regarding PCSK9 inhibitors and safety, particularly with low LDL-C levels achieved, previous study results, our PMS study results, and those of FOURIER-OLE, support an overall favorable safety profile of evolocumab in patients with very low LDL-C (< 20 mg/dL).
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In clinical trials in patients with elevated LDL-C despite LLT, including in patients with at least one CV risk factor [10] or with ASCVD (MI, non-hemorrhagic stroke, PAD) in FOURIER [11], evolocumab significantly reduced LDL-C, by about 60%. Overall, in this study, a third of the patients with ASCVD had diabetes and, in FOURIER, it was shown that reductions in LDL-C with evolocumab were similar regardless of the presence of high-risk comorbid conditions such as diabetes [26]. This was also seen in our study; median LDL-C was reduced from baseline to week 12 by 70.6% in the overall effectiveness analysis set and by 68.0% in the subgroup with diabetes. In FOURIER-OLE, LDL-C reductions observed early post-evolocumab initiation were maintained long term, during up to 8.6 years of follow-up [6, 7]. In the analysis of FOURIER that compared evolocumab treatment between Asian and other patients (baseline LDL-C 89 mg/dL and 92 mg/dL, respectively), at 48 weeks, mean percentage (66% vs 58%) and absolute (61 mg/dL vs 55 mg/dL) LDL-C reductions were greater in Asian patients [25].
The LDL-C lowering effect of evolocumab was observed regardless of the baseline LLT regimen, which, despite guideline recommendations for the use of ezetimibe in high-risk patients with ASCVD receiving maximally tolerated statin therapy [14, 15], included high-intensity statin plus ezetimibe in just over half of all patients (51.9%), statin only in a third (33.2%), and ezetimibe only in 1.3%. This is a reflection of real-life clinical practice where adherence to guidelines/treatment may be suboptimal, yet additional LDL-C lowering for CV risk reduction in high-risk patients WITH ASCVD is paramount to reduce the burden of further CV events [9]. Additionally, patients who were on-treatment with evolocumab at specific time points (week 12, 24, or 52) maintained their LDL-C levels. However, with the caveat of the limited interpretation due to the small sample size, patients on off-treatment (≤ 20 patients) at these time points experienced an increase in LDL-C levels, with the week-52 data appearing similar to the week-12 data. This underscores the importance of continuing evolocumab treatment for sustained LDL-C reduction. In a previous study of Korean AMI patients who underwent PCI, those who received a single-dose injection of evolocumab during PCI, along with statin/ezetimibe, had a greater LDL-C reduction (78.4% vs. 45.6%) and a higher rate of achieving LDL-C < 55 mg/dL (97.7% vs. 60.0%) within 1–3 weeks compared to those without evolocumab [21]. Importantly, evolocumab has shown consistent LDL-C lowering in various populations, including those at increased risk of further CV events. In the observational real-world HEYMANS (cHaractEristics of hYperlipidaeMic pAtieNts at the initiation of evolocumab and treatment patternS) European registry of 1951 patients with hypercholesterolemia (many not on LLT) initiating evolocumab in routine clinical practice [30, 31], and in patients with ASCVD or FH across North and South America, the Middle East and Western Asia (ZERBINI) [20], baseline LDL-C was 153.9 mg/dL and 131.5 mg/dL, respectively; with evolocumab treatment, median reduction from baseline was 58.0% and 70.2%, respectively, which remained stable over follow-up.
This multicenter PMS study provides evidence by including a considerable number of evolocumab-treated patients from 43 centers (539 patients for safety evaluation and 361 patients for effectiveness evaluation), with up to three follow-up LDL-C assessments during up to 56 weeks of follow-up, and fills a gap in the real-world clinical evidence of evolocumab in Asian populations. Nevertheless, there are several limitations of this study. First, the absence of a control group in this study limits the ability to determine comparative safety or effectiveness and whether the observed effects of evolocumab are due to the treatment itself or other external factors. Second, the clinical information for evolocumab-treated patients was collected by physicians using CRFs; hence, there are limitations to the collected information regarding AEs and effectiveness, particularly as LDL-C was measured as part of routine clinical practice and not as part of the study procedure. Lastly, the population with FH in our study does not appear to include patients with HoFH, although 1.3% were of unknown type.
In conclusion, evolocumab demonstrated a favorable safety profile and effectively reduced LDL-C levels in Korean patients with ASCVD or FH. There were no cases of hemorrhagic stroke following evolocumab treatment, and achieving very low LDL-C levels (< 20 mg/dL) at week 12 was not associated with increased incidence of AEs. Additionally, evolocumab led to a 70.6% median LDL-C reduction at 12 weeks, with levels sustained below 30 mg/dL through week 52 in on-treatment patients, regardless of ASCVD subtype. These findings support the use of evolocumab as a valuable therapeutic option.
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Acknowledgements
The authors thank the patients included in this study, the investigators and staff at all participating study centers, the independent Data Monitoring Committee, and the study team at Amgen, Korea.
Medical Writing/Editorial Assistance
Under the direction of the authors, medical writing assistance in the preparation of this manuscript was provided by Nila Bhana, MSc (Hons), on behalf of Content Ed Net, according to Good Publication Practice guidelines (https://doi.org/10.7326/M15-0288). Support for this assistance was funded by Amgen, Korea.
Declarations
Conflict of Interest
JinSeon Jeong is an employee of Amgen. Kyung Hoon Cho has received an institutional research grant from Amgen; speaker/consulting honoraria from Amgen, Sanofi-Aventis, Viatris, Jeil Pharm, Aju Pharm, and JW Pharm. Donggyu Moon, Seung-Ho Hur, Sang-Rok Lee, Myung Ho Jeong, Osung Kwon, and Ki Dong Yoo declare no conflicts of interest.
Ethical Approval
This study was approved by the Institutional Review Board at each study site (representatively, no. VC21OSDE0224 of the St Vincent's Hospital Ethics Review Committee), and the study was conducted in accordance with the Declaration of Helsinki. For a complete list of the ethics committees of participating hospitals, see the electronic supplementary file, Supplementary Material. All enrolled patients provided informed consent to participate in the study.
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Real-World Safety and Effectiveness of Evolocumab in Korean Patients with Atherosclerotic Cardiovascular Disease or Familial Hypercholesterolemia: A Post-Marketing Surveillance Study
Verfasst von
Donggyu Moon
Seung-Ho Hur
Sang-Rok Lee
Myung Ho Jeong
Kyung Hoon Cho
Osung Kwon
JinSeon Jeong
Ki Dong Yoo
Evolocumab Post-Marketing Surveillance Research Group
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