Abstract
Purpose
Coronary heart disease (CHD) remained a leading cause of morbidity and mortality, necessitating innovative treatment strategies. This study aimed to evaluate the efficacy and safety of evolocumab combined with atorvastatin compared to atorvastatin monotherapy in patients with CHD.
Methods
This retrospective cohort study included CHD patients admitted between February 2023 and April 2024. Patients were divided into two groups: the Monotherapy Group received atorvastatin alone (75 patients) and the Combination Therapy Group received both evolocumab and atorvastatin (76 patients) for a duration of three months. Lipid profiles, inflammatory markers, and endothelial function parameters were assessed before and after treatment completion.
Results
In the Combination Therapy Group, significant improvements were observed in total cholesterol (2.65 ± 0.77 mmol/L vs. 2.27 ± 0.76 mmol/L, P = 0.002), low-density lipoprotein cholesterol (1.71 ± 0.49 mmol/L vs. 1.08 ± 0.32 mmol/L, P < 0.001), and apolipoprotein B (0.49 ± 0.16 g/L vs. 0.42 ± 0.13 g/L, P = 0.004). Inflammatory markers interleukin-1β and tumor necrosis factor-α also decreased significantly in the Combination Therapy Group. Endothelial function improved, as indicated by flow-mediated dilation (5.01 ± 1.67% vs. 4.27 ± 1.32%, P = 0.003) and vascular activity range (4.20 ± 1.39 mm vs. 3.68 ± 1.22 mm, P = 0.017). The incidence of adverse cardiovascular events was lower in the Combination Therapy Group (3.95% vs. 14.67%, P = 0.023).
Conclusion
Compared to statin monotherapy, the combination of evolocumab with atorvastatin synergistically improved lipid control, reduced early inflammation, enhanced endothelial function, and decreased cardiovascular events.
Keywords: Evolocumab, Statins, Coronary heart disease, Inflammation, Endothelial function, Lipid control
Introduction
Coronary heart disease (CHD) was a leading cause of morbidity and mortality worldwide, characterized by the narrowing or blockage of coronary arteries due to atherosclerosis [1]. Patients with CHD often experienced symptoms such as chest pain (angina), shortness of breath, and fatigue [2]. The pathophysiology involved lipid accumulation in arterial walls, inflammation, and subsequent plaque formation, which could lead to myocardial ischemia and infarction [3]. Advances in treatment included the use of statins to lower low-density lipoprotein cholesterol (LDL-C) levels and reduce cardiovascular events [4]. However, despite these advancements, significant limitations remained, including residual inflammatory risk and inadequate LDL-C control in high-risk patients, leading to adverse cardiovascular outcomes [5]. Additional therapeutic strategies were necessary. Evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, emerged as a promising adjunctive therapy [6]. However, its long-term efficacy and safety, particularly when combined with statins, especially concerning the combined effects on inflammation pathways and endothelial repair in CHD patients, remained areas of active research. We followed the methods of Lu et al. (2025) to further investigate whether this combination therapy, in addition to its lipid-lowering effects, also has a synergistic improvement on inflammatory markers and endothelial function [7]. This study aimed to evaluate the effects of atorvastatin monotherapy versus combination therapy with evolocumab on lipid profiles, inflammatory markers, and endothelial function in CHD patients.
Recent studies emphasized the role of inflammatory pathways in the progression of atherosclerosis [8]. Inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α), contributed to the destabilization of atherosclerotic plaques, promoted thrombosis, and exacerbated vascular injury [9, 10]. IL-1β and TNF-α directly impaired nitric oxide bioavailability, promoting vasoconstriction and thrombosis, while IL-6 stimulated the liver to produce acute-phase reactants like C-reactive protein. Targeting inflammation could reduce cardiovascular events independently of lipid levels, highlighting inflammation as a therapeutic target [11, 12].
Endothelial dysfunction represented another critical factor, characterized by impaired vasodilation and increased vascular stiffness, contributing to the development and progression of CHD [13, 14]. Researchers found that pharmacological interventions improving endothelial function could lower cardiovascular risk [15]. Additionally, PCSK9 inhibitors like evolocumab enhanced LDL receptor recycling, reducing circulating LDL-C levels more effectively than statins alone. However, the synergistic effects of combining these therapies and their impact on inflammatory markers and endothelial function required further clarification.
The primary aim of this retrospective study was to investigate whether adding evolocumab to atorvastatin therapy provided superior benefits in improving lipid profiles, reducing inflammatory markers, and enhancing endothelial function compared to atorvastatin monotherapy. Our innovation lay in assessing early anti-inflammatory effects (at 72 h) alongside comprehensive endothelial repair and lipid changes. The findings aimed to clarify the pleiotropic effects of combination therapy, address residual risk factors inadequately managed by statins alone, and inform strategies for optimizing secondary prevention in CHD. By employing a rigorous study design and comprehensive evaluation methods, this research sought to provide new insights into the potential advantages of combination therapy for CHD management. The results could highlight the importance of addressing both lipid metabolism and inflammation in the comprehensive treatment of CHD, paving the way for future investigations into integrated therapeutic approaches.
Methods
Case selection
This retrospective cohort study included 151 coronary heart disease patients admitted to our hospital from February 2023 to April 2024 as study subjects, and demographic information of the patients was collected through the case system. Since this retrospective study uses de-identified patient data, it will not cause any potential harm to the patients, thus informed consent is exempted. This exemption and the study have been approved by Hubei No.3 People’s Hospital’s ethics review committee, in compliance with relevant regulatory and ethical standards. Furthermore, all procedures followed were in accordance with the Helsinki Declaration.
Inclusion and exclusion criteria
Inclusion criteria: (1) patients had a confirmed diagnosis of CHD. The diagnostic criteria for CHD adhered to “Guidelines for Primary Diagnosis and Treatment of Stable Coronary Heart Disease” [16]; (2) patients had no cognitive, linguistic, or intellectual impairment with basic literacy skills; (3) patients had no prior statin or evolocumab treatment within the last month; (4) patients had no history of allergies to the study drugs; and (5) patients had excellent treatment compliance; (6) Individuals aged 45–75 years old.
Exclusion criteria: (1) patients with severe liver insufficiency (glutamic pyruvic transaminase and glutamic oxaloacetic transaminase) levels exceeding 3 times the normal range or renal dysfunction (estimated glomerular filtration rate ≤ 30 ml/min/1.73 m2); (2) patients with other significant cardiovascular diseases, such as severe arrhythmia or cardiac insufficiency (left ventricular ejection fraction (LVEF) < 30%); (3) patients with other severe illnesses, including severe infection, thyroid disease, tuberculosis, or malignancy; and (4) patients with incomplete or missing clinical data. (5) statin intolerance; (6) inability to image the brachial artery and to perform endothelial function assessment.
Grouping standards
Patients were grouped according to the treatment regimen they received. The monotherapy group (n = 75) received 40 mg of atorvastatin daily (Approval Number H20133127, Lepu Pharmaceutical Technology Co., Ltd., People’s Republic of China). The combination therapy group (n = 76) additionally received 140 mg of evolocumab every two weeks (Approval Number SJ20180022, Amgen Manufacturing Limited LLC, United States) on top of the atorvastatin treatment. The treatment duration for both groups was three months.
Evaluation method for related indicators
Patients were informed to fast and abstain from smoking, alcohol, caffeine and antioxidant vitamin supplements on the day of examination. All measurements were conducted in the morning, with subjects being fasted overnight. Before the initiation of treatment, fasting blood samples were collected from all subjects to compare the blood lipid levels and the levels of inflammatory factors between the monotherapy group and the combination therapy group. Endothelial function parameters were also compared between the two groups using the UNEX EF device (UNEX, Nagoya, Japan). In addition, the levels of various inflammatory factors were retested 72 h after administration, and the patient’s blood lipid levels and endothelial function parameters were retested after completion of treatment. The methods for measuring each index are described below.
Assessment of blood lipid levels
On the day of the test, collect 5 ml of fasting venous blood and immediately centrifuge at 3000 rpm for 10 min (Avanti JXN-30, Beckman Coulter, USA) to separate the serum. Once the centrifugation was complete, the inspector promptly aliquoted the serum samples into tubes designated for testing and transported them to the laboratory within 4–6 h for analysis. Using an automatic biochemical analyzer (7600; Hitachi, Tokyo, Japan), the concentrations of LDL-C, total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol were measured by enzymatic methods with different kits (LDL-C Gen 2, Roche, Switzerland; L Type Wako CHO-H, Hitachi, Japan; Triglycerides Gen 2, Roche, Switzerland; HDL-C Gen 3, Roche, Switzerland) respectively. Meanwhile, the concentrations of apolipoprotein A1 (Apo A1) and apolipoprotein B (Apo B) were measured using immunoturbidimetric methods with different kits (cobas® c Apo A1, Roche, Switzerland; cobas® c Apo B, Roche, Switzerland;) respectively.
Assessment of inflammatory factors
Blood samples were centrifuged (Avanti JXN-30, Beckman Coulter, USA) within 30 min of collection at 3,000 × g for 10 min, and plasma aliquots were stored at −80℃ until further analysis. According to the manufacturer’s recommendations, the levels of inflammatory factors were measured using the Bio-Plex Pro Human Cytokine 27-plex Immunoassay Kit (LQ00006JK0K0RR, NovoBio Beijing, People’s Republic of China). Bio-Rad, a human cytokine standard, was utilized to detect the plasma concentration of the following 3 cytokines based on the Luminex 200 system: IL-6, IL-1β, TNF-α.
Assessment of endothelial function parameters
Flow-Mediated Dilation (FMD) was measured using the UNEX EF device (UNEX, Nagoya, Japan). In this system, long and short axis images of the brachial artery were recorded using a 10- MHz high-resolution H- shaped ultrasound linear array transducer. The diastolic diameter of the brachial artery was determined semi-automatically using an instrument equipped with a software for monitoring the brachial artery diameter and tracked automatically in real time by synchronization with electrocardiographic R-wave. B- mode images and A- mode waves of the brachial artery were simultaneously and continuously recorded with a probe attached to a stereotactic probe- holding device. An occlusion cuff was wrapped around the forearm with the proximal edge of the cuff at the elbow (1–2 cm above the elbow). After obtaining the rest diameter, the occlusion cuff was inflated to 50 mmHg above the systolic BP and kept inflated for 5 min. Again, images of the brachial artery were recorded continuously for 2 min following cuff deflation.
During a measurement, the diameter of the brachial artery changes. Three diameters of the brachial artery are obtained: baseline diameter (pre-cuff-inflation diameter), minimum diameter (pre-cuff-deflation diameter) and maximum diameter (post-cuff-deflation diameter). The calculation formulas for FMD and VAR are as follows:
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Adverse reactions and prognosis
The incidence of adverse reactions and adverse cardiovascular events was determined during the three-month treatment period. The adverse reactions observed in this study include Creatinine Abnormality, Muscle Soreness, Vertigo, and Gastrointestinal Discomfort. Definitions for these four types of adverse reactions are provided below. Abnormal creatinine refers to creatinine levels falling outside the normal range, typically 53–106 µmol/L for males and 44–97 µmol/L for females. Muscle soreness describes discomfort in muscles caused by various factors such as infection or exercise. Vertigo, a common brain functional disorder, is characterized by dizziness, a heavy sensation, and possibly visual disturbances, nausea, and vomiting. Gastrointestinal discomfort encompasses symptoms such as abdominal pain, bloating, nausea, vomiting, retching, and acid regurgitation. The adverse cardiovascular events observed in this study include Recurrent Angina Pectoris, Arrhythmia, Myocardial Infarction, and Heart Failure. Definitions for these four types of adverse cardiovascular events are provided below. Recurrent angina pectoris refers to the reappearance of chest discomfort after treatment, often accompanied by other symptoms. Arrhythmia denotes irregularities in heart rate or rhythm resulting from abnormal electrical activity in the heart. Myocardial infarction occurs due to prolonged ischemia and hypoxia of the coronary arteries, leading to myocardial necrosis and typically presenting with severe and persistent chest pain. Heart failure is a condition in which the heart’s ability to pump blood effectively is compromised, resulting in insufficient blood flow to meet the body’s demands.
Statistical analysis
Data analysis was conducted using SPSS version 29.0 statistical software (SPSS Inc., Chicago, IL, USA). Continuous variables were assessed for normality using the Shapiro-Wilk test; all data were found to be normally distributed and are presented as mean ± standard deviation (x̄ ± s), with comparisons made using t-tests. Categorical data are presented as n (%). Chi-square test (χ²) was used when expected frequency ≥ 5; Yates’ correction was applied if expected frequency was 1–5. Statistical significance was set at p < 0.05.
To control for confounding bias, propensity score matching was employed. Propensity scores were calculated using a logistic regression model that included age, gender, body mass index (BMI), fasting glucose, smoking history, drinking history, diabetes, hypertension, history of stroke or TIA, peripheral artery disease, education level, family history of coronary heart disease, and baseline LDL-C levels. Matching was performed using a 1:1 nearest neighbor method. After matching, the absolute values of the standardized mean differences for all variables were less than 0.1, indicating good baseline balance. Post-matching, there were no statistically significant differences in any of the baseline covariates between the two groups (all P > 0.05).
Results
General characteristics before propensity score matching
Before propensity score matching, there were no significant differences between the two groups in demographic baseline characteristics including age, gender, weight, BMI, smoking history, drinking history, peripheral artery disease, and family medical history (P > 0.05; Table 1). The fasting plasma glucose levels were significantly higher in the combination therapy group compared to the monotherapy group (P = 0.027), and the prevalence of diabetes was also significantly higher in the combination therapy group (P = 0.029). A history of non-hemorrhagic stroke or TIA was significantly more common in the combination therapy group (P = 0.016). Additionally, baseline LDL-C levels were significantly higher in the combination therapy group (P < 0.001). These results indicate that before propensity score matching, patients in the combination therapy group had higher baseline risks in certain cardiovascular risk factors such as blood glucose control, diabetes history, history of non-hemorrhagic stroke or TIA, and LDL-C levels. There was some distribution difference in education level, but it did not reach statistical significance (P = 0.187).
Table 1.
Comparison of demographic baseline characteristics among the two groups before propensity score matching
| Parameter | Monotherapy Group (n = 96) | Combination Therapy Group (n = 102) | t/χ² | P |
|---|---|---|---|---|
| Age (years) | 60.30 ± 7.14 | 59.92 ± 6.58 | 0.384 | 0.702 |
| Gender [n (%)] | 0.264 | 0.608 | ||
| Male | 53 (55.21%) | 60 (58.82%) | ||
| Female | 43 (44.79%) | 42 (41.18%) | ||
| Weight (kg) | 84.98 ± 12.85 | 86.54 ± 13.12 | 0.845 | 0.399 |
| BMI (kg/m2) | 27.75 ± 4.46 | 27.84 ± 4.24 | 0.147 | 0.883 |
| Fasting Plasma Glucose(mg/dl) | 101.53 ± 16.48 | 106.87 ± 17.24 | 2.227 | 0.027 |
| Smoking history [n (%)] | 25 (26.04%) | 30 (29.41%) | 0.280 | 0.597 |
| Drinking History [n (%)] | 22 (22.92%) | 26 (25.49%) | 0.178 | 0.673 |
| Medical history | 0.200 | 0.978 | ||
| Diabetes mellitus [n (%)] | 18 (18.75%) | 33 (32.35%) | 4.785 | 0.029 |
| Arterial hypertension [n (%)] | 49 (51.04%) | 62 (60.78%) | 1.906 | 0.167 |
| Non-haemorrhagic stroke or TIA [n (%)] | 13 (13.54%) | 28 (27.45%) | 5.827 | 0.016 |
| Peripheral artery disease [n (%)] | 8 (8.33%) | 12 (11.76%) | 0.641 | 0.423 |
| Educational Level [n (%)] | 3.358 | 0.187 | ||
| Primary | 17 (17.71%) | 15 (14.71%) | ||
| Secondary | 47 (48.96%) | 40 (39.22%) | ||
| Tertiary | 32 (33.33%) | 47 (46.08%) | ||
| Family history [n (%)] | 42 (43.75%) | 48 (47.06%) | 0.218 | 0.640 |
| Baseline LDL-C (mmol/L) | 3.30 ± 0.41 | 3.82 ± 0.55 | 7.522 | < 0.001 |
BMI Body mass index, TIA Transient Ischemic Attack, LDL-C Low-density lipoprotein cholesterol
General characteristics after propensity score matching
Demographic and baseline characteristics were compared between the Monotherapy Group and the Combination Therapy Group to ensure comparability (Table 2). No significant differences were observed in age (P = 0.856), gender (P = 0.941), weight (P = 0.707), or BMI (P = 0.479). Similarly, there were no significant differences in fasting plasma glucose (P = 0.707), smoking history (P = 0.894), or drinking history (P = 0.873). Regarding medical history, no significant differences were found for diabetes mellitus, arterial hypertension, non-haemorrhagic stroke or TIA, or peripheral artery disease (all P > 0.05). Educational level (P = 0.968) and family history (P = 0.927) were also similar between the groups. In summary, demographic and baseline characteristics were well-balanced between the two groups, supporting their comparability.
Table 2.
Comparison of demographic baseline characteristics among the two groups after propensity score matching
| Parameter | Monotherapy Group (n = 75) | Combination Therapy Group (n = 76) | t/χ² | P |
|---|---|---|---|---|
| Age (years) | 60.11 ± 6.89 | 59.92 ± 6.23 | 0.182 | 0.856 |
| Gender [n (%)] | 0.005 | 0.941 | ||
| Male | 41 (54.67%) | 42 (55.26%) | ||
| Female | 34 (45.33%) | 34 (44.74%) | ||
| Weight (kg) | 85.32 ± 12.64 | 86.12 ± 13.46 | 0.376 | 0.707 |
| BMI (kg/m2) | 27.62 ± 4.12 | 27.13 ± 4.34 | 0.709 | 0.479 |
| Fasting Plasma Glucose(mg/dl) | 104.25 ± 15.56 | 105.23 ± 16.43 | 0.376 | 0.707 |
| Smoking history [n (%)] | 20 (26.67%) | 21 (27.63%) | 0.018 | 0.894 |
| Drinking History [n (%)] | 15 (20.00%) | 16 (21.05%) | 0.026 | 0.873 |
| Medical history | ||||
| Diabetes mellitus [n (%)] | 15 (20.00%) | 16 (21.05%) | 0.026 | 0.873 |
| Arterial hypertension [n (%)] | 38 (50.67%) | 40 (52.63%) | 0.058 | 0.809 |
| Non-haemorrhagic stroke or TIA [n (%)] | 10 (13.33%) | 9 (11.84%) | 0.076 | 0.782 |
| Peripheral artery disease [n (%)] | 6 (8.00%) | 5 (6.58%) | 0.113 | 0.737 |
| Educational Level [n (%)] | 0.064 | 0.968 | ||
| Primary | 13 (17.33%) | 14 (18.42%) | ||
| Secondary | 37 (49.33%) | 38 (50.00%) | ||
| Tertiary | 25 (33.33%) | 24 (31.58%) | ||
| Family history [n (%)] | 33 (44.00%) | 34 (44.74%) | 0.008 | 0.927 |
Comparison of the blood lipid profiles
Blood lipid profiles were compared between the Monotherapy Group and the Combination Therapy Group before treatment to ensure baseline comparability (Table 3). No significant differences were observed in TC (P = 0.447), TG (P = 0.085), LDL-C (P = 0.849), HDL-C (P = 0.790), ApoA1 (P = 0.795), or ApoB (P = 0.720) between the two groups. In summary, the baseline blood lipid profiles were similar between the Monotherapy Group and the Combination Therapy Group, indicating that the two groups were well-matched at the start of the study.
Table 3.
Comparison of blood lipid profiles between the two groups of patients before treatment
| Parameter | Monotherapy Group (n = 75) | Combination Therapy Group (n = 76) | t | P |
|---|---|---|---|---|
| TC (mmol/L) | 4.92 ± 0.78 | 4.78 ± 1.35 | 0.763 | 0.447 |
| TG (mmol/L) | 1.87 ± 0.64 | 2.06 ± 0.71 | 1.732 | 0.085 |
| LDL-C (mmol/L) | 3.49 ± 0.41 | 3.47 ± 0.56 | 0.191 | 0.849 |
| HDL-C (mmol/L) | 1.14 ± 0.26 | 1.13 ± 0.29 | 0.267 | 0.790 |
| ApoA1 (g/L) | 1.21 ± 0.23 | 1.20 ± 0.24 | 0.261 | 0.795 |
| ApoB (g/L) | 1.04 ± 0.20 | 1.03 ± 0.27 | 0.359 | 0.720 |
TC Total cholesterol, TG Triglycerides, HDL-C High-density lipoprotein cholesterol, LDL-C Low-density lipoprotein cholesterol, Apo Apolipoprotein
After treatment completion, significant differences were noted in several lipid profile parameters (Table 4). The TC levels were lower in the Combination Therapy Group compared to the Monotherapy Group (P = 0.002). Similarly, LDL-C was also significantly lower in the Combination Therapy Group compared to the Monotherapy Group (P < 0.001). Additionally, ApoB levels were significantly lower in the Combination Therapy Group compared to the Monotherapy Group (P = 0.004). No significant differences were observed in TG (P = 0.724), HDL-C (P = 0.200), or ApoA1 (P = 0.918) between the two groups. Indicating potential advantages of combination therapy in improving these lipid parameters.
Table 4.
Comparison of blood lipid profiles between the two groups of patients after the completion of treatment
| Parameter | Monotherapy Group (n = 75) | Combination Therapy Group (n = 76) | t | P |
|---|---|---|---|---|
| TC (mmol/L) | 2.65 ± 0.77 | 2.27 ± 0.76 | 3.115 | 0.002 |
| TG (mmol/L) | 1.06 ± 0.53 | 1.09 ± 0.56 | 0.354 | 0.724 |
| LDL-C (mmol/L) | 1.71 ± 0.49 | 1.08 ± 0.32 | 9.304 | < 0.001 |
| HDL-C (mmol/L) | 1.08 ± 0.22 | 1.13 ± 0.25 | 1.287 | 0.200 |
| ApoA1 (g/L) | 1.26 ± 0.23 | 1.26 ± 0.24 | 0.104 | 0.918 |
| ApoB (g/L) | 0.49 ± 0.16 | 0.42 ± 0.13 | 2.889 | 0.004 |
Comparison of inflammatory factors
Before treatment, no significant differences were observed in IL-1β (P = 0.536), IL-6 (P = 0.988), or TNF-α (P = 0.936) between the Monotherapy Group and the Combination Therapy Group (Fig. 1). Thus, the baseline levels of inflammatory factors were comparable between the two groups, indicating that they were well-matched at the start of the study.
Fig. 1.
Comparison of inflammatory factors between the two groups of patients before treatment and 72 h after drug administration. Note: (a) IL-1β (pg/ml); (b) IL-6 (pg/ml); (c) TNF-α(pg/ml). ns: no significant; **: P < 0.01. IL-1β: interleukin-1 beta; IL-6: interleukin-6; TNF-α: Tumor Necrosis Factor-αlpha
Seventy-two hours after drug administration, significant differences were noted in several inflammatory factors. IL-1β levels were significantly lower in the Combination Therapy Group compared to the Monotherapy Group (P = 0.002). Similarly, TNF-α levels were also significantly lower in the Combination Therapy Group compared to the Monotherapy Group (P = 0.002). However, no significant difference was observed in IL-6 levels between the two groups (P = 0.111). These findings indicate that the Combination Therapy Group showed greater reductions in key inflammatory markers compared to the Monotherapy Group.
Comparison of the endothelial function parameters
Before treatment, no significant differences were observed in several endothelial function parameters (Table 5). There were no significant differences in baseline diameter (P = 0.528), minimum diameter (P = 0.939), or maximum diameter (P = 0.530) between the Monotherapy Group and the Combination Therapy Group. Similarly, the difference between maximum and minimum diameter (P = 0.365), VAR (P = 0.337), and FMD (P = 0.617) also showed comparable values between the two groups.
Table 5.
Comparison of endothelial function parameters between the two groups of patients before treatment
| Parameter | Monotherapy Group (n = 75) | Combination Therapy Group (n = 76) | t | P |
|---|---|---|---|---|
| Baseline diameter (mm) | 4.34 ± 0.52 | 4.28 ± 0.53 | 0.633 | 0.528 |
| Minimum diameter (mm) | 4.34 ± 0.53 | 4.35 ± 0.58 | 0.077 | 0.939 |
| Maximum diameter (mm) | 4.50 ± 0.54 | 4.44 ± 0.57 | 0.630 | 0.530 |
| Difference of maximum diameter and minimum diameter (mm) | 0.16 ± 0.05 | 0.15 ± 0.05 | 0.908 | 0.365 |
| VAR (mm) | 3.85 ± 1.28 | 3.66 ± 1.21 | 0.963 | 0.337 |
| FMD (%) | 3.91 ± 1.30 | 4.01 ± 1.32 | 0.500 | 0.617 |
Baseline diameter: pre-cuff-inflation diameter; minimum diameter: pre-cuff-deflation diameter; maximum diameter: post-cuff-deflation diameter
VAR Vasoactive range, FMD Flow mediated vasodilation
After the completion of treatment, several endothelial function parameters were compared between the Monotherapy Group and the Combination Therapy Group (Table 6). No significant differences were observed in baseline diameter (P = 0.637), minimum diameter (P = 0.633), maximum diameter (P = 0.739), or the difference between maximum and minimum diameter (P = 0.393) between the two groups. However, significant differences were noted in VAR (P = 0.017) and FMD (P = 0.003). The Combination Therapy Group showed significantly higher values for both VAR and FMD compared to the Monotherapy Group. These findings indicate that while most endothelial function parameters remained similar between the groups, the Combination Therapy Group demonstrated significantly better improvements in vascular reactivity as measured by VAR and FMD.
Table 6.
Comparison of endothelial function parameters between the two groups of patients after the completion of treatment
| Parameter | Monotherapy Group (n = 75) | Combination Therapy Group (n = 76) | t | P |
|---|---|---|---|---|
| Baseline diameter (mm) | 4.29 ± 0.53 | 4.25 ± 0.61 | 0.473 | 0.637 |
| Minimum diameter (mm) | 4.32 ± 0.52 | 4.27 ± 0.63 | 0.478 | 0.633 |
| Maximum diameter (mm) | 4.45 ± 0.54 | 4.42 ± 0.62 | 0.334 | 0.739 |
| Difference of maximum diameter and minimum diameter (mm) | 0.16 ± 0.05 | 0.17 ± 0.05 | 0.857 | 0.393 |
| VAR (mm) | 3.68 ± 1.22 | 4.20 ± 1.39 | 2.410 | 0.017 |
| FMD (%) | 4.27 ± 1.32 | 5.01 ± 1.67 | 3.037 | 0.003 |
Comparison of adverse reactions between the two groups of patients
No significant differences were observed in the incidence of creatinine abnormality, muscle soreness, vertigo, or gastrointestinal discomfort between the two groups (Fig. 2). Specifically, the Monotherapy Group reported one case each of creatinine abnormality, muscle soreness, and vertigo, as well as two cases of gastrointestinal discomfort. The Combination Therapy Group reported one case of muscle soreness. Overall, the total incidence of adverse reactions was also not significantly different between the two groups (P = 0.205). These results suggest that both treatment groups had similar safety profiles, with no significant difference in the overall incidence of adverse reactions.
Fig. 2.
Comparison of incidence of adverse reactions between the two groups of patients
No significant differences were observed in the incidence of individual events such as recurrent angina pectoris, arrhythmia, myocardial infarction, or heart failure between the two groups (Table 7). However, the total incidence of adverse cardiovascular events was significantly different between the two groups (P = 0.023). The Monotherapy Group had a higher incidence of adverse cardiovascular events compared to the Combination Therapy Group. These results suggest that the Combination Therapy Group had a lower overall incidence of adverse cardiovascular events, indicating potential benefits in terms of cardiovascular safety.
Table 7.
Comparison of incidence of adverse cardiovascular events between the two groups of patients
| Parameter | Monotherapy Group (n = 75) | Combination Therapy Group (n = 76) | χ² | P |
|---|---|---|---|---|
| Recurrent angina pectoris [n (%)] | 4 (5.33%) | 1 (1.32%) | ||
| Arrhythmia [n (%)] | 5 (6.67%) | 2 (2.63%) | ||
| Myocardial infarction [n (%)] | 0 (0.00%) | 0 (0.00%) | ||
| Heart failure [n (%)] | 2 (2.67%) | 0 (0.00%) | ||
| Total [n (%)] | 11 (14.67%) | 3 (3.95%) | 5.156 | 0.023 |
Discussion
This study confirmed that the combination of evolocumab with atorvastatin provided multiple therapeutic benefits for CHD, extending beyond traditional lipid-lowering effects. The advantages of combination therapy in reducing inflammation, restoring endothelial homeostasis, and decreasing early cardiovascular events highlighted the synergistic regulation of interconnected pathological pathways. These findings elucidated previously underappreciated pleiotropic mechanisms that could address residual cardiovascular risk remaining after statin therapy.
The reduction in atherogenic lipids, particularly LDL-C, TC, and ApoB, observed with combination therapy laid a critical foundation for subsequent anti-inflammatory effects and endothelial improvements. These findings were consistent with previous studies emphasizing the efficacy of PCSK9 inhibitors in lowering circulating LDL-C levels [17, 18]. The lipid-lowering effects reflected the synergistic pharmacology of statins and PCSK9 inhibitors: atorvastatin upregulated hepatic LDL receptor expression, while evolocumab prevented its degradation, thereby enhancing the clearance of circulating atherogenic particles [19, 20]. In the combination therapy group, LDL-C levels reached ultra-low levels, aligning with the contemporary paradigm of “the lower, the better” for high-risk CHD populations [21]. Notably, the significant reduction in ApoB held particular pathophysiological importance. ApoB represents the structural protein of all atherogenic lipoproteins (LDL, VLDL, IDL) and was a stronger predictor of cardiovascular risk than LDL-C alone [22]. The differential reduction in atherogenic burden likely initiated the cascade of benefits observed in inflammation and endothelial parameters.
To investigate the early direct effects of PCSK9 inhibitors beyond significant lipid-lowering, this study chose to evaluate inflammatory factors at 72 h after medication initiation. This time point was selected to capture the potential early and direct modulation of vascular inflammation. The rapid suppression of IL-1β and TNF-α within 72 h indicated that evolocumab had direct anti-inflammatory properties, which was consistent with previous studies on PCSK9 inhibitors modulating innate immune responses [23, 24]. This phenomenon might have originated from disrupting the oxidized low-density lipoprotein (oxLDL)-NLRP3 inflammasome axis. Mechanistically, PCSK9 inhibition reduced circulating PCSK9, limiting the oxidation of LDL particles and their subsequent uptake via lectin-like oxidized LDL receptor 1 (LOX-1) on macrophages [25]. This process usually triggered NADPH oxidase-derived reactive oxygen species (ROS), activated the NLRP3 inflammasome, and led to caspase-1-mediated maturation of IL-1β and IL-18 [26, 27]. Furthermore, the reduction in TNF-α could significantly impact endothelial function by reversing the uncoupling of endothelial nitric oxide synthase (eNOS) [28, 29]. In this process, TNF-α promoted the accumulation of asymmetric dimethylarginine (ADMA), oxidized tetrahydrobiopterin (BH4), and enhanced caveolin-1 binding to eNOS. The notable improvement in FMD observed in the combination therapy group likely reflected restored nitric oxide (NO) bioavailability through this pathway.
This study found that combination therapy rapidly (within 72 h) inhibited IL-1β and TNF-α and improved endothelial function, consistent with the pleiotropic effects of PCSK9 inhibitors on the cholesterol-inflammation axis [30]. Recent studies also confirmed that adding PCSK9 inhibitors for 6 months in patients with familial hypercholesterolemia already on high-intensity statins reduced LDL-C, neutrophil/monocyte ratio, and pulse wave velocity. Those findings demonstrated mid-term improvements in arterial stiffness in very high-risk populations, while this study captured early-specific inflammatory suppression and concurrent benefits in microvascular endothelial function in routine coronary artery disease patients. These findings collectively suggest that PCSK9 inhibitors promote vascular health by co-regulating lipids and inflammation, potentially explaining their mechanism in reducing cardiovascular events.
This study observed a reduction in IL-1β and TNF-α while IL-6 remained stable, which is mechanistically consistent with literature reports that PCSK9 inhibitors do not reduce hs-CRP [31]. IL-6 is the key factor driving hepatic production of hs-CRP, and its unchanged levels directly explain why hs-CRP did not decrease. This indicates that the anti-inflammatory effects of evolocumab are pathway-selective, specifically inhibiting local arterial wall inflammation pathways (such as the NLRP3/IL-1β axis) rather than systemic IL-6/CRP pathways [32]. This supports the precise pleiotropy of its anti-inflammatory effects and suggests that evaluating its efficacy should go beyond hs-CRP to include more specific vascular inflammation markers.
The enhancement of endothelial function observed in the combination therapy group supported the notion that targeting lipid metabolism and inflammation might have a synergistic effect on vascular health [33]. The combination therapy group showed significant improvements in FMD, an NO-dependent process, and vascular activity range (VAR), consistent with previous findings on PCSK9 inhibitors improving vascular endothelial function [34]. Combination therapy resulted in higher FMD compared to the monotherapy group. Previous studies have suggested that in patients with coronary heart disease, every 1% improvement in FMD is generally associated with a reduced risk of cardiovascular events [35]. This selective benefit suggested that evolocumab specifically targeted mechanisms for endothelial repair beyond cholesterol regulation. New evidence indicated that PCSK9 directly bound to LDL receptors on endothelial cells, inducing LDL receptor degradation and impairing cholesterol efflux [36]. This led to lipid raft accumulation and internalization of vascular endothelial (VE) cadherin, compromising barrier integrity. Additionally, upregulation of LOX-1 perpetuated oxLDL uptake, establishing a vicious cycle of endothelial injury. Improvements in these processes might explain the enhanced FMD, while improvements in VAR likely reflected reduced vascular stiffness due to decreased lipid infiltration.
In this study, we observed a trend towards a lower incidence of adverse cardiovascular events, particularly recurrent angina, in the combination therapy group during the 3-month follow-up period. This phenomenon may be related to the comprehensive plaque stabilization mechanisms brought about by combination therapy. The rapid inhibition of cytokines (IL-1β, TNF-α) may reduce the secretion of matrix metalloproteinases, thereby helping to maintain fibrous cap integrity [37]. Meanwhile, improved endothelial function may also enhance coronary microvascular perfusion [38]. However, these findings must be interpreted with caution. Given the short follow-up period and the low number of events, the current observations are only preliminary indications and are insufficient to prove that combination therapy improves hard clinical endpoints. These findings need to be validated through studies with longer follow-up periods and larger sample sizes.
Despite these promising findings, several limitations required cautious interpretation. This study’s retrospective, single-center design introduces inherent selection bias and indication confounding risks. In clinical practice, the decision to prescribe evolocumab may be based on patients having higher residual cardiovascular risk. These factors are themselves associated with adverse outcomes and may constitute indication confounding in this study. Although baseline characteristics were largely balanced between the two groups, this non-randomized treatment allocation may have introduced unmeasured confounding variables, potentially indicating that patients in the combination therapy group had higher baseline risks. Single-center studies often faced challenges related to patient diversity and local practice variations, which could affect the generalizability of the results. Additionally, the 3-month follow-up period excluded assessments of long-term outcomes or changes in plaque morphology. Another limitation involved the evaluation of adverse reactions. Although there were no significant differences in adverse event rates between the two groups, the small sample size might have limited the statistical power to detect rare adverse events. Larger, prospective studies with longer follow-up periods were necessary to comprehensively assess the safety of combination therapy. Additionally, in the analysis of multiple related inflammatory markers, we did not perform multiple testing correction, which may increase the risk of false positives. Future research should incorporate advanced imaging techniques such as intravascular ultrasound (IVUS) or optical coherence tomography (OCT) to correlate biomarker changes with plaque regression and quantify oxidative stress markers to validate the proposed pathways.
In conclusion, this study demonstrated that combination therapy with evolocumab and atorvastatin offered significant advantages over atorvastatin monotherapy in lipid control, reduction of inflammatory markers, and improvement of endothelial function. These findings suggested that combination therapy might provide a more effective approach for managing CHD, particularly in high-risk patients. However, further research was necessary to validate these results and explore the long-term implications of this therapeutic strategy. Addressing the limitations identified in this study would be crucial for advancing the field and optimizing treatment regimens for CHD patients.
Acknowledgements
None.
Authors’ contributions
Xueqin Jin: Conceptualization, Formal analysis, Investigation. Chang Li: Methodology, Formal analysis, Data Curation. Jingyi Zhang: Conceptualization, Formal analysis, Data Curation. Di Liang: Data Curation, Supervision. Ming Zhang: Data Curation, Methodology, Writing - Original Draft.
Funding
None.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
This study received approval from the Institutional Review Board and Ethics Committee of the Hubei No.3 People’s Hospital, and was conducted in accordance to the tenets of the Declaration of Helsinki. Given the exclusive use of de-identified patient data, which presented no potential harm or impact on patient care, the need for informed consent was waived by the Hubei No.3 People’s Hospital. This exemption was granted in line with regulatory and ethical standards for retrospective research.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.