PCSK-9 inhibitors improve cardiovascular events after PCI in patients with chronic kidney disease

doi:10.21203/rs.3.rs-4836351/v1

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Research Article

PCSK-9 inhibitors improve cardiovascular events after PCI in patients with chronic kidney disease

https://doi.org/10.21203/rs.3.rs-4836351/v1

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Objective:

To investigate the correlation between Lp(a) levels and the degree of coronary artery stenosis in patients with coronary artery disease (CAD) complicated with chronic kidney disease (CKD); evaluate the predictive value of Lp(a) in patients with CAD complicated with CKD; and evaluate the clinical value of PCSK-9 inhibitors in patients with CAD complicated with CKD.

Method:

A total of 494 patients admitted to our hospital for coronary angiography from October 2017 to December 2019 were included in this study. The patients were divided into a CKD group (n = 247) and a non-CKD group (n = 247). The CKD patients were divided into 3 groups according to the glomerular filtration rate (eGFR). The Gensini score was used to evaluate the coronary plaque load. Changes in the blood lipid index and its correlation with the coronary Gensini score were analyzed. CAD patients with CKD who received PCI were further divided into a PCSK-9 inhibitor treatment group and a conventional treatment group to explore the lipid-lowering effect of a PCSK-9 inhibitor on major adverse cardiac events (MACEs)(cardiac death, nonfatal myocardial infarction, heart failure and angina readmissions).

Result:

The levels of TG and Lp(a) in the CKD group were greater than those in the non-CAD combined CKD group (P < 0.05). The HDL-C level in the CAD combined with CKD group was lower than that in the non-CAD combined with CKD group (P < 0.05). However, there were no significant differences in TC or HDL-C levels between the two groups (P > 0.05). Lp(a) was significantly positively correlated with the coronary Gensini score (r = 0.135, P < 0.05), and this correlation was observed only in the moderate renal insufficiency group (r = 0.222, P < 0.05). PCSK-9 inhibitors significantly reduced LDL-D (-30.28% vs. -4.44%, P = 0.000) and Lp(a) levels (-25.22% vs. -10%, P = 0.006) in patients with CKD. In addition, PCSK-9 inhibitors reduced the occurrence of MACEs in patients (HR: 0.27, 95% CI 0.07–0.99; P = 0.013).

Conclusion:

In CAD patients with CKD, the degree of coronary stenosis becomes increasingly severe with increasing Lp(a) levels, and the Lp(a) level can be used as a predictor of the degree of coronary stenosis in CAD patients with CKD. PCSK-9 inhibitors reduce the incidence of cardiovascular events in patients with CKD.

Lipoprotein a

Cronary heart disease

Chronic kidney disease

Gensini score PCSK-9 inhibitors

Currently, the prevalence of coronary artery disease (CAD) and chronic kidney disease (CKD) is progressively increasing in the population. Furthermore, CKD patients exhibit elevated mortality rates due to a heightened incidence of adverse cardiovascular outcomes, with kidney disease serving as an independent risk factor. While coronary angiography remains the gold standard for CAD diagnosis, its use of contrast media can impose additional strain on patients' kidneys and increase the risk of contrast-induced nephropathy¹. Lipoprotein (a), a particle resembling low-density lipoprotein (LDL) cholesterol that binds to apolipoprotein (a), is regulated primarily by hepatic expression of the LPA gene and secondarily by renal expression. There has been an increase in studies investigating Lp(a). This study aimed to assess coronary lesions in CKD patients through the measurement of Lp(a) levels, providing valuable insights for clinicians.

At present, existing studies have shown that the Lp(a) level in CKD patients is greater than that in normal people, but current studies have not further analyzed the Lp(a) level in patients with different CKD grades, and there is a lack of treatment measures. The aim of this study was to measure Lp(a) levels to evaluate coronary lesions in patients with CKD and propose treatment measures.

2.1 Study population

This study included 494 patients with coronary heart disease (25–80 years old). Firstly, we collected CAD patients with CKD who underwent coronary angiography in our hospital between June 2017 and June 2019 (n = 247), and then we matched them according to age sex and BMI to screen patients with coronary heart disease for inclusion in the non-CKD group (n = 247). The patients in the CKD group were divided into three groups according to the glomerular filtration rate (eGFR) : mild renal insufficiency group (eGFR ≥ 60ml/min*1.73m²), 55 cases (22.27%). There were 93 cases (37.65%) in the moderate renal insufficiency group (eGFR 30-59ml/min*1.73m²); There were 99 cases (40.08%) in severe renal insufficiency group (eGFR < 30ml/min*1.73m²). Gensini score (Table 1)was used to evaluate the level of coronary plaque load.

All patients received standard medication. CKD patients receiving PCI were screened, and patients in the CKD group receiving PCSK-9 inhibitor treatment were included in the PCSK-9 inhibitor treatment group (n = 63). Patients in the CKD group who were not treated with PCSK-9 inhibitors were matched to the usual treatment group based on Gensini scores and baseline cholesterol levels (n = 63). The rest of the treatment drugs were used according to current guidelines, and there were no potential differences in drug treatment between the two groups.

The exclusion criteria are as follows:

1) Previously diagnosed CHD was treated with PCI or PTCA

2) There are other diseases that affect the lipid metabolism of patients

3) Over the age of 80

Flow chart

Table : Simplified comparison table

logogram	Official name
Lp (a)	Lipoprotein a
CAD	coronary heart disease
CKD	chronic kidney disease
PCSK-9	Proprotein Convertase Subtilisin/Kexin Type 9
PCI	Percutaneous coronary stent implantation
TG	triglyceride
TC	total cholesterol
LDL-C	Low density lipoprotein cholesterol
HDL-C	High density lipoprotein cholesterol
MACEs	major adverse cardiovascular events
LAD	Anterior descending branch
LCX	Circumflex branch
D	Diagonal branch
RCA	Right coronary artery
eGFR	Estimate glomerular filtration rate
BMI	Body Mass Index
CRP	C-reactive protein
PT	Prothrombin time
D-D	D-dimer
ALT	Glutamic-pyruvic transaminase
AST	Glutamic oxalacetic transaminase
CK	Creatine kinase
CK-MB	Creatine kinase isoenzyme

2.2 Experimental endpoint

In the subgroup of patients followed for 1 year, terminal events were defined as major adverse cardiovascular events(MACEs), including cardiac death, non-fatal myocardial infarction, heart failure and angina readmissions.

2.3 Statistical Methods

SPSS 25.0 software was used for statistical analysis. The normal or approximate normal distribution of quantitative data was expressed as x ± s. Comparison between the two groups was performed by T-test. The skewness distribution of quantitative data was represented by Md (UQ-LQ), and Mann-Whitney test was used to compare the two groups. Qualitative data were presented as examples (%), and the comparison between the two groups was performed by X² test; Analysis of variance was used to compare the groups. Correlation analysis was performed by Pearson correlation analysis or Spearman correlation analysis. Logistic regression analysis was used for multivariate analysis. The ROC curve assesses Lp(a) predictive value. COX regression analysis and survival curves were used to assess the impact of the measures on patient outcomes.

A two-sided test was used, with a = 0.05 as the test level, and P < 0.05 as statistically significant.

Table 1

Gensini score for coronary stenosis
Degree of vessel stenosis	Gensini score:	Lesion site	Coefficient of correlation
≤ 25%	1	LM	5
26%-50%	2	Proximal segment of LAD and LCX	2.5
51%-75%	4	Midsection of LAD	1.5
76%-90%	8	Far section of LAD	1.0
91%-99%	16	Medial and distal branches of LCX	1.0
> 99%	32	RCA、D1	1.0
		Other small branches	0.5

3.1.1 General Information

A total of 494 patients were enrolled, comprising 315 males (63.77%), 162 smokers (32.79%), 95 alcohol-consuming individuals (19.84%), 348 hypertensive subjects (70.45%), and 196 diabetic participants (39.68%). The mean age of the cohort was 63.02 ± 9.95 years, with a mean BMI of 25.58 ± 3.65 kg/m².(Table 2)

Table 2

General information [‾x ± s;ratio(%)]
Items	Value
Age(years)	63.02 ± 9.95
BMI(kg/m²)	25.58 ± 3.65
Male	315(63.77%)
Smoking history	162(32.79%)
Drinking history	95(19.84%)
History of high blood pressure	348(70.45%)
History of diabetes	196(39.68%)

3.1.2 Comparison of clinical data between CKD group and non-CKD group

A comparison between the two groups revealed that the CKD group had higher rates of smoking history, diabetes history, hypertension history, and coronary stenosis degree compared to the non-CKD group (P < 0.05). The levels of TG 、Lp(a) and coronary artery disease were found to be higher in the CKD group than in the non-CKD group (P < 0.05), whereas HDL-C level was lower in the CKD group compared to its counterpart (P < 0.05). Nevertheless, no significant differences were noted regarding TC and LDL-C levels between these two groups (P > 0.05). (Table 3)

Table 3

Comparision of two groups ‾[x ± s;ratio(%);Md (UQ-LQ)]
Items	non-CKD group(n = 247)	CKD group(n = 247)	χ²/t/Z value	P value
Age(years)	62.28 ± 9.89	63.77 ± 9.98	-1.662	0.097
BMI (kg/m2)	25.67 ± 3.39	25.50 ± 3.89	0.516	0.606
Male	148(59.9%)	167(67.6%)	3.163	0.075
Smoking history	66(26.7%)	96(38.9%)	8.266	0.004
Drinking history	46(18.6%)	52(21.1%)	0.458	0.498
History of high blood pressure	145(58.7%)	203(82.2%)	32.708	0.000
History of diabetes	64(25.9%)	132(53.4%)	39.109	0.000
TC (mmol/l)	4.42 ± 1.10	4.48 ± 1.41	-0.503	0.615
LDL-C(mmol/l)	2.67 ± 0.90	2.70 ± 1.09	-0.291	0.771
HDL-C(mmol/l)	1.18 ± 0.30	1.11 ± 0.29	2.392	0.017
TG (mmol/l)	1.35(0.94,1.89)	1.76(1.19,2.52)	-5.088	0.000
Lp(a)(mg/l)	137(60,326)	232(126.4,438)	-5.469	0.000
Gensini score	28(13,54)	61(41,88)	-10.196	0.000
creatinine(µmol/l)	86.10(77.30,96.40)	151.00(112.00,337.00)	-14.724	0.000

3.1.3 Correlation between blood lipid indexes and degree of coronary artery stenosis in two groups.

The results of the non-CKD group demonstrated a significant positive correlation between TC, LDL-C, and Lp(a) levels and coronary Gensini score (r = 0.138, 0.142, 0.14; P < 0.05). (Table 4)However, in the CKD group, only Lp(a) exhibited a significant positive correlation with coronary Gensini score (r = 0.135; P < 0.05). Notably, no association was observed between LDL-C levels and Gensini score (P > 0.05), underscoring the significance of Lp(a) in patients with CAD and CKD. (Table 5, Fig. 1)

Table 4

Correlation between blood lipid level and Gensini score in non-CKD group
Items	Correlation coefficient	P value
TC(mmol/l)	0.138	0.030
LDL-C(mmol/l)	0.142	0.026
HDL-C(mmol/l)	-0.005	0.941
TG(mmol/l)	0.104	0.103
Lp(a) (mg/l)	0.14	0.028

Table 5

Correlation between Gensini score and blood lipid in CKD group
items	Correlation coefficient	P value
TC(mmol/l)	-0.005	0.940
LDL-C(mmol/l)	-0.013	0.837
HDL-C(mmol/l)	0.039	0.545
TG(mmol/l)	-0.045	0.479
Lp(a) (mg/l)	0.135	0.034

3.2.1 Comparison of blood lipid levels among subgroups in CKD group.

There were no significant differences in TG levels observed among different subgroups (P > 0.05). Notably, a decrease in renal function was associated with a statistically significant increase in Lp(a) levels (P < 0.05). Interestingly, the group with moderate renal insufficiency exhibited significantly elevated TC, LDL-C, and HDL-C levels (P > 0.05).(Table 6)

Table 6

Subgroup analysis ‾[x ± s;ratio(%); Md (UQ-LQ)]
Items	mild renal insufficiency group(n = 55)	moderate renal insufficiency group(n = 93)	severe renal insufficiency group(n = 99)	H/F value	P value
TC(mmol/l)	4.17 ± 0.97	4.85 ± 1.67	4.29 ± 1.27	5.179	0.007
LDL-C(mmol/l)	2.49 ± 0.73	2.92 ± 1.28	2.61 ± 1.03	3.478	0.033
HDL-C(mmol/l)	1.12 ± 0.25	1.19 ± 0.33	1.04 ± 0.26	6.772	0.001
TG(mmol/l)	1.47(0.95,2.40)	1.65(1.25,2.51)	1.86(1.27,2.65)	3.26	0.196
Lp(a) (mg/l)	183(130,312)	195(107.65, 390.4)	277(143,477)	7.542	0.023
Gensini score	56(28,88)	61(47,88)	64(40,92)	2.247	0.325

3.2.2 Correlation between blood lipid level and Gensini score among subgroups in CKD group.

According to the statistical analysis results, Lp(a) was significantly correlated with Gensini score in the moderate renal dysfunction group (r = 0.222, P < 0.05), (Fig. 2)while there was no correlation between Lp (a) and Gensini score in the other two groups (P > 0.05). (Table 7)

Table 7

Correlation between blood lipid level and Gensini score among subgroups in CKD group.
Items	mild renal insufficiency group(n = 55)(r/P)	moderate renal insufficiency group (n = 93)(r/P)	severe renal insufficiency group (n = 99)(r/P)
TC (mmol/l)	0.165/0.227	0.091/0.386	-0.186/0.066
LDL-C (mmol/l)	0.043/0.755	0.057/0.589	-0.127/0.210
HDL-C(mmol/l)	0.116/0.401	0.126/0.228	-0.072/0.481
TG(mmol/l)	0.055/0.689	-0.106/0.312	-0.115/0.255
Lp(a) (mg/l)	0.01/0.942	0.222/0.033	0.111/0.272

3.3 Comparison of blood lipid levels between the non- CKD group and the moderate renal insufficiency group

We conducted separate comparisons between patients in the non-CKD group and those in the CAD combined with moderate renal insufficiency group. In the latter group, blood lipid levels were found to be higher compared to the former, with statistically significant differences observed only for TC and Lp(a) (P < 0.05).( Table 8)

Table 8

Subgroup analysis ‾[x ± s;ratio(%); Md (UQ-LQ)]
Items	non-CKD group(n = 247)	moderate renal insufficiency group (n = 93)	t/Z value	P value
TC (mmol/l)	4.42 ± 1.10	4.85 ± 1.67	-2.321	0.022
LDL-C(mmol/l)	2.67 ± 0.90	2.92 ± 1.28	-1.722	0.087
HDL-C(mmol/l)	1.18 ± 0.30	1.19 ± 0.33	-0.323	0.747
TG(mmol/l)	1.35(0.94,1.89)	1.65(1.25,2.51)	-3.946	0.000
Lp(a) (mg/l)	137(60,326)	195(107.65, 390.4)	-3.411	0.001
3.4 Evaluation of efficacy of PCSK-9 inhibitors

Baseline data for 126 patients included in the PCSK-9 inhibitor treatment group and the usual treatment group were comparable. (Table 9) At the one-year follow-up, a combined MACE occurred in 27% (n = 17) of patients receiving conventional treatment compared to12.7% (n = 8) of those treated with PCSK-9 inhibitors (p = .013). The incidence rates for angina readmission, nonfatal myocardial infarction, heart failure, and cardiac death were as follows: conventional treatment group -angina readmission(9.5%, n = 6),nonfatal myocardial infarction(7.9%,n = 5), heart failure(6.3%,n = 4), cardiac death(3.2%,n = 2); PCSK-9 inhibitor treatment group - angina readmission(3.2%, n = 2),nonfatal myocardial infarction(9.5%,n = 6), heart failure(0%,n = 0), cardiac death(0%,n = 0) (all p > 0.05).

Table 9

Comparision of two groups ‾[x ± s;ratio(%); Md (UQ-LQ)]
Items	PCSK-9 inhibitor group(n = 63)	Conventional treatment(n = 63)	χ²/t/Z value	P value
Age(years)	66(56.5, 72.5)	67(61, 74)	-0.959	0.337
BMI (kg/m2)	25.91 ± 3.29	25.09 ± 3.28	1.271	0.206
Male	37(58.7%)	40(63.5%)	0.301	0.584
Smoking history	9(14.3%)	9(14.3%)	0	1.000
Drinking history	7(11.1%)	9(14.3%)	0.286	0.593
History of high blood pressure	51(81.0%)	51(81.0%)	0	1.000
History of diabetes	29(46.0%)	33(52.4%)	0.508	0.476
CRP(mg/l)	1.26(0.50, 6.73)	3.61(1.14, 13.00)	-1.974	0.048
PT (%)	97.77 ± 23.32	94.95 ± 21.18	0.665	0.508
D-D(ng/ml)	370(280, 530)	390(300, 570)	-0.408	0.684
ALT (U/L)	20.20(14.00, 35.00)	21.00(14.00, 29.5)	-0.5	0.617
AST (U/L)	21.6(15, 27)	21(14, 29.5)	-0.815	0.415
CK (U/L)	82(54, 121)	82(41.5, 118)	-1.034	0.301
CK-MB (U/L)	14(11, 19)	14(11.10.18.05)	-0.039	0.969
TG (mmol/l)	1.62(1.08, 2.20)	1.22(0.99, 1.77)	-1.881	0.060
LDL-C (mmol/l)	2.83 ± 0.94	2.30 ± 0.74	3.49	0.001
HDL-C (mmol/l)	1.15 ± 0.32	1.11 ± 0.25	0.875	0.383
TC (mmol/l)	1.15 ± 0.32	4.05 ± 1.13	2.754	0.007
Lp(a) (mg/l)	357(189.5, 557.5)	285.0(145.0, 468.0)	-1.593	0.206
creatinine(µmol/l)	140.7(111, 240.9)	144.3(106.35, 266.50)	-0.299	0.765
Gensini score	29(23, 34)	32(18, 44)	-0.677	0.499
As shown in the table, PCSK-9 inhibitors significantly reduced LDL-D (-30.28% vs -4.44%, P = 0.000) and Lp(a) (-25.22% vs -10%, P = 0.006) in patients with CKD. In addition, PCSK-9 inhibitors reduced the occurrence of MACEs events in patients (HR:0.27, 95% CI 0.07–0.99, P = 0.013). (Table 10) Survival curves adjusted by Cox proportional risk models showed that patients treated with PCSK-9 inhibitors had a better prognosis than those treated with conventional therapy. (Fig. 3)

Table 10

Comparision of two groups ‾[x ± s;ratio(%); Md (UQ-LQ)]
Items	PCSK-9 inhibitor group(n = 63)	Conventional treatment(n = 63)	χ²/t/Z value	P value
TG (mmol/l)	-3.85(-20.25, 21.33)	3.4(-13.90, 30.05)	-0.776	0.438
LDL-C (mmol/l)	-30.28 ± 23.07	4.44 ± 36.13	0.094	0.000
HDL-C (mmol/l)	4.20 ± 23.66	3.85 ± 21.19	0.088	0.93
TC (mmol/l)	-19.25 ± 23.69	-0.68 ± 27.36	-4.073	0.000
Lp(a) (mg/l)	-25.22(-39.23, -11.11)	-10(-30.64, -7.45)	-2.754	0.006
MACEs	8(12.7%)	17(27.0%)	14.456	0.013

4.1 The significance of Lp(a) for cardiovascular disease

Current research suggests that elevated levels of Lp (a) not only serve as a risk factor for cardiovascular diseases such as heart failure ^2–3, aortic valve calcification ⁴ and chronic heart disease ^5–6 but are also associated with a decline in kidney function⁷. In a meta-analysis of 75 studies, elevated levels of Lp (a) (above 50 mg/dL or 125 nmol/L) ⁵ were found to be significantly associated with increased all-cause mortality and increased risk of cardiovascular disease-related mortality in the population⁸. In a study involving 263 patients diagnosed with coronary artery disease through coronary angiography, an independent association was observed between the plasma Lp(a) concentration and vascular severity⁶. Lotte C A Stiekema et al. suggested that this finding may be attributed to the ability of Lp(a) to promote the inflammatory activation response of monocytes within the body⁹.

In patients with coronary artery disease (CAD), elevated levels of Lp(a) are not only correlated with the severity of coronary arterial stenosis¹⁰ but also serve as a predictive marker for clinical outcomes following percutaneous coronary intervention (PCI). The associations between elevated plasma Lp(a) levels and increased platelet aggregation as well as increased risk of ischemic events in patients following PCI have been demonstrated in previous studies ^11–12. Additionally, elevated levels of Lp(a) are associated with inferior long-term clinical outcomes^13–14. In a 2.4-year study of 10,059 patients with coronary atherosclerotic heart disease who underwent PCI, the results revealed that for patients > 65 years of age and those with left main and/or three-vessel disease, Lp(a) levels were more strongly associated with major adverse cardiovascular and cerebrovascular events (MACE, defined as all-cause death, myocardial infarction, stroke, or unplanned revascularization) ¹⁵. These studies suggest that prolonged antiplatelet therapy may be required for patients with high plasma Lp(a) levels ¹⁶. Yannick Kaiser et al. proposed that these results may be due to the accelerated progression of lipoprotein (a) with the necrotic core of the coronary artery ¹⁷. However, findings from a 3-year cohort study revealed no significant associations between elevated Lp(a) levels and adverse clinical outcomes ¹⁸. This contradictory finding may be attributed to variations in the baseline characteristics of the enrolled patients across the studies. The present study revealed a positive correlation between Lp(a) levels and the severity of coronary artery lesions in patients (r = 0.14, P < 0.05), which is consistent with previous findings.

4.2 Kidney function affects Lp(a) levels

Several recent studies have demonstrated that kidney function is among the limited number of nongenetic factors known to influence plasma Lp(a) levels¹⁹, whereby Lp(a) concentrations increase in response to serum creatinine levels²⁰. This effect is particularly pronounced for high-molecular-weight apo(a), thereby providing compelling evidence for the involvement of kidneys in Lp(a) catabolism ²¹.

In individuals diagnosed with end-stage renal disease (ESRD), there is a significant elevation in Lp(a) concentrations ^22–24. Following renal transplantation, patients exhibit lower levels of Lp(a) than do those with ESRD; however, the concentrations of Lp(a) still remain relatively high compared with those in individuals with normal renal function²⁵. Recent studies have demonstrated a significant correlation between elevated levels of Lp(a) in patients and a decline in the eGFR, an increase in proteinuria, and the progression of renal pathology. Consequently, monitoring changes in Lp(a) levels can serve as a valuable tool for assessing CKD patients^26–27. The present study revealed that the increase in Lp(a) levels in patients with CKD may be caused by increased Lp(a) synthesis ²⁸. However, in patients with early renal failure, the mechanism of elevated lipoprotein (a) may be attributed to a reduction in renal catabolism²⁹. A subsequent investigation revealed that elevated Lp(a) levels were unrelated to genetic factors and could be attributed to renal failure itself ²². In our study, Lp(a) levels gradually increased as renal function decreased (P < 0.05).

Currently, hemodialysis or peritoneal dialysis serves as the primary life-sustaining treatment for end-stage chronic kidney disease (CKD) patients, and accurate assessment of Lp(a) levels is particularly important in this patient population because of its ability to predict cardiovascular events during hemodialysis^30–32. Furthermore, in patients undergoing hemodialysis, Lp(a) can serve as a biomarker for the acute phase response³³. In a study involving patients undergoing peritoneal dialysis, consistent findings were reported, indicating that serum Lp(a) levels are associated with both hemorrhagic stroke ³⁴ and cardiovascular events in this patient population ^35–36. Borazan et al. noted that peritoneal dialysis patients had higher Lp(a) levels than did hemodialysis patients ³⁷.

Ongoing investigations are being conducted to explore the role of Lp(a) in patients with both chronic kidney disease (CKD) and coronary artery disease (CAD). A comprehensive study involving 1003 individuals diagnosed with stage 3–5 CKD revealed a significant association between elevated levels of Lp(a) and the presence of coronary atherosclerotic heart disease. Furthermore, patients with higher Lp(a) concentrations also display increased severity of coronary lesions³⁸; moreover, a positive correlation was observed between Lp(a) levels and the occurrence of cardiovascular events ^39–40. These studies provide evidence that Lp(a) causes atherosclerosis in patients with CKD ⁴¹. In this study, we further investigated the associations between Lp(a) levels and coronary lesions. The results revealed a significant positive correlation between Lp(a) levels and the coronary Gensini score (r = 0.135, P < 0.05) in patients with CKD combined with CAD, indicating that higher Lp(a) levels were associated with more severe coronary lesions. However, this relationship was observed only among patients with moderate renal insufficiency. In addition, current studies have demonstrated that elevated levels of Lp(a), VLDL-C, apolipoprotein B, HDL-C, apolipoprotein A ⁴², and triglyceride-rich lipoprotein cholesterol ⁴³ are associated with an increased risk of atherosclerotic vascular events in patients with CKD.

4.3 Treatment to reduce Lp(a)

Currently, the Lp(a) hypothesis posits that a decrease in Lp(a) levels is associated with a concomitant reduction in cardiovascular risk ⁴⁴. Therapeutic approaches for reducing Lp(a) primarily include ezetimibe (a cholesterol absorption inhibitor), niacin, proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors, bates, aspirin, hormone replacement therapy, selective endothelin receptor antagonism (ETA), antisense oligonucleotide therapy, and small interfering RNA therapy. A comprehensive retrospective study revealed the potential benefits of these interventions in enhancing cardiovascular outcomes⁴⁵; however, certain limitations are also associated with them.

Statins, a cornerstone in the regulation of blood lipids for cardiovascular disease, continue to demonstrate efficacy in patients with CKD; however, their benefits are limited. Combining statins with ezetimibe may enhance cardiovascular advantages in patients^46–47, although the underlying mechanism does not involve reducing Lp(a) levels. A class of drugs called Bates effectively reduces triglycerides and the incidence and mortality of cardiovascular disease. However, previous studies have reported nephrotoxicity associated with Bates, leading to its limited usage. Nevertheless, fenofibrate therapy has a renoprotective effect by reducing inflammation and fibrosis. Additionally, pemafibrate enhances selectivity for peroxisome proliferator-activated receptor alpha (PPR-A), thereby providing renal benefits⁴⁸. The administration of niacin has been shown to elicit a reduction in Lp(a) levels⁴⁹; however, this reduction is limited (< 30%), and the concomitant use of statins with niacin may increase susceptibility to serious adverse events in patients⁵⁰. Some studies have also shown that the intestinal flora plays a role in lipid metabolism in CKD patients ⁵¹, which provides a new therapeutic direction for lipid regulation in CKD patients. In addition, to improve lipid metabolism, a Mediterranean diet and a low-protein diet are recommended for patients with CKD⁵¹.

Previously, researchers reported a positive correlation between circulating PCSK-9 concentrations and an elevated risk of coronary atherosclerotic heart disease ^52–53. Therefore, PCSK-9 inhibitors have been clinically applied as novel approaches to reduce Lp(a) levels. Moreover, the utilization of PCSK-9 inhibitors has significantly reduced all-cause mortality and adverse cardiovascular outcomes among patients⁵⁴, with no observed increase in adverse reactions during the study ⁵⁵. The treatment was well tolerated by the patients ⁵⁶. However, the benefit in patients with CKD was not clearly identified in the initial study ⁵¹, and recent studies have indicated that the beneficial effect of PCSK-9 inhibitors in patients with CKD appears to increase as the GFR decreases ⁵⁷.

In this study, we found that PCSK-9 inhibitors can not only reduce Lp(a) levels in CAD patients with CKD but also significantly reduce MACEs and improve patient survival.

Furthermore, the administration of selective endothelin (ETA) receptor antagonists has been shown to enhance lipid profiles in individuals with chronic kidney disease (CKD), potentially through a reduction in circulating PCSK-9 levels ⁵⁸.

AKCEA-APO (a)-LRx, a hepatocellular-targeted antisense oligonucleotide specifically designed to inhibit the expression of the LPA gene messenger RNA, has a favorable safety profile and dose-dependent efficacy in reducing Lp(a) levels by 35–80%, with up to 92%⁵⁹ reduction observed. Furthermore, treatment with AKCEA-APO (a)-LRx has been associated with a significant decrease in the incidence of cardiovascular events9 among patients⁹. However, patients whose estimated renal function was less than 60 mL/min or whose urinary albumin-to-creatinine ratio exceeded 100 mg/g were excluded from the study. This raises concerns regarding the suitability of pelacarsen for patients with chronic kidney disease (CKD) ⁵¹. Olpasiran, a small interfering RNA (siRNA), has demonstrated promising outcomes in preliminary trials as an additional therapeutic agent for lowering Lp(a) levels ⁶⁰. These drugs present a novel therapeutic target for reducing Lp(a); however, their clinical application will require a considerable amount of time.

4.4 Research significance

In conclusion, for patients with coronary artery disease (CAD) and chronic kidney disease (CKD), the level of Lp(a) increases as renal function decreases. Furthermore, higher levels of Lp(a) are associated with more severe coronary artery lesions in CAD patients, particularly those with moderate renal insufficiency. However, there is no correlation between LDL-C levels and the degree of coronary disease in CAD patients with CKD. This discrepancy may be attributed to dysregulated lipid metabolism in individuals with renal insufficiency, whereas Lp(a) is influenced primarily by genetic factors and remains relatively stable in patients with moderate renal insufficiency. Therefore, compared with LDL-C, Lp(a) can serve as a better predictor for assessing the severity of coronary disease in CKD patients. PCSK-9 inhibitors are still effective in CKD patients and can effectively reduce the blood lipid level of CKD patients after PCI, effectively reduce the occurrence of cardiovascular events, and improve the survival rate of patients.

4.5 Conclusion

In CAD patients with CKD, the degree of coronary artery stenosis becomes increasingly severe with increasing Lp(a) levels. The Lp(a) level can be used as a predictor of coronary artery stenosis in patients with moderate renal insufficiency. PCSK-9 inhibitors reduce the incidence of cardiovascular events in patients with CKD.

Authors' information

Hao Xu ，Email:[email protected] Affiliated Hospital of Qingdao University Qingdao, China

Jian Li ，Email:[email protected] Affiliated Hospital of Qingdao University

Qingdao, China

Corresponding author Dr. Jian Li，Email: [email protected] Affiliated Hospital of Qingdao University Qingdao, China

Ethics approval and consent to participate

The ethical approval was obtained from the Ethics Committee of the Affiliated Hospital of Qingdao University (QYFY WZLL 28957). Informed consent was obtained from all patients. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding Statement

This work was supported by Natural Science Foundation of Shandong Province (ZR2023MH083).

Authors' contributions

HX: Writing – original draft.

JL: Writing – original draft, Writing – review & editing.

Acknowledgements

Not applicable.

Availability of data and material

The data used to support the findings of this study are available from the corresponding author upon reasonable request.

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PCSK-9 inhibitors improve cardiovascular events after PCI in patients with chronic kidney disease

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