Background
Diabetes mellites (DM) is regarded as coronary artery disease (CAD) equivalent and associated with an obvious increase in the risk of atherosclerotic cardiovascular disease (ASCVD) [
1,
2]. Meanwhile, ASCVD-related mortality has been reported to be significantly higher in diabetic patients than that in nondiabetic patients (20
vs 3.5%) [
3]. Additionally, DM is commonly accompanied with multifaceted metabolic disorders and the risk of ASCVD in patients with DM would be amplified by several concurrent atherogenic metabolic factors [
4]. More importantly, atherogenic dyslipidemia is one of the major common clinical manifestations, which is an important predictive factor of cardiovascular risks in diabetic individuals. The management of this type of dyslipidemia, especially targeting low-density lipoprotein cholesterol (LDL-C) levels with optimal strategies, can significantly bring cardiovascular benefits in diabetic patients [
5‐
7].
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease belonging to the proteinase K subfamily of subtilases, is a critical player in cholesterol metabolism by increasing the degradation of hepatic low-density lipoprotein cholesterol receptors (LDLR), thereby resulting in increasing circulating LDL-C levels [
8,
9]. Recently, a large number of studies have demonstrated that PCSK9 can directly or indirectly contribute to atherosclerosis from initiation to progression by leading to endothelial dysfunction, promoting inflammatory response and inhibiting platelet activation, which is independent on its effects on regulation of cholesterol metabolism [
10‐
12]. Consequently, several large-scale event reduction trials have found that human PCSK9 monoclonal antibodies markedly reduce LDL-C levels and show a great promise for a reduction of future cardiovascular events [
13,
14]. It is worth noting that circulating PCSK9 concentration has been proposed as an adverse factor for cardiovascular risks in patients with CAD [
15,
16]. What’s more, a growing number of studies have explored the association of PCSK9 with cardiovascular metabolic disorders beyond dyslipidemia [
17‐
19]. Nevertheless, the study on the association between plasma PCSK9 levels and cardiovascular metabolic markers (CVMMs) is limited in diabetic patients with CAD and whether plasma PCSK9 concentration can predict major adverse cardiovascular events (MACEs) in these patients has not been evaluated.
Hence, in the current study, we try to investigate the association of plasma PCSK9 levels at baseline with CVMMs and the future MACEs in stable CAD patients with DM or without DM, who did not take any lipid-lowering therapy before admission and received a standard treatment after admission.
Discussion
In this study, we investigated the association of PCSK9 with CVMMs and the predictive value of PCSK9 for cardiovascular events in stable CAD patients with DM or without DM. Firstly, we found that plasma PCSK9 levels were significantly correlated with LCI and HGI, the novel CVMMs related to cardiovascular risks, in all CAD patients and positively associated with lipid- and glucose-related CVMMs including TC, LDL-C, non-HDL-C and HbA1C in DM participants with stable CAD. Besides, our results showed that circulating PCSK9 concentration at baseline was positively associated with the risk of MACEs in diabetic patients with stable CAD even after adjusting for established cardiometabolic factors. Finally, data also indicated that the combination of high PCSK9 levels and DM had significantly higher cardiovascular events in our studied patients. To the best of our knowledge, this is the first study showing that PCSK9 can predict worse clinical cardiovascular outcomes in diabetic patients with stable CAD and the combination of plasma PCSK9 levels and diabetes status enhanced predictive value in CAD patients.
DM has become the one of major worldwide healthy issues and its prevalence has been rapidly growing in the past decades [
28]. Of note, DM patients are more likely to have higher risk of cardiovascular events when accompanied by other metabolic disorders, especially in patients with ASCVD [
1,
4]. Furthermore, atherogenic dyslipidemia has been reported to have an essential role in the prognosis of these two diseases, DM and ASCVD [
29]. Even if receiving standard treatment, diabetic patients with CAD still have high cardiovascular risk. Therefore, further knowledge of cardiovascular risks related to diabetic patients with CAD will be helpful for better prevention and management for such kind of patients.
The best-known function of PCSK9 is posttranslational regulation of LDLR on hepatocytes to clear LDL-C from the circulation [
30]. In recent years, it has been reported that PCSK9 is linked to atherosclerosis and become an attractive treatment target for CAD [
10,
15,
27]. Meanwhile, PCSK9 levels were associated with several CVMMs which have been proposed as predictor of cardiovascular risks [
18,
24‐
26]. However, the predictive role of PCSK9 on cardiovascular outcomes is currently controversial. A positive association with PCSK9 and cardiovascular events was found in the general population, in FH subjects, and in patients with acute coronary syndrome or stable CAD [
15,
16,
20,
31]. In contrast, a prospective cohort study of primary prevention included 716 initially healthy American women and displayed that the baseline plasma levels of PCSK9 cannot predict future cardiovascular events [
32]. Moreover, the SURDIAGENE study found a similar result in DM population [
33]. Hence, whether PCSK9 can be a novel predictor of prognosis and its correlation with metabolic factors need more investigations, especially in CAD patients with or without DM.
The associations of PCSK9 with cardiovascular metabolic parameters including lipid- and diabetes-related indicators, BMI and BP, have been found in different populations [
17‐
19]. In patients with stable CAD, low plasma levels of PCSK9 were linked with a particular metabolic phenotype (low HDL-C, the metabolic syndrome, obesity, insulin resistance and DM) [
19]. In CAD patients with DM who had high non-HDL-C/LDL-C levels, PCSK9 inhibitor significantly reduced atherogenic cholesterol and LDL-particle number versus control [
34]. What’s more, an animal study using obese-insulin resistant rat model, found that PCSK9 inhibition attenuated metabolic impairment and also ameliorated cardiovascular dysfunction more efficiently than atorvastatin [
35]. In the current study, our results also showed a significant correlation between plasma PCSK9 levels and multiple CVMMs including traditional, novel and derived parameters in CAD patients with DM or without DM. Interestingly, in whole stable CAD patients, we found that PCSK9 was significantly and positively related to LCI and HGI, two novel lipid- or glycemic derived indicators and the potential cardiovascular outcomes predictors.[
26,
36]. It was worth mentioning that, we did not find the association between PCSK9 and some indictors, mainly HDL-C, TG and their derived indexes in DM patients, which may be due to the higher heterogeneous in metabolic phenotypes. In addition, the present study showed that patients with high plasma PCSK9 concentration were more likely to be female, which was consistent with previous studies [
37,
38]. The reason for this phenomenon may be that plasma PCSK9 levels are influenced by hormones such as estrogen [
39]. Besides, we found that low PCSK9 levels were associated with the feature of smoking and drinking was inconsistent with other studies [
40,
41], which may need to investigate further in a large sample study.
In literature, the close relation between PCSK9 and DM has been documented. The results of available epidemiology and clinical studies showed a higher PCSK9 levels in diabetic patients [
17,
18]. Moreover, it is well-established that insulin resistance is the main cause of DM. Previous data suggested that insulin resistance and subsequent hyperinsulinemia could enhance PCSK9 expression and increased plasma levels of PCSK9 were related to poor glycemic control in DM [
42]. Besides, it has been demonstrated that insulin resistance plays a pivotal role in PCSK9 homeostasis in severely obese patients [
43]. PCSK9 critically controls LDLR expression in pancreas perhaps contributing to the maintenance of a proper physiological balance to limit cholesterol overload in beta cells [
44]. Regarding pharmacology, it has been found that liraglutide can suppress PCSK9 expression through hepatocyte nuclear factor 1 alpha-dependent mechanism in HepG2 cells and db/db mice [
45]. In addition, as found above in this study, PCSK9 was significantly correlated with glycemic parameters including FPG and HbA
1C. Meanwhile, our results indicated that PCSK9 or DM was independently predictors for MACEs respectively. The PCSK9 levels categorized according to its median and as a continuous variable were all independently related to poor outcomes even after adjustment for established cardiovascular risk factors in DM patients with CAD. Clearly, we not only analyzed the prognostic ability of PCSK9 but also further demonstrated the combined impact of elevated PCSK9 levels plus diabetic status. When added PCSK9 stratification and diabetic status to stratifying factors, patients in high PCSK9 group appeared to have the highest risk of subsequent cardiovascular events with DM (HR: 5.233, 95% CI: 2.546–10.757). These findings suggested that the measurement of PCSK9 might be useful to predict the occurrence of MACEs in diabetic patients with CAD and high PCSK9 levels plus DM could enhance the prediction of worse clinical outcomes.
The previous studies including ours have demonstrated that some lipid-lowering medications, such as statins, ezetimibe, can up-regulated the expression of PCSK9 genes and increased the circulating concentration of PCSK9 [
46‐
48]. A meta-analysis of 15 clinical trials have demonstrated a significant increase in plasma PCSK9 levels after statin therapy, irrespective of the type of statin [
49].Besides, recent data have indicated that PCSK9 inhibitors can significantly reduce circulating PCSK9 levels [
48]. That is the reason why we chose the diabetic patients with stable CAD, who did not receive any lipid-lowering therapy before admission as the participants to performed such study [
48,
50].
Nevertheless, several limitations must be given consideration. First of all, the sample size and follow-up time of the current study were relatively small and short, which could lead to insufficient statistical power in analyses of subgroups. Moreover, due to fewer events, we could not further perform subgroup analyses for nonfatal MI, stroke and cardiovascular death. Secondly, we only measured the baseline of plasma PCSK9 levels and did not evaluate the effects of its longitudinal change (especially the effects of lipid-lowering drugs on PCSK9 levels after discharge) on cardiovascular events during follow-up time. Lastly, as with the feature of any observational and prospective study, only association but no causal link could be determined. Further prospective studies with larger sample size and long-term follow-up are required to confirm our findings.
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