Atherosclerotic cardiovascular disease (ASCVD) remains a major threat to human life safety (Martin et al., 2024; Pirillo et al., 2023). Research on various risk factors of ASCVD remains a current hot topic. Blood lipid levels, particularly LDL-C, are widely recognized as independent risk factors closely associated with the occurrence and progression of atherosclerosis (Pirillo et al., 2023; Ference et al., 2024).

Currently, there are various lipid-lowering regimens, and statins have remained the cornerstone of lipid-lowering therapy due to robust evidence supporting their ability to reduce LDL-C and ASCVD risk (Collins et al., 2016). However, many patients, even when using the maximum tolerated dose of statins or adding other lipid-lowering drugs like ezetimibe, fail to achieve the ideal lipid levels recommended by guidelines (Serban et al., 2017).

While, the emergence of PCSK9 inhibitors may offer clinical promise to lipid-lowering therapy. By specifically binding to PCSK9, they prevent PCSK9 from binding to LDLR, inhibit PCSK9-mediated LDLR degradation, increase the number of LDLRs on the surface of hepatocytes, and thus significantly lower LDL-C levels and even further reduce the risk of major adverse cardiovascular events (MACE) (Shimada and Cannon, 2015). Numerous clinical trials have confirmed the potent LDL-C lowering effect of PCSK9 inhibitors (Sabatine et al., 2017; Schwartz et al., 2018; Raal et al., 2020). Consequently, more cardiovascular disease guidelines have recommended PCSK9 inhibitors; however, it is also noted that the recommended treatment regimens still involve the use of statins (Mach et al., 2020; Visseren et al., 2021; Grundy et al., 2019). That leads us to consider whether PCSK9 inhibitors can be used alone, without statins, to reduce the risk of MACE.

However, existing research lacks direct comparisons between different PCSK9 inhibitors and between monotherapy and combination therapy with statins. Therefore, this study is to explore the efficacy and safety of different lipid-lowering regimens in moderate to high-risk cardiovascular populations, including monotherapy with different PCSK9 inhibitors, combination therapy with different PCSK9 inhibitors and statins, and oral lipid-lowering drugs (statins or ezetimibe) alone, aiming to determine the optimal lipid-lowering regimen.

This study included a total of 29 RCTs aimed at evaluating various lipid-lowering regimens, including monotherapy with different PCSK9 inhibitors, combination therapy of different PCSK9 inhibitors with statins, and monotherapy with statins or ezetimibe, to assess their effectiveness in reducing MACE events and determining the optimal lipid-lowering regimen. According to our results, in terms of reducing MACE events, PCSK9 inhibitors combination with statins was significantly superior to other lipid-lowering regimens, among which Inclisiran combined with statins emerged with the highest probability of being the optimal choice based on SUCRA rankings. Additionally, as in the population included in the oral lipid-lowering drug group, more than 95% of the individuals used statins, our results indicate that the clinical benefits of statin monotherapy are not inferior to those of any PCSK9 inhibitor monotherapy.

Previous studies have consistently demonstrated the potent LDL-C lowering effects of statins and PCSK9 inhibitors (Sabatine et al., 2017; Schwartz et al., 2018; Raal et al., 2020; Cannon et al., 2004; LaRosa et al., 2005; Nissen et al., 2006). Statins inhibit cholesterol synthesis by limiting the action of HMG-CoA reductase, additionally, they upregulate LDL receptor (LDLR) expression and increase LDLR activity, enhancing the uptake and metabolism of LDL particles in the bloodstream. In contrast, PCSK9 inhibitors do not affect cholesterol synthesis directly. They primarily bind to free PCSK9, preventing it from attaching to LDL receptors (LDLRs), thereby reducing LDLR degradation and prolonging LDLR lifespan, which increases the clearance of LDL-C throughout its lifecycle (Norata et al., 2014; Roth and Davidson, 2018). Additionally, the efficacy of PCSK9 inhibitors in lowering LDL-C is limited by the concentration of free PCSK9. Once free PCSK9 levels reach zero, administering higher doses of PCSK9 inhibitors does not yield additional LDL-C reduction. Higher doses only prolong the duration of action without increasing the intensity of LDL-C lowering. It can be seen that statins and PCSK9 inhibitors have a synergistic effect in lowering LDL-C levels. Their combined use can further enhance lipid-lowering pathways, strengthen their respective mechanisms, and achieve a dual increase in the quantity and lifespan of LDLR. This leads to better LDL-C clearance capacity and significantly reduces LDL-C levels while providing additional clinical benefits by further lowering the risk of MACE. It’s consistent with our conclusions and aligns with the recommendations of various cardiovascular-related guidelines. Moreover, our subgroup analyses demonstrated that adding PCSK9 inhibitors to background statin therapy did not significantly reduce all-cause mortality compared to statin monotherapy. Additionally, no statistically significant differences were observed among various PCSK9 inhibitor agents regarding mortality outcomes. These findings suggest a consistent mortality profile across different PCSK9 inhibitors when used as adjunctive lipid-lowering therapy. This aligns with prior large-scale randomized controlled trials, which have similarly reported limited evidence for mortality reduction despite significant improvements in lipid parameters and major adverse cardiovascular event rates.

Current clinical paradigms regard PCSK9 inhibitors as novel potent lipid-lowering agents, which demonstrate enhanced LDL-C reduction efficacy compared to statins, thereby enabling superior clinical outcomes. However, as shown in Figure 2, the clinical benefits of statin monotherapy are not inferior to those of evolocumab and may even surpass those of alirocumab. This outcome surpassed our anticipated results. This may be due to the anti-inflammatory effects and improvement of endothelial function provided by statins beyond lipid-lowering (Liao and Laufs, 2005). Emerging evidence suggests that inflammation may play an even more pivotal role than dyslipidemia in the pathogenesis and progression of atherosclerosis (Ridker et al., 2023). The findings imply that the clinical benefits observed with certain interventions may not be solely attributable to their lipid-modifying effects. Rather, a more comprehensive mechanism—encompassing anti-inflammatory actions and improvements in endothelial function—may underlie the observed reduction in MACE risk. However, these effects are not yet well-documented for PCSK9 inhibitors, necessitating further research for confirmation. Furthermore, considering the factors of cost and administration route (Kazi et al., 2016; Khan et al., 2022), combined with treatment recommendations from both domestic and international guidelines, statins remain the most cost-effective and feasible monotherapy option for lipid lowering in most ASCVD patients requiring medication. Of course, the number of studies and participants in this subgroup was limited, and further research is warranted to validate these findings.

Additionally, among the three PCSK9 inhibitors currently widely used in clinical practice, the SCURA values indicate that the most beneficial treatment regimen may be the combination of inclisiran and statins. Of course, this result only comes from SUCRA rankings, without direct or statistical comparison supports. Based on the current evidence base, the optimal PCSK9 inhibitor cannot be definitively ascertained at present. Based on the SCURA ranking framework, we believe that this result may be due to inclisiran’s exceptionally long half-life, allowing it to maintain a stable low level of LDL-C in patients over a longer period, thereby reducing LDL-C fluctuations and minimizing the incidence and progression of ASCVD and MACE events. We keenly anticipates further evidence generation regarding inclisiran’s long-term clinical profile. However, due to cost considerations, its widespread use among ASCVD patients is currently limited, and we look forward to its promising performance once included in medical insurance coverage.

In terms of safety, we limited our discussion to newly diagnosed diabetes and neurocognitive impairment, as these outcomes were both clinically significant and sufficiently represented in our dataset. There is no statistically significant difference in the occurrence of new-onset diabetes or neurocognitive impairment. Several factors may explain this finding. First, most included trials investigated PCSK9 inhibitors as add-on therapy to established statin treatment, and the incremental risk for these adverse events may not substantially exceed that already associated with statins. Second, some trials reported a relatively low number of events and had limited follow-up durations, which could reduce the statistical power to detect rare adverse outcomes. Third, heterogeneity in diagnostic definitions and event reporting may have influenced the pooled estimates. Furthermore, these findings are consistent with the results of major outcome trials such as FOURIER and ODYSSEY OUTCOMES, which reported no significant increase in diabetes or neurocognitive adverse events with PCSK9 inhibitor therapy, even at very low LDL-C levels. Collectively, these observations suggest that while safety concerns warrant ongoing surveillance, current evidence does not indicate a substantial additional risk of diabetes or neurocognitive impairment when PCSK9 inhibitors are used on top of statins.

Our study has several limitations. Firstly, there is a lack of relevant studies directly comparing different types of PCSK9 inhibitors, and further large-scale studies are needed. Secondly, studies on monotherapy with PCSK9 inhibitors are limited, including the number of studies, number of participants, and follow-up duration. Thirdly, some studies may employ slightly different definitions of MACE, which may create bias.

The emergence of PCSK9 inhibitors has provided us with more tools for lowering cholesterol, when combined with statins, it can provide the greatest clinical benefit for ASCVD patients. However, it is important to emphasize that statins remain the cornerstone of lipid-lowering therapy, with well-established clinical benefits. The long-term benefits of PCSK9 inhibitor monotherapy still require further clinical observation and validation. Therefore, when choosing monotherapy for lipid-lowering treatment, it is still recommended to first use statins in accordance with guideline recommendations.