In the present retrospective study, levels of Lp(a) and IL6 were markedly and quickly decreased with 2-times administration of alirocumab, especially in UA patients with Lp(a) levels ≥ 50 mg/dL. Meanwhile, the LDL-C and TC also significantly decreased as in other clinical studies [29, 30]. Therefore, different from the previous oral lipid-lower medications, the PCSK9i indeed restored our confidence in the management of Lp(a) [31].
Lp(a) is a particle in which apolipoprotein a [Apo(a)] is linked to LDL-like particles via a disulfide bond [32]. The Lp(a) concentration is genetically determined and largely independent of sex, age, and diet [33]. The emergence of pathophysiological and epidemiologic data strongly supports, excluding various stress-induced conditions, that Lp(a) is a causal factor in CVD [34]. For now, Lp(a) disorder has become the most prevalent lipid disorder globally, with elevated levels estimated at > 1.4 billion people [1, 35], especially prevalent among Chinese population with CVD [36, 37]. Elevated level of Lp(a) is related to increasing risk with varied clinical phenotypes, ranging from myocardial infarction, to stroke in individuals [2]. Accordingly, the rationale for managing Lp(a)-mediated atherosclerotic cardiovascular disease risk is stronger than ever before. Meanwhile, Lp(a) level is associated with the residual risk of UA [13], which may be the best single marker in assessing UA [11]. Moreover, studies based on East Asian populations highlight the importance of Lp(a) intervention to improve atherosclerosis and prevent cardiovascular risks [36, 38]. Therefore, a Chinese population with UA is the valuable target to study the effect of PCSK9i on Lp(a).
Meanwhile, Lp(a) associated vascular inflammation plays multiple maladaptive roles, which contribute to the progression and the destabilization of CVD [39]. Lp(a) could penetrate into the intima of arteries and promote macrophage infiltration [40], further activate pro-inflammatory signaling activation, and trigger inflammatory responses in the arterial wall [41]. A large body of evidence has accumulated supporting the use of IL6 as a clinical measure of inflammation [42, 43]. Accordingly, IL6 may be a marker and evaluation indicator of Lp(a)-associated inflammatory progression in CVD [44, 45]. In additional, IL-6 has emerged as a potential factor in individuals at high atherosclerotic risk, but without any systemic inflammatory disorder [46]. However, there are no studies on the relationship between Lp(a) and IL6 in Chinese patients with UA so far. In our results, there was a positive linear correlation between Lp(a) and IL6 at baseline, which suggested that Lp(a) may contribute to the elevated inflammation in patients with UA. Additionally, the alirocumab had an inhibiting impact on IL6 in patients with UA, which was construed as the anti-inflammation effect of alirocumab. Although recent studies have revealed that Lp(a) and chronic inflammation can interact to rapidly promote the progression of CVD [47, 48], the short-time inhibition of IL6 could not influence Lp(a) levels. [49]. Therefore, we speculate that the decrease of IL6 level is caused by the inhibiting action of alirocumab on Lp(a), and more studies are needed to unequivocally assess the impact of alirocumab.
Furthermore, the effects of lipids-lowering therapy with alirocumab or evolocumab on individual clinical efficacy and safety endpoints are always been a hot pot in clinical research [50, 51]. Importantly, the benefits of different types of PCSK9i of lipid-lowering are homogenous. Then, compared with the study based on evolocumab and Korean population with stable angina [52], in our work, we found that alirocumab appeared to have better short-term efficacy in reducing Lp(a) and similarly efficacious in anti-inflammation. Further evidence-based researches are required to determine the different selections between PCSK9i and clinical phenotypes. We believe that our clinical practice will provide useful reference information and clinical guidance for the high-quality management of the UA populations in China, especially for those patients with high Lp(a) level.
Limitation
There were several potential limitations to the study owing to the retrospective study design and availability of data: First, this was a single-center, small sample retrospective study, the statistical power was relatively weak. Second, other information, such as changes in diet and lifestyle, could not be measured precisely. Third, lipid-lowering therapies at baseline were not uniform. Furthermore, it was hardly to derive a concrete clinical outcome of monitoring the lipid-lowering effects for only 4 weeks. The long-term effect of alirocumab in Chinese patients with UA, particularly on Lp(a) and IL6 should also be in-depth investigated in the future.