For a long time, high-density lipoprotein cholesterol (HDL-C) has been regarded as a cardiovascular disease (CVD) protective factor. Recently, several epidemiological studies, while confirming low plasma levels of HDL-C as an established predictive biomarker for atherosclerotic CVD, indicated that not only people at the lowest levels but also those with high HDL-C levels are at increased risk of cardiovascular (CV) mortality. This “U-shaped” association has further fueled the discussion on the pathophysiological role of HDL in CVD. In fact, genetic studies, Mendelian randomization approaches, and clinical trials have challenged the notion of HDL-C levels being causally linked to CVD protection, independent of the cholesterol content in low-density lipoproteins (LDL-C). These findings have prompted a reconsideration of the biological functions of HDL that can be summarized with the word “HDL functionality”, a term that embraces the many reported biological activities beyond the so-called reverse cholesterol transport, to explain this lack of correlation between HDL levels and CVD. All these aspects are summarized and critically discussed in this review, in an attempt to provide a background scenario for the “HDL story”, a lipoprotein still in search of a role.

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Aim: Epidemiological studies, Mendelian randomized studies, and genome-wide association studies confirmed that elevated lipoprotein(a) [Lp(a)] concentration is an independent risk factor for cardiovascular diseases. However, no approved therapy for patients with elevated Lp(a) levels is available. Our aim is to investigate to what extent PCSK9 inhibitors (PCSK9i), statins, and ezetimibe affect Lp(a) level. Methods: This meta-analysis was conducted according to the PRISMA guidelines. Databases were searched from inception to February 2023. Inclusion criteria were: (1) randomized controlled trials (RCTs) in adults (≥18 years), phase II, III or IV; (2) English language; (3) reporting the effects on Lp(a) levels; (4) with intervention duration more than 3 weeks. Pooled estimates were assessed by a random-effects model. Between-study heterogeneity was tested and measured by Cochrane’s Q test and I2 statistics. Results: Overall, 51 RCTs were included for PCSK9i (39,271 participants), 35 RCTs for statins (15,425 participants), and 14 RCTs for ezetimibe (5,607 participants). Starting from a baseline Lp(a) level of 33.12 mg/dL, participants treated with PCSK9i compared to placebo experienced an additional reduction in Lp(a) levels of -26.34% (95%CI -28.83 to -23.85). Lp(a) levels were marginally reduced by statins by -3.43% (95%CI -9.09 to 2.23) from a baseline Lp(a) level of 15.87 mg/dL, although this reduction was not statistically significant. Finally, ezetimibe had a negligible and still not statistically significant effect on Lp(a) levels (0.51% [95%CI -1.67 to 2.70]), from a baseline Lp(a) level of 20.80 mg/dL. Conclusions: Among the lipid-lowering approaches evaluated, only PCSK9i seemed to lower Lp(a) levels. Further research is requested to understand whether it translates into a clinically relevant cardiovascular benefit.