Effects of Lipid-Modifying and Other Drugs on Lipoprotein(a) Levels—Potent Clinical Implications

Abstract

The past few years have shown an ongoing interest in lipoprotein(a) (Lp(a)), a lipid molecule that has been proven to have atherogenic, thrombogenic, and inflammatory properties. Several lines of evidence, indeed, have demonstrated an increased risk of cardiovascular disease as well as calcific aortic valve stenosis in patients with elevated Lp(a) levels. Statins, the mainstay of lipid-lowering therapy, slightly increase Lp(a) levels, while most other lipid-modifying agents do not significantly alter Lp(a) concentrations, except for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The latter have been shown to reduce Lp(a) levels; however, the clinical significance of this effect has not been clearly elucidated. Of note, the pharmaceutical lowering of Lp(a) may be achieved with novel treatments specifically designed for this purpose (i.e., antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs)). Large clinical trials with cardiovascular outcomes with these agents are ongoing, and their results are eagerly awaited. Furthermore, several non-lipid-modifying drugs of various classes may influence Lp(a) concentrations. We have searched MEDLINE, EMBASE, and CENTRAL databases up to 28 January 2023 and summarized the effects of established and emerging lipid-modifying drugs and other medications on Lp(a) levels. We also discuss the potent clinical implications of these alterations.

Treatment of Lp(a): Is It the Future or Are We Ready Today?

“…The currently used hypolipidemic drugs only modestly affect the plasma Lp(a) as well as OxPL/ApoB levels (Table 1 ) [ 27 ]. In this regard, several studies [ 28 , 29 ] and a meta-analysis [ 30 ] have demonstrated that statins increase Lp(a) and OxPL/ApoB levels compared with placebo (Table 1 ).…”

Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Where Do We Stand?

“…Conditions such as hypothyroidism, growth hormone deficiency in adults, and the depletion of endogenous sex hormones (e.g., menopause, ovariectomy, castration, orchidectomy) have been associated with increased Lp(a) concentration [ 60 , 61 , 62 , 63 ]. Conversely, hormonal replacement therapy with thyroxine or in cases of hyperthyroidism, as well as hormonal replacement treatment in postmenopausal women, have been shown to reduce Lp(a) levels in a case-dependent manner [ 64 , 65 , 66 ]. However, the impact of this reduction on cardiovascular disease (CVD) risk remains a topic of debate [ 67 ].…”

“…FDA approval in July 2023 extended the use of inclisiran to patients at increased ASCVD risk with elevated LDL-C levels and comorbidities, such as hypertension and T2DM, even without a prior cardiovascular event [ 8 ]. Besides its efficacy against LDL-C, several large clinical trials have shown promising results in reducing Lp(a) levels [ 66 ].…”

“…Larger outcome trials will provide more conclusive evidence regarding inclisiran’s impact on Lp(a) levels and its ability to reduce MACE. ORION-4, enrolling participants with pre-existing ASCVD, and VICTORION-2 PREVENT, enrolling participants with established CVD, are ongoing phase 3 trials expected to evaluate inclisiran’s effects on MACE reduction [ 8 , 66 ].…”

Neutrophil Extracellular Traps (NETs) and Atherosclerosis: Does Hypolipidemic Treatment Have an Effect?

“…Beyond LDL-C, new treatments targeting triglyceride-rich lipoproteins and Lp(a) have become available or entered clinical development. The potential mechanisms of action of current and emerging Lp(a)-lowering therapies have recently been reviewed [ 24 ]. Biological and RNA-directed agents have joined traditional small-molecule approaches while gene-editing approaches have appeared on the horizon of lipid management [ 23 ].…”