Lipoprotein(a) Reduction With Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Systematic Review and Meta-analysis

Abstract

Lipoprotein(a) [Lp(a)] is a cardiovascular factor, for which there is no approved specific lowering treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to have lowering effects on Lp(a). Aim of this systematic review is to synthesize the current literature and quantify the effects of PCSK9 inhibitors on the serum Lp(a) levels in human subjects. Double-blind, phase 2 or 3, randomized-controlled trials comparing PCSK9 inhibitors (alirocumab or evolocumab) to placebo and/or ezetimibe and/or other lipid-lowering therapy were deemed eligible for inclusion. We searched MEDLINE (via PubMed), CENTRAL, Scopus, and Web of Science as of 17 June 2020. Quality assessment was performed using the Revised Cochrane risk-of-bias tool for randomized trials. Forty-three studies were identified (64,107 patients randomized) and 41 studies were included in the quantitative analysis. PCSK9 inhibitors reduced Lp(a) levels by −26.7% (95% CI, −29.5% to −23.9%) with a significant heterogeneity within studies. There was significant difference in Lp(a) change from baseline according to comparator (placebo: mean −27.9%; 95% CI, −31.1% to −24.6% vs. ezetimibe: mean, −22.2%; 95% CI, −27.2% to −17.2%; P = 0.04) and duration of treatment (≤12 weeks: mean, −30.9%; 95% CI, −34.7% to −27.1% vs. >12 weeks: mean, −21.9%; 95% CI, −25.2% to −18.6%; P < 0.01). Meta-regression analysis showed that only the mean percentage change from baseline low-density lipoprotein cholesterol due to the intervention is significantly associated with the effect size difference (P < 0.0001). PCSK9 inhibitors reduced low-density lipoprotein cholesterol by −54% (95% CI −57.6% to −50.6%). There is substantial efficacy of the currently approved PCSK9 inhibitors in the lowering of Lp(a) levels. Dedicated randomized controlled trials are needed to establish the benefit of this intervention.

Sex Differences in Low-Density Lipoprotein Cholesterol Reduction With PCSK9 Inhibitors in Real-world Patients: The LIPID-REAL Registry

“…Evolocumab and alirocumab reduce LDLc by 50%–65%, even on top of statin treatments, 1–3,27,28 but to the best of our knowledge, there is no evidence on efficacy gender differences in real-world setting. The ODYSSEY APPRISE was a prospective study designed with the objective to assess the safety and efficacy of alirocumab in a real-life setting among high cardiovascular risk patients.…”

Lp(a) and the Risk for Cardiovascular Disease: Focus on the Lp(a) Paradox in Diabetes Mellitus

“…Consequently, LDL-C may be lowered by up to 50% and more. Interestingly, PCSK-9 inhibitors also lower plasma Lp(a) by 10–30%, yet the mechanism of their action on Lp(a) has not been fully explored [ 35 ].…”

Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications

“…The statin treatment and lifestyle interventions hardly affect circulating Lp(a) levels, which brings a real challenge for successfully managing elevated Lp(a) levels in patients. Conversely, PCSK9 inhibitors dramatically reduce plasma Lp(a) levels up to ∼35% in patients (54,55). Inhibition of PCSK9 reduces the risk of coronary heart disease to a much greater degree in patients with a high plasma Lp(a) level compared to patients with a low plasma Lp(a) level (23 vs. 7%) (54).…”