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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Lipoprotein(a) and PCSK9 inhibition: clinical evidence
Massimiliano Ruscica1, Maria Francesca Greco1, Nicola Ferri2
1Dipartimento di Science Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
Insights
Elevated lipoprotein(a) [Lp(a)] is a significant risk factor for atherosclerotic cardiovascular diseases (ASCVD). While PCSK9 inhibitors show promise in lowering Lp(a), they do not yet achieve the levels needed for substantial cardiovascular benefit.
Area of Science:
- Cardiovascular Medicine
- Lipidology
- Genetics
Background:
- Elevated lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular diseases (ASCVD), independent of LDL-C levels.
- Current therapies do not sufficiently lower Lp(a) to achieve significant cardiovascular (CV) benefit.
Purpose of the Study:
- To evaluate the role of PCSK9 inhibition in lowering Lp(a) and its association with cardiovascular outcomes.
- To assess the impact of PCSK9 inhibition on Lp(a) levels in individuals with and without PCSK9 loss-of-function mutations.
Main Methods:
- Analysis of data from cardiovascular outcomes trials (FOURIER, ODYSSEY OUTCOMES) investigating PCSK9 inhibitors.
- Examination of Lp(a) and related markers in carriers of PCSK9 loss-of-function mutations versus non-carriers.
Main Results:
- PCSK9 inhibition with evolocumab and alirocumab demonstrated reductions in Lp(a), correlating with decreased cardiovascular risk.
- A reduction of 12 mg/dL in Lp(a) was associated with a 15% relative risk reduction in cardiovascular disease.
- PCSK9 inhibition decreased Lp(a) and oxPL-apoB levels in PCSK9 mutation carriers.
- PCSK9 inhibitors led to increased discontinuation of lipoprotein apheresis in some patients.
Conclusions:
- PCSK9 inhibition offers a potential therapeutic strategy for managing elevated Lp(a) in ASCVD.
- While not achieving target Lp(a) reduction, PCSK9 inhibitors show a trend towards CV benefit.
- Further research is needed to optimize Lp(a) lowering therapies for maximal CV protection.
Abstract:
Compelling evidence has emerged from epidemiological and Mendelian randomization analyses relative to the causality of lipoprotein(a) [Lp(a)] in atherosclerotic cardiovascular diseases (ASCVD), being elevated Lp(a) a strong risk factor regardless of the reduction of LDL-C achieved by statins. So far, no specific available agent can lower Lp(a) to the extent required to achieve a cardiovascular (CV) benefit, i.e. approximately 100 mg/dL. The most recent outcomes trial FOURIER with evolocumab showed that a 25 nmol/L (12 mg/dL) reduction in Lp(a) corresponded to a 15% decrement in the relative risk of cardiovascular disease. The ODYSSEY OUTCOMES trial with alirocumab has been the first demonstrating that a reduction in Lp(a) associates with less major adverse cardiovascular events (MACE), i.e. hazard ratio: 0.994 per 1 mg/dL decrement in Lp(a). The Lp(a) lowering effect driven by PCSK9 inhibition was confirmed in carriers of PCSK9 loss-of-function mutations in which Lp(a) and oxPL-apoB levels were decreased compared to non-carriers as was for a slight larger number of apo(a) Kringle IV repeats. Although PCSK9 inhibitors are not able to decrease Lp(a) to the extent required to achieve a CV benefit, their use has led to a higher discontinuation rate in lipoprotein apheresis in patients with progressive ASCVD and high plasma Lp(a).
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