Lp(a) Assay Methods Similarly Predictive of MACE Reduction with Alirocumab

Michael Scarek, PhD

Credit: University of Colorado

Each of three lipoprotein(a) assay methods comparably predicted reductions in major adverse cardiovascular events (MACE) after alirocumab treatment, independent of reductions in low-density lipoprotein cholesterol (LDL-C), according to a new analysis.¹

Methods to test Lp(a) concentration can include immunoassays (IA) reporting in mass or molar units and mass spectrometry (MS) reporting molar concentration without isoform dependence.

This analysis used data from the ODYSSEY OUTCOMES trial to investigate whether an assay method can influence the relationship between a change in Lp(a) concentration and the reduction of cardiovascular events with a PCSK9 inhibitor.

“Regardless of the measurement method, in unselected populations relatively modest lp(a) reductions under treatment with a PCSK9 inhibitor should translate to modest clinical benefit on cardiovascular events,” wrote the investigative team led by Michael Scarek, PhD, division of cardiology, University of Colorado School of Medicine.

Alirocumab was the first PCSK9 inhibitor approved by the US Food and Drug Administration (FDA) for lowering LDL-C in primary hyperlipidemia and homozygous familial hypercholesterolemia.² Its most recent approval came in March 2024 as an adjunct to diet and other LDL-C lowering therapy to treat heterozygous familial hypercholesterolemia (HeFH) in pediatric patients aged ≥8 years.

Lp(a) is a genetically determined risk factor for incident and recurrent atherosclerotic cardiovascular disease events.³ Prior evidence has suggested Lp(a) presents an effect modifier for the cardiovascular benefits of PCSK9 inhibitors, suggesting those with higher baseline Lp(a) derive greater reductions in levels with treatment.⁴

Methods to measure Lp(a) challenged clinicians in interpreting Lp(a) levels and changes in treatment. In a subgroup of trial participants from ODYSSEY OUTCOMES, the relationships between change in Lp(a) and the three tests were estimated by Spearman correlations.¹

For those in the alirocumab group, the analysis used proportional hazards models to relate Lp(a) changes from baseline to month 4 with the subsequent risk of primary efficacy outcome, MACE. Models were adjusted for changes from baseline to month 4 in Lp(a) and baseline LDL-C levels, as well as patient characteristics related to MACE.

Among 5500 participants randomized to alirocumab, with available data from all three Lp(a) assays, 443 experienced a MACE after their four-month assessments, with a median follow-up of 2.4 years. Scarek and colleagues noted, as anticipated, that the participants with higher baseline concentrations had more substantial absolute reductions with alirocumab.

Upon analysis, the change in Lp(a) IA-mass, IA-molar, and MS concentrations were found to be correlated, with the strongest correlation between IA-molar and MS (r = .834; P <.0001). Weaker correlations were observed between IA-mass and MS (r = .693; P <.0001) and IA-mass and IA-molar (r = .690; P <.0001).

Among all participants, reductions in Lp(a) IA-mass and MS-molar concentrations were significantly associated with reductions in first MACE risk. On the other hand, the association for IA-molar was only marginally significant. When LDL-C was replaced by a measure incorporating an approximation of cholesterol in Lp(a), the results were mostly identical.

Scarek and colleagues noted the MACE hazard ratios (HRs) for median Lp(a) change were similar across the three tests. The finding was clearer in analyses restricted to individuals with lp(a) ≥50 mg/dL or ≥125 nmol/L, representing thresholds of enhanced cardiovascular risk and when future use of Lp(a)-lowering therapies may be clinically necessary. LDL-C reductions with alirocumab did not depend on baseline Lp(a) concentration.

Despite the relatively low number of MACE available for analysis, only moderately elevated Lp(a) levels, and intra-patient variability in serial value, Scarek and colleagues noted each of the 3 Lp(a) assay methods were similarly predictive of modest MACE reductions with alirocumab treatment.

“With the emergence of new potent Lp(a) lowering agents, greater clinical benefits might be observed,” investigators wrote.

References

1. _{Szarek M, Reijnders E, Steg PG, et al. Comparison of Change in Lipoprotein(a) Mass and Molar Concentrations by Alirocumab and Risk of Subsequent Cardiovascular Events in ODYSSEY OUTCOMES. Eur J Prev Cardiol. Published online March 19, 2024. doi:10.1093/eurjpc/zwae110}
2. _{Campbell P. Alirocumab approved for heterozygous familial hypercholesterolemia in patients 8 years and older. HCP Live. March 11, 2024. Accessed March 20, 2024. https://www.hcplive.com/view/alirocumab-approved-for-heterozygous-familial-hypercholesterolemia-in-patients-8-years-and-older.}
3. _{Nordestgaard BG, Langsted A. Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J Lipid Res 2016;57:1953-1975. doi: 10.1194/jlr.R071233}
4. _{Szarek M, Bittner VA, Aylward P, et al. Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial. Eur Heart J 2020;41:4245-4255. doi: 10.1093/eurheartj/ehaa649}