REDUCE-IT Lp(a) Analysis Details Icosapent Ethyl Effect on MACE Across Lp(a) Range

Philipe Gabriel Steg, MD
Credit: BAIM Institute

An analysis of the landmark REDUCE-IT trial offers additional insight into the value of Lp(a) for identifying patients at increased risk of major adverse cardiovascular events (MACE).

Beyond providing additional data of the prognostic value of Lp(a) in predicting cardiovascular risk, results also indicate the effects of icosapent ethyl (Vascepa) on risk reduction were consistent across Lp(a) range, which they purport could prove clinically relevant if ongoing trials for Lp(a) lowering agents prove successful.^1,2

“In participants at high risk for [cardiovascular] events with elevated triglyceride levels and receiving statin therapy, baseline Lp(a) mass concentration was prognostic for first and total MACE. Importantly, icosapent ethyl consistently reduced MACE risk across the range of Lp(a) levels, including a subset of participants with clinically relevant elevations,” wrote investigators.¹ “Consequently, any potential benefit of Lp(a) lowering from drugs currently being tested in clinical trials might be expected to be complementary to the [cardiovascular] risk reduction benefits of icosapent ethyl.”

Few discoveries have been met with the same fervor as recent revelations outlining the atherogenicity of Lp(a). With some data suggesting Lp(a) may be 6 times as atherogenic as LDL per unit change, the cardiology community has placed an emphasis on increasing testing rates as they await results of clinical development programs for Lp(a)-lowering agents, such as olpasiran and lepodisiran.^1,2

In the current study, a team led by Philippe Gabriel Steg, MD, chief of the Department of Cardiology at the Bichat-Claude Bernard Hospital, sought to better understand the cardiovascular benefit of icosapent ethyl across varying levels of baseline Lp(a) from within the REDUCE-IT trial. Originally presented at the American Heart Association 2018 Scientific Sessions, the multicenter, randomized, double-blind, placebo-controlled REDUCE-IT trial compared the effects of icosapent ethyl 2 mg twice daily against placebo therapy among a cohort of patients with hypertriglyceridemia.^1,3

A total of 8179 patients underwent randomization in the study, which concluded use of icosapent ethyl was associated with a 25% relative risk reduction for a composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina (Hazard ratio [HR], 0.75; 95% Confidence Interval [CI], 0.68 to 0.83; P <.001). In the years that followed, dozens of additional analyses from the trial would evidence of its risk-benefit profile across a multitude of patient subgroups, including based on EPA levels, use of statins, diabetes status, event history, and more.³

Among the 8179 participants included in the trial, 7026 had baseline Lp(a) assessments. This cohort had a median Lp(a) concentration of11.6 mg/dL (Q1-Q3, 5.0 to 37.4 mg/dL). The primary outcome of interest in the study by Steg and colleagues was to describe the relationships between Lp(a) mass concentration and risk for first and total MACE. The secondary aim of the study was to assess the effects of icosapent ethyl on first MACE event among those with baseline Lp(a) concentrations less than or equal to 50 mg/dL compared to those with concentrations greater than or equal to 50 mg/dL.¹

Upon analysis, result suggested Lp(a) concentrations had significant associated with both first and total MACE events (P <.0001). Further analysis providing evidence of event reductions with icosapent ethyl across the range of Lp(a) levels (P for interaction >.10), with reductions in risk observed for those with concentrations less than 50 mg/dL (HR, 0.75; 95% CI, 0.66 to 0.84) and those with concentrations greater than or equal to 50 mg/dL (HR, 0.79; 95% CI, 0.64-0.97).¹

"The data highlight VASCEPA/VAZKEPA’s effect on reducing MACE in patients with different baseline levels of Lipoprotein(a) [Lp(a)] including among those with clinically relevant Lp(a) elevation as well as among patients with high and low LDL-C baseline levels,” said Nabil Abadir, MBCHB, senior vice president, chief medical officer, and head of Global Medical Affairs at Amarin.⁴ “These data demonstrate the molecule’s impact in reducing patients’ residual cardiovascular event risk across these patient sub-groups regardless of their baseline Lp(a) or LDL-C levels.”

In an accompanying editorial, Michael Blaha, MD, MPH, of the Johns Hopkins Ciccarone Center for the Prevention of Atherosclerotic Cardiovascular Disease, and Harpreet Bhatia, MD, of the Division of Cardiovascular Medicine at the University of California San Diego, provide an overview of the growing evidence base supporting the causal role of Lp(a) in cardiovascular disease and how this stands in contrast to rates of testing and recognition, which they suggest is lagging because of the lack of therapies to address elevated Lp(a).⁵

“These results suggest that the reduction in cardiovascular risk associated with IPE is consistent across Lp(a) levels, leaving us again wanting for targeted therapies that allow a mechanistic approach to residual risk reduction. The holy grail will be the time when, after basic standard of care therapy, we can carefully select the next therapy based on biomarkers or indicators of the mechanisms driving residual risk. This may be residual inflammatory risk, residual cardiometabolic risk, residual thrombotic risk, or residual Lp(a)-mediated risk among other pathways,” wrote the pair.⁵

References:

Szarek M, Bhatt DL, Miller M, et al. Lipoprotein(a) Blood Levels and Cardiovascular Risk Reduction With Icosapent Ethyl. J Am Coll Cardiol. Published online March 15, 2024. doi:10.1016/j.jacc.2024.02.016

Björnson, E, Adiels, M, Taskinen, M. et al. Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis. J Am Coll Cardiol. 2024 Jan, 83 (3) 385–395. https://doi.org/10.1016/j.jacc.2023.10.039

Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi:10.1056/NEJMoa1812792

Research evaluating benefits of VASCEPA®/VAZKEPA® (icosapent ethyl) to be presented at the American College of Cardiology’s (ACC) annual Scientific Session & Expo: Amarin global. Research Evaluating Benefits of VASCEPA®/VAZKEPA® (icosapent ethyl) to be Presented at the American College of Cardiology’s (ACC) Annual Scientific Session & Expo | Amarin Global. March 25, 2024. Accessed March 27, 2024. https://amarincorp.com/news-and-media/research-evaluating-benefits-vasceparvazkepar-icosapent-ethyl-be.

Blaha, M, Bhatia, H. Lipoprotein(a), Residual Cardiovascular Risk, and the Search for Targeted Therapy. J Am Coll Cardiol. null2024, 0 (0) . https://doi.org/10.1016/j.jacc.2024.03.370.