Icosapent Ethyl Reduces MACE Across Range of Baseline Lp(a): REDUCE-IT Analysis

Two new subgroup analyses from the landmark REDUCE-IT outcomes trial of icosapent ethyl (IPE) (Vascepa/Vazkepa; Amarin) will be presented at the American College of Cardiology 73rd Scientific Sessions, April 6-8, 2024, in Atlanta, GA, according to a statement from Amarin.¹

Notable findings will be reported on the effect of IPE on reducing major adverse cardiovascular events (MACE) in individuals across a spectrum of baseline levels of lipoprotein(a) (Lp[a]) and across a similar spectrum of baseline LDL-C.

REDUCE-IT At-a-Glance²

• A total of 8179 participants were randomly assigned in a 1:1 ratio to receive 2 g twice daily of IPE or matching placebo.
• Key inclusion criteria
  • age 45 years and older with established CV disease or age 50 years and older with diabetes and at least 1 additional risk factor
  • Fasting triglycerides 150-499 mg/dL, LDL-C 41-100 mg/dL, and stable statin dose for at least 4 weeks
• Results: use of IPE was associated with a 25% relative reduction in risk for the composite endpoint of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina (HR, 0.75; 95% CI, 0.68 to 0.83; P < .001) in individuals with elevated triglycerides (TG), with or at high risk for CVD, well managed on statin treatment.

IPE reduces MACE across Lp(a) concentrations³

For the current analysis the primary outcome of interest to lead investigator Philippe Gabriel Steg, MD, chief of the Department of Cardiology at the Bichat-Claude Bernard Hospital, in Paris, France, and colleagues was the relationship between Lp(a) mass concentration and the risk for first and total MACE in addition to the effects of IPE on first MACE among participants with baseline concentrations of Lp(a) equal to or less than 50 mg/dL or equal to or greater than 50 mg/dL.

Among the Among 7,026 participants (86% of those randomized) with baseline Lp(a) assessments, the median concentration was 11.6 mg/dL (Q1-Q3: 5.0-37.4 mg/dL).

Steg et al reported that concentrations of Lp(a) had a significant relationship with first and with total MACE independent of baseline TGs, LDL-C, and treatment assignment (P < .001) while the treatment benefit of IPE was found consistent across Lp(a) concentrations (interaction P = .66), either low or high. The researchers reported absolute risk reductions in MACE at 5 years with IPE of 6.5% and 5.7% for those with Lp(a) equal to or greater than 50 mg/dL or equal to or less than 50 mg/dL, respectively.

This analysis was published in full in advance of ACC.24 as an article in press in the Journal of the American College of Cardiology. Writing in the paper’s conclusion, Steg and colleagues stated, “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. 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.”²

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 wrote about the findings in an editorial accompanying the study ³:

"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.”³

IPE reduces MACE across LDL-C levels⁴

The second post-hoc analysis explored the effects of IPE on the REDUCE-IT composite CV outcome among individuals at high CV risk according to baseline levels of LDL-C.

Among the 8179 participants, 1058 (12.9%) had LDL-C levels below 55 mg/dL.

The rate of the primary outcome among the group with LDL-C less than 55 mg/dL was 16.2% in the IPE 22.8% in the placebo group (NNT: 15; HR 0.66, 95% CI, 0.50, 0.87; P = .003). The researchers reported very similar findings among those with LDL-C levels of equal to or greater than 55 mg/dL, with a composite CV outcome rate of 17.4% in the IPE group and 21.9% in the placebo group (NNT, 22; HR 0.76, 95% CI, 0.69, 0.85; P < .001). There were no significant interaction observed by baseline LDL-C (P = 0.40).⁴

"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,” Nabil Abadir, MBCHB, senior vice president, chief medical officer, and head of Global Medical Affairs at Amarin, said in the press statement from Amarin.¹ “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.”¹

References

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

Bhatt DL, Steg PG, Miller M, et al, for the REDUCE-IT investigators. N Engl J Med 2019;380:11-2. doi:10.1056/NEJMoa1812792

3. Szarek M, Bhatt BL, Miller M, et al, for the REDUCE-IT investigators. Lipoprotein(a) blood levels and cardiovascular risk reduction with icosapent ethyl. J Am Coll Cardiol. Published online March 25, 2024. https://doi.org/10.1016/j.jacc.2024.02.016

4. Aggarwal R, Bhatt DL, Steg G, et al. Efficacy of icosapent ethyl for reducing cardiovascular outcomes by baseline low density lipoprotein cholesterol level. Presented at the American College of Cardiology 73rd Scientific Sessions; April 6-8, 2024; Atlanta, GA. Accessed March 26, 2024. https://www.abstractsonline.com/pp8/#!/10973/presentation/12627