Icosapent ethyl by baseline small dense low-density lipoprotein cholesterol: an analysis of REDUCE-IT
Authors: Aggarwal R , Bhatt D , Steg G , Miller M , Brinton E , Dunbar R , Martens F , Ketchum S , Tardif J , Mason P , Ballantyne C 
Published: October 2024

Abstract

Background
Small dense low-density lipoprotein cholesterol (sdLDL-C) is associated with cardiovascular (CV) risk.

Purpose
We assessed if baseline sdLDL-C modified the effect of icosapent ethyl among patients in REDUCE-IT.

Methods
REDUCE-IT randomized patients to icosapent ethyl vs placebo. In this post hoc analysis, patients ≥45 years with CV disease or ≥50 years with diabetes and CV risk factors were included. Patients were required to have triglycerides of 135-499 mg/dL and low-density lipoprotein cholesterol (LDL-C) of 41-100 mg/dL. Exclusion criteria included severe heart failure, acute severe liver disease, or hemoglobin A1c &gt;10%.
Patients were stratified by baseline calculated sdLDL-C. A threshold of 46 mg/dL was chosen because sdLDL-C greater than this cutoff has predicted CV risk despite well-controlled LDL-C. The primary outcome included a composite of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or unstable angina. The key secondary composite outcome included CV death, nonfatal MI, or nonfatal stroke. Outcomes were assessed with Cox proportional hazard models and interaction analyses were conducted to assess heterogeneity in treatment effect by baseline sdLDL-C.

Results
REDUCE-IT included 8179 patients, with 8157 (99.7%) patients having sdLDL-C data. Among these patients, 7698 (94.4%) had sdLDL-C &lt;46 mg/dL and 459 (5.6%) had sdLDL-C ≥46 mg/dL. Median sdLDL-C was 34.2 mg/dL (interquartile range [IQR]: 30.3, 38.4 mg/dL) in the lower sdLDL-C group and 48.4 mg/dL (IQR: 47.1, 50.6 mg/dL) in the higher sdLDL-C group (Table).
The placebo group had a greater event rate in the higher sdLDL-C group compared to the lower sdLDL-C group (72.0 vs 56.4 events per 1000 p-y), though event rates in the icosapent ethyl group were similar by sdLDL-C group (44.1 vs 43.3 events per 1000 p-y, respectively). Icosapent ethyl reduced the rate of the primary outcome compared with placebo (17.2% vs 22.0%; hazard ratio [HR]: 0.75 [95% CI: 0.68, 0.83]; P&lt;0.0001). The number needed to treat [NNT] to avoid one primary endpoint event was 21. In the lower sdLDL-C group, icosapent ethyl decreased rates of the primary outcome (43.3 events per 1000 patient-years [p-y]) compared with the placebo group (56.4 events per 1000 p-y) (17.3% vs 21.7%; HR: 0.77 [95% CI: 0.69, 0.85]; NNT: 22). Similarly, in the higher sdLDL-C group, icosapent ethyl decreased the rate of the primary outcome (44.1 events per 1000 p-y) compared with the placebo group (72.0 events per 1000 p-y) (16.6% vs 26.4%; HR: 0.58 [95% CI: 0.38, 0.88]; NNT: 10). There was no significant interaction between treatment benefit and baseline sdLDL-C for the primary (Pinteraction = 0.22) and key secondary outcome (Pinteraction = 0.82). Findings were overall similar for the other secondary outcomes (Figure).

Conclusion
Icosapent ethyl reduced CV outcomes in patients with high CV risk and elevated triglycerides irrespective of low or high sdLDL-C.