Small dense LDL-c does not modify treatment effect of icosapent ethyl

ESC 2024 – In a post-hoc analysis of REDUCE-IT, icosapent ethyl reduced the risk of MACE compared with placebo, irrespective of baseline sdLDL-c.

This summary is based on the presentation of Rahul Aggarwal, MD (Boston, MA, US) at the ESC Congress 2024 - Icosapent ethyl by baseline small dense low-density lipoprotein cholesterol: an analysis of REDUCE-IT.

Introduction and methods

Icosapent ethyl, a highly-purified omega 3 fatty acid, reduced the risk of MACE in statin-treated patients with elevated triglyceride levels and established CVD or elevated CVD risk in the REDUCE-IT trial compared with placebo. Small dense LDL-c (sdLDL-c) is a subtype of LDL-c that is highly atherogenic, and associated with CVD risk. It has a high concentration of cholesterol and is formed from triglyceride rich containing LDL particles. Nevertheless, sdLDL-c is currently infrequently used as a biomarker in clinical practice. This post-hoc analysis of REDUCE-IT evaluated whether the treatment effect of icosapent ethyl is modified by sdLDL-c levels.

REDUCE-IT was an international, double-blind, placebo-controlled trial in which 8179 statin-treated patients with established CVD or with diabetes and at least one additional risk factor, elevated triglycerides (150-499 mg/dL [1.69-5.63 mmol/L]) and controlled LDL-c levels (41-100 mg/dL [1.06-2.59 mmol/L]) were randomized to icosapent ethyl 4 g/day or placebo.

In this REDUCE-IT sdLDL-c post-hoc analysis, patients of REDUCE-IT were stratified by sdLDL-c at baseline (threshold set a 46 mg/dL). A total of 7698 patients had sdLDL-c levels below 46 mg/dL (n=3860 treated with icosapent ethyl; n=3838 treated with placebo; median value at baseline in both groups ~34 mg/dL), whereas 459 patients had a sdLDL-c level above this threshold (n=217 treated with icosapent ethyl; n=242 treated with placebo; median value at baseline in both groups ~48 mg/dL).

The primary outcome was 5-point MACE, a composite of CV death, non-fatal MI, non-fatal stroke, coronary revascularization, or unstable angina.

Main results

• In placebo-treated patients, the incidence rate of the primary outcome was higher in patients who had higher sdLDL-c levels at baseline compared with patients who had values below the threshold (31.7% vs. 28.0%; P=0.02). This was not the case for icosapent ethyl-treated patients (25.5% vs. 21.5%; P=0.92).
• Icosapent ethyl versus placebo reduced 5-point MACE in patients with sdLDL-c <46 mg/dL (HR: 0.77; 95%CI: 0.69-0.85; P<0.0001) and in patients with sdLDL-c ≥46 mg/dL (HR: 0.58; 95%CI: 0.38-0.88; P=0.0086) (P for interaction=0.22).
• Icosapent ethyl reduced the rate of recurrent events compared with placebo, irrespective of sdLDL-c at baseline.
• The safety outcomes in this analysis were consistent with the previously reported findings in REDUCE-IT.

Conclusion

In this post-hoc analysis of REDUCE-IT, higher sdLDL-c levels at baseline were associated with higher rates of 5-point MACE in the placebo group, but not in the icosapent ethyl group. Icosapent ethyl reduced MACE risk in statin-treated patients with elevated triglyceride levels and established CVD or elevated CVD risk irrespective of baseline sdLDL-c.

- Our reporting is based on the information provided at the ESC Congress 2024 -