Patients with optimal LDL-c control also benefit from icosapent ethyl

In a secondary analysis of REDUCE-IT among statin-treated patients with high CVD risk and elevated triglycerides, icosapent ethyl reduced the risk of CV events compared with placebo regardless of baseline LDL-c.

This summary is based on the publication of Aggarwal R, Bhatt DL, Steg PG, et al. - Cardiovascular Outcomes With Icosapent Ethyl by Baseline Low-Density Lipoprotein Cholesterol: A Secondary Analysis of the REDUCE-IT Randomized Trial. J Am Heart Assoc. 2025 Mar 4;14(5):e038656. doi: 10.1161/JAHA.124.038656.

Introduction and methods

Background

Several publications on the REDUCE‐IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) trial have reported that icosapent ethyl reduced the risk of CV events in statin‐treated patients with high CVD risk, hypertriglyceridemia, and LDL‐c ≤100 mg/dL compared with placebo [1-8]. It is unknown whether patients with very well-controlled LDL-c levels will gain similar benefits.

Aim of the study

In a post-hoc secondary analysis of the REDUCE-IT trial, the authors examined the efficacy of icosapent ethyl in high CVD risk patients with hypertriglyceridemia stratified by baseline LDL-c levels.

Methods

The REDUCE-IT trial was an international, multicenter, double-blind, placebo-controlled, phase 3 RCT in which 8179 patients with established CVD or at high CVD risk (DM and ≥1 CVD risk factor), elevated triglyceride levels (135–499 mg/dL; 1.52–5.63 mmol/L), and LDL-c 41–100 mg/dL (1.06–2.59 mmol/L) who were receiving statin therapy were randomized to icosapent ethyl 2 g twice daily or placebo. Baseline LDL-c data were available for 8175 patients.

Outcomes

The primary endpoint was a composite outcome of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint was a composite outcome of CV death, nonfatal MI, or nonfatal stroke. Safety endpoints included treatment‐emergent adverse events.

Main results

Efficacy

• In the subgroup of participants with baseline LDL-c <55 mg/dL (n=1058; 12.9%), 16.2% of the patients treated with icosapent ethyl experienced a primary endpoint event compared with 22.8% of those receiving placebo (HR: 0.66; 95%CI: 0.50–0.87; absolute risk reduction (ARR): 6.6%; number needed to treat (NNT): 15; P=0.003).
• Among participants with LDL-c ≥55 mg/dL (n=7117; 87.1%), the rate of the primary endpoint was also lower in patients treated with icosapent ethyl than those receiving placebo (17.4% vs. 21.9%; HR: 0.76; 95%CI: 0.69–0.85; ARR: 4.5%; NNT: 22; P<0.0001). There was no interaction between the baseline LDL-c level and treatment group (P for interaction=0.40).
• Similar results were found when patients were stratified by a higher LDL-c threshold (70 mg/dL) (P for interaction=0.29).
• When baseline LDL-c levels were analyzed as a continuous variable, there was also no difference in the relative treatment effect of icosapent ethyl versus placebo P for interaction=0.59).
• In addition, the risk of the key secondary endpoint was reduced in patients randomized to icosapent ethyl compared with those receiving placebo, both in the subgroup with LDL-c <55 mg/dL (9.5% vs. 15.9%; HR: 0.55; 95%CI: 0.39–0.78; ARR: 6.4%; NNT: 16; P=0.0007) and that with LDL-c ≥55 mg/dL (11.5% vs. 14.7%; HR: 0.76; 95%CI: 0.67–0.87; ARR: 3.2%; NNT: 32; P<0.0001; P for interaction=0.11).

Safety

• In the icosapent ethyl and placebo groups, similar frequencies of severe treatment‐emergent adverse events (19.7% vs. 20.0%; P=0.78) and drug‐related treatment‐emergent adverse events (12.6% vs. 12.2%; P=0.61) were observed, with no significant interaction by baseline LDL‐c level.
• The rate of AF/atrial flutter was higher in the icosapent ethyl group than the placebo group (5.8% vs. 4.5%; P=0.008), and there was a trend toward an increased rate of serious adverse bleeding (2.7% vs. 2.1%; P=0.06), with no significant interaction by baseline LDL‐c level.

Conclusion

In this secondary analysis of the REDUCE-IT trial among statin-treated patients with high CVD risk and elevated triglyceride levels, icosapent ethyl reduced the risk of CV events compared with placebo regardless of baseline LDL-c levels. Patients with optimal LDL-c control (i.e., <55 mg/dL) benefited as much from icosapent ethyl treatment as those with LDL-c ≥55 mg/dL.

Find this article online at J Am Heart Assoc.

References

1. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT, Juliano RA, Jiao L, Granowitz C, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11–22. doi: 10.1056/NEJMoa1812792
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