Relationship between triglycerides and CV outcomes during alirocumab treatment

In additional analyses of ODYSSEY OUTCOMES, higher baseline triglyceride levels were associated with increased MACE risk in patients with recent ACS on optimized statin therapy. The triglyceride reduction achieved with alirocumab did not contribute to its clinical benefit.

This summary is based on the publication of Zahger D, Schwartz GG, Du W, et al. - Triglyceride Levels, Alirocumab Treatment, and Cardiovascular Outcomes After an Acute Coronary Syndrome. J Am Coll Cardiol. 2024 Sep 10;84(11):994-1006. doi: 10.1016/j.jacc.2024.06.035

Introduction and methods

Background

Studies in patients with recent ACS have shown baseline triglyceride levels are associated with the risk of MACE [1,2]. Although fibrates and omega-3 fatty acids have a moderate triglyceride-lowering effect, this either has not translated into a CV benefit or such benefit was mostly unrelated to the triglyceride reduction [3-7]. In the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the PCSK9 inhibitor alirocumab reduced LDL-c levels and the risk of MACE compared with placebo in patients with recent ACS [8]. However, it is unknown whether and to what extent the clinical benefit of PCSK9 inhibitors is associated with baseline and on-treatment triglyceride levels.

Aim of the study

In prespecified and post-hoc analyses of the ODYSSEY OUTCOMES trial, the authors examined the prognostic effects of triglyceride levels at baseline and during treatment with alirocumab versus placebo on CV outcomes in patients with recent ACS.

Methods

The ODYSSEY OUTCOMES trial was an international, double-blind, placebo-controlled, phase 3 RCT in which 18,924 patients with recent ACS (1–12 months prior) and elevated levels of atherogenic lipoproteins (LDL-c ≥70 mg/dL, non–HDL-c ≥100 mg/dL, and/or apoB ≥80 mg/dL) despite high-intensity or maximum-tolerated statin therapy were enrolled. Those with fasting triglycerides >400 mg/dL at the qualifying visit were excluded. Participants were then randomized to subcutaneous alirocumab 75 mg every 2 weeks or placebo. Median follow-up duration was 2.8 years.

Outcome

The primary endpoint was MACE, defined as CHD death, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization.

Main results

Effect of baseline triglycerides on MACE risk

• At baseline, the median triglyceride concentration was 129 mg/dL (Q1–Q3: 94.0–182.0).

• Prespecified analysis in the entire study population showed patients with triglycerides ≥150 mg/dL at baseline had a higher risk of MACE than those with triglycerides <150 mg/dL (HR: 1.18; 95%CI: 1.08–1.23; P=0.0003). After adjustment for baseline covariates such as age, sex, diabetes, and HDL-c levels, there was no difference in MACE risk between the groups (adjusted HR (aHR): 1.09; 95%CI: 0.99–1.20; P=0.0845).

• When baseline triglyceride levels were analyzed as a continuous variable, each 10-mg/dL increase was associated with a 1% higher MACE risk (aHR: 1.008; 95%CI: 1.003–1.013; P<0.005).

Effect of alirocumab on triglycerides

• Alirocumab treatment reduced triglyceride levels throughout the trial, compared with baseline and placebo.

• At 4 months, the median absolute change in triglyceride levels from baseline was −17.7 mg/dL in patients treated with alirocumab and −0.9 mg/dL in those receiving placebo (P<0.0001). Thereafter, the triglyceride reduction with alirocumab slowly diminished, until –3.8 mg/dL at 48 months.

Effect of alirocumab on MACE risk

• In post-hoc analyses, alirocumab reduced the MACE risk compared with placebo in patients with baseline triglycerides <150 mg/dL (HR: 0.87; 95%CI: 0.77–0.98; P=0.022) and those with baseline triglycerides ≥150 mg/dL (HR: 0.82; 95%CI: 0.72–0.94; P=0.006; P for interaction=0.820).

• Each 10-mg/dL decrease in triglyceride levels from baseline to 4 months was associated with a lower MACE risk after 4 months in the placebo group (HR: 0.988; 95%CI: 0.982–0.995; P<0.005) but not the alirocumab arm (HR: 0.999; 95%CI: 0.987–1.010; P=0.82).

Conclusion

These prespecified and post-hoc analyses of the ODYSSEY OUTCOMES trial showed higher baseline triglyceride levels were associated with increased MACE risk in patients with recent ACS on high-intensity or maximum-tolerated statin therapy. Although alirocumab reduced both triglyceride levels and MACE risk compared with placebo, the triglyceride reduction from baseline to 4 months did not predict the subsequent MACE risk in the alirocumab group.

Find this article online at J Am Coll Cardiol.

References

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