More from REDUCE-IT: Does lipoprotein(a) modify risk reduction with icosapent ethyl?

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Macrovascular Residual Risk Studies

27 June 2024

In this post hoc analysis of the REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), icosapent ethyl consistently reduced the risk of major adverse cardiovascular events (MACE) across the range of lipoprotein(a) [Lp(a)] levels, including among patients with clinically relevant elevated Lp(a) levels.

Szarek M, Bhatt DL, Miller M, et al. Lipoprotein(a) blood levels and cardiovascular risk reduction with icosapent ethyl. J Am Coll Cardiol 2024; 83:1529–39.

STUDY SUMMARY

Objective

To investigate the cardiovascular benefit of icosapent ethyl across a range of Lp(a) levels in the REDUCE-IT study cohort.

Study design

Post hoc analysis of REDUCE-IT, a randomized, double-blind, placebo-controlled trial.

Study population

REDUCE-IT included 8,179 patients with cardiovascular disease or aged ≥50 years with diabetes and ≥1 additional risk factor and fasting triglycerides 1.69 to 5.63 mmol/L (150-499 mg/dL) with stable low-density lipoprotein cholesterol (LDL-C) levels. Patients were randomized to treatment with icosapent ethyl 2 g twice daily or matching placebo. This analysis included 7,026 patients (86% of the randomized cohort) with baseline Lp(a) assessments, 3,515 in the icosapent ethyl group and 3,511 in the placebo group.

Main study variables

Primary outcome: The primary efficacy outcome of REDUCE-IT and this analysis was first MACE, a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina.
Key secondary outcome: a composite of first cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke

Methods

Relationships between continuous baseline Lp(a) mass concentration and risk for first and total (first and subsequent) MACE were analysed, as well as the effects of icosapent ethyl on first MACE across the range of baseline Lp(a) levels and among patient subgroups with Lp(a) concentration ≥50 or <50 mg/dL.

Results

Baseline characteristics of the two treatment groups were similar; median age was 64 years, 28-29% were female, 71-72% were secondary prevention patients and 30-32% were receiving a high-intensity statin. The overall median Lp(a) concentration at baseline was 11.6 mg/dL (interquartile range [IQR] 5.0-37.4 mg/dL) for the total study cohort, and 77.1 mg/dL (IQR 63.1-102.3 mg/dL) among those with baseline Lp(a) levels ≥50 mg/dL. The distribution of Lp(a) was right-skewed, with values ≥50 mg/dL in 20.4% of patients.

Over a median of 4.9 years (IQR 3.6-5.3 years) first MACE was experienced by 804 patients in the placebo group and 635 patients in the icosapent ethyl group. Baseline Lp(a) concentration had significant relationships with first and total MACE (p < 0.0001); these relationships were not changed by baseline levels of TG or LDL-C. Relative to the median Lp(a) value, estimated Hazard ratios (HRs) for first MACE were 1.03 (95% CI: 0.98-1.09) at 25 mg/dL, 1.12 (95% CI: 1.06-1.19) at 50 mg/dL, and 1.32 (95% CI: 1.17-1.49) at 100 mg/dL.

There was no evidence of reduced efficacy of icosapent ethyl at higher or lower baseline Lp(a) concentrations. Treatment with icosapent ethyl reduced first MACE across the range of Lp(a) levels, including in subgroups with concentrations ≥50 and <50 mg/dL (Table 1).

Table 1. Estimated hazard ratios for first MACE at different Lp(a) levels in REDUCE-IT

Baseline Lp(a), mg/dL	HR (95% confidence interval)
25	0.78 (0.65-0.94)
50	0.79 (0.68-0.92)
100	0.81 (0.66-0.99)

<50	0.75 (0.66-0.84), p<0.0001
≥50	0.79 (0.64-0.97), p=0.0248

Author conclusion

Baseline Lp(a) concentration was prognostic for MACE among participants with elevated TG levels receiving statin therapy. Importantly, icosapent ethyl consistently reduced MACE across a range of Lp(a) levels, including among those with clinically relevant elevations.

COMMENT

Accumulating evidence from epidemiologic and genetic studies supports elevated Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease, as summarized in a recent consensus statement from the European Atherosclerosis Society (1). Furthermore, in outcomes studies in patients with ASCVD and well controlled LDL-C levels, reduction in Lp(a) levels was shown to be a contributor to the reduction in cardiovascular risk observed with PCSK9 inhibitor treatment, albeit in patients with elevated Lp(a) levels at baseline (2,3). However, it is uncertain whether the relationship between Lp(a) and cardiovascular risk is also evident in patients with elevated levels of other lipids, such as elevated TG, or whether this relationship is modified by treatment with therapeutics that target other lipid parameters, such as icosapent ethyl in REDUCE-IT. This post hoc analysis of REDUCE-IT aimed to address this question.

There are two key findings from this analysis. First, the results are consistent with a continuous and relatively linear relationship between Lp(a) concentration and cardiovascular event risk in patients with elevated TG at baseline, as has been previously reported (1). Second, the analysis shows that the magnitude of clinical benefit associated with icosapent ethyl treatment was consistent across the range of baseline Lp(a) levels, including in patients with baseline Lp(a) levels <50 mg/dL and ≥50 mg/dL. Given that elevated Lp(a) has been identified as a factor conferring increased cardiovascular risk (4), this latter finding implies that the efficacy of icosapent ethyl is maintained in settings in which Lp(a) concentrations are a significant determinant of cardiovascular risk.

Despite the caveats associated with post hoc analysis and the fact that few patients in REDUCE-IT had elevated Lp(a) levels, the results of this study suggest that any potential benefit derived from Lp(a) lowering therapeutics is likely to be complementary to the cardiovascular risk reduction observed with icosapent ethyl.

References

1. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022;43:3925–46.
2. Bittner VA, Szarek M, Aylward PE, et al. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol 2020;75:133–44.
3. O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 2019;139:1483–92.
4. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88.

Key words

Lipoprotein(a); cardiovascular risk; REDUCE-IT; post hoc analysis.