Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol

Abstract

BACKGROUND Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. OBJECTIVES In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. METHODS ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was <70 mg/dL (median 69.4 mg/dL; interquartile range: 64.3–74.0 mg/dL); in 14,573 patients (77.0%), both determinations were ≥70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2–111.0 mg/dL). RESULTS In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [Cl]: 0.52–0.90) and 1.11 (95% Cl: 0.83–1.49), with treatment-lipoprotein(a) interaction on MACE ( P interaction = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% Cl: 0.72–0.92) and 0.89 (95% Cl: 0.75–1.06), with P interaction = 0.43. CONCLUSIONS In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402 )

A New Look at Novel Cardiovascular Risk Biomarkers: The Role of Atherogenic Lipoproteins and Innovative Antidiabetic Therapies

“…As reported by the investigators of the ODYSSEY Outcomes trial, the greatest benefit of PCSK9i on MACE risk among patients with recent acute coronary syndrome were those with optimal LDL-C levels and mildly elevated Lp(a) [43]. Taking into account that similar findings were obtained in the FOURIER study [44], Lp(a) could be a reliable biomarker of residual risk, although certain confounding effects remain due to its potential role in atherothrombosis.…”

The Effect of Bariatric Surgery on Circulating Levels of Lipoprotein (a): A Meta-analysis

“…Mipomersen, an antisense oligonucleotide against apolipoprotein B [68][69][70][71], had the potential benefit to reduce Lp(a) by 20%, but this drug is approved by the FDA only as an orphan drug for homozygous familial hypercholesterolemia [72]. Currently, the only drugs on the market which can decrease Lp(a) significantly (about 25%) are proprotein subtilisin/kexin type 9 (PCSK9) inhibitors-alirocumab and evolocumab [73,74]. A post hoc analysis of the Odyssey outcomes study suggested that a part of the benefits of alirocumab in reducing ASCVD events could be ascribed to its Lp(a) lowering effects, mainly on a subgroup of patients with high Lp(a) levels that had a recent myocardial infarction [75].…”

Proprotein convertase subtilisin/kexin type 9 inhibitors on the horns of a dilemma: which lipoprotein we should primarily target – low-density lipoprotein or lipoprotein(a)?

“…12 However, a most recent study in 18 924 patients with recent acute coronary syndromes and LDL-C 70 mg/dl on optimized statin therapy demonstrated that PCSK9i offered incremental clinical benefit only when Lp(a) levels were at least mildly elevated. 13 Another study revealed recently a substantial prevalence of discordance in LDL-C and Lp(a) reduction in response to PCSK9i administration, particularly when considering higher baseline Lp(a) levels. 14 Hence, based on the above, we understand that it remains difficult to separate the protective effects of PCSK9i through LDL-C and/or Lp(a) lowering.…”

“…A post hoc ODYSSEY pooled analysis, investigating the PCSK9i-induced Lp(a) reductions in association with MACCE occurrence, concluded that Lp(a) reductions were not associated with MACCE independently of LDL-C reductions 12 . However, a most recent study in 18 924 patients with recent acute coronary syndromes and LDL-C ∼70 mg/dl on optimized statin therapy demonstrated that PCSK9i offered incremental clinical benefit only when Lp(a) levels were at least mildly elevated 13 . Another study revealed recently a substantial prevalence of discordance in LDL-C and Lp(a) reduction in response to PCSK9i administration, particularly when considering higher baseline Lp(a) levels 14 …”