Safety of low lipoprotein(a) levels: the FOURIER trial

BACKGROUND AND AIMS: Lipoprotein(a) (Lp(a)) is considered a causal risk factor for atherogenesis. A higher prevalence of certain adverse events, including diabetes mellitus (DM), has been reported for patients with low Lp(a) concentrations. Therapeutics that lower Lp(a) are now in clinical testing. Thus, the association between lower Lp(a) concentration and safety outcomes is of clinical importance. METHODS: The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial randomized 27 564 patients with stable atherosclerotic cardiovascular disease (ASCVD) to evolocumab versus placebo on a background of statin therapy. The relationship between Lp(a) and the risk of prevalent and incident adverse outcomes of interest was examined, adjusting for relevant predictors. RESULTS: Lp(a) was assessed in 25 090 participants at baseline (median 37 nmol/L, interquartile range 13-165). There was no association between Lp(a) concentration and incident risk of haemorrhagic stroke, serious bleeding, neurocognitive events, malignancy, or atrial fibrillation, including those with Lp(a) levels ≤13 nmol/L. There was an inverse association between lower baseline Lp(a) levels and prevalent DM at baseline (adjusted odds ratio 1.03, 95% confidence interval [CI] 1.02-1.04, P < .001; for every 50 nmol/L lower Lp(a)), as well as the incident risk of developing DM during follow-up (adjusted hazard ratio [HR] 1.05, 95% CI 1.02-1.08, P = .002; for every 50 nmol/L lower Lp(a)), with consistent results by treatment arm. Evolocumab did not increase the risk of DM irrespective of baseline Lp(a), even in participants in the top decile of baseline Lp(a) (adjusted HR .72, 95% CI .38-1.35) in whom evolocumab reduced Lp(a) by a median of 71 nmol/L. CONCLUSIONS: In patients with ASCVD, low Lp(a) concentration was not associated with an increased risk of most adverse safety outcomes, but lower Lp(a) was associated with an increased risk of prevalent and incident DM.