Apabetalone reduces cardiovascular risk: a meta-analysis

Abstract

Introduction: Epigenetic inhibition of bromodomain and extra-terminal protein (BET) is a rapidly emerging therapeutic approach in reducing residual cardiovascular risk. Apabetalone is a novel drug that reduces inflammation and thrombosis through selective BET inhibition. Three phase II trials suggested benefits while the recent phase III BETonMACE trial did not. To reconcile these inconsistencies, we performed a meta-analysis of all trials of apabetalone. Methods: We searched MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov for randomised controlled trials of apabetalone up to 5 May 2020. The outcomes of interest were cardiovascular events (major adverse cardiovascular events [MACE] and hospitalisation for heart failure) and inflammatory markers (alkaline phosphatase [ALP] and C-reactive protein [CRP]), and lipid parameters (high-density lipoprotein cholesterol [HDL]), low-density lipoprotein cholesterol (LDL), apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB). Pooled risk ratios (RRs) or mean differences (MD) and 95% confidence intervals (95% CIs) in a fixed-effects model were generated using the “meta” package in R (version 3.6.3). Results: Four trials with altogether 3223 patients were included. All patients had coronary artery disease and received standard statin therapy. Apabetalone significantly reduced MACE (RR=0.78, 95% CI=0.63-0.96), hospitalisation for HF (RR=0.48, 95% CI=0.33-0.70) and ALP (MD= -9.35%, 95% CI= -12.17 to -6.53), and significantly increased HDL (MD=4.43%, 95% CI=2.74-6.13) and apoA-I (MD=2.82%, 1.36-4.28). No significant differences were observed for CRP (MD= -0.32%, 95% CI= -1.42 to 0.77), apoB (MD= -0.42%, 95% CI= -3.61 to 2.76), and LDL (MD= -0.10%, 95% CI= -0.41 to 0.22). There was no significant heterogeneity. Conclusion: Our meta-analysis shows that apabetalone reduces cardiovascular events and inflammation, and improved lipid profiles. While BET inhibition shows promising potential in eliminating residual cardiovascular risk, larger outcome trials are urgently needed to investigate the cardiovascular benefits and underlying mechanisms of BET inhibition.