Reduction in the risk of major adverse cardiovascular events with the BET protein inhibitor apabetalone in patients with recent acute coronary syndrome, type 2 diabetes, and moderate to high likelihood of non-alcoholic fatty liver disease

Peter P Toth; Gregory G Schwartz; Stephen J Nicholls; Aziz Khan; Michael Szarek; Henry N Ginsberg; Jan O Johansson; Kamyar Kalantar-Zadeh; Ewelina Kulikowski; Ken Lebioda; Norman C W Wong; Michael Sweeney; Kausik K Ray; BETonMACE Investigators

doi:10.1016/j.ajpc.2022.100372

Reduction in the risk of major adverse cardiovascular events with the BET protein inhibitor apabetalone in patients with recent acute coronary syndrome, type 2 diabetes, and moderate to high likelihood of non-alcoholic fatty liver disease

Am J Prev Cardiol. 2022 Aug 8:11:100372. doi: 10.1016/j.ajpc.2022.100372. eCollection 2022 Sep.

Authors

Affiliations

¹ CGH Medical Center Sterling, Sterling, IL, USA.
² Division of Cardiology, Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA.
⁴ Monash Cardiovascular Research Centre, Monash University, Melbourne, Australia.
⁵ Resverlogix Corp., Calgary, Alberta, Canada.
⁶ CPC Clinical Research and University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁷ State University of New York Downstate School of Public Health, Brooklyn, NY, USA.
⁸ Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
⁹ Division of Nephrology and Hypertension, University of California Irvine, Irvine, CA, USA.
¹⁰ Imperial Centre for Cardiovascular Disease Prevention, Imperial College, London, UK.

Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) is common among patients with type 2 diabetes mellitus (T2DM) and is associated with increased risk for coronary atherosclerosis and acute cardiovascular (CV) events. We employed the validated, non-invasive Angulo NAFLD fibrosis score (FS) in an intervention study in patients with T2DM and recent acute coronary syndrome (ACS) to determine the association of FS with CV risk and treatment response to apabetalone. Apabetalone is a novel selective inhibitor of the second bromodomain of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression.

Methods: The Phase 3 BETonMACE trial compared apabetalone with placebo in 2,425 patients with T2DM and recent ACS. In this post hoc analysis, we evaluated the impact of apabetalone therapy on CV risk, defined as a composite of major adverse cardiovascular events (MACE: CV death, non-fatal myocardial infarction [MI], or stroke) and hospitalization for heart failure (HHF) in two patient categories of FS that reflect the likelihood of underlying NAFLD. Patients were initially classified into three mutually exclusive categories according to a baseline Angulo FS <-1.455 (F0-F2), -1.455 to 0.675 (indeterminant), and >0.675 (F3-F4), where F0 through F4 connote fibrosis severity none, mild, moderate, severe, and cirrhosis, respectively. The composite of ischemic MACE and HHF in the placebo group was higher in indeterminant and F3-F4 categories compared to the F0-F2 category (17.2% vs 15.0% vs 9.7%). Therefore, for the present analysis, the former two categories were combined into an elevated NAFLD CVD risk group (FS+) that was compared with the F0-F2 group (lower NAFLD risk, FS_0-2).

Results: In 73.7% of patients, FS was elevated and consistent with a moderate-to-high likelihood of advanced liver fibrosis (FS+); 26.3% of patients had a lower FS (FS_0-2). In the placebo group, FS+ patients had a higher incidence of ischemic MACE and HHF (15.4%) than FS_0-2 patients (9.7%). In FS+ patients, addition of apabetalone to standard of care treatment lowered the rate of ischemic MACE compared with placebo (HR = 0.79; 95% CI 0.60-1.05; p=0.10), HHF (HR = 0.53; 95% CI 0.33-0.86; p=0.01), and the composite of ischemic MACE and HHF (HR = 0.76; 95% CI 0.59-0.98; p=0.03). In contrast, there was no apparent benefit of apabetalone in FS_0-2 patients (HR 1.24; 95% CI 0.75-2.07; p=0.40; HR 1.12; 95% CI 0.30-4.14; p=0.87; and HR 1.13; 95% CI 0.69-1.86; p=0.62, respectively). Over a median duration of 26.5 months, FS increased from baseline in both treatment groups, but the increase was smaller in patients assigned to apabetalone than to placebo (p=0.04).

Conclusions: Amongst patients with T2DM, recent ACS, and a moderate-to-high likelihood of advanced liver fibrosis, apabetalone was associated with a significantly lower rate of ischemic MACE and HHF and attenuated the increase in hepatic FS over time.

Keywords: ACS, Acute coronary syndrome; ALP, Alkaline Phosphatase; ALT, Alanine aminotransferase; APR, Acute phase reactant; AST, Aspartate aminotransferase; Apabetalone; ApoAI, Aproprotein-AI; BD, Bromodoamin; BET, Bromodomain and extraterminal proteinfamily; BMI, Body mass index; CV, Cardiovascular; CVD, Cardiovascular Disease; Cardiovascular events; FS, Fibrosis score; Fibrosis; HDL-C, High density lipoprotein cholesterol; HHF, Hospitalization for heart Failure; HR, Hazard ratio; MACE, Major acute coronary event; NAFLD, Nonalcoholic fatty liver disease; Nonalcoholic fatty liver disease; T2DM, Type 2 diabetes mellitus.