A study called the BETonMACE trial, which was presented at the American Heart Association Scientific Sessions 2019, tested the hypothesis that adding the use of apabetalone to standard of care therapies improves cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus (T2DM) and low HDL-C after an acute coronary syndrome (ACS).
To conduct this international, multi-center, randomized, double-blind, placebo-controlled trial, researchers enrolled 2,425 participants (median age, 62, 25% female, 87% white) with recent ACS and T2DM at 195 sites across 13 countries between November 2015 and July 2018 with an average follow-up of 26.5 months. Subsequently, all patients with ACS in the preceding 8-90 days, T2DM, as well as an HDL-C of 40 and below mg/dl for men, or 45 and below mg/dl for women, were assigned in double-blind fashion 1:1 to receive 100 mg of apabetalone orally twice daily or a matching placebo in conjunction with guideline recommended standard of care. The primary endpoint defined as the was time to the first occurrence of CV death, non-fatal myocardial infarction (MI), or stroke, with the study concluding upon the accrual of 250 primary endpoints. Apabetalone and placebo groups were compared using a two-sided stratified log-rank test, while assuming a 2-sided type 1 error rate of 5% and cumulative incidence of the primary endpoint of 10.5% in the placebo arm at 18 months, which yielded an 80% power to detect a 30% relative risk reduction with apabetalone.
According to the results of the study, apabetalone did not significantly reduce CV death, non-fatal MI or stroke (HR=0.82; 95% CI, 0.65 to 1.04; P=0.11). However, the therapy exhibited a favorable trend of 18% difference in relative risk, which approached statistical significance (HR=0.70; 95% CI, 0.62 to 1.01; P=0.06). Apabetalone was generally well-tolerated, although discontinuation due to elevated liver function tests was observed more frequently with apabetalone.
“[This is the] first CV outcomes trial assessing the potential of epigenetic modification with BET protein inhibition shows promise,” according to the presentation given by Kausik K. Ray, MBChB, MD, of the Imperial College of London. “Favorable trends were observed for the primary endpoint and key components except stroke with a nominal difference in heart failure hospitalization. Further studies of this approach are warranted.”