BET inhibition may lower CV events in high risk CVD patients, suggests hypothesis-generating analysis
Selective BET Protein Inhibition with Apabetalone and Cardiovascular Events: A Pooled Analysis of Trials in Patients with Coronary Artery DiseaseLiterature - Nicholls SJ, Ray KK, Johansson JO et al. - Am J Cardiovasc Drugs. 2017 Oct 12. doi: 10.1007/s40256-017-0250-3
- Apabetalone treatment yielded dose-dependent increases in apoA-I (up to median change from baseline: 6.7% vs. 2.69% with placebo, P<0.001) and HDL-c (median: 6.52% vs. 0.00% with placebo, P<0.001), and a median increase in the concentration of large HDL particles of 23.3% was seen (vs. 1.74% with placebo, P<0.001), as well as an increase in HDL particle size of 1.15% (vs 0.0% with placebo, P<0.001).
- A dose-dependent decrease in hsCRP of -21.1% (median change from baseline, vs. -13.33 with placebo, P=0.04).
- Change in LDL-c from baseline did not differ significantly between treatments (-4.98% vs. -3.57% from baseline, P=0.33).
- Patients treated with apabetalone experienced fewer major adverse CV events (MACE: death, myocardial infarction, coronary revascularization, and hospitalization for cardiovascular causes, 5.9% (24/556) vs 10.4% (19/242) with placebo, P=0.02).
- In exploratory subgroup analyses, less MACE was associated with apabetalone treatment in in patients with diabetes (5.4% vs. 12.7%, P=0.02), but not in those without diabetes (6.2% vs. 9.0%, P=0.30).
- Similarly, in those with HDL-c <39 mg/dL, apabetalone was associated with fewer MACE (5.5% vs. 12.8%, P-0.01) or with baseline hsCRP >2 mg/L (5.4% vs. 9.0%, P=0.02), but in those with HDL-c ≥39 mg/dL or with normal hsCRP levels, treatment did not affect the rate of MACE.
- After adjustment for baseline risk factors and study duration, apabetalone treatment remained associated with fewer CV events in the pooled cohort (HR: 0.51, 95%CI: 0.27-0.93, P=0.03), in those with diabetes (HR: 0.38, 95%CI: 0.15-0.99, P=0.04) and in those with elevated hsCRP levels at baseline (HR: 0.39, 95%CI: 0.19-0.83, P=0.01).
- Overall, apabetalone was well tolerated. Treatment was associated with a higher incidence of liver transaminase elevation (>3 ULN occurred in 8%, none with placebo), without concomitant elevation in total bilirubin or cases of Hy’s law.
This study provides hypothesis-generating data for a reduction in CV events with apabetalone treatment. This BET-inhibitor may provide CV benefit in high-risk patients. Note that the individual studies were not powered to detect an effect on CV outcomes. Since previously, no effect of apabetalone on coronary plaque volume could be detected, the current findings may suggest a potential influence on atherosclerotic plaque stability. These findings strengthen the rationale for the ongoing BET-on-MACE outcome trial evaluating apabetalone in patients with T2DM and recent ACS