Effect of Apabetalone Added to Standard Therapy on Major Adverse Cardiovascular Events in Patients With Recent Acute Coronary Syndrome and Type 2 Diabetes

Abstract

; for the BETonMACE Investigators and Committees IMPORTANCE Bromodomain and extraterminal proteins are epigenetic regulators of gene transcription. Apabetalone is a selective bromodomain and extraterminal protein inhibitor targeting bromodomain 2 and is hypothesized to have potentially favorable effects on pathways related to atherothrombosis. Pooled phase 2 data suggest favorable effects on clinical outcomes. OBJECTIVE To test whether apabetalone significantly reduces major adverse cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled trial, conducted at 190 sites in 13 countries. Patients with an acute coronary syndrome in the preceding 7 to 90 days, type 2 diabetes, and low high-density lipoprotein cholesterol levels were eligible for enrollment, which started November 11, 2015, and ended July 4, 2018, with end of follow-up on July 3, 2019. INTERVENTIONS Patients were randomized (1:1) to receive apabetalone, 100 mg orally twice daily (n = 1215), or matching placebo (n = 1210) in addition to standard care. MAIN OUTCOMES AND MEASURES The primary outcome was a composite of time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke. RESULTS Among 2425 patients who were randomized (mean age, 62 years; 618 women [25.6%]), 2320 (95.7%) had full ascertainment of the primary outcome. During a median follow-up of 26.5 months, 274 primary end points occurred: 125 (10.3%) in apabetalonetreated patients and 149 (12.4%) in placebo-treated patients (hazard ratio, 0.82 [95% CI, 0.65-1.04]; P = .11). More patients allocated to apabetalone than placebo discontinued study drug (114 [9.4%] vs 69 [5.7%]) for reasons including elevations of liver enzyme levels (35 [2.9%] vs 11 [0.9%]). CONCLUSIONS AND RELEVANCE Among patients with recent acute coronary syndrome, type 2 diabetes, and low high-density lipoprotein cholesterol levels, the selective bromodomain and extraterminal protein inhibitor apabetalone added to standard therapy did not significantly reduce the risk of major adverse cardiovascular events.

Epigenetic Modulation by Apabetalone Counters Cytokine-Driven Acute Phase Response In Vitro, in Mice and in Patients with Cardiovascular Disease

“…Apabetalone treatment downregulates circulating cytokine targets, including the APR pathway components, in stable CAD patients on standard-of-care therapy, potentially dampening chronic inflammatory signaling in a disease. Apabetalone's impact on inflammatory mediators could contribute to a reduction in CVD risk and disease outcomes [43,44].…”

“…These proteins are linked to atherosclerotic plaque development and rupture, and their circulating levels correlate with CVD risk [18,[36][37][38][39][40][41][42]. Thus, downregulation of cytokine pathways that lead to APR protein expression may reduce CVD risk in apabetalonetreated patients [43,44].…”

Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease

“…A phase-3 clinical trial, BETonMACE, was recently completed [156,157]. It enrolled 2425 patients with recent acute coronary syndrome, type 2 diabetes and low HDL cholesterol on statins to apabetalone 100 mg/12 h or placebo for 120 weeks.…”

“…It enrolled 2425 patients with recent acute coronary syndrome, type 2 diabetes and low HDL cholesterol on statins to apabetalone 100 mg/12 h or placebo for 120 weeks. The trial failed to meet the primary endpoint of cardiovascular death, myocardial infarction, or stroke [157]. During a median follow-up of 26.5 months, 274 primary end points occurred: 125 (10.3%) in apabetalone-treated patients and 149 (12.4%) in placebo-treated patients (hazard ratio, 0.82 [95% CI, 0.65-1.04]; p = 0.11).…”

“…However, no impact on inflammation, as assessed by C reactive protein levels, was observed. More patients were allocated to apabetalone than the placebo discontinued study drug (114 [ [157]. The incidence of alanine aminotransferase elevation exceeding five times the upper limit of normal was 4.7-fold higher in the apabetalone than in the placebo groups, but this was fully reversible and Hy´s law thresholds for liver toxicity were not met in any patient.…”