Effect of Apabetalone on Cardiovascular Events in Diabetes, CKD, and Recent Acute Coronary Syndrome: Results from the BETonMACE Randomized Controlled Trial

Abstract

Background and objectives: CKD and type 2 diabetes mellitus interact to increase the risk of major adverse cardiovascular events (i.e., cardiovascular death, nonfatal myocardial infarction, or stroke) and congestive heart failure. A maladaptive epigenetic response may be a cardiovascular risk driver and amenable to modification with apabetalone, a selective modulator of the bromodomain and extraterminal domain transcription system. We examined this question in a prespecified analysis of BETonMACE, a phase 3 trial.

Design, setting, participants, & measurements: BETonMACE was an event-driven, randomized, double-blind, placebo-controlled trial comparing effects of apabetalone versus placebo on major adverse cardiovascular events and heart failure hospitalizations in 2425 participants with type 2 diabetes and a recent acute coronary syndrome, including 288 participants with CKD with eGFR <60 ml/min per 1.73 m² at baseline. The primary end point in BETonMACE was the time to the first major adverse cardiovascular event, with a secondary end point of time to hospitalization for heart failure.

Results: Median follow-up was 27 months (interquartile range, 20-32 months). In participants with CKD, apabetalone compared with placebo was associated with fewer major adverse cardiovascular events (13 events in 124 patients [11%] versus 35 events in 164 patients [21%]; hazard ratio, 0.50; 95% confidence interval, 0.26 to 0.96) and fewer heart failure-related hospitalizations (three hospitalizations in 124 patients [3%] versus 14 hospitalizations in 164 patients [9%]; hazard ratio, 0.48; 95% confidence interval, 0.26 to 0.86). In the non-CKD group, the corresponding hazard ratio values were 0.96 (95% confidence interval, 0.74 to 1.24) for major adverse cardiovascular events, and 0.76 (95% confidence interval, 0.46 to 1.27) for heart failure-related hospitalization. Interaction of CKD on treatment effect was P=0.03 for major adverse cardiovascular events, and P=0.12 for heart failure-related hospitalization. Participants with CKD showed similar numbers of adverse events, regardless of randomization to apabetalone or placebo (119 [73%] versus 88 [71%] patients), and there were fewer serious adverse events (29% versus 43%; P=0.02) in the apabetalone group.

Conclusions: Apabetalone may reduce the incidence of major adverse cardiovascular events in patients with CKD and type 2 diabetes who have a high burden of cardiovascular disease.

Keywords: CKD stage 5; alkaline phosphatase; apabetalone; cardiovascular; chronic kidney disease; diabetes; diabetes mellitus; epigenetic pharmacotherapy; major adverse cardiovascular events.

Graphical abstract

Figure 1.

Patient flow in the CKD subgroup of the BETonMACE trial of apabetalone for reduction of adverse cardiovascular events in patients with acute coronary syndrome and type 2 diabetes. ¹Discontinuation due to patient preference. LFTs, liver function tests; MACE, major adverse cardiovascular events.

Figure 2.

Kaplan–Meier estimates by treatment and CKD/non-CKD group for (A) MACE, (B) HCHF, and (C) the composite MACE plus HCHF. In each panel, four curves are shown: CKD subjects receiving placebo (solid blue) and apabetalone (solid red), and non-CKD subjects receiving placebo (dashed blue) and apabetalone (dashed red). Number of subjects at risk is shown for CKD and non-CKD groups, aggregated over treatment. HCHF, hospitalization for congestive heart failure.