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Effect of Apabetalone on Cardiovascular Events in Diabetes, CKD, and Recent Acute Coronary Syndrome: Results from the
Kamyar Kalantar-Zadeh1, Gregory G Schwartz2, Stephen J Nicholls3
1Division of Nephrology, Hypertension and Kidney Transplantation, University of California Irvine School of Medicine, Orange, California.
Insights
Apabetalone reduced major adverse cardiovascular events and heart failure hospitalizations in patients with chronic kidney disease (CKD) and type 2 diabetes. This suggests apabetalone may be a beneficial treatment for this high-risk population.
Area of Science:
- Cardiovascular Medicine
- Nephrology
- Pharmacology
Background:
- Chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) synergistically increase the risk of major adverse cardiovascular events (MACE) and heart failure.
- Maladaptive epigenetic responses are implicated as a driver of cardiovascular risk in these patients.
- Apabetalone, a selective bromodomain and extraterminal domain (BET) transcription system modulator, is being investigated for its potential to modify this risk.
Purpose of the Study:
- To investigate the efficacy of apabetalone in reducing MACE and heart failure hospitalizations in patients with T2DM and CKD.
- To assess the interaction between CKD and the treatment effect of apabetalone on cardiovascular outcomes.
Main Methods:
- A prespecified analysis of the phase 3 BETonMACE trial was conducted.
- The trial was a randomized, double-blind, placebo-controlled study involving 2425 participants with T2DM and recent acute coronary syndrome.
- A subgroup of 288 participants with CKD (eGFR <60 ml/min/1.73 m²) was analyzed for primary (MACE) and secondary (heart failure hospitalization) endpoints.
Main Results:
- In the CKD subgroup, apabetalone significantly reduced MACE (HR: 0.50; 95% CI: 0.26-0.96) and heart failure hospitalizations (HR: 0.48; 95% CI: 0.26-0.86) compared to placebo.
- The interaction between CKD and treatment effect was statistically significant for MACE (P=0.03).
- No significant benefit was observed in the non-CKD group for either endpoint.
- Serious adverse events were fewer in the apabetalone group (29% vs. 43%; P=0.02).
Conclusions:
- Apabetalone demonstrated a significant reduction in MACE and heart failure hospitalizations in patients with CKD and T2DM.
- The findings suggest that apabetalone may be a valuable therapeutic option for patients with CKD and type 2 diabetes at high cardiovascular risk.
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.
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