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American Journal of Cardiovascular Drugs

, Volume 18, Issue 2, pp 109–115 | Cite as

Selective BET Protein Inhibition with Apabetalone and Cardiovascular Events: A Pooled Analysis of Trials in Patients with Coronary Artery Disease

  • Stephen J. Nicholls
  • Kausik K. Ray
  • Jan O. Johansson
  • Alan Gordon
  • Michael Sweeney
  • Chris Halliday
  • Ewelina Kulikowski
  • Norman Wong
  • Susan W. Kim
  • Gregory G. Schwartz
Original Research Article

Abstract

Background

Inhibition of bromodomain and extra-terminal (BET) proteins can modulate lipoprotein and inflammatory factors that mediate atherosclerosis. The impact of the BET inhibitor, apabetalone, on cardiovascular events is unknown.

Objective

Our objective was to investigate the impact of apabetalone on cardiovascular event rates in a pooled analysis of clinical studies in patients with established coronary artery disease.

Methods

We conducted a pooled analysis of patients (n = 798) with coronary artery disease who participated in clinical trials (ASSERT, ASSURE, SUSTAIN) that evaluated the impact of 3–6 months of treatment with apabetalone on lipid parameters and coronary atherosclerosis. The incidence of major adverse cardiovascular events (death, myocardial infarction, coronary revascularization, hospitalization for cardiovascular causes) in the treatment groups was evaluated.

Results

At baseline, patients treated with apabetalone were more likely to be Caucasian, have a history of dyslipidemia, and be undertreated with ß-blocker and anti-platelet agents. Treatment with apabetalone produced the following dose-dependent changes compared with placebo: increases in apolipoprotein A-I (apoA-I) of up to 6.7% (P < 0.001), increases in high-density lipoprotein cholesterol (HDL-C) of up to 6.5% (P < 0.001), increases in large HDL particles of up to 23.3% (P < 0.001), and decreases in high-sensitivity C-reactive protein (hsCRP) of − 21.1% (P = 0.04). Apabetalone treatment did not affect atherogenic lipoproteins compared with placebo. Patients treated with apabetalone experienced fewer major adverse cardiovascular events than those treated with placebo (5.9 vs. 10.4%; P = 0.02), a finding that was more prominent in patients with diabetes (5.4 vs. 12.7%; P = 0.02), with baseline HDL-C < 39 mg/dl (5.5 vs. 12.8%; P = 0.01), or with elevated hsCRP levels (5.4 vs. 14.2%; P = 0.02).

Conclusion

Pooled analysis of short-term studies demonstrated fewer cardiovascular events among patients treated with the BET protein inhibitor, apabetalone, than among those treated with placebo. BET protein inhibition warrants further investigation as a novel approach to cardiovascular risk reduction.

Notes

Compliance with Ethical Standards

Funding

The studies were funded by Resverlogix.

Conflicts of interest

SJN has received research support from AstraZeneca, Amgen, Anthera, Eli Lilly, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience and is a consultant for AstraZeneca, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. KKR reports grants and/or personal fees from Pfizer, MSD, Astra Zeneca, Sanofi, Aegerion, Regeneron, Abbvie, Kowa, Cerenis, Medicines Company, Lilly, Esperion, Amgen, Cipla, Algorithm, Takeda, Boehringer Ingelheim, and Novo Nordisk within the last 12 months outside of the submitted work. GGS, through his institution, has received research support from Cerenis, The Medicines Company, Resverlogix, Roche, and Sanofi. JOJ, AG, MS, CH, EK, and NW are employees of Resverlogix. SWK has no conflicts of interest.

Supplementary material

40256_2017_250_MOESM1_ESM.docx (26 kb)
Supplementary material 1 (DOCX 27 kb)

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Stephen J. Nicholls
    • 1
  • Kausik K. Ray
    • 2
  • Jan O. Johansson
    • 3
  • Alan Gordon
    • 3
  • Michael Sweeney
    • 3
  • Chris Halliday
    • 3
  • Ewelina Kulikowski
    • 3
  • Norman Wong
    • 3
  • Susan W. Kim
    • 1
  • Gregory G. Schwartz
    • 4
  1. 1.South Australian Health and Medical Research InstituteUniversity of AdelaideAdelaideAustralia
  2. 2.School of Public HealthImperial College LondonLondonUK
  3. 3.Resverlogix CorporationDenverUSA
  4. 4.University of Colorado School of MedicineDenverUSA

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