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FR-PO1048 Poster Friday Hypertension and CVD: Clinical Outcomes, Trials
Apabetalone Lowers Serum Alkaline Phosphatase in CVD Patients with and Without CKD and Improves Cardiovascular Risk
Mathias Haarhaus, 1,2 Jan O. Johansson,3 Michael Sweeney,3 Ewelina Kulikowski,4 Norman C. Wong,4 Christopher Halliday,4 Aziz Khan,4 Kenneth E. Lebioda,4 Vincent Brandenburg,5 Srinivasan Beddhu,6 Marcello Tonelli,7 Carmine Zoccali,8 Kamyar Kalantar-Zadeh.9,10 1 Division of Renal Medicine and Baxter Novum, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; 2 Diaverum Sweden, Stockholm, Sweden; 3 Resverlogix Inc., San Francisco, CA; 4 Resverlogix Corp., Calgary, AB, Canada; 5 Department of Cardiology and Nephrology, Rhein-Maas-Klinikum, Würselen, Germany; 6 Division of Nephrology and Hypertension and Medical Service, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT; 7 Department of Medicine, University of Calgary, Calgary, AB, Canada; 8 CNR IFC, Clinical Epidemiology of Renal Diseases and Hypertension, Reggio Calabria, Italy; 9 Division of Nephrology and Hypertension, Harold Simmons Center for Kidney Disease Research and Epidemiology, University of California Irvine, School of Medicine, Orange, CA; 10Nephrology Section, Tibor Rubin Veterans Affairs Medical Center, Long Beach, CA.
Background: Patients with cardiovascular disease (CVD) with or without chronic kidney disease (CKD) have considerable residual risk despite optimal standard of care. Alkaline phosphatase (ALP) has been suggested as a modifiable CVD risk factor. Apabetalone, a bromodomain and extraterminal (BET) inhibitor selective for bromodomain 2 (BD2) lowers ALP in a dose-response fashion. In phase 2 studies apabetalone treatment was associate with a significant 44% reduction in CVD events. We sought to determine whether this CVD risk reduction by apabetalone is associated with the concomitant lowering of serum ALP.
Methods: In a pooled phase 2 post-hoc analysis of 795 CVD patients on standard of care treatment including statins, of which 11.8% had CKD as defined by eGFR <60 m/ min/1.73m2 (n=94; 71=apabetalone; 23=placebo) we assessed the effect of apabetalone vs. placebo treatment for up to 24 weeks on the incidence of CVD events and serum ALP.
Results: Apabetalone treatment decreased serum ALP in CKD and non-CKD CVD patients by 10.2% and 6.5%, respectively (12 weeks), and 7.7% and 7.2%, respectively (24 weeks) (all p<0.01). Further analysis on the whole population showed that baseline ALP (median 72 U/L) predicted MACE (death, non-fatal myocardial infarction, coronary revascularization, or hospitalization for cardiovascular causes), independent of highsensitivity C-reactive protein (hsCRP), sex, age, study, established CVD risk factors, CKD, and treatment allocation (hazard ratio [HR] per standard deviation [SD] 1.6, 95% CI 1.2-2.1, p<0.001). In the apabetalone group, a 1 SD reduction in ALP was associated with a HR for MACE of 0.58 (95% CI 0.43-0.78, p<0.001).
Conclusions: Serum ALP predicts strongly the residual cardiovascular risk, independent of hsCRP, established cardiovascular risk factors and CKD, in patients with cardiovascular disease on statin treatment. Apabetalone lowers serum ALP and may prevent the incidence of new cardiovascular events. The phase 3 BETonMACE CVD outcomes study reporting H2 2019, will provide further insights about apabetalone’s ALP reduction and potential causality for CVD events.