Mathias Haarhaus1, Kausik K Ray2, Stephen J Nicholls3, Gregory G Schwartz4, Ewelina Kulikowski5, Jan O Johansson6, Michael Sweeney6, Christopher Halliday5, Kenneth Lebioda5, Norman Wong5, Vincent Brandenburg7, Srinivasan Beddhu8, Marcello Tonelli9, Carmine Zoccali10, Kamyar Kalantar-Zadeh11. 1. Division of Renal Medicine and Baxter Novum, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Electronic address: mathias.loberg-haarhaus@sll.se. 2. Imperial Centre for Cardiovascular Disease Prevention, School of Public Health, Imperial College London, London, UK. 3. South Australian Health and Medical Research Institute, University of Adelaide, PO Box 11060, Adelaide, SA, 5001, Australia. 4. University of Colorado School of Medicine, Aurora, CO, USA. 5. Resverlogix Corp, Calgary, AB, Canada. 6. Resverlogix Inc, San Francisco, CA, USA. 7. Department of Cardiology and Nephrology, Rhein-Maas Klinikum Wuerselen, Wuerselen, Germany. 8. Division of Nephrology and Hypertension and Medical Service, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT, USA. 9. Department of Medicine, University of Calgary, Calgary, AB, Canada. 10. CNR-IFC Clin Epid Renal Diseases and Hypertension, Reggio C. c/o Ospedali Riuniti, 89124, Reggio C. Italy. 11. Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine Medical Center, Orange, CA, USA; Nephrology Section, Tibor Rubin Veterans Affairs Medical Center, Long Beach, CA, USA; Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA. Electronic address: kkz@uci.edu.
Abstract
BACKGROUND AND AIMS: In patients with cardiovascular disease, considerable residual risk remains despite evidence-based secondary prevention measures. Alkaline phosphatase (ALP) has been suggested as a modifiable cardiovascular risk factor. We sought to determine whether cardiovascular risk reduction by the bromodomain and extra-terminal (BET) protein inhibitor apabetalone is associated with the concomitant lowering of serum ALP. METHODS: In a post-hoc analysis of 795 patients with established coronary heart disease and statin treatment, who participated in phase 2 placebo-controlled trials of apabetalone, we determined the effect of assigned treatment for up to 24 weeks on the incidence of major adverse cardiovascular events (MACE) and serum ALP. RESULTS: Baseline ALP (median 72 U/L) predicted MACE (death, non-fatal myocardial infarction, coronary revascularization, or hospitalization for cardiovascular causes), independent of high-sensitivity C-reactive protein (hsCRP), sex, age, race, study, cardiovascular risk factors, chronic kidney disease (CKD), liver function markers and treatment allocation (hazard ratio [HR] per standard deviation [SD] 1.6, 95% CI 1.19-2.16, p = 0.002). Mean placebo-corrected decreases in ALP from baseline were 9.2% (p < 0.001) after 12-14 weeks and 7.7% (p < 0.001) after 24-26 weeks of apabetalone treatment. In the apabetalone group, a 1-SD reduction in ALP was associated with a HR for MACE of 0.64 (95% CI 0.46-0.90, p = 0.009). CONCLUSIONS: Serum ALP predicts residual cardiovascular risk, independent of hsCRP, established cardiovascular risk factors and CKD, in patients with cardiovascular disease on statin treatment. Apabetalone lowers serum ALP, which was associated with a lower risk of cardiovascular events. Whether the beneficial cardiovascular effects of apabetalone are causally related to ALP reduction remains undetermined. Crown
BACKGROUND AND AIMS: In patients with cardiovascular disease, considerable residual risk remains despite evidence-based secondary prevention measures. Alkaline phosphatase (ALP) has been suggested as a modifiable cardiovascular risk factor. We sought to determine whether cardiovascular risk reduction by the bromodomain and extra-terminal (BET) protein inhibitor apabetalone is associated with the concomitant lowering of serum ALP. METHODS: In a post-hoc analysis of 795 patients with established coronary heart disease and statin treatment, who participated in phase 2 placebo-controlled trials of apabetalone, we determined the effect of assigned treatment for up to 24 weeks on the incidence of major adverse cardiovascular events (MACE) and serum ALP. RESULTS: Baseline ALP (median 72 U/L) predicted MACE (death, non-fatal myocardial infarction, coronary revascularization, or hospitalization for cardiovascular causes), independent of high-sensitivity C-reactive protein (hsCRP), sex, age, race, study, cardiovascular risk factors, chronic kidney disease (CKD), liver function markers and treatment allocation (hazard ratio [HR] per standard deviation [SD] 1.6, 95% CI 1.19-2.16, p = 0.002). Mean placebo-corrected decreases in ALP from baseline were 9.2% (p < 0.001) after 12-14 weeks and 7.7% (p < 0.001) after 24-26 weeks of apabetalone treatment. In the apabetalone group, a 1-SD reduction in ALP was associated with a HR for MACE of 0.64 (95% CI 0.46-0.90, p = 0.009). CONCLUSIONS: Serum ALP predicts residual cardiovascular risk, independent of hsCRP, established cardiovascular risk factors and CKD, in patients with cardiovascular disease on statin treatment. Apabetalone lowers serum ALP, which was associated with a lower risk of cardiovascular events. Whether the beneficial cardiovascular effects of apabetalone are causally related to ALP reduction remains undetermined. Crown
Authors: Kausik K Ray; Stephen J Nicholls; Kevin A Buhr; Henry N Ginsberg; Jan O Johansson; Kamyar Kalantar-Zadeh; Ewelina Kulikowski; Peter P Toth; Norman Wong; Michael Sweeney; Gregory G Schwartz Journal: JAMA Date: 2020-04-28 Impact factor: 56.272
Authors: Kamyar Kalantar-Zadeh; Gregory G Schwartz; Stephen J Nicholls; Kevin A Buhr; Henry N Ginsberg; Jan O Johansson; Ewelina Kulikowski; Kenneth Lebioda; Peter P Toth; Norman Wong; Michael Sweeney; Kausik K Ray Journal: Clin J Am Soc Nephrol Date: 2021-04-27 Impact factor: 8.237
Authors: Massimiliano Ruscica; Alberto Corsini; Nicola Ferri; Maciej Banach; Cesare R Sirtori Journal: Pharmacol Res Date: 2020-05-20 Impact factor: 7.658
Authors: Jeffrey Cummings; Gregory G Schwartz; Stephen J Nicholls; Aziz Khan; Chris Halliday; Peter P Toth; Michael Sweeney; Jan O Johansson; Norman C W Wong; Ewelina Kulikowski; Kamyar Kalantar-Zadeh; Kenneth Lebioda; Henry N Ginsberg; Bengt Winblad; Henrik Zetterberg; Kausik K Ray Journal: J Alzheimers Dis Date: 2021 Impact factor: 4.472
Authors: Brecht Van Berkel; Chantal Van Ongeval; Amaryllis H Van Craenenbroeck; Hans Pottel; Katrien De Vusser; Pieter Evenepoel Journal: Clin Kidney J Date: 2021-10-05
Authors: Annette E Neele; Lisa Willemsen; Hung-Jen Chen; Kim E Dzobo; Menno P J de Winther Journal: Curr Opin Lipidol Date: 2020-12 Impact factor: 4.616