THU584 Comparison Of The Cardiovascular Benefits Of Bempedoic Acid With Statins- Analysis By The Cholesterol Treatment Trialists’ Methodology

Abstract

Abstract Disclosure: A. Lincoff: Advisory Board Member; Self; Novo Nordisk, Eli Lilly & Company. Consulting Fee; Self; GlaxoSmithKline, Medtronic, Ardelyx, Akebia, Endologix, Provention Bio. Grant Recipient; Self; Abbvie, Novartis Pharmaceuticals, Esperion, AstraZeneca, CSL Behring. Stock Owner; Self; Cadrenal. K. Ray: Consulting Fee; Self; Amgen Inc, Sanofi, Regeneron, Pfizer, Inc., Viatris, Abbott Laboratories, AstraZeneca, Eli Lilly & Company, Kowa, Novo Nordisk, Boehringer Ingelheim, Esperion, Cargene, Resverlogix, Novartis Pharmaceuticals, Silence Therapeutics, New Amsterdam, SCRIBE, CRISPR, VAXXINITY, CSL Behring, Bayer, Inc., Biologixpharma, Amarin. Grant Recipient; Self; Amgen Inc, Sanofi, Regeron, Merck, Pfizer, Inc. W. Sasiela: Consulting Fee; Self; Esperion. Employee; Self; Esperion. Stock Owner; Self; Esperion. T. Haddad: None. S. Nicholls: Consulting Fee; Self; Amgen Inc, Akcea Therapeutics, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly & Company, Esperion, Kowa, Merck, Takeda, Pfizer, Inc., Sanofi-Regeneron, Novo Nordisk. Grant Recipient; Self; AstraZeneca, Amgen Inc, Anthera, CSL Behring, Cerenis, Eli Lilly & Company, Esperion, Resverlogix, Novartis Pharmaceuticals, InfraReDx, Sanofi-Regeneron. N. Li: Employee; Self; Esperion. L. Cho: Consulting Fee; Self; Merck, AstraZeneca. Grant Recipient; Self; AstraZeneca, Novartis Pharmaceuticals. D. Mason: None. P. Libby: Advisory Board Member; Self; Amgen Inc, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Eulicid Bioimaging, Kancera, Kowa Pharamceuticals, Olatec Therapeutics, Medimmune, Novartis Pharmaceuticals, PlaqueTec, TenSixteen Bio, Soley Therapeutics, XBiotech, Inc. Grant Recipient; Self; Novartis Pharmaceuticals, Novo Nordisk, Genentech, Inc. S. Nissen: Grant Recipient; Self; Abbvie, AstraZeneca, Amgen Inc, Bristol-Myers Squibb, Eli Lilly & Company, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis Pharmaceuticals, Pfizer, Inc., Silence Therapeutics. Background: Statins are the foundation of treatment for atherosclerotic cardiovascular (CV) disease. The Cholesterol Treatment Trialists’ (CTT) Collaboration calculated in their meta-analyses of statin trials that every 1 mmol/L (39 mg/dL) reduction in LDL-C was associated with a 22% reduction in major vascular events (MVE), a benefit which increased with cumulative duration of therapy. In the CLEAR Outcomes trial, treatment of statin-intolerant pts with the ATP citrate lyase inhibitor bempedoic acid (BA) was associated with a 21% decrease in LDL-C compared with placebo and a 13% relative reduction in the risk of major adverse CV events (MACE) [hazard ratio (HR) 0.87, 95% CI 0.79-0.96. p=0.004]. It is unknown whether the relationship between LDL-C reduction and magnitude of CV benefits achieved with non-statin therapies such as BA differs from statins. Methods: The CLEAR Outcomes trial enrolled 13,970 pts with or at high risk for CV disease, 46% of whom had diabetes and 42% pre-diabetes, and with a baseline mean LDL-C of 3.60 mmol/L. We applied the CTT methodology and endpoint definitions to CLEAR Outcomes to derive normalized HRs associated with BA treatment for the composite MVE endpoint (fatal coronary heart disease, non-fatal MI, stroke, or revascularization) and individual CV outcomes per 1 mmol/L LDL-C reduction at 1 year. We assessed treatment effect of BA on CV events relative to LDL-C reduction in the Intention to Treat (ITT) population (all randomized pts) and in an on-treatment Per Protocol Set (PPS) population (censoring events occurring >30 days after early study drug discontinuation, which occurred in 29% and 32% of pts allocated to BA and placebo, respectively). Cumulative HRs were calculated per year of treatment duration. Results: In the ITT analysis, placebo-corrected absolute LDL-C reduction by BA at month 12 was 0.58 mmol/L with a HR (95% CI) for MVE of 0.85 (0.77, 0.94). In the PPS analysis, LDL-C reduction was 0.71 mmol/L with a HR for MVE of 0.80 (0.71, 0.89). When normalized to 1.0 mmol/L LDL-C reduction, HRs for ITT and PPS were 0.75 (0.63, 0.90) and 0.73 (0.62, 0.85), respectively and were comparable to normalized risk reduction with statins observed in the CTT meta-analyses [risk ratio (RR) 0.78, 95% CI 0.76, 0.80]. The cumulative normalized HR for MVE improved from 0.77 at year 1 to 0.72 by year 4 of BA treatment. Normalized HRs for individual endpoints of major coronary events, non-fatal MI, revascularization, and stroke for BA vs placebo in CLEAR Outcomes were comparable to the RRs for those endpoints with statins in the CTT meta-analyses. Conclusions: CV benefits achieved with BA are comparable to those obtained with statins, being proportional to the magnitude of absolute reductions in LDL-C, and increase over time. Use of and adherence to BA can provide substantial reductions in CV risk, in particular for those pts at high CV risk due to statin intolerance and high baseline LDL-C. Presentation: Thursday, June 15, 2023