Effect of bempedoic acid in the absence of background lipid-lowering therapy on LDL cholesterol, hsCRP, and cardiovascular outcomes, among statin-intolerant patients: a post-hoc analysis of the CLEAR outcomes trial

Statins remain the cornerstone therapy for cardiovascular risk reduction, however 7% to 30% of patients do not tolerate statins and need additional lipid-lowering therapies (LLTs).1,2 Bempedoic acid (BA), an oral non-statin inhibitor of ATP citrate lyase, targets cholesterol synthesis upstream of HMG-CoA reductase, and reduced low-density lipoprotein (LDL) cholesterol and major adverse cardiovascular events (MACE) in the CLEAR outcomes trial.3,4 Upon enrolment, 8217 (58.8%) were not receiving any background LLT. This analysis assessed whether there were differences in efficacy and safety of BA in patients with and without any background LLT at baseline. The methods and main results of the CLEAR Outcomes trial were previously reported.4,5 CLEAR Outcomes was an international, double-blind, placebo-controlled trial that randomized statin-intolerant patients with a history of, or at high risk for, atherosclerotic cardiovascular disease to oral BA 180 mg daily or matching placebo.4 Statin intolerance was defined as the inability to tolerate any dose of at least two different statins, or inability to tolerate one statin at any dose and unwilling or advised not to try another. Patients taking very-low doses of statins (e.g. average daily dose below the lowest approved dose) were also considered intolerant. We analysed time to MACE according to baseline presence or absence of background LLT, using Cox-proportional hazards models with treatment as a factor. The primary outcome assessed was a composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, or coronary revascularization (MACE-4). Key secondary outcomes included hierarchically a composite of death from cardiovascular causes, nonfatal myocardial infarction, or non-fatal stroke (MACE-3); and the following endpoints assessed separately: fatal or nonfatal myocardial infarction; coronary revascularization; fatal or nonfatal stroke; death from cardiovascular causes; and death from any cause. Participants without background LLT were defined as participants who were not taking any LLT at the time of randomization. Biomarkers analysed included changes in LDL cholesterol and high-sensitivity c-reactive protein (hsCRP). All MACE endpoints were independently adjudicated by the Cleveland Clinic Coordinating Center for Clinical Research. Among 13970 patients, 8217 (58.8%) were not taking any background LLT at baseline; 4103 (58.7%) randomized to BA, and 4114 (59.0%) randomized to placebo. Baseline characteristics did not differ between participants with or without background LLT except for higher baseline LDL cholesterol in the no background LLT subgroup (mean ± standard deviation, 143.8 ± 35.4 mg/dL compared with 132.2 ± 33.4 mg/dL). Among 5753 participants taking background LLT, 3111 of 5753 (54.1%) were taking a very-low dose statin, 1612 of 5753 (28%) ezetimibe, 764 of 5753 (13.3%) a fibrate, 85 of 5753 (1.5%) a proprotein convertase subtilisin/kexin type 9 inhibitor, 84 of 5753 (1.5%) bile acid sequestrant, and 83 of 5753 (1.4%) a niacin derivative. Among participants on no background LLT, BA significantly reduced MACE-4 compared with placebo [HR 0.86 (95% CI, 0.76–0.97)], as well as fatal and nonfatal myocardial infarction [HR 0.79 (95% CI, 0.64–0.99)] and coronary revascularization [HR 0.80 (95% CI, 0.68–0.95)] (Figure 1A) These findings are similar to the primary (MACE-4) and secondary outcomes in the overall trial population (Figure 1A). The absolute risk reduction for MACE-4 at 36 months was, respectively, 1.6% and 1.4% among participants with and without background LLT (number-needed-to-treat 61 and 70). In subgroup analyses among participants without background LLT, only primary vs. secondary prevention demonstrated a significant interaction for MACE-4 (Pinteraction = 0.006) and MACE-3 (Pinteraction < 0.001), with BA treatment associated with greater relative risk reduction in primary prevention. The mean placebo-corrected change in LDL cholesterol for BA among participants on no background LLT was −20.6% (95% CI, −21.6 to −19.6%) and median placebo-corrected change in hsCRP was −21.0% (95% CI, −23.6 to −18.4%) at 6 months (Figure 1B/C). These findings are comparable to the overall trial results.4 Cardiovascular outcomes and biomarker changes over time for bempedoic acid monotherapy. Panel A displays a forest plot of hazard ratios comparing bempedoic acid’s impact on major adverse cardiovascular events with placebo in the overall trial population and when participants are grouped by the presence or absence of background lipid-lowering therapy. Panel B displays LDL cholesterol change at 6 months grouped by the presence or absence of background lipid-lowering therapy. Panel C displays high-sensitivity c-reactive protein change at 6 months grouped by the presence or absence of background lipid-lowering therapy. CI, confidence interval; MACE-4, composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, or coronary revascularization; MACE-3, composite of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke; LLT, lipid-lowering therapy; LDL, low-density lipoprotein; CRP, C-reactive protein. Serious adverse events (AE) were reported in 24.5% and 23.8% of patients without background LLT receiving BA and placebo, respectively. AEs that led to study drug discontinuation occurred in 11.3% of those receiving BA, and 11.0% of those receiving placebo. The incidence of AE and serious AE among participants without background LLT did not meaningfully differ from those reported in the overall trial population.4 This analysis was designed to determine if the efficacy and safety profile of BA persisted when utilized as a patient’s sole LLT. BA monotherapy reduced MACE, LDL cholesterol, and hsCRP similarly to the overall trial results, suggesting the benefits of BA are not dependent on synergistic interactions with other LLT. This supports the use of BA alone or in combination, aligned with current guideline recommendations.6 Despite lower LDL cholesterol in participants on baseline LLT compared with those without, this did not seem to influence our results given the relative and absolute benefits were similar irrespective of background LLT. Mirroring the overall trial population, the benefits associated with BA in the absence of other LLT were more pronounced in primary prevention.4 Current evidence demonstrating the effect of non-statin LLT on cardiovascular outcomes in the absence of concomitant statin use is limited. One post-hoc analysis of ODYSSEY OUTCOMES suggested that alirocumab is an effective stand-alone medication by analysing a small subgroup of participants not taking any statin (460 participants, which was 2.4% of the total trial population).7 Additionally, the EWTOPIA 75 trial enrolled 3796 participants aged ≥75 with elevated LDL cholesterol without history of coronary artery disease who were not on LLT.8 Compared with usual care, ezetimibe reduced a composite of sudden cardiac death, coronary revascularization, or stroke by 44%.8 This current analysis of BA use without background LLT adds evidence for the underexplored intervention of non-statin lipid-lowering monotherapy, in which robust cardiovascular outcome trial data are limited. The main limitation of this analysis is that these findings derive from a post-hoc analysis of a subgroup from a randomized trial. The study was not powered for this analysis, and the findings should be interpreted as exploratory and hypothesis-generating. In conclusion, BA was effective and safe when taken as monotherapy. These data support the use of BA as a safe and effective therapy to reduce MACE among statin-intolerant patients. This work was presented as an oral abstract presentation at the American Heart Association’s Scientific Sessions 2025 on 9 November 2025. Carolina Pires Zingano (Conceptualization, Writing—original draft [lead], Writing—review & editing [equal]), Danielle M. Brennan (Formal analysis, Visualization [equal], Writing—review & editing [supporting]), Leanne Bloedon (Conceptualization, Data curation, Formal analysis [equal], Writing—review & editing [supporting]), Na Li (Data curation [equal], Writing—review & editing [supporting]), Peter M Herout (Conceptualization, Data curation, Formal analysis [equal], Project administration, Supervision, Writing—review & editing [supporting]), Heather A. Powell (Conceptualization, Data curation, Formal analysis [equal], Writing—review & editing [supporting]), Bernardo F. Spiazzi [Writing—review & editing (supporting)], Kausik K. Ray [Supervision, Writing—review & editing (supporting)], Stephen J. Nicholls [Supervision, Writing—review & editing (supporting)], Steven E. Nissen [Supervision, Writing—review & editing (supporting)], and Luke Joseph Laffin (Conceptualization [equal], Supervision, Writing—review & editing [lead]) The trial was funded by Esperion Therapeutics. The data from this analysis will not be shared.