1. Executive Summary

This report summarizes a study published in the Journal of the American College of Cardiology (JACC) by Lincoff et al. (DOI: 10.1016/j.jacc.2024.04.048), which aimed to evaluate the cardiovascular (CV) risk reduction associated with bempedoic acid in comparison to the well-established benefits of statin therapy.¹ The core objective was to determine if the relationship between low-density lipoprotein cholesterol (LDL-C) lowering and CV event reduction observed with bempedoic acid mirrors that seen with statins when standardized per unit of LDL-C change.¹

The analysis employed the rigorous methodology of the Cholesterol Treatment Trialists’ Collaboration (CTTC) applied to data from the large-scale CLEAR Outcomes trial.² This trial involved 13,970 patients characterized as statin-intolerant, who received either bempedoic acid or placebo.¹ The primary outcome evaluated was the CTTC-defined composite “major vascular event”.²

Key findings indicate that bempedoic acid treatment resulted in a 15% relative reduction in the risk of major vascular events compared to placebo (Hazard Ratio: 0.85; 95% Confidence Interval [CI]: 0.77-0.94).¹ Critically, when this benefit was normalized per 1 mmol/L reduction in LDL-C, the resulting HR was 0.75 (95% CI: 0.63-0.90). This normalized effect size is comparable to the rate ratio (RR) of approximately 0.78 reported for statins in the landmark CTTC meta-analysis.¹ Similar comparable normalized risk reductions were observed for major coronary events, nonfatal myocardial infarction (MI), and coronary revascularization.¹ However, this similarity in normalized benefit was not observed for stroke or coronary heart disease (CHD) death.²

The study concludes that bempedoic acid provides a reduction in cardiovascular risk that is similar in magnitude to that achieved with statins for a given absolute amount of LDL-C lowering, particularly for major vascular and coronary events.¹ This positions bempedoic acid as a valuable therapeutic option for patients unable to tolerate statins or those requiring further LDL-C reduction beyond statin therapy.² The findings lend support to the central role of LDL-C reduction itself as a primary driver of cardiovascular benefit, irrespective of the specific pharmacological mechanism (ACLY inhibition for bempedoic acid versus HMG-CoA reductase inhibition for statins) for certain key cardiovascular endpoints.⁵

2. Introduction: The Context of Bempedoic Acid and Statin Intolerance

The management of dyslipidemia, particularly elevated LDL-C, is a cornerstone of cardiovascular disease prevention. Statins, inhibitors of HMG-CoA reductase, have long been established as the first-line pharmacological therapy, demonstrating robust efficacy in lowering LDL-C and reducing the risk of cardiovascular events across a wide range of patient populations.² The extensive body of evidence supporting statin therapy underpins the “LDL hypothesis,” which posits a causal relationship between LDL-C levels and atherosclerotic cardiovascular disease, suggesting that lowering LDL-C directly translates to reduced cardiovascular risk.⁵

Despite the proven benefits of statins, a significant clinical challenge persists: statin intolerance. A notable proportion of patients experience adverse effects, most commonly muscle-related symptoms, which limit their ability to take or adhere to guideline-recommended statin doses.² Furthermore, some patients fail to achieve their target LDL-C levels even with maximally tolerated statin therapy, necessitating additional or alternative lipid-lowering strategies.⁴ This unmet need highlights the importance of developing and evaluating effective non-statin therapies.

Bempedoic acid has emerged as a novel, orally administered, non-statin agent for lipid management. It functions by inhibiting ATP-citrate lyase (ACLY), an enzyme operating upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway.⁶ This mechanism allows it to lower LDL-C without causing the muscle-related side effects sometimes associated with statins.⁵ The pivotal CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) Outcomes trial provided initial evidence of its clinical benefit. In this trial involving nearly 14,000 statin-intolerant patients, bempedoic acid demonstrated a significant reduction in LDL-C levels (approximately 21% relative to placebo) and a corresponding 13% relative reduction in the risk of major adverse cardiovascular events (MACE).¹ These findings contributed to the expansion of its FDA-approved indications to include primary prevention of cardiovascular risk.⁴

While the CLEAR Outcomes trial established the efficacy of bempedoic acid in a statin-intolerant population, a critical question remained: how does the cardiovascular benefit achieved with bempedoic acid compare to the established standard of statin therapy, particularly when considering the magnitude of LDL-C reduction? Directly comparing the results of the CLEAR Outcomes trial with historical statin trials is challenging due to differences in patient populations and study designs. Therefore, the JACC study by Lincoff et al. was undertaken to address this specific question.¹ The researchers sought to determine whether the relationship between the extent of LDL-C lowering achieved with bempedoic acid and the resultant cardiovascular benefit aligns with the well-characterized relationship observed over decades of statin research, as synthesized by the CTTC.² Applying this standardized analytical framework allows for a more direct comparison and helps to position bempedoic acid appropriately within the therapeutic landscape relative to the gold standard. This comparative assessment is crucial for clinicians seeking to understand the predictability and relative potency of bempedoic acid’s cardiovascular protective effects based on its LDL-lowering capacity.

3. The JACC Study: Comparative Cardiovascular Benefits of Bempedoic Acid and Statin Drugs

3.1. Bibliographic Details and Abstract

• Title: Comparative Cardiovascular Benefits of Bempedoic Acid and Statin Drugs.³
• Authors: A Michael Lincoff, Kausik K Ray, William J Sasiela, Tariq Haddad, Stephen J Nicholls, Na Li, Leslie Cho, Denise Mason, Peter Libby, Shaun G Goodman, and Steven E Nissen.¹
• Journal & Publication Date: Journal of the American College of Cardiology (JACC), Volume 84, Issue 2, Pages 152-162, published July 9, 2024.¹
• DOI: 10.1016/j.jacc.2024.04.048.¹
• Abstract Summary: The study abstract highlights the background context from the CLEAR Outcomes trial, where bempedoic acid reduced LDL-C by 21% and MACE by 13% in statin-intolerant patients.³ The primary objective was to compare the LDL-C lowering-to-cardiovascular benefit relationship of bempedoic acid with that established for statins.³ To achieve this, the investigators applied the CTTC methodology to the CLEAR Outcomes trial data (N=13,970).³ Results showed an overall HR of 0.85 for major vascular events with bempedoic acid versus placebo. When normalized per 1 mmol/L LDL-C reduction, the HR was 0.75, which the abstract describes as comparable to the RR of 0.78 reported for statins in the CTTC meta-analysis.³ The abstract concludes that the cardiovascular risk reduction per unit of LDL-C lowering is similar for bempedoic acid and statins.³

3.2. Study Objectives and Research Design

The primary objective of this JACC study was explicitly stated: to determine whether the observed relationship between LDL-C lowering and cardiovascular benefit achieved with bempedoic acid resembles the well-established relationship observed with statin therapies, specifically when standardized per unit change in LDL-C.¹

The study design employed was a post-hoc analysis [Inferred Limitation 1]. It leveraged the extensive dataset from the previously completed CLEAR Outcomes trial and applied the specific analytical methodology developed and utilized by the Cholesterol Treatment Trialists’ Collaboration (CTTC).¹ The CLEAR Outcomes trial itself was a robustly designed international, multicenter, randomized, double-blind, placebo-controlled, event-driven phase 3 study.² The application of the CTTC framework is significant; this methodology is the internationally recognized standard for pooling and analyzing data from large-scale lipid-lowering trials, particularly the numerous statin trials conducted over the past decades. Its use allows for a standardized comparison of treatment effects based on the magnitude of LDL-C reduction, thereby facilitating the benchmarking of newer therapies like bempedoic acid against the extensive historical data on statins.²

The participants analyzed were the 13,970 individuals enrolled in the CLEAR Outcomes trial.² This population was specifically defined as being “statin-intolerant,” although the precise criteria defining intolerance were not detailed in the provided summaries.² Participants either had established atherosclerotic cardiovascular disease (constituting the secondary prevention cohort, n=9764) or were at high risk for developing cardiovascular disease (the primary prevention cohort, n=4206).² A key inclusion criterion for the CLEAR Outcomes trial was a baseline LDL-C level of 100 mg/dL (2.6 mmol/L) or higher.² The median duration of follow-up in the trial was 40.6 months.² It was noted that 22.7% of participants were taking some dose of statin at the time of randomization, suggesting the “intolerance” likely referred to an inability to tolerate guideline-recommended or effective doses rather than complete cessation in all cases.²

The intervention in the parent CLEAR Outcomes trial, and thus the basis for this analysis, was randomization to either bempedoic acid 180 mg administered orally once daily or a matching placebo.¹

The endpoints analyzed in this JACC study were specifically chosen to align with the standard definitions used by the CTTC, enabling direct comparison with historical statin meta-analyses.¹ The key endpoints were:

• Major Vascular Event: A composite outcome including death from coronary heart disease (CHD), nonfatal myocardial infarction (MI), fatal or nonfatal stroke, or coronary revascularization.
• Major Coronary Event: A composite outcome including CHD death or nonfatal MI.

A crucial aspect of the methodology was the normalization process.¹ The investigators first calculated the Hazard Ratios (HRs) comparing the incidence of the CTTC-defined endpoints between the bempedoic acid and placebo groups in the CLEAR Outcomes trial. Subsequently, these HRs were mathematically adjusted, or normalized, to reflect the expected risk reduction corresponding to a standardized 1 mmol/L (approximately 38.7 mg/dL) difference in LDL-C levels achieved between the treatment and placebo groups. This normalization step is fundamental because it allows for a comparison of the efficiency of risk reduction per unit of LDL-C lowering, independent of the actual average LDL-C difference observed in the specific trial. The resulting normalized HRs for bempedoic acid could then be directly compared to the similarly normalized rate ratios (RRs) reported by the CTTC for statins, which are also expressed per 1 mmol/L LDL-C reduction.²

4. Key Findings: Quantifying the Benefit of Bempedoic Acid

4.1. Impact on Major Cardiovascular Events (Overall)

The analysis first examined the overall impact of bempedoic acid on the primary CTTC-defined endpoint of major vascular events within the CLEAR Outcomes trial population. Over the median follow-up period of 40.6 months, a first major vascular event occurred in 703 out of 6992 patients (10.1%) assigned to the bempedoic acid group.¹ In comparison, 816 out of 6978 patients (11.7%) assigned to the placebo group experienced such an event.¹

This difference in event rates translated into a statistically significant Hazard Ratio (HR) of 0.85, with a 95% Confidence Interval (CI) ranging from 0.77 to 0.94.¹ This HR indicates that treatment with bempedoic acid was associated with a 15% relative reduction in the risk of experiencing a major vascular event compared to placebo among these statin-intolerant patients.

4.2. Table: Bempedoic Acid vs. Placebo – Reduction in Cardiovascular Events

The following table summarizes the key efficacy findings from the analysis, presenting incidence rates, hazard ratios, and the calculated relative risk reduction for major endpoints where data were available in the reviewed sources.

Endpoint	Bempedoic Acid Incidence	Placebo Incidence	Hazard Ratio (HR) [95% CI]	Relative Risk Reduction (RRR) [%]	Data Source(s)
Major Vascular Event^	10.1% (703/6992)	11.7% (816/6978)	0.85 [0.77-0.94]	15%	1
Major Coronary Event^^	4.8%*	5.9%*	0.81 [0.70-0.93]	19%	2
Nonfatal MI	Not specified	Not specified	HR suggests reduction**	Not calculable	1
Coronary Revascularization	Not specified	Not specified	HR suggests reduction**	Not calculable	1
Fatal/Nonfatal Stroke	Not specified	Not specified	No similar reduction***	Not applicable	2
CHD Death	Not specified	Not specified	No similar reduction***	Not applicable	2

Table Footnotes:

• ^ Composite of CHD death, nonfatal MI, fatal/nonfatal stroke, or coronary revascularization (CTTC definition). Incidence rates reflect the overall trial duration. HR and RRR calculated from overall trial data.¹ RRR = (1-HR)*100%.
• ^^ Composite of CHD death or nonfatal MI (CTTC definition). Incidence rates reported at 12 months.² HR reported for the overall trial duration.² RRR = (1-HR)*100%. Note: Use of 12-month incidence rates may differ slightly from overall trial rates but reflects available data.
• ** HR suggests reduction based on text stating similar normalized risk reductions were seen for bempedoic acid and statins for these endpoints.¹ Specific overall (non-normalized) HRs or incidences for these individual components were not provided in the summaries.
• *** Text indicates that similar normalized risk reductions compared to statins were not seen for these endpoints.²

This table provides a clear, quantitative overview of bempedoic acid’s impact on key cardiovascular outcomes compared to placebo in the CLEAR Outcomes trial population, directly addressing the request for percentage reduction data.

4.3. Comparative Efficacy: Benefit per Unit of LDL-C Lowering

The central analysis of the JACC study involved normalizing the observed risk reduction to a standard 1 mmol/L decrease in LDL-C. For the primary endpoint of a first major vascular event, the normalized HR for bempedoic acid was calculated to be 0.75 (95% CI: 0.63-0.90).¹

This normalized effect size was then directly compared to the established benchmark for statin therapy derived from the comprehensive CTTC 2010 meta-analysis. That analysis reported a rate ratio (RR) of 0.78 (95% CI: 0.76-0.80) for major vascular events per 1 mmol/L reduction in LDL-C achieved with statins.¹ The close similarity between the normalized HR for bempedoic acid (0.75) and the historical RR for statins (0.78) is the cornerstone finding of this JACC paper. It suggests that, for this broad composite endpoint, the efficiency of cardiovascular risk reduction per unit of LDL-C lowering is comparable between bempedoic acid and statins.¹ This implies that the magnitude of LDL-C reduction itself is a strong predictor of the proportional reduction in major vascular events, regardless of whether that reduction is achieved via ACLY inhibition (bempedoic acid) or HMG-CoA reductase inhibition (statins).

4.4. Findings Across Different Endpoints and Patient Groups

The analysis extended this normalized comparison to other specific endpoints and patient subgroups:

• Major Coronary Events: For the composite endpoint of CHD death or nonfatal MI, the normalized HR per 1 mmol/L LDL-C reduction with bempedoic acid was 0.69 (95% CI: 0.54-0.89).² This was compared to the CTTC 2010 meta-analysis RR for statins, which was 0.76 (95% CI: 0.73-0.78).² Although the point estimates differ numerically (0.69 vs 0.76), the authors characterized these normalized risk reductions as being similar between bempedoic acid and statins for this endpoint as well.¹
• Nonfatal MI & Coronary Revascularization: The reports explicitly state that similar normalized risk reductions (per 1 mmol/L LDL-C lowering) were observed for bempedoic acid compared to the historical statin data for these individual components of the major vascular event endpoint.¹ However, the specific normalized HR values for bempedoic acid for these endpoints were not provided in the available summaries.
• Stroke & CHD Death: In contrast to the findings for MI and revascularization, the analysis revealed that similar normalized risk reductions were not seen when comparing bempedoic acid to the statin data for the endpoints of fatal or nonfatal stroke, or for CHD death specifically.² This divergence is noteworthy. It suggests that while the principle of “lower LDL-C is better” holds true for bempedoic acid regarding overall major vascular events, MI, and revascularization, the equivalence in benefit per unit of LDL-C lowering compared to statins may not extend to cerebrovascular events or coronary mortality. Potential explanations could involve differences in the underlying pathophysiology targeted by each drug class, pleiotropic effects of statins not shared by bempedoic acid that might influence stroke or mortality pathways, or limitations in statistical power within the CLEAR Outcomes trial to detect effects on these specific endpoints [Inferred Limitation 3].
• Primary vs. Secondary Prevention Cohorts: The analysis also examined the normalized benefit for major vascular events separately within the primary and secondary prevention cohorts defined in the CLEAR Outcomes trial, comparing them to relevant subgroup data from CTTC meta-analyses ²:

• In the Primary Prevention cohort (n=4206, patients at high risk but without established CVD), the normalized HR per 1 mmol/L LDL-C reduction with bempedoic acid was 0.55 (95% CI: 0.35-0.86). This was compared to a statin RR of 0.75 (95% CI: 0.70-0.80) reported for statin-treated patients with no prior vascular disease in an updated CTTC analysis (2012).² The point estimate for bempedoic acid (0.55) appears numerically lower (suggesting a stronger relative effect per unit LDL-C lowering) than both the secondary prevention cohort result and the comparable statin RR, although the wide confidence interval reflects considerable uncertainty, possibly due to fewer events in this lower-risk group.
• In the Secondary Prevention cohort (n=9764, patients with established CVD), the normalized HR per 1 mmol/L LDL-C reduction with bempedoic acid was 0.79 (95% CI: 0.66-0.96). This was highly comparable to the statin RR of 0.80 (95% CI: 0.77-0.82) reported for statin-treated patients with pre-existing vascular disease in the 2012 CTTC meta-analysis.²
• Sensitivity Analysis: A sensitivity analysis focusing on the per-protocol population (patients who adhered more closely to the study treatment) within the CLEAR Outcomes trial reportedly showed even greater risk reductions for cardiovascular endpoints compared to the primary intention-to-treat analysis.² This suggests that adherence to bempedoic acid therapy is important for maximizing its cardiovascular benefits.

5. Authors’ Conclusions and Clinical Significance

Based on their application of the CTTC methodology to the CLEAR Outcomes trial data, the primary conclusion drawn by Lincoff and colleagues is that the magnitude of cardiovascular risk reduction achieved with bempedoic acid is similar to that achieved with statin therapy for a given absolute level of LDL-C lowering.¹ This conclusion holds particularly true for the composite endpoints of major vascular events and major coronary events, as well as for nonfatal MI and coronary revascularization.¹

This conclusion carries significant clinical implications:

1. Validation for Statin-Intolerant Patients: The findings strongly reinforce bempedoic acid as a viable and evidence-based therapeutic option for the substantial population of patients who are unable to tolerate effective doses of statins due to side effects, or for those who require additional LDL-C lowering despite maximally tolerated statin therapy.² It provides quantitative evidence that the benefits extend beyond just LDL-C reduction to meaningful cardiovascular event reduction.
2. Reinforcing the LDL Hypothesis: The comparability of normalized risk reduction between bempedoic acid (acting on ACLY) and statins (acting on HMG-CoA reductase) for key coronary endpoints lends further support to the central role of LDL-C itself as a causal factor in atherosclerotic cardiovascular disease.¹ It suggests that, for these outcomes, the degree of LDL-C lowering achieved is a primary determinant of the proportional risk reduction, largely independent of the specific mechanism used to achieve that lowering.
3. Achieving Treatment Goals: Bempedoic acid can be viewed as a predictable tool to help patients achieve guideline-recommended LDL-C targets, particularly when statins alone are insufficient or cannot be used at optimal doses.² The study provides clinicians with greater confidence that the observed LDL-C reduction with bempedoic acid will translate into a cardiovascular benefit comparable in efficiency to that expected from a similar degree of LDL-C lowering with a statin.
4. Place in Therapy: While statins undoubtedly remain the first-line therapy for most patients requiring lipid lowering for cardiovascular disease prevention ², this study elevates bempedoic acid beyond simply being an alternative. It establishes a predictable relationship between its LDL-lowering effect and its impact on major vascular and coronary event risk, comparable to the relationship established for statins. This allows clinicians to integrate bempedoic acid into treatment strategies with a clearer understanding of its expected contribution to risk reduction based on achieved LDL-C levels, particularly for the significant group of statin-intolerant individuals or those needing combination therapy.

In essence, the study provides a quantitative justification, using a widely accepted comparative methodology, for incorporating bempedoic acid into the lipid management armamentarium as a tool with predictable cardiovascular benefits tied to its LDL-C lowering efficacy.

6. Study Considerations

When interpreting the findings of the Lincoff et al. JACC article, several considerations are pertinent.

• Limitations: The provided summaries did not explicitly detail the limitations acknowledged by the original study authors.² However, based on the study design and findings described, several potential limitations can be inferred:

• Post-Hoc Analysis: The study represents a post-hoc analysis of the CLEAR Outcomes trial data [Inferred Limitation 1]. While applying a standardized methodology like the CTTC framework enhances comparability, post-hoc analyses are generally considered hypothesis-generating rather than definitive proof, as the analysis plan was not pre-specified before the original trial data were known.
• Historical Comparison: The comparison relies on contrasting the normalized results from the contemporary CLEAR Outcomes trial (conducted in a specific statin-intolerant population) with historical data from the CTTC meta-analyses of statin trials [Inferred Limitation 2]. These historical trials included different patient populations (largely statin-tolerant), varying background therapies, and potentially different baseline event rates and standards of care over time. Such indirect comparisons, even when normalized, carry inherent limitations compared to a head-to-head randomized trial.
• Endpoint Divergence: The observation that the normalized risk reduction similarity between bempedoic acid and statins did not extend to stroke or CHD death warrants caution [Inferred Limitation 3]. This suggests that extrapolating the equivalence found for major vascular/coronary events to all cardiovascular outcomes may be an oversimplification. Further research might be needed to understand the reasons for this divergence.
• Statin Intolerance Definition: The precise definition and verification of “statin intolerance” in the CLEAR Outcomes trial participants were not detailed in the summaries, which could influence the generalizability of the findings.

• Search for Related Editorials/Commentaries: A review of the provided research material, including searches intended to find related perspectives (e.g.⁷), did not identify any accompanying editorials, commentaries, or related articles published in JACC or elsewhere that specifically discussed this Lincoff et al. study (DOI: 10.1016/j.jacc.2024.04.048). The identified snippets discussed other topics or general reviews.
• Overall Significance: Despite potential limitations, this study makes a valuable contribution to the field of lipid management. By applying the rigorous CTTC methodology, it provides the most direct comparison available to date of the cardiovascular risk reduction efficiency of bempedoic acid relative to statins, normalized for the degree of LDL-C lowering. The finding of comparability for major vascular and coronary events strengthens the evidence base supporting the use of bempedoic acid, particularly in statin-intolerant patients or those requiring additional lipid lowering. It reinforces the central importance of achieving target LDL-C levels for cardiovascular risk reduction and provides clinicians with greater confidence in the predictable benefits of bempedoic acid based on its LDL-lowering capacity.

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