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Bempedoic acid lowers high-sensitivity C-reactive protein and low-density lipoprotein cholesterol: Analysis of pooled data from four phase 3 clinical trials
Corresponding author. Department of Vascular Medicine, Academic Medical Centre, D3.330 Amsterdam UMC, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
Department of Preventive Cardiology and Lipidology, Medical University of Łódź and Polish Mother's Memorial Hospital Research Institute (PMMHRI), Łódź, Poland
Bempedoic acid significantly and consistently lowers hsCRP independent of statins.
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Weak statistical correlations were observed between changes in LDL-C and hsCRP.
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Bempedoic acid may have anti-inflammatory effects beyond LDL-C lowering.
Abstract
Background and aims
High-sensitivity C-reactive protein (hsCRP), a marker for atherosclerotic cardiovascular disease risk, is reduced by bempedoic acid. We assessed the relationship between changes in low-density lipoprotein cholesterol (LDL-C) and hsCRP in relation to baseline statin use.
Methods
Pooled data from four phase 3 trials (patients on maximally tolerated statins [Pool 1] and patients receiving no or low-dose statins [Pool 2]) were used to determine the proportion of patients with baseline hsCRP ≥2 mg/L who achieved hsCRP <2 mg/L at week 12. The percentage of patients who achieved hsCRP <2 mg/L and guideline-recommended LDL-C (Pool 1, <70 mg/dL; Pool 2, <100 mg/dL) was determined for patients on statins in Pool 1 and those not on statins in Pool 2, as was the correlation between percent changes in hsCRP and LDL-C.
Results
Overall, 38.7% in Pool 1 and 40.7% in Pool 2 with baseline hsCRP ≥2 mg/L achieved hsCRP <2 mg/L with bempedoic acid, with little effect from background statin. Among patients taking a statin in Pool 1 or not taking a statin in Pool 2, 68.6% and 62.4% achieved hsCRP <2 mg/L. Both hsCRP <2 mg/L and United States guideline–recommended LDL-C were achieved more often with bempedoic acid vs. placebo (20.8% vs. 4.3%, respectively, in Pool 1 and 32.0% vs. 5.3%, in Pool 2). Changes in hsCRP and LDL-C were only weakly correlated (Pool 1, r = 0.112; Pool 2, r = 0.173).
Conclusions
Bempedoic acid significantly reduced hsCRP irrespective of background statin therapy; the effect was largely independent of LDL-C lowering.
Atherosclerotic cardiovascular disease (ASCVD) is a multistep process initiated by endothelial dysfunction and accumulation of low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich remnant particles in the subendothelial space [
Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel.
Although not a causal factor in atherosclerosis, high-sensitivity C-reactive protein (hsCRP) may serve as a reliable indicator for ASCVD risk independent of LDL-C [
Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study.
High-sensitivity C-reactive protein discordance with atherogenic lipid measures and incidence of atherosclerotic cardiovascular disease in primary prevention: the ARIC study.
]. Reductions in hsCRP levels are independently associated with a lower risk of MACE, with statin therapy showing the greatest reduction in cardiovascular events in patients who achieved both LDL-C <70 mg/dL and hsCRP <2 mg/L [
Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial.
Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial.
]. The recent CANTOS trial has shown that an anti-inflammatory intervention using an interleukin (IL)-1β antibody reduces the risk of MACE, predominantly in patients with the greatest hsCRP reduction with therapy, independently of baseline levels of LDL-C [
Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial.
Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial.
], these data imply that therapies with a combined anti-inflammatory and LDL-C–lowering effect may increase cardiovascular benefit over either therapeutic strategy alone [
From CANTOS to CIRT to COLCOT to clinic: will all atherosclerosis patients soon be treated with combination lipid-lowering and inflammation-inhibiting agents?.
Bempedoic acid is an oral, first-in-class inhibitor of ATP-citrate lyase that inhibits cholesterol biosynthesis upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the enzyme inhibited by statins [
Prevention of diet-induced metabolic dysregulation, inflammation, and atherosclerosis in Ldlr(-/-) mice by treatment with the ATP-citrate lyase inhibitor bempedoic acid.
Four phase 3, double-blind, randomized clinical trials were carried out to assess the efficacy and safety of bempedoic acid when added to stable background lipid-lowering therapy (LLT) ranging between no LLT to maximally tolerated statin with or without non-statin LLT, including ezetimibe, in patients with hypercholesterolemia [
Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom randomized clinical trial.
Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
]. Pooled analyses of these phase 3 trials found that high hsCRP levels, absence of statin use, female sex, history of diabetes, and ezetimibe use were factors associated with LDL-C lowering with bempedoic acid [
Association of bempedoic acid administration with atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia.
]. Compared with placebo, bempedoic acid lowered LDL-C and hsCRP by an average of 17.8% and 18.1%, respectively, in patients using maximally tolerated statin and by an average of 24.5% and 27.4%, respectively, in patients who had a history of statin intolerance using low-intensity or no statin [
Association of bempedoic acid administration with atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia.
]. As differences in the percent reduction in hsCRP were noted between these two patient populations, we examined the potential influence of background statin use and baseline hsCRP level on hsCRP reduction, as well as the correlation between reductions in hsCRP and LDL-C with bempedoic acid.
2. Patients and methods
2.1 Patients
Data were pooled from patients enrolled in four phase 3, randomized, double-blind, placebo-controlled bempedoic acid studies. Patients in the four phase 3 studies were randomized (2:1) to receive bempedoic acid 180 mg or placebo. The overall designs of these studies were previously published in detail [
Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom randomized clinical trial.
Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom randomized clinical trial.
] studies had a history of ASCVD and/or heterozygous familial hypercholesterolemia (HeFH), were receiving maximally tolerated statins (91.1% were receiving moderate- to high-intensity statins), and were combined to form the ASCVD and/or HeFH Pool (Supplemental Fig. 1). The CLEAR Serenity [
Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
] studies included patients with a history of statin intolerance who were receiving no more than low-dose statin therapy, defined as no more than the lowest approved starting dose of a statin; 81.9% of these patients were not receiving any statin therapy. These patients formed the Low-Dose or No Statin Pool [
Association of bempedoic acid administration with atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia.
]. Analyses evaluating the influence of background statin were performed on those patients from the ASCVD and/or HeFH Pool who were using statins vs. patients from the Low-Dose or No Statin Pool who were not using statins (Supplemental Fig. 1).
2.2 Efficacy and safety endpoints
All four bempedoic acid phase 3 studies assessed the percent change from baseline to week 12 in LDL-C levels as a prospective endpoint. Baseline LDL-C was ≥70 mg/dL in the ASCVD and/or HeFH Pool and was ≥100 mg/dL in the Low-Dose or No Statin Pool, per inclusion criteria. The percent change in hsCRP levels from baseline to week 12 was a secondary endpoint in all four studies. In each of these trials, hsCRP quantification was performed at a central laboratory using the Tina-quant® Cardiac C-Reactive Protein (Latex) High Sensitive immunoturbidimetric assay according to the manufacturer's instructions (Roche Diagnostics, Indianapolis, IN).
This analysis evaluated the median percent change in hsCRP from baseline amongst all patients stratified by baseline hsCRP ≥2 mg/L or <2 mg/L for both Pools, as well as the proportion of patients with baseline hsCRP ≥2 mg/L who achieved hsCRP <2 mg/L overall and by background statin use. For the ASCVD and/or HeFH Pool, the comparative groups were overall, high-intensity statin, and any other statin [
Association of bempedoic acid administration with atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia.
Association of bempedoic acid administration with atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia.
To examine the influence of background statin, the percentage of patients who achieved hsCRP <2 mg/L was determined for only patients on statins in the ASCVD and/or HeFH Pool and only patients not on statins in the Low-Dose or No Statin Pool. Other evaluations in these two Pools were the percentage of patients who achieved LDL-C <70 mg/dL in the ASCVD and/or HeFH Pool and LDL-C <100 mg/dL in the Low-Dose or No Statin Pool, and the proportion of patients in each Pool who met both LDL-C and hsCRP goals.
To investigate the relationship between changes in hsCRP and LDL-C levels, we examined the correlation between these parameters at baseline and week 12. Because statins can influence the percent change in LDL-C with the addition of bempedoic acid, we assessed the correlation between reductions in hsCRP and LDL-C levels only among patients in the ASCVD and/or HeFH Pool who were receiving a statin and among patients in the Low-Dose or No Statin Pool who were not receiving a statin.
The safety of bempedoic acid during the four phase 3 studies has been reported [
Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom randomized clinical trial.
Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
]. We assessed the overall safety of bempedoic acid based on baseline hsCRP (<2 mg/L and ≥2 mg/L) for the two Pools. Safety data, including treatment-emergent adverse events (TEAEs), serious adverse events (AEs), and TEAEs leading to discontinuation of the study or death, are reported as exposure-adjusted incidence per 100 patient years.
2.3 Statistical analyses
The least-squares mean difference in LDL-C between bempedoic acid and placebo was based on an analysis of covariance model with the percent change from baseline as the dependent variable, stratification of study treatment and patient responses on an interactive voice response system as fixed factors, and baseline LDL-C as a covariate. Difference in percent change for hsCRP from baseline between bempedoic acid and placebo was presented as the location shift; an asymptotic 95% confidence interval (CI) was calculated using the Hodges–Lehman estimation with change from baseline as the dependent variable. Correlations between percent change of LDL-C and hsCRP were calculated using the Pearson correlation coefficient (r) between log-transformed hsCRP and LDL-C.
3. Results
3.1 Patients
The baseline demographics for the 3009 patients in the ASCVD and/or HeFH Pool and the 614 patients in the Low-Dose or No Statin Pool have previously been published [
Association of bempedoic acid administration with atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia.
]. More than 90% of patients in the ASCVD and/or HeFH Pool were receiving moderate- or high-intensity statin (2.8% were receiving no statin therapy). In contrast, 81.9% of patients in the Low-Dose or No Statin Pool received no statin therapy. Baseline demographics and characteristics stratified by baseline statin therapy or baseline hsCRP levels are presented in Table 1 and Supplemental Table 1, respectively. In total, 2925 patients in the ASCVD and/or HeFH pool were taking a statin at baseline and 503 in the Low-Dose or No Statin Pool were not taking a statin at baseline (Table 1). There were more men receiving statins in the ASCVD and/or HeFH Pool and more women not receiving statins in the Low-Dose or No Statin Pool (Table 1). With the Pools combined, 1592 patients and 2014 patients had baseline hsCRP levels of ≥2 mg/L and <2 mg/L, respectively (Supplemental Table 1). More patients with baseline hsCRP levels of ≥2 mg/L had a history of diabetes and more were not taking statins at baseline compared with patients with baseline hsCRP levels <2 mg/L. The percentage of women with baseline hsCRP ≥2 mg/L was higher than the percentage of women with baseline hsCRP <2 mg/L, and patients in the baseline hsCRP ≥2 mg/L group had a higher mean body mass index than those in the hsCRP <2 mg/L group. These differences were not adjusted in the analyses since they were fairly balanced between treatment groups within each statin pool and baseline hsCRP group, when statin use and baseline hsCRP, the two most important confounding factors, were adjusted as strata.
Table 1Baseline demographics and characteristics stratified by baseline statin use.
Characteristic
ASCVD and/or HeFH receiving statin therapy
Low-Dose or No Statin not receiving statin therapy
Median percent changes in hsCRP from baseline to week 12 by baseline hsCRP are shown in Fig. 1. Among patients in the ASCVD and/or HeFH Pool with baseline hsCRP ≥2 mg/L (n = 1237), the median percent change in hsCRP was −41.9% with bempedoic acid vs. −15.8% with placebo (median change of −1.53 mg/L vs. −0.68 mg/L, respectively). In the Low-Dose or No Statin Pool with baseline hsCRP ≥2 mg/L (n = 355), the median percent change in hsCRP was −43.3% with bempedoic acid vs. −6.6% with placebo (median change of −1.55 mg/L vs. −0.31 mg/L, respectively). Among patients with baseline hsCRP levels <2 mg/L, changes were smaller, with a median change with bempedoic acid of −3.7% vs. 9.1% for placebo among patients in the ASCVD and/or HeFH Pool (n = 1766; median change of −0.03 mg/L vs. +0.07 mg/L, respectively) and −5.1% vs. 13.0% for placebo among patients in the Low-Dose or No Statin Pool (n = 248; median change of −0.04 mg/L vs. 0.12 mg/L, respectively).
Fig. 1Median percent change in hsCRP from baseline to week 12 by baseline hsCRP levels.
Overall, 38.7% of patients in the ASCVD and/or HeFH Pool and 40.7% of patients in the Low-Dose or No Statin Pool who had hsCRP ≥2 mg/L at baseline achieved hsCRP <2 mg/L after 12 weeks of treatment with bempedoic acid (Fig. 2A), compared with 26.6% of patients in the ASCVD and/or HeFH Pool and 15.6% of patients in the Low-Dose or No Statin Pool who were treated with placebo.
Fig. 2Proportion of patients achieving hsCRP <2 mg/L and LDL-C <70 mg/dL or <100 mg/dL.
Background LLT had little effect on the proportion of patients who achieved a reduction in hsCRP to <2 mg/L. Among 1836 patients treated with bempedoic acid in the ASCVD and/or HeFH Pool who were receiving statin therapy and assessed at week 12, 68.6% achieved hsCRP <2 mg/L as compared with 62.4% of the 319 patients not receiving statins in the Low-Dose or No Statin Pool (Fig. 2B).
3.4 Correlation of changes in hsCRP and LDL-C
Reductions in hsCRP with bempedoic acid at week 12 appeared to be mostly independent of changes in LDL-C (Supplemental Table 2). The percent change in hsCRP was only weakly correlated with the percent change in LDL-C at week 12 among patients in the ASCVD and/or HeFH Pool who were taking statins and bempedoic acid (r = 0.112), with no correlation observed in patients receiving placebo (Fig. 3A). A weak correlation was also identified between the percent change in hsCRP and percent change in LDL-C among patients in the Low-Dose or No Statin Pool who were not taking a statin but were receiving bempedoic acid (r = 0.173) but not in those receiving placebo (Fig. 3B).
Fig. 3Scatterplots of LDL-C and hsCRP data from individual patients.
(A) Statin-treated patients in ASCVD and/or HeFH Pool. (B) Non-statin-treated patients in the Low-dose or No Statin Pool. Pearson correlation coefficient and log transformed data are shown. ASCVD, atherosclerotic cardiovascular disease; HeFH, heterozygous familial hypercholesterolemia; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol.
3.5 Achieving hsCRP <2 mg/L and guideline-recommended LDL-C levels
Among 1836 patients treated with bempedoic acid in the ASCVD and/or HeFH Pool who were receiving statin therapy and assessed at week 12, 20.8% of patients achieved both hsCRP <2 mg/L and LDL-C <70 mg/dL with bempedoic acid compared with 4.3% of 945 patients with placebo (Fig. 4A). Among 319 patients in the Low-Dose or No Statin Pool not taking a statin assessed at week 12, 32.0% of patients achieved both hsCRP <2 mg/L and LDL-C <100 mg/dL with bempedoic acid compared with 5.3% of 152 patients with placebo (Fig. 4B).
Fig. 4Proportion of patients achieving both hsCRP <2 mg/L and guideline-recommended LDL-C levels.
(A) Proportion of statin-treated patients in the ASCVD and/or HeFH Pool who achieved hsCRP <2 mg/L and LDL-C <70 mg/dL at week 12. (B) Proportion of non-statin-treated patients in the Low-dose or No Statin Pool who achieved hsCRP <2 mg/L and LDL-C <100 mg/dL at week 12. ASCVD, atherosclerotic cardiovascular disease; HeFH, heterozygous familial hypercholesterolemia; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol.
A comparable safety profile of bempedoic acid was observed between patients with baseline hsCRP levels <2 mg/L and ≥2 mg/L (Supplemental Table 3). Treatment-related AEs in the bempedoic acid group occurred in 28.4% and 28.6% of patients with baseline hsCRP levels <2 mg/L and ≥2 mg/L, respectively (vs. 23.1% and 23.4% with placebo, respectively).
4. Discussion
Bempedoic acid, alone or combined with other LLT, significantly lowers both LDL-C and hsCRP levels [
Association of bempedoic acid administration with atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia.
Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT.
], greater absolute and relative reductions in hsCRP were observed in patients treated with bempedoic acid who had higher baseline hsCRP levels. In this study, among patients with baseline hsCRP ≥2 mg/L, the percent change in hsCRP with bempedoic acid treatment was similar for both Pools (−41.9% in the ASCVD and/or HeFH Pool and −43.3% in the Low-Dose or No Statin Pool). In contrast, among patients with baseline hsCRP <2 mg/L, the percent change in hsCRP with bempedoic acid treatment was −3.7% in the ASCVD and/or HeFH Pool and −5.1% in the Low-Dose or No Statin Pool. It is well established that statin treatment lowers levels of hsCRP [
Effect of statins on serum level of hs-CRP and CRP in patients with cardiovascular diseases: a systematic review and meta-analysis of randomized controlled trials.
], there may be a common pathway through which these two classes of drugs are able to reduce hsCRP levels.
However, it is worth noting that, compared with no background statin therapy, there is less reduction in LDL-C levels observed when bempedoic acid is added to a background of statin therapy [
Association of bempedoic acid administration with atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia.
]. As shown in current analyses, reductions in hsCRP levels with bempedoic acid are similar irrespective of background statin therapy. Background LLT also had little effect on the proportion of patients who achieved a reduction in hsCRP to <2 mg/L. Among patients treated with bempedoic acid in the ASCVD and/or HeFH Pool who were receiving statin therapy, 68.6% achieved hsCRP <2 mg/L as compared with 62.4% of the patients not receiving statins in the Low-Dose or No Statin Pool. This may indicate a difference in the mechanisms involved in LDL-C and hsCRP lowering with these two drugs. Mechanistic differences have also been observed between bempedoic acid and ezetimibe: both drugs had an additive effect on LDL-C lowering, while hsCRP reductions were mostly driven by bempedoic acid [
Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy.
]. In in vitro and in vivo animal studies, bempedoic acid mediated the activation of hepatic AMP-activated protein kinase (AMPK), a protein involved in inflammatory signaling, resulting in reduced low-grade inflammation [
AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism.
]. While further human studies are warranted, activation of AMPK may contribute to hsCRP lowering observed with bempedoic acid.
The absence of a strong correlation between changes in levels of hsCRP and LDL-C following bempedoic acid treatment is consistent with results from the JUPITER trial, in which there was also little correlation between changes in hsCRP and LDL-C levels in patients receiving rosuvastatin [
Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial.
Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT.
Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators.
]. Notably, in the JUPITER trial, reductions in hsCRP levels following statin treatment were associated with significant decreases in the incidence of a first major cardiovascular event and death, independent of changes in LDL-C levels [
]. Many other trials have substantiated that, among patients treated with statins, lower hsCRP levels are associated with a reduced risk of cardiovascular events [
Creating controversy where none exists: the important role of C-reactive protein in the CARE, AFCAPS/TexCAPS, PROVE IT, REVERSAL, A to Z, JUPITER, HEART PROTECTION, and ASCOT trials.
]. Interestingly, results from a meta-analysis showed that statin treatment may reduce cardiovascular risk to a lesser extent in patients with higher baseline C-reactive protein (CRP) levels [
Association between baseline, achieved, and reduction of CRP and cardiovascular outcomes after LDL cholesterol lowering with statins or ezetimibe: a systematic review and meta-analysis.
]. Results from the Atherosclerosis Risk in Communities trial reported a discordance between levels of atherogenic lipoproteins and hsCRP, with elevated hsCRP levels being associated with increased ASCVD risk, incident heart failure, and all-cause death, even when atherogenic lipid profiles are favorable [
Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study.
High-sensitivity C-reactive protein discordance with atherogenic lipid measures and incidence of atherosclerotic cardiovascular disease in primary prevention: the ARIC study.
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.
], depending on patient characteristics and risk of ASCVD. A hsCRP concentration <2 mg/L has also been proposed as a level below which better cardiovascular outcomes are achieved, while hsCRP ≥2 mg/L is used as a risk-enhancing marker for stratification of estimated ASCVD risk [
Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial.
]. In our analysis, almost 5 times more patients in the ASCVD and/or HeFH Pool who were receiving statins and were treated with bempedoic acid achieved both LDL-C <70 mg/dL and hsCRP <2 mg/L than patients receiving statins and placebo (20.8% vs. 4.3%), irrespective of baseline hsCRP levels. Six times more patients in the Low-Dose or No Statin Pool who were not taking statins but were treated with bempedoic acid achieved both LDL-C <100 mg/dL and hsCRP <2 mg/L than patients receiving placebo (32.0% vs. 5.3%, respectively). In the IMPROVE-IT study, patients treated with a statin alone or in combination with ezetimibe who achieved both LDL-C <70 mg/dL and hsCRP <2 mg/L had better cardiovascular outcomes (cardiovascular death, major coronary event, or stroke) than patients with higher LDL-C and hsCRP levels (adjusted hazard ratio of 0.73 [95% CI, 0.66–0.81]) [
Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT.
]. Data from the recently completed CLEAR Outcomes trial (clinicaltrials.gov identifier NCT02993406) in a population of 13,970 patients with similar characteristics to the Low-Dose or No Statin Pool will elucidate the impact of dual reductions in LDL-C and hsCRP following long-term bempedoic acid treatment on the risk of MACE [
Current treatment guidelines for the management of blood cholesterol indicate that elevated hsCRP levels (≥2 mg/L) enhance the risk of atherothrombotic events and may justify statin therapy in patients who are at intermediate risk [
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.
]. The monoclonal antibody canakinumab is an IL-1β blocker that downregulates the inflammatory response and the IL-6 signaling pathway, which has a key role in atherothrombosis [
]. In the CANTOS study, canakinumab reduced the risk of MACE by 15% relative to placebo in patients with a history of prior myocardial infarction and baseline hsCRP ≥2 mg/L (91.1% of patients taking statins at randomization) [
]. Levels of hsCRP decreased by approximately 40% compared with placebo without clinically meaningful reductions in LDL-C. A secondary analysis of the CANTOS data showed that the achieved level of hsCRP during treatment with canakinumab was directly related to the risk of MACE, with levels of hsCRP <2 mg/L associated with a 25% reduction in risk of MACE compared with placebo, while those with hsCRP ≥2 mg/L had comparable risk of MACE on canakinumab or placebo [
Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial.
]. In two other recent studies, the anti-inflammatory drug colchicine reduced the risk of MACE by 31% (without clinically meaningful reductions in LDL-C) in patients with chronic coronary artery disease compared with placebo [
The current analysis has several limitations. The data in this post-hoc analysis were prospectively collected in a randomized and controlled setting as part of the phase 3 program analyzing bempedoic acid use. Although the pooled populations used in this analysis were planned, a change in hsCRP levels was not a primary endpoint of the studies (it was a secondary endpoint) [
Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom randomized clinical trial.
Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
]. This study might therefore be limited by the fact that tobacco smoking status was not included in our analyses. Furthermore, to control for the effect of statins, patients in the ASCVD and/or HeFH Pool not taking statins (2.8%, n = 84) were excluded from several analyses including the correlation analysis; patients in the Low-Dose or No Statin Pool who were taking statins were also excluded (18.1%, n = 111). Although the overall data were based on large randomized controlled studies, some subgroups receiving smaller doses of background statin therapy were quite small. Furthermore, fewer female patients were included in the ASCVD and/or HeFH pool (30%) than in the Low-Dose or No Statin pool (60%). This variation may be explained by the fact that women are less likely to use statins than men, which may in turn be due to the higher incidence of statin-associated adverse events in women compared with men [
Gender differences in side effects and attitudes regarding statin use in the Understanding Statin Use in America and Gaps in Patient Education (USAGE) study.
Cholesterol Treatment Trialists’ (CTT) Collaboration Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials.
In conclusion, bempedoic acid significantly reduces hsCRP levels, an established marker of systemic inflammation and cardiovascular disease risk. The weak correlation between changes in levels of LDL-C and hsCRP suggests that the anti-inflammatory effects of bempedoic acid may go beyond lowering of LDL-C alone. The differential effects of LDL-C and hsCRP lowering on ASCVD risk are being evaluated in the recently completed CLEAR Outcomes trial of bempedoic acid.
Financial support
This study was supported by Esperion Therapeutics, Inc., Ann Arbor, MI, USA.
CRediT authorship contribution statement
Erik S.G. Stroes: Investigation, Writing – review & editing. Harold E. Bays: Investigation, Writing – review & editing. Maciej Banach: Investigation, Writing – review & editing. Alberico L. Catapano: Conceptualization, Methodology, Investigation, Writing – review & editing. P. Barton Duell: Investigation, Writing – review & editing. Ulrich Laufs: Investigation, Writing – review & editing. G.B. John Mancini: Investigation, Writing – review & editing. Kausik K. Ray: Investigation, Writing – review & editing. William J. Sasiela: Conceptualization, Methodology, Writing – review & editing. Yang Zhang: Validation, Formal analysis, Writing – review & editing. Antonio M. Gotto, Jr: Investigation, Writing – review & editing.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Stroes has received research grant(s)/support to his institution from Amgen, Sanofi, Resverlogix, and Athera and has received lecturing/advisory board fees from Amgen, Sanofi, Akcea/IONIS, Esperion Therapeutics, Inc., and Novartis.
Dr. Bays’s research site has received research grants from 89Bio, Acasti, Akcea, Allergan, Alon Medtech/Epitomee, Amarin, Amgen, AstraZeneca, Axsome, Boehringer Ingelheim, Civi, Eli Lilly, Esperion Therapeutics, Inc., Evidera, Gan and Lee, Home Access, Janssen, Johnson and Johnson, Lexicon, Matinas, Merck, Metavant, Novartis, NovoNordisk, Pfizer, Regeneron, Sanofi, Selecta, TIMI, and Urovant. He has served as a consultant/advisor for 89Bio, Amarin, Esperion Therapeutics, Inc., Matinas, and Gelesis and as a speaker for Esperion.
Dr. Banach has received research grant(s)/support from Amgen, Sanofi, Valeant, and Viatris, has served as a consultant for or received honoraria from Abbott Medical, Abbott Vascular, Amgen, Esperion Therapeutics, Inc., Freia Pharmaceuticals, Herbapol, Kogen, KRKA, Mylan/Viatris, Novartis, Novo Nordisk, Polpharma, Polfarmex, Regeneron, Sanofi-Aventis, Servier, Valeant, Daichii Sankyo, Teva, and Zentiva, and is CMO at Nomi Biotech Corporation Ltd.
Dr. Catapano has received research grant(s)/support from Sanofi, Sanofi Regeneron, Amgen, Amarin, Mylan, and Menarini (all paid to the institution, not to the individual), and has served as a consultant for or received honoraria from Akcea, Amarin, Amgen, Sanofi, Esperion Therapeutics, Inc., Kowa, Novartis, Ionis Pharmaceuticals, Medco, Mylan, Menarini, MSD, Recordati, Regeneron, and Daiichi Sankyo.
Dr. Duell has received institutional research grant(s)/support from Travere/Retrophin and Regenxbio, and served as a consultant for Akcea/Ionis, Kaneka, Novo Nordisk, Retrophin, and Regeneron.
Dr. Laufs has served as a consultant for Amgen, Daiichi Sankyo, Esperion Therapeutics, Inc., and Sanofi.
Dr. Mancini received research grant(s)/support from Merck, AstraZeneca, Amgen, Sanofi, Novo Nordisk, Boehringer Ingelheim, Lilly, Pfizer, HLS Therapeutics, and Bayer and has served as a consultant for these companies as well as for Esperion Therapeutics, Inc., Novartis, and Servier.
Dr. Ray has received research grant(s)/support from Amgen, Daiichi Sankyo, MSD, Pfizer, Regeneron, and Sanofi (all paid to the institution, not to the individual), and served as a consultant for or received honoraria from AbbVie, Akcea, Algorithm, Amgen, AstraZeneca, Boehringer Ingelheim, Cerenis, Cipla, Daiichi Sankyo, Dr. Reddy’s Laboratories, Lilly, Esperion Therapeutics, Inc., Kowa, Medco, MSD, Novo Nordisk, Pfizer, Regeneron, Resverlogix, Sanofi, Takeda, and Zuellig Pharma.
Dr. Gotto is an Esperion Therapeutics, Inc. board member and Akcea DSMB chair. He has also served as a consultant for Kowa.
Dr. Sasiela is a former employee of Esperion Therapeutics, Inc., and may hold stock and/or stock options. He is currently the principal of Cardiometabolic Consulting, LLC.
Dr. Zhang was an employee of Esperion Therapeutics, Inc. when the analysis was carried out and may hold stock and/or stock options.
Acknowledgments
All authors had access to the data and participated in the development, review, and approval of the manuscript. The authors would like to acknowledge Lei Lei for her expert opinion and for generating statistical analysis outputs. Medical writing assistance, funded by Esperion Therapeutics, Inc., was provided by Callie A. S. Corsa, PhD, and Lamara D. Shrode, PhD, CMPP™, of JB Ashtin, who developed the first draft based on an author-approved outline and assisted in implementing author revisions while adhering to Good Publication Practice (GPP3) guidelines and International Committee of Medical Journal Editors (ICMJE) recommendations. Further medical writing and editorial support on later drafts, funded by Esperion Therapeutics, was provided by Katerina Pipili, PhD, Laurel Riemann, PharmD, BCPS, and Isobel Markham, MSc, of Spark Medica Inc.
Dr. Ray acknowledges support from the NIHR Imperial Biomedical Research Centre. Dr. Catapano acknowledges support from the Ministry of Health – Ricerca Corrente – IRCCS MultiMedica.
Appendix A. Supplementary data
The following is the Supplementary data to this article.
Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel.
Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study.
High-sensitivity C-reactive protein discordance with atherogenic lipid measures and incidence of atherosclerotic cardiovascular disease in primary prevention: the ARIC study.
Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial.
Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial.
From CANTOS to CIRT to COLCOT to clinic: will all atherosclerosis patients soon be treated with combination lipid-lowering and inflammation-inhibiting agents?.
Prevention of diet-induced metabolic dysregulation, inflammation, and atherosclerosis in Ldlr(-/-) mice by treatment with the ATP-citrate lyase inhibitor bempedoic acid.
Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom randomized clinical trial.
Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
Association of bempedoic acid administration with atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia.
Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT.
Effect of statins on serum level of hs-CRP and CRP in patients with cardiovascular diseases: a systematic review and meta-analysis of randomized controlled trials.
Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy.
AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism.
Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators.
Creating controversy where none exists: the important role of C-reactive protein in the CARE, AFCAPS/TexCAPS, PROVE IT, REVERSAL, A to Z, JUPITER, HEART PROTECTION, and ASCOT trials.
Association between baseline, achieved, and reduction of CRP and cardiovascular outcomes after LDL cholesterol lowering with statins or ezetimibe: a systematic review and meta-analysis.
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.
Gender differences in side effects and attitudes regarding statin use in the Understanding Statin Use in America and Gaps in Patient Education (USAGE) study.
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