LDL-c response to bempedoic acid using statin intensity categories

Factors Associated With Enhanced Low-Density Lipoprotein Cholesterol Lowering With Bempedoic Acid

Literature - Ballantyne CM, Bays HE, Louie MJ, et al. - J Am Heart Assoc. 2022 Aug 2;11(15):e024531. doi: 10.1161/JAHA.121.024531

Introduction and methods


The LDL-c reduction that can be accomplished with lipid-lowering therapies varies between patients [1,2]. Both extrinsic factors (f.e., nonadherence to lipid-lowering therapies and inaccurate measurement of baseline LDL‐c levels) and intrinsic factors (f.e., age, sex, baseline lipid or hs-CRP levels, and drug–drug interactions) may contribute to this varied response.

In phase 3 studies, treatment with bempedoic acid resulted in an average LDL‐c reduction of 18% compared with placebo in patients who were concurrently on moderate‐ to high‐intensity statin treatment and a mean 25%-reduction in patients receiving low‐dose or no statins [3].

Aim of the study

The authors sought to characterize the LDL‐c response to bempedoic acid using statin intensity categories and identify clinical factors associated with a ≥30% LDL‐c reduction with bempedoic acid treatment.


In this post-hoc analysis, data from 4 randomized, double‐blind, placebo‐controlled, phase 3 studies on bempedoic acid were pooled. In all studies, patients at high cardiovascular risk who required additional LDL-c reduction despite receiving stable lipid-lowering therapy were randomized (2:1 ratio) to bempedoic acid 180 mg once daily or placebo for 12–52 weeks. In the CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL‐Inhibiting Regimen) Harmony and CLEAR Wisdom studies, patients with established ASCVD or heterozygous familial hypercholesterolemia received maximally tolerated statin treatment. In the CLEAR Serenity and CLEAR Tranquility studies, patients had a history of statin‐associated side effects and were therefore treated with stable low‐dose statins or no statins at all. All patients in the CLEAR Tranquility study received ezetimibe.

Patients were grouped based on the percent change in their LDL‐c level from baseline to week 12 (i.e., primary endpoint for all 4 studies) using the statin intensity categories outlined in the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol [4]. For the current study, the following categories were of interest: ≥50% LDL‐c reduction compared with baseline (comparable to taking high‐intensity statin) and ≥30% LDL‐c reduction (comparable to taking moderate‐ to high‐intensity statin).

To identify factors associated with a ≥30% LDL-c reduction in patients who were treated with bempedoic acid, simple logistic regression modeling of the LDL‐c response was performed using each baseline variable, including age, sex, race, BMI, eGFR category, CVD risk, history of DM, history of hypertension, baseline LDL‐c level, log of baseline hs-CRP level, baseline statin use, and baseline ezetimibe use.

Main results

LDL-c reduction

  • At baseline, 81% of the patients were receiving statin therapy, 75.8% were on moderate‐ to high‐intensity statins, 5.0% were on low‐ or very‐low‐intensity statins, 19.2% did not take statins, and 14.9% were on ezetimibe.
  • At baseline, mean LDL‐c levels were 114.2 mg/dL (SD: 36.7) in patients treated with bempedoic acid (n=2321) and 113.0 mg/dL (SD: 36.6) in patients in the placebo group (n=1167).
  • The mean percent change in LDL‐c level between baseline and week 12 was −17.98% (SD: 21.32%) in the bempedoic acid group and 1.79% (SD: 22.65%) in the placebo group. In both treatment groups, interindividual variation in the LDL-c response was seen.
  • From baseline to week 12, a ≥30% LDL-c reduction was found in 28.9% of the bempedoic acid–treated patients compared with 4.4% of the placebo-treated patients, while a ≥50% LDL-c reduction was observed in 4.7% and 1.1%, respectively.
  • When factoring in background statin treatment, 50.9% of the bempedoic acid–treated patients who were not on statins and 24.6% of the bempedoic acid–treated patients taking additional statins achieved a ≥30% LDL-c reduction, while 9.5% and 3.7%, respectively, met the ≥50% LDL-c reduction criterion.
  • Among the placebo groups, <5% of the patients (with or without statin treatment) achieved a ≥30% LDL-c reduction.

Factors associated with ≥30% LDL-c reduction in patients treated with bempedoic acid

  • Univariable logistic regression analysis showed that a ≥30% LDL-c reduction was associated with younger age, female sex, DM history, higher baseline LDL‐c level, higher baseline hs-CRP level, absence of baseline statin treatment, and presence of baseline ezetimibe treatment (all P<0.03).
  • After covariate adjustment, female sex, DM history, higher baseline hs-CRP level, absence of baseline statin treatment, and presence of baseline ezetimibe treatment were associated with a ≥30% LDL-c reduction (all P<0.01).


This post-hoc analysis of 4 RCTs showed that 25% of the patients who were receiving background statin therapy and were started on bempedoic acid treatment achieved a ≥30% LDL-c reduction. Of note, in the group of bempedoic acid–treated patients who were not on statins more than half met the ≥30% LDL-c reduction criterion.

Factors associated with a ≥30% LDL-c reduction were female sex, DM history, higher baseline hs-CRP level, absence of baseline statin treatment, and presence of baseline ezetimibe treatment.


1. Boekholdt SM, Hovingh GK, Mora S, Arsenault BJ, Amarenco P, Pedersen TR, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol. 2014;64:485-494. doi: 10.1016/j.jacc.2014.02.615

2. Karlson BW, Wiklund O, Palmer MK, Nicholls SJ, Lundman P, Barter PJ. Variability of low-density lipoprotein cholesterol response with different doses of atorvastatin, rosuvastatin, and simvastatin: results from VOYAGER. Eur Heart J Cardiovasc Pharmacother. 2016;2:212-217. doi: 10.1093/ehjcvp/pvw006

3. Banach M, Duell PB, Gotto AM Jr, Laufs U, Leiter LA, Mancini GBJ, et al. Association of bempedoic acid administration with atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia. JAMA Cardiol. 2020;5:1124-1135. doi: 10.1001/jamacardio.2020.2314

4. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 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. Circulation. 2019;139:e1082-e1143. doi: 10.1161/CIR.0000000000000625

Find this article online at J Am Heart Assoc.

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