Physicians' Academy for Cardiovascular Education

Combination therapy of bempedoic acid and PCSK9i reduces LDL-c further in hypercholesterolemia

Lipid lowering with bempedoic acid added to a proprotein convertase subtilisin/kexin type 9 inhibitor therapy: A randomized, controlled trial

Literature - Rubino J, MacDougall DE, Sterling LR, et al. - J Clin Lipidol. 2021, DOI:

Introduction and methods

Statins are the first-line therapy for lowering LDL-c. However, patients can be statin intolerant and fewer than half of eligible patients receive recommended high-intensity statin therapy [1-4]. Therefore, combination therapies with and without statins need to be explored.

Bempedoic acid is an ATP-citrate lyase inhibitor that significantly lowered LDL-c levels in patients with hypercholesterolemia as a single treatment or as adjunct to statins and/or ezetimibe [5-7]. Both bempedoic acid and PCSK9i results in upregulated levels of hepatic LDL receptors; bempedoic acid by increasing the expression of LDLR and PCSK9i by inhibiting the degradation of the receptor. Whether these two therapies combined might further reduce LDL-c has not been investigated yet.

This phase 2, randomized, double-blind, placebo-controlled, parallel-group study included patients with hypercholesterolemia from April 7, 2017, to January 29, 2018 from the United States. The study was conducted in three phases: 1) a 1.5 month screening/wash-out period with discontinuation of all LLTs, 2) a 3-month period in which patients initiated PCSK9i therapy (evolocumab 420 mg/3.5mL monthly injection), and 3) a 2-month period wherein patients were randomized (1:1) to bempedoic acid 180 mg once daily or placebo, while continuing PCSK9i background therapy. Eligible patients (n=59) had fasting LDL-c levels of ≥160 mg/dL prior to PCSK9i treatment and after wash-out of other LLT, and LDL-c levels of ≥70 mg/dL while receiving stable PCSK9i therapy prior to randomization. Patients with FH, hypertriglyceridemia, diabetes and known CVD, PAD or cerebrovascular disease were excluded. The primary endpoint was LDL-c percent change at 2 months after randomization. Secondary efficacy endpoints in the randomization phase included percent change from baseline to month 2 in ApoB, non-HDL-c, total cholesterol (TC), and hsCRP levels. The exploratory endpoints were percent change from baseline to month 2 in TG, Lp(a), and HDL-c levels. Also, safety and tolerability were assessed by adverse events.

Main results


2 Months of bempedoic acid treatment added to a PCSK9i therapy in patients with hypercholesterolemia reduced LDL-c levels further compared to those with a PCSK9i and placebo. The addition of bempedoic acid was safe and well-tolerated.


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Find this article online at J Clin Lipidol

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