Long-term and safe reduction of LDL-c levels with bempedoic acid
Long-Term Safety and Efficacy of Bempedoic Acid in Patients With Atherosclerotic Cardiovascular Disease and/or Heterozygous Familial Hypercholesterolemia (from the CLEAR Harmony Open-Label Extension Study)
Introduction and methods
In patients with ASCVD and/or heterozygous familial hypercholesterolemia (HeFH), long-term reduction of LDL-c levels is recommended [1,2]. Despite statin or other lipid-lowering therapy, many patients at high CVD risk are unable to achieve risk-based LDL-c–lowering goals [3,4]. To help them reach these goals while minimizing side effects, there is a need for nonstatin treatments.
Aim of the study
The authors set out to investigate the long-term safety and efficacy of the prodrug bempedoic acid, an oral ATP -citrate lyase inhibitor that lowers LDL-c levels in patients with hypercholesterolemia.
This 78-week open-label extension (OLE) study was a follow-up study of the CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Harmony trial . In this previous multicenter, double-blind, placebo-controlled, parallel-group, phase 3 RCT, patients with ASCVD and/or HeFH had been randomized (2:1) to receive bempedoic acid 180 mg or placebo once daily for 52 weeks. At the time, inclusion criteria were baseline LDL-c level ≥70 mg/dL and maximally tolerated background statin therapy with or without additional lipid-lowering therapy.
In the OLE study, 970 patients who had been assigned to the experimental arm continued treatment for 78 weeks (total duration of bempedoic acid therapy: ≤ 130 weeks), while bempedoic acid treatment was initiated in 492 patients in the control arm (≤ 78 weeks of bempedoic acid therapy). All patients enrolled in the OLE study received ≥1 bempedoic acid dose. At baseline, patient demographics and characteristics were generally similar regardless of whether patients had received bempedoic acid or placebo in the parent study (i.e., CLEAR Harmony trial).
The primary endpoint was safety, as assessed by the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and adverse events of special interest (AESIs). The secondary endpoint was efficacy, as assessed by absolute and relative changes from baseline of the parent study to week 52 and to week 78 of the OLE study (total of 130 weeks) in levels of LDL-c, total cholesterol (TC), non–HDL-c, HDL-c, triglycerides, apoB , and high-sensitivity CRP (hsCRP).
- The overall incidence of TEAEs (regardless of causality) were similar in patients who received bempedoic acid ≤130 weeks or ≤78 weeks (78.1% vs. 78.3%).
- The most frequently reported TEAEs that were considered to be related to bempedoic acid use were muscle spasms (1.7%), myalgia (1.4%), and extremity pain (0.7%).
- The overall incidence of serious TEAEs (regardless of causality) were also comparable between patients who received bempedoic acid ≤130 weeks or ≤78 weeks (20.8% vs. 19.7%).
- The overall incidence of TEAEs with fatal outcome was 0.9% (10 patients [1.0%] receiving bempedoic acid ≤130 weeks vs. 3 patients [0.6%] receiving bempedoic acid ≤78 weeks).
- The overall incidence of prespecified AESIs (based on theoretical risks) was similar to that in the parent study, for example 5.5% for new onset or worsening diabetes mellitus , 2.8% for renal disorders, and 2.6% for gout.
- In the OLE study, similar patterns of laboratory abnormalities were seen as those observed in the parent study (such as increased blood urea nitrogen, uric acid, and creatinine levels). The laboratory abnormalities did not worsen with a longer duration of bempedoic acid exposure.
- The overall incidence of positively adjudicated treatment-emergent cardiovascular clinical events, such as MACE , was comparable in patients who received bempedoic acid ≤130 weeks or ≤78 weeks (7.6% vs. 6.9%).
- The mean percent change in LDL-c levels from week 0 (parent study) to week 130 was –14.2 ± 0.9% for the patients who had also received bempedoic acid in the parent study (n = 970 ) and –15.0 ± 1.1% for those who were switched to bempedoic acid in the OLE study (n = 492).
- Within the first 12 weeks of initiating bempedoic acid treatment in the OLE study, patients who had received placebo in the parent study showed a similar degree of LDL-c–lowering (−14.5 ± 1.0% [−15.4 ± 1.0 mg/dL]).
- Non –HDL-c, apoB, TC, and hsCRP levels were also reduced in both groups during bempedoic acid treatment.
- In patients who received bempedoic acid for 130 weeks, reductions in levels of LDL-c, other lipid parameters, and hsCRP remained relatively stable.
- The proportions of patients who achieved LDL-c–lowering goals (<100, <70, or <55 mg/dL) at week 78 of the OLE study were similar regardless of bempedoic acid treatment duration.
- Bempedoic acid treatment was discontinued in 7% of the patients taking bempedoic acid ≤130 weeks and in 9% of the patients receiving the study drug ≤78 weeks, mostly because of myalgia (0.6%) or muscle spasms (0.5%).
Bempedoic acid as an adjunct to maximally tolerated statins was generally well tolerated and showed sustained efficacy in lowering LDL-c levels with up to 2.5 years of continuous treatment in patients with ASCVD and/or HeFH. Safety profiles were similar between the parent and OLE studies, and no new safety signals were identified.