Fixed combination of two non-statin cholesterol-lowering agents lowers LDL-c in high-risk patients

Phase 3 data for fixed combination bempedoic acid-ezetimibe in high risk patients not at LDL cholesterol goal

Presented at EAS 2019 in Maastricht, The Netherlands, by Christie Ballantyne (Baylor College of Medicine, Houston, TX, USA)

Introduction and methods

Many patients, despite taking maximally tolerated statin treatment, fail to attain LDL-c goal. Moreover, patients unable to tolerate statin therapy need further options to attain LDL-c targets. Ezetimibe is a cholesterol absorption inhibitor that is routinely recommended by guidelines as an add-on treatment to statin therapy, or as an alternative to statin therapy. Still, further LDL-c lowering may be needed in high risk patients.

Bempedoic acid is a first-in-class non-statin agent that inhibits ATP citrate lyase, an enzyme that acts one step upstream of 3-hydroxy-3-mehtylglutaryl-coenzyme A reductase, the enzyme that is inhibited by statins. Thus, bempedoic acid reduces cholesterol biosynthesis and lowers LDL-c by upregulating the LDL receptor. Like statins, bempedoic acid also reduces hsCRP, a marker of inflammation. Previous studies have shown that bempedoic acid is effective in lowering LDL-c and well tolerated when administered on top of statins, or as monotherapy in patients unable to tolerate statins.

Since bempedoic acid and ezetimibe are orally administered agents with mechanisms of action complementary to statins, they may be combined. In addition, phase 2 data showed that adding bempedoic acid to ezetimibe led to further LDL-c lowering. Thus, this study evaluates a fixed combination of bempedoic acid and ezetimibe. This is a double-blind study that enrolled patients at high risk of CV events who are not at guideline-recommended LDL-c goal despite maximally tolerated statin therapy. Patients unable to tolerate statins were also included. Eligible patients had clinical CV disease and/or heterozygous familial hypercholesterolemia and LDL-c ≥2.6 mmol/L (100 mg/dL), or if they had no clinical CV disease but multiple risk factors and LDL-c ≥3.4 mmol/L (130 mg/dL). Patients were randomized (2:2:2:1) to once-daily treatment with bempedoic acid 180 mg, ezetimibe 10 mg, the fixed combination, or placebo, for 12 weeks. 301 patients were enrolled, 65% of whom were taking statins.

Main results

• At 12 weeks, an absolute LDL-c lowering of 1.5 mmol/L was seen with the fixed combination, as compared with -1.0 mmol/L with ezetimibe, -0.7 mmol/L with bempedoic acid, and + <0.1 mmol/L with placebo.
• The fixed combination reduced LDL-c by 36.2% (least square mean value), which was significantly greater than with ezetimibe alone (23.2%) or bempedoic acid alone (17.2%).
• With placebo, an increase of 1.8% in LDL-c was seen, thus the placebo-corrected reduction with the fixed combination was 38% (95%CI: -46.5 to – 29.6).
• LDL-c lowering was consistent, regardless of background statin intensity.
• The fixed combination of bempedoic acid plus ezetimibe also significantly reduced non-HDL-c (-31.9±2.2), hsCRP (-35.1%, vs increase of 21.6% with placebo), total cholesterol (-26.4±1.9) , and apolipoprotein B (-24.6±2.4), to a greater extent than the individual components.
• The fixed combination was well tolerated, when added to maximally tolerated statin therapy. Serious adverse events (AEs) were seen in 9.3% of patients receiving the combination, as compared with 8.0% on bempedoic acid, 10.5% on ezetimibe, and 2.4% on placebo. Study drug-related AEs were seen in 15.3%, 13.6%, 10.5% and 9.5% of the respective treatment groups. Muscle-related AEs were seen in 7.1%, 8.0%, 8.1% and 72% of patients, respectively.

Conclusion

This phase 3 study showed that an oral once-daily fixed combination of bempedoic acid plus ezetimibe provides effective LDL-c lowering in high risk patients not at goal and was well tolerated. The magnitude of the LDL-c lowering effect suggests additive effects of bempedoic acid and ezetimibe. Thus, the fixed combination of bempedoic acid plus ezetimibe may provide a potent and convenient therapy complementary to existing lipid-modifying therapy regimens.

Our reporting is based on the information provided at the EAS 2019 congress