Impact of Bempedoic Acid on Total CV Events

Quick Takes

  • As compared to placebo, treatment with bempedoic acid in persons unable to tolerate guideline-recommended statins resulted in reductions in the primary composite MACE endpoint by 20% for total events, compared with 13% for the first event and the key secondary composite MACE endpoint, which was reduced by 17% for total events, compared with 15% for the first event. The total incidence of MI was reduced by 31% and coronary revascularization by 22%.
  • A favorable reduction in total risk results in a greater absolute risk reduction after 5 years in the total number of primary MACE-4 events (4.7% vs. 2.0%), and key secondary composite MACE-3 events (2.7% vs. 2.0%) results in more favorable reductions in the number needed to treat (21 vs. 48) and (37 vs. 51) for both endpoints, respectively.
  • Bempedoic acid with or without ezetimibe are both well tolerated compared to statins, and can be used safely with high-intensity statins. In contrast to statins, it does not impact risk of diabetes, and similar to statins, has the added benefit of lowering hsCRP not seen with PCSK9 inhibitors. While not frequent, major adverse effects include increase in uric acid and gout and tendonitis and tendon rupture for which patients should be informed and monitored.

Study Questions:

To what degree does bempedoic acid reduce the total burden of cardiovascular (CV) events in high-risk patients?


Patients included in this prespecified analysis of the CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-lnhibiting Regimen) trial were aged 18-85 years and had cardiovascular disease (CVD) (secondary prevention) or at high risk for CVD (primary prevention), with baseline low-density lipoprotein cholesterol (LDL-C) ≥100 mg/dL and inability to take guideline-recommended statins. Patients were randomized to bempedoic acid 180 mg or matching placebo. Concomitant treatment with a very low average daily statin dose without adverse effects was permitted, as was administration of other lipid-lowering therapy such as ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The primary endpoint was time to first occurrence of the 4-component composite MACE-4. Key secondary endpoints included a 3-component composite of CV death, myocardial infarction (MI), and stroke (MACE-3), as well as the individual components of the composite outcomes.


A total of 13,970 patients (mean [standard deviation] age, 65 [9] years; 7,230 male [51.8%]) were included in the study. A total of 9,764 participants (69.9%) had prior atherosclerotic CVD; baseline was LDL-C 139 mg/dL and high-sensitivity C-reactive protein (hsCRP) 2.3 mg/dL; treatment with bempedoic acid resulted in a 21% reduction in LDL-C and a 22% reduction in hsCRP level at 6 months. Median (interquartile range) follow-up was 3.4 (3.1-3.9) years.

A total of 1,746 positively adjudicated first MACE-4 events and 915 additional MACE events in 612 patients were recorded, with coronary revascularization representing 32.8% (573 of 1,746) of first events and 69.4% (635 of 915) of additional events. For the total incidence of CV events, treatment with bempedoic acid was associated with a reduction in risk of MACE-4 (hazard ratio [HR], 0.80; 95% confidence interval [Cl], 0.72-0.89; p < 0.001), MACE-3 (HR, 0.83; 95% Cl, 0.73-0.93; p = 0.002), myocardial infarction (HR, 0.69; 95% Cl, 0.58-0.83; p < 0.001), and coronary revascularization (HR, 0.78; 95% Cl, 0.68-0.89; p < 0.001). No statistically significant difference was observed for stroke (HR, 0.80; 95% Cl, 0.63-1.03). A lower HR for protection with bempedoic acid was observed with increasing number of MACE events experienced by patients.


Lowering LDL-C level with bempedoic acid reduced the total number of CV events in patients with high CV risk, statin therapy intolerance, and elevated LDL-C levels.


Bempedoic acid is one of the novel Food and Drug Administration–approved nonstatins that up-regulates LDL receptor activity resulting in lowering of LDL-C via inhibiting hepatic ATP citrate lyase, a prodrug that is converted to active by enzymes in the liver but not in muscle, explaining why it can be used in statin-intolerant patients and as an adjunct to maximal tolerated statins in patients not at goal. In addition, the combination of bempedoic acid 180 mg with ezetimibe 10 mg is safe and decreases LDL-C by about 40% as compared to bempedoic acid alone, which in CLEAR Outcomes lowered LDL-C by 21%. It can be used safely in persons with mild to moderate kidney and liver disease and, in contrast to statins, does not increase risk of new-onset diabetes.

Significant adverse effects of bempedoic acid include upper respiratory infections and urinary tract infections; back and abdominal pain; muscle weakness, myalgia, and muscle spasm less than statins; and increase in uric acid (0.6-0.9 mg/dL), gout, and tendonitis, which can lead to tendon rupture (0.5% in persons on statins, or with diabetes, gout, or rheumatoid arthritis). Bempedoic acid should be discontinued in case of tendonitis.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Prevention

Keywords: Cholesterol, LDL, Dyslipidemia

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