Introduction and methods

Efficacy and Safety of Bempedoic Acid Added to Maximally Tolerated Statins in Patients with Hypercholesterolemia and High Cardiovascular Risk: The CLEAR Wisdom Trial

Presented at ACC.19 by Anne Carol Goldberg (Washington University, St Louis, MO, USA)

Despite statin or other lipid-lowering therapy, many patients with high CV risk have elevated LDL-c levels. This can be due to an insufficient response to high-intensity statins, or intolerability. Therefore, additional therapies are needed to lower LDL-c in those patients with elevated LDL-c levels. Bempedoic acid is an oral, small molecule drug that inhibits synthesis of cholesterol in the liver, but unlike statins, does not inhibit production in the muscles.

The efficacy and safety of bempedoic acid was investigated in high CV risk patients who were on maximally tolerated statins and/or other lipid-modifying therapies. A phase 3, double-blind, placebo-controlled, parallel-group study was performed, in which patients were randomized in a 2:1 ratio to receive bempedoic acid (n=522) or placebo (n=257) for 52 weeks in addition to maximally tolerated statin and/or other lipid-lowering therapy. Patients had pre-existing atherosclerotic CVD (ASCVD) or heterozygous FH and baseline LDL-c ≥70 mg/dL. Primary endpoint was percent change in LDL-c from baseline to week 12.

Main results

• Over 90% of patients had existing ASCVD, thus representing a high risk population. Around 30% had diabetes, and over 80% had hypertension. Mean LDL-c level was around 120 mg/dL. Around 52% were on high-intensity statin, around 32% on moderate-intensity statin and about 15% received low-intensity or no statin.
• The primary endpoint of change in LDL-c at week 12 was -15.1% in those treated with bempedoic acid and 2.4% in placebo group, resulting in a 17.4% placebo-corrected difference (P<0.001).
• When patients were stratified for statin intensity, reductions in LDL-c with bempedoic acid vs placebo on top of statin background therapy were: -24.6% vs -2.6% for no statins, 14.9% vs 3.2% for low/moderate intensity use, -14.4% vs 2.8% for high intensity use (all P<0.001).
• There was no difference in adverse events (any, serious, fatal) between bempedoic acid and placebo groups.
• Positively adjudicated 3-points MACE occurred in 2.7% and 4.7% in bempedoic acid and placebo groups, respectively.
• In patients with diabetes history, mean percentage change in HbA1c at week 12 was -0.08% in patients treated with bempedoic acid vs 0.13% in those treated with placebo.

Conclusion

Data of the CLEAR Wisdom trial showed that bempedoic acid is effective and safe and might be an additional therapeutic option to lower LDL-c in high CV risk patients with elevated LDL-c treated with maximally tolerated statins and/or other lipid-modifying therapies.

Discussion

Discussant Valentin Fuster said that he had expected a greater LDL-c reduction, based on how the drug works. It blocks cholesterol synthesis and acts proximal to how statins work. But, he makes the comparison with ezetimibe, which was found to be more beneficial when subsequent events were included in efficacy analyses. The same may be true for bempedoic acid. He thinks this was a great study and is looking forward to following what bempedoic acid will show in the future.

During the discussion, it was emphasized that bempedoic acid should be considered another add-on option, in patients already on statins and/or ezetimibe, but who still have elevated LDL-c and are at high risk. By lack of outcome data for bempedoic acid, it should not replace currently recommended therapies with demonstrated CV benefit.

- Our coverage of ACC.19 is based on the information provided during the congress –

Watch our video of the CLEAR Wisdom trial