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Study Summary

The phase 3, double-blind, placebo-controlled, parallel-group CLEAR Wisdom Study sought to evaluate the long-term efficacy and safety of bempedoic acid in high-risk cardiovascular patients (with pre-existing atherosclerotic cardiovascular disease and/or heterozygous familial hypercholesterolemia, and baseline low-density lipoprotein cholesterol [LDL-C] greater than 100 mg/dL) receiving maximally tolerated statins with or without other lipid lowering therapy. A total of 779 patients were randomized 2:1 to bempedoic acid 180 mg or placebo daily for 52 weeks; no significant differences were observed between the groups at baseline. Of note, mean LDL-C was 122 mg/dL and 119 mg/dL in the placebo group and treatment group, respectively, and only 53% of patients in each group were on high-intensity statin at baseline. The primary end point was percent change in LDL-C from baseline to week 12 (see accompanying Hurst's Central Illustration). Bempedoic acid showed a net 17.4% reduction in LDL-C at week 12 when compared to placebo (mean LDL-C 122.8 mg/dL vs. 97.6 mg/dL), with sustained reductions seen at 52 weeks (mean LDL-C 116.9 mg/dL vs. 99.6 mg/dL). The largest reduction in LDL-C was seen in patients who were not on statin therapy at baseline. There was also a significantly greater reduction in high-sensitivity-C-reactive protein (hsCRP) seen in the bempedoic acid group compared with placebo (-9.4% vs. -18.7%). Overall, there was no significant difference in safety and tolerability or drug discontinuations due to adverse events of bempedoic acid when compared with placebo.

Commentary

Study Strengths: This study evaluated a high-risk group for whom LDL-C reduction would be most beneficial. The study was double-blinded, placebo-controlled, and international. In addition to LDL-C, the effect of bempedoic acid on non-LDL-C lipids and hsCRP was also measured.

Study Limitations: The study size was modest, with a total of 779 patients. Cardiovascular outcomes were not measured to evaluate if LDL-C reductions with bempedoic acid were associated with fewer major adverse cardiovascular events. The primary end point follow-up was 12 weeks, with 52-week follow-up being a tertiary end point.

Next Steps/Clinical Perspective: Additional studies to assess longer-term durable reductions in LDL-C with bempedoic acid are needed. Clinical correlation with cardiovascular outcomes are also required to evaluate the efficacy of bempedoic acid on cardiovascular outcomes and all-cause mortality in this high-risk population. The role of bempedoic acid in LDL-C reduction and reduction in atherosclerotic cardiovascular disease in patients not on statin therapy should be better evaluated as well, as this drug may be a better alternative (as lone therapy) for patients who are unable to tolerate statin therapy at baseline. The recently published CLEAR Harmony Trial (Ray KK et al. N Engl J Med. 2019;380(11):1022-1032), which primarily assessed the safety of bempedoic acid as compared with placebo and secondarily its efficacy in LDL-C reduction, also suggests that bempedoic acid is well tolerated without a significant difference in adverse effects. Future studies may also compare bempedoic acid against other nonstatin lipid-lowering agents such as ezetimibe and PCSK9 inhibitors.

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