Although the use of lipid-lowering drugs such as statins has resulted in a substantial decline in cardiovascular events, statin therapy alone is often insufficient for reducing plasma LDL-cholesterol levels to below target values. Two papers published in the NEJM investigated whether the pharmacological or genetic inhibition of ATP citrate lyase, a key enzyme in the cholesterol biosynthesis pathway, can reduce plasma LDL-cholesterol levels without increasing adverse events.

Credit: V. Summersby/Springer Nature Limited

Bempedoic acid has been shown to reduce cholesterol synthesis through inhibition of ATP citrate lyase. Investigators of the CLEAR Harmony randomized, phase III trial sought to examine the efficacy and safety of bempedoic acid therapy added to maximally tolerated statins for 1 year in patients with atherosclerosis and/or familial hypercholesterolaemia.

In total, 1,488 patients were assigned to receive bempedoic acid and 742 to placebo. LDL-cholesterol levels were lower in the bempedoic acid group than in the placebo group at both week 12 (difference −18.1 percentage points, 95% CI –20.0 to −16.1, P < 0.001) and at week 24 (difference −16.1 percentage points, 95% CI –18.2 to –14.0, P < 0.001). The incidence of adverse events was similar in the two treatment groups; however, the percentage of patients who discontinued treatment owing to a reported adverse event was higher among those receiving bempedoic acid than placebo (10.9% versus 7.1%).

“The present trial provides substantial evidence that bempedoic acid as an adjunct to guideline-based statin regimens appeared to have an acceptable safety profile,” conclude the authors of the paper. Two studies on bempedoic acid are ongoing: a long-term, open-label extension of the CLEAR Harmony trial to assess safety data on longer-term exposure and a cardiovascular outcomes study.

In an accompanying article, Ference and colleagues performed a Mendelian randomization study to predict the clinical effect of lowering plasma LDL-cholesterol levels through inhibition of ATP citrate lyase. This enzyme lies upstream of 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR), the target for statins, in the cholesterol biosynthesis pathway, but whether lowering LDL-cholesterol levels by inhibiting ATP citrate lyase will reduce the risk of cardiovascular events to the same extent as HMGCR inhibition with statins is unclear.

The researchers constructed genetic scores comprising independently inherited variants in ACLY (encoding ATP citrate lyase) or in HMGCR, to mimic the effects of ATP citrate lyase inhibitors and HMGCR inhibitors, respectively. A total of 654,783 individuals, including 105,429 who had a major cardiovascular event, were included in the analysis. For each 10 mg/dl decrease in plasma LDL-cholesterol level, the ACLY and HMGCR scores showed a similar degree of reduction in the risk of major cardiovascular events. Neither score was associated with increased risk of cancer. “The results of our study thus confirm the mechanism by which ATP citrate lyase inhibition lowers plasma LDL cholesterol levels,” remark the authors. “They provide validation for ATP citrate lyase inhibition as a genetic target.”