Study of ACLY and Cardiovascular Disease

Study Questions:

What is the clinical effect of lowering plasma low-density lipoprotein (LDL) cholesterol levels through inhibition of ATP citrate lyase (ACLY) by comparing variants in ACLY that mimic the effect of an ATP citrate lyase inhibitor?

Methods:

The investigators constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (ACLY) and 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR) to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. They then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer. The primary efficacy outcome for the study was major cardiovascular events (defined as a composite of the first occurrence of myocardial infarction, coronary revascularization, ischemic stroke, or coronary death). The authors estimated the association of each genetic score with continuous outcomes, including plasma lipid and lipoprotein levels, using linear regression, and the association of each genetic score with the risk of major cardiovascular events and other dichotomous outcomes using logistic regression.

Results:

A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The ACLY and HMGCR scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg/dl in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval [CI], 0.78-0.87; p = 4.0×10−14) for the ACLY score and 0.836 (95% CI, 0.81-0.87; p = 3.9×10−19) for the HMGCR score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer.

Conclusions:

The authors concluded that genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level.

Perspective:

This study reports that variants in ACLY and HMGCR were associated with similar changes in the levels and composition of lipoproteins and had a nearly identical effect on the risk of cardiovascular events for each unit decrease in the LDL cholesterol level. Overall, the results confirm the mechanism by which ATP citrate lyase inhibition lowers plasma LDL cholesterol levels, and provide potential validation for ATP citrate lyase inhibition as a future therapeutic target. Future studies will need to assess off-target and adverse effects of ATP citrate lyase inhibition as well as hard cardiovascular benefits.

Clinical Topics: Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Cardiac Surgery and Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: ATP Citrate (pro-S)-Lyase, Brain Ischemia, Cholesterol, LDL, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Metabolic Syndrome X, Myocardial Infarction, Myocardial Revascularization, Neoplasms, Primary Prevention, Stroke, Vascular Diseases


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