Adenosine Triphosphate Citrate Lyase and Fatty Acid Synthesis Inhibition: A Narrative Review

JAMA Cardiol. 2023 Sep 1;8(9):879-887. doi: 10.1001/jamacardio.2023.2402.


Importance: Adenosine triphosphate citrate lyase (ACLY) is a key regulatory enzyme of glucose metabolism, cholesterol and fatty acid synthesis, and the inflammatory cascade. Bempedoic acid, an ACLY inhibitor, significantly reduces atherogenic lipid markers, including low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, and apolipoprotein B. Additional effects of ACLY inhibition include antitumor growth; reduction of triglycerides and proinflammatory molecules such as high-sensitivity C-reactive protein; less insulin resistance; reduction of hepatic lipogenesis; and weight loss.

Observations: While numerous ACLY inhibitors have been identified, most of the clinical data have focused on bempedoic acid. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) program was a series of phase 3 clinical trials that evaluated its effects on lipid parameters and safety, leading to US Food and Drug Administration approval in 2020. CLEAR Outcomes was a phase 3, double-blind, randomized, placebo-controlled trial in individuals with a history of statin intolerance, serum LDL-C level of 100 mg/dL or higher, and a history of, or at high risk for, cardiovascular disease. Bempedoic acid modestly reduced the primary 4-way cardiovascular composite end point as well as the individual components of myocardial infarction and coronary revascularization but did not reduce stroke, cardiovascular death, or all-cause mortality. Rates of gout and cholelithiasis were higher with bempedoic acid, and small increases in serum creatinine, uric acid, and hepatic-enzyme levels were also observed.

Conclusions and relevance: ACLY inhibition with bempedoic acid has been established as a safe and effective therapy in high-risk patients who require further LDL-C lowering, particularly for those with a history of statin intolerance. The recently published CLEAR Outcomes trial revealed modest reductions in cardiovascular events with bempedoic acid, proportional to its LDL-C lowering, in high-risk individuals with statin intolerance and LDL-C levels of 100 mg/dL or higher. The additional effects of ACLY inhibition have prompted a more thorough search for novel ACLY inhibitors for conditions such as cancer, hypertriglyceridemia, chronic inflammation, type 2 diabetes, fatty liver disease, obesity, and metabolic syndrome. Similarly, therapies that reduce fatty acid synthesis are being explored for their use in cardiometabolic conditions.

Publication types

  • Review

MeSH terms

  • ATP Citrate (pro-S)-Lyase* / antagonists & inhibitors
  • ATP Citrate (pro-S)-Lyase* / metabolism
  • Cholesterol
  • Cholesterol, LDL
  • Clinical Trials, Phase III as Topic
  • Diabetes Mellitus, Type 2* / drug therapy
  • Fatty Acids* / antagonists & inhibitors
  • Fatty Acids* / metabolism
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
  • Lipogenesis
  • Randomized Controlled Trials as Topic


  • 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid
  • Cholesterol
  • Cholesterol, LDL
  • Fatty Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • ATP Citrate (pro-S)-Lyase