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.
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.
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Accepted for Publication: June 15, 2023.
Published Online: August 16, 2023. doi:10.1001/jamacardio.2023.2402
Corresponding Author: Robert P. Giugliano, MD, SM, TIMI Study Group, 60 Fenwood Rd, Hale BTM Ste 7022, Boston, MA 02115 (firstname.lastname@example.org).
Conflict of Interest Disclosures: Dr Giugliano reported grants to Brigham and Women's Hospital from Amgen Research, Ionis Research, and Daiichi Sankyo Research; consulting and continuing medical education (CME) program and lectures fees from Amgen, Daiichi Sankyo, and Pfizer; CME programs and lectures fees from Medscape, Menarini, and Merck; personal fees from Dr Reddy's Laboratories (academic lecture), Medical Education Resources (CME lectures), and Voxmedia (consulting and CME programs); and consulting fees from Amarin, Esperion, CVS Caremark, Novartis, and Sanofi outside the submitted work. No other disclosures were reported.
Additional Contributions: We thank Maria J. Monterroso, BA, for designing Figure 1. We thank Freddy E. Duarte Sis, CIA, for designing Figure 2. Compensation was not received.
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