A 54-year-old woman with a medical history of hypertension (HTN), type 2 diabetes mellitus (DM), and previous pre-eclampsia presents as a new patient for a routine health maintenance examination.
She has a family history of premature coronary artery disease. Her father had a myocardial infarction at 48 years of age and underwent three-vessel coronary artery bypass grafting at 54 years of age. She works as a computer programmer, spending most of her day sitting at her computer. She has been smoking one-half pack of cigarettes daily for the previous 15 years. She has been told of "high cholesterol" at previous visits and has been recommended for statin therapy. She was initially started on atorvastatin but could not tolerate any dose because of muscle aches. She has been able to tolerate rosuvastatin 5 mg daily; however, repeated attempts to uptitrate her dose have been unsuccessful. She is adamant that she will not take an injectable medication for her cholesterol levels.
Her current medications include telmisartan 40 mg daily, metformin 1000 mg daily, empagliflozin 10 mg daily, rosuvastatin 5 mg daily, and ezetimibe 10 mg daily. On examination, her height is 157.5 cm, weight is 77 kg, body mass index is 31.1 kg/m2, and blood pressure is 126/72 mm Hg. The remainder of her physical examination findings are unremarkable. She is of self-reported Black race.
Laboratory evaluation includes a metabolic panel with significant findings of blood urea nitrogen level 20 mg/dL, creatinine (Cr) level 1.3 mg/dL, aspartate aminotransferase level 24 U/L, alanine aminotransferase level 29 U/L, and fasting glucose level 137 mg/dL. Urine albumin-to-Cr ratio is found to be 100 mcg/mg, hemoglobin A1c concentration is 7%, thyroid-stimulating hormone level is within the reference range, and uric acid level is 5.3 mg/dL. A fasting lipid profile reveals total cholesterol level 164 mg/dL, low-density lipoprotein cholesterol (LDL-C) level 88 mg/dL, high-density lipoprotein cholesterol (HDL-C) level 43 mg/dL, and triglyceride (TG) level 138 mg/dL. A coronary artery calcium (CAC) score obtained before her visit was found to be 347 Agatston units (AU).
In addition to aggressive lifestyle modification including dietary intervention and smoking cessation, shared decision making leads to adding bempedoic acid into her treatment regimen to further reduce her risk of an atherosclerotic cardiovascular disease (ASCVD) event.
Which one of the following best describes the mechanism of action of bempedoic acid?
Show Answer
The correct answer is: D. Adenosine triphosphate (ATP)–citrate lyase inhibitor.
Answer choice D is the correct choice. Bempedoic acid is a novel lipid-lowering therapy that works via inhibition of ATP-citrate lyase, an enzymatic reaction upstream of HMG-CoA reductase (the target of statins) in the cholesterol synthesis pathway.1 Bempedoic acid is delivered as a prodrug that is activated by very-long-chain acyl-coenzyme A synthetase-1, an enzyme present in hepatic muscle cells but not skeletal muscle cells. This mechanism provides a potential explanation for the reduced muscle-related symptoms that have been known to occur with statin therapy. Inhibiting the production of intrahepatic cholesterol leads to an upregulation in hepatic low-density lipoprotein (LDL) receptors and increases clearance of LDL particles from circulation.
In this case, the patient was 54 years of age and had numerous risk factors for ASCVD, including HTN, DM, family history of ASCVD in a first-degree relative before 55 years of age, and smoking. In addition, she had numerous risk-enhancing factors, including previous pre-eclampsia, a sedentary lifestyle, obesity, metabolic syndrome, microalbuminuria, and HDL-C level <50 mg/dL. Finally, having a CAC score >300 is a clear marker of elevated risk warranting more aggressive preventive therapies.2 Patients with CAC scores >300 have rates of ASCVD similar to those of secondary-prevention populations.2
According to the 2022 ECDP, a patient with CAC score >100 AU or >75th percentile for age/sex/race should be treated to an LDL-C threshold of <70 mg/dL. If patients cannot achieve this threshold with maximally tolerated statin therapy alone, the addition of nonstatin therapies can be considered. This patient maintained LDL-C level >70 mg/dL. She had been unable to tolerate uptitration of her statin therapy and had not achieved the appropriate LDL-C level reduction on moderate-intensity statin and ezetimibe; therefore, additional lipid-lowering therapies would be warranted. Given her wishes to avoid injectable therapies, such as the proprotein convertase subtilisin/kexin type 9 inhibitors evolocumab or alirocumab, the next most reasonable choice would be the addition of bempedoic acid, an oral medication.
The CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) trial enrolled secondary-prevention and primary-prevention patients at high risk who had intolerance of statin therapy and maintained LDL-C levels >100 mg/dL.5 Trial participants were 48% female and 46% had DM. Over a median follow-up of 40 months, bempedoic acid significantly reduced four-point major adverse cardiovascular events (MACE) by 13%. Reductions in MACE were even greater in the primary-prevention subgroup. Therefore, bempedoic acid is a good choice for this patient for ASCVD risk reduction.
Lomitapide is an inhibitor of MTP, which is a protein located in the endoplasmic reticulum that is responsible for the transfer of TGs onto apolipoprotein (b) (Apo[b]) particles to create chylomicrons in enterocytes and very-low-density lipoproteins in hepatocytes.6 Lomitapide is approved as an adjunct to a low-fat diet and other lipid-lowering therapies for reduction of total cholesterol, LDL-C, and Apo(b) levels in patients with homozygous familial hypercholesterolemia (FH).7 She did not have homozygous FH; therefore, the use of lomitapide was not indicated.
HMG-CoA reductase is the rate-limiting enzyme in the cholesterol synthesis pathway, and the target of statin therapy. She was already taking maximally tolerated statin therapy, making this answer choice an incorrect choice.
ANGPTL3 is responsible for the inhibition of lipoprotein lipase and endothelial lipase, and is the mechanism of action of the novel lipid-lowering therapy evinacumab.8 Evinacumab is approved by the Food and Drug Administration (FDA) for lowering LDL-C levels in patients with homozygous FH,9 and is given by intravenous infusion once monthly. This patient did not have homozygous FH; therefore, the use of evinacumab was not indicated.
This patient case quiz is part of an ACC course titled Bempedoic Acid: New Evidence Transforming the LDL-C Treatment Landscape. Educational grant support is provided by Esperion. To visit the Online Course page for the Bempedoic Acid: New Evidence Transforming the LDL-C Treatment Landscape Grant, click here.
References
Pinkosky SL, Filippov S, Srivastava RA, et al. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J Lipid Res 2013;54:134-51.
Budoff MJ, Kinninger A, Gransar H, et al.; CONFIRM Investigators. When does a calcium score equate to secondary prevention?: Insights from the multinational CONFIRM Registry. JACC Cardiovasc Imaging 2023;16:1181-9.
Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285-e350.
Lloyd-Jones DM, Morris PB, Ballantyne CM, et al.; Writing Committee. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2022;80:1366-418.
Nissen SE, Lincoff AM, Brennan D, et al.; CLEAR Outcomes Investigators. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med 2023;388:1353-64.
Rader DJ, Kastelein JJ. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation 2014;129:1022-32.
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