ACC Updates LDL-Cholesterol Lowering Recommendations, Making Room for Ezetimibe and PCSK9 Inhibitors

The American College of Cardiology has updated their recommendations for the management of elevated LDL cholesterol levels in high-risk patients, specifically addressing the use of non-statin therapies, such as protein convertase subtilisin/kexin 9 (PCSK9) inhibitors and ezetimibe (Zetia, Merck/Schering-Plough), in patients unable to achieve sufficient LDL-cholesterol lowering.

Take Home. ACC Updates LDL-Cholesterol Lowering Recommendations, Making Room for Ezetimibe and PCSK9 Inhibitors

For many high-risk patients who require additional LDL-cholesterol lowering beyond that achieved with a statin, the first second-line agent should be ezetimibe 10 mg daily, a recommendation based on the safety and efficacy of the drug in the IMPROVE-IT study of patients with acute coronary syndromes.

Only after ezetimibe has been tried should physicians consider adding or replacing ezetimibe with one of the PCSK9 inhibitors, alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) or evolocumab (Repatha, Amgen), according to the expert consensus statement published online April 1, 2016, in the Journal of the American College of Cardiology.

The updated “decision pathway,” whose development was led by chair Donald Lloyd-Jones, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), and vice-chair Pamela Morris, MD (Medical University of South Carolina, Charleston),is intended to provide guidance for doctors and patients regarding the use of non-statin therapies not currently covered by the existing clinical guidelines.

In the 2013, the American College of Cardiology/American Heart Association (ACC/AHA) shifted away from traditional LDL- and non-HDL–cholesterol targets and instead recommended statin therapy based on patient risk. As part of those guidelines, patients who fell into one of four patient groups were eligible for statin therapy, with the goal to achieve at least a 50% reduction in LDL cholesterol levels with a high-intensity statin for those with atherosclerotic cardiovascular disease or those with a baseline LDL-cholesterol level ≥ 190 mg/dL. Others were recommended a moderate-dose statin to achieve a 30% to 50% reduction in LDL cholesterol levels.

For high-risk patients with clinical atherosclerotic cardiovascular disease, the updated ACC consensus document recommends ezetimibe first if the patient fails to achieve at least a 50% reduction in LDL cholesterol. If adding ezetimibe doesn’t achieve that goal, evolocumab or alirocumab can either be added or used to replace ezetimibe. For the patient with clinical atherosclerotic cardiovascular disease and a baseline LDL-cholesterol ≥ 190 mg/dL not due to secondary causes, a bile-acid sequestrant can also be considered as second-line therapy before adding the PCSK9 inhibitor.

In primary prevention, the ACC states ezetimibe can be considered for patients without existing cardiovascular disease who have a baseline LDL cholesterol level ≥ 190 mg/dL and who are unable to achieve the desired reduction in LDL cholesterol levels. In addition, a bile-acid sequestrant can also be considered as second-line therapy. If those two options fail, PCSK9 inhibition can be used as treatment.  

As part of the 2013 cholesterol guidelines, the ACC/AHA highlighted treatment options for adults aged 40-75 years old without cardiovascular disease but who have diabetes and LDL-cholesterol level ranging from 70 to 189 mg/dL. The updated consensus opinion states that in the absence of atherosclerotic cardiovascular disease or baseline LDL cholesterol levels ≥ 190 mg/dL, PCSK9 inhibitors “do not have an established role for primary prevention” in individuals with diabetes. Instead, consider ezetimibe first, or a bile-acid sequestrant second.

In addition, the guidelines recommend treatment for individuals without evidence of cardiovascular disease or diabetes but who have a 10-year risk ≥ 7.5%. In these primary-prevention patients, PCSK9 inhibitors should not be considered, according to the new consensus statement. If the patient is unable achieve success with a moderate-dose statin—success defined as a 30% to 50% reduction in LDL cholesterol—consider a switch to a high-intensity statin if that fails. Should those efforts not work, the addition of ezetimibe is an option.

In addition to the non-statin options, the ACC experts also emphasize the importance of addressing statin intolerance and intensifying lifestyle efforts in all clinical scenarios, or increasing the intensity of statin therapy (if not already on a maximally tolerated dose), as part of the decision pathway before adding non-statin drugs. 





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Michael O’Riordan is the Managing Editor for TCTMD. He completed his undergraduate degrees at Queen’s University in Kingston, ON, and…

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  • Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2-16 ACC Expert Consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk. J Am Coll Cardiol. 2016; Epub ahead of print.

  • Lloyd-Jones reports no conflicts of interest.
  • Morris reports serving as a consultant to Amgen, AstraZeneca, Sanofi/Regeneron and reports conducting research funded by Amgen.