Understanding Secondary Prevention Goals, Novel Lipid Therapies from 2026 Dyslipidemia Guidelines

Secondary prevention in the 2026 ACC/AHA Dyslipidemia Guideline is defined by an intensified focus on achieving LDL cholesterol goals rapidly and systematically, with a tiered framework distinguishing very high-risk patients from the broader ASCVD population and introducing updated guidance on sequencing of both established and newer lipid-lowering agents.

Ann Marie Navar, MD, PhD, a writing committee member and cardiovascular prevention specialist, outlines the characteristics defining very high-risk status: two or more prior cardiovascular events, or a single prior event accompanied by two or more high-risk features such as age over 65, active smoking, diabetes, heart failure, hypertension, or LDL above 100 mg/dL despite statin and ezetimibe therapy. For these individuals, the LDL cholesterol goal is less than 55 mg/dL.

The guideline acknowledges this threshold represents an area of ongoing evidence generation. Data from the VESALIUS trial, which examined PCSK9 inhibition in a lower-risk ASCVD population, were unavailable during the evidence review period closing in April 2025. For patients with ASCVD not meeting very high-risk criteria, an LDL target of less than 70 mg/dL is recommended, though the guideline offers an optional recommendation of less than 55 mg/dL for clinicians preferring a uniform target across the ASCVD population.

When statins alone are insufficient to achieve goal, the guideline provides Class I recommendations for the addition of ezetimibe and/or bempedoic acid and/or a PCSK9 monoclonal antibody. Bempedoic acid, newly approved since the 2018 guideline, now carries cardiovascular outcomes support from clinical trial data in statin-intolerant patients across both primary and secondary prevention settings. Inclisiran, a small interfering RNA targeting PCSK9, receives a Class IIa recommendation for patients unable to access or tolerate PCSK9 monoclonal antibodies, with cardiovascular outcomes data still pending.

Navar and committee vice chair Pamela B. Morris, MD, note ezetimibe and statins remain the most accessible starting point given their generic availability and tolerability profile. Selection among newer agents depends on patient preference, comorbidities, bempedoic acid is contraindicated in patients with gout, and the realities of insurance coverage and drug access, which vary substantially across practice settings.

Morris has no relevant disclosures to report. Navar reports disclosures with Amge, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Eli Lilly and Company, Esperion, Johnson & Johnson, Merck, Miga Health, NewAmsterdam Pharma, Novartis, Novo Nordisk, Sanofi, and Silence Therapeutics, among others.

References:

1. Blumenthal RS, Morris PB, Gaudino M, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. Published online March 13, 2026. doi:10.1016/j.jacc.2025.11.016
2. American College of Cardiology. ACC/AHA Issue Updated Guideline for Managing Lipids, Cholesterol - American College of Cardiology. American College of Cardiology. Published March 13, 2026. Accessed March 23, 2026. https://www.acc.org/About-ACC/Press-Releases/2026/03/13/18/01/ACCAHA-Issue-Updated-Guideline-for-Managing-Lipids-Cholesterol