New U.S. Lipid Guideline Redefines Risk Categories, Boosts Non-Cholesterol Tests

Risk calculations guiding lipid-lowering therapy are given an overhaul in new guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA).

Now, in adults 30-79 years old without atherosclerotic cardiovascular disease (ASCVD) or subclinical atherosclerosis and with LDL cholesterol in the 70-189 mg/dL (1.8-4.9 mmol/L) range, the PREVENT-ASCVD equations are strongly endorsed (class I recommendation) to estimate 10-year ASCVD risk, which is to be categorized as low (<3%), borderline (3% to <5%), intermediate (5% to <10%), or high (≥10%).

A 10-year risk of 5% by PREVENT is thus considered equivalent to 7.5% by the old pooled cohort equations (PCE) featured in prior guidelines as the risk threshold for primary prevention statin therapy, according to the ACC/AHA guideline writing committee chaired by Roger Blumenthal, MD, of Johns Hopkins Medicine in Baltimore, Maryland.

“Given the enhanced accuracy of the PREVENT-ASCVD equations, which provide risk estimates that are approximately 40% to 50% lower than the PCE, the current guideline panel selected the 10-year estimated ASCVD risk threshold of ≥3% for beginning consideration of [lipid-lowering therapy],” explained Blumenthal and colleagues in the guideline, published in Journal of the American College of Cardiology and in Circulation.

They cited an estimate that out of U.S. adults not already taking statins, 25 million would be eligible for statins based on their PREVENT-ASCVD risk hitting 3%, compared with 26 million per a PCE-calculated ASCVD risk of 5% or higher.

“While we want to try to optimize healthy lifestyle habits as the first step to lower cholesterol, we realize that if lipid numbers aren’t within the desirable range after a period of lifestyle optimization, we should consider adding lipid-lowering medication earlier than we would have considered 10 years ago. And lower LDL cholesterol for longer, just like lower blood pressure for longer, results in much greater protection against future heart attack and stroke risk,” Blumenthal said in a press release.

Last year, American guidelines for identifying candidates for blood pressure medication also switched over to the PREVENT framework.

Risk Enhancers, Tests Besides Cholesterol

In the new lipid guideline, for primary prevention in adults with borderline risk by PREVENT, consideration of risk enhancers is reasonable to weigh the benefit of initiating lipid-lowering therapy as an adjunct to lifestyle management (class IIa recommendation).

These risk enhancers include history of premature ASCVD in a parent or sibling, higher-risk ancestry (e.g., South Asian, Filipino), high polygenic risk, chronic inflammatory disease, lipoprotein(a) ≥125 nmol/L or ≥50 mg/dL, high-sensitivity C-reactive protein ≥2 mg/L on more than one occasion, nonfasting triglycerides persistently ≥175 mg/dL (2 mmol/L), and fasting triglycerides ≥150 mg/dL (1.7 mmol/L).

Meanwhile, biomarker assessments outside LDL and HDL cholesterol are newly encouraged to help gauge ASCVD risk in the new guideline.

• Lipoprotein(a) should be measured at least once in all adults (class I)
• Noncontrast coronary artery calcium (CAC) scans should be performed if the decision to initiate lipid-lowering therapy is uncertain for adults at intermediate risk and select adults at borderline risk with no prior ASCVD (class I)
• Apolipoprotein B is a reasonable test to perform in people already on lipid-lowering therapy who may be candidates for further therapeutic intervention once LDL and non-HDL cholesterol goals are achieved (class IIa)

“Having healthy LDL-cholesterol levels or [HDL]-cholesterol, traditionally thought of as ‘good’ cholesterol, isn’t necessarily a ‘get out of jail free’ card,” Blumenthal said. “Measuring other biomarkers can give a more complete picture of someone’s cardiovascular risk and help inform decisions about whether lipid-lowering therapy is needed sooner rather than later or if more intensive therapy is warranted.”

Lipid-lowering therapy is recommended, for example, when a CAC score turns out to be >0 AU (especially if it is ≥100 AU or ≥75th standardized percentile) in adults at intermediate risk and select adults at borderline risk (class I).

For patients with moderate subclinical atherosclerosis, the general goal is to lower LDL cholesterol to <70 mg/dL for those with a CAC score ≥100 AU (and an optional goal of LDL cholesterol <55 mg/dL for those with CAC score ≥300 AU).

In the case of elevated lipoprotein(a), reaching ≥125 nmol/L or ≥50 mg/dL, optimal early control of modifiable cardiovascular risk factors is recommended to reduce ASCVD risk (class I); those with clinical ASCVD and elevated lipoprotein(a) not meeting cholesterol target goals on maximally tolerated statin therapy should start PCSK9 monoclonal antibody therapy to reduce ASCVD risk (class I).

More Non-Statin Treatments Endorsed

The landscape of lipid-lowering therapies is also changed in the new ACC/AHA guideline, with newer options pushed to greater prominence.

Ezetimibe (Zetia), a PCSK9 monoclonal antibody, and bempedoic acid (Nexletol) are equally recommended as adjunct therapies to achieve LDL cholesterol <100 mg/dL and a non-HDL cholesterol goal of <130 mg/dL and to reduce ASCVD risk in adults with severe hypercholesterolemia (LDL cholesterol ≥190 mg/dL) without clinical ASCVD, additional ASCVD risk factors, heterozygous familial hypercholesterolemia, or subclinical atherosclerosis who are on maximally tolerated statin therapy (class I).

These three options are also recommended for bringing LDL cholesterol down to <55 mg/dL and non-HDL cholesterol down to <85 mg/dL in adults with severe hypercholesterolemia and clinical ASCVD already on maximally tolerated statin therapy (class I).

Inclisiran (Leqvio) gets a weaker class IIa recommendation for lowering LDL cholesterol in adults with severe hypercholesterolemia with or without clinical ASCVD and LDL cholesterol ≥100 mg/dL despite maximally tolerated statin with or without ezetimibe therapy.

On the other hand, the guideline explicitly recommends against dietary supplements for cholesterol- or triglyceride-lowering in people with dyslipidemia, on account of limited and inconsistent data and/or limited benefits (class III).

Dietary supplements had not been addressed in the last American lipid guideline from 2018.

The latest guideline was developed in collaboration with and is endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, Association of Black Cardiologists, American College of Preventive Medicine, American Diabetes Association, American Geriatrics Society, American Pharmacists Association, American Society for Preventive Cardiology, National Lipid Association, and Preventive Cardiovascular Nurses Association.

Of note, revisions to this new guideline are already being planned in the wake of the recent VESALIUS-CV trial report, according to guideline writing committee leaders.

In that study, addition of the PCSK9 inhibitor evolocumab (Repatha) to stable lipid-lowering therapy reduced cardiovascular risk in patients with atherosclerosis or high-risk diabetes but no history of myocardial infarction (MI) or stroke — proving benefit in a broader spectrum of patients earlier in the atherosclerotic disease process than previously studied.

“The significant cardiovascular benefits with more intensive lowering of LDL cholesterol to <55 mg/dL in patients without previous MI or stroke in VESALIUS-CV now blur the distinction between ASCVD risk categories when defining a 'goal' LDL cholesterol value," according to Blumenthal and guideline committee vice-chair Pamela Morris, MD, of Medical University of South Carolina in Charleston.

“Thus, future updates to the 2026 ACC/AHA/Multisociety Dyslipidemia Guideline should include a single pathway of care for all patients with ASCVD … with an optimal LDL-C goal of <55 mg/dL to be achieved via pharmacotherapy as well as lifestyle optimization," the duo wrote in an editorial.

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