Updated Clinical Guidelines Expand Role of Non-Statin Therapies in Proactive Approach to Dyslipidemia Management

The release of the 2026 American College of Cardiology/American Heart Association Multisociety Guideline on the Management of Dyslipidemia [1] marks a shift in the primary prevention and management of cardiovascular conditions, toward personalized treatment goals and strategies for individuals living with or at risk of developing atherosclerotic cardiovascular disease (ASCVD). The new recommendations, which replace the 2018 guidelines, emphasize earlier screening and more intensive interventions to reduce lifetime exposure to atherogenic lipoproteins, along with special considerations for the management of adults and adolescents in certain high-risk categories.

Non-Statin Therapies Provide Safe, Effective Options for Decreasing Cholesterol

While statins remain the cornerstone of lipid management, multiple non-statin medications have emerged as effective add-on therapies that can help patients achieve optimal low-density lipoprotein cholesterol (LDL-C) goals, and as alternative therapies for individuals with statin intolerance. Non-statin agents have demonstrated incremental reductions in LDL-C levels when combined with low- or moderate-intensity statin therapy [2]. According to expert recommendations, adding a non-statin lipid-lowering agent often provides a more predictable and significant reduction in LDL-C levels than simply increasing statin doses. Moreover, this strategy can reduce the incidence of statin-associated muscle symptoms. Different oral and injectable agents may be used to tailor treatment and prevention to individual patient characteristics and cardiovascular risk levels. Evidence-based options for achieving LDL-C targets include oral medications such as ezetimibe, administered alone or in combination with bempedoic acid, and bile acid sequestrants. Ezetimibe, a daily oral drug with a low incidence of side effects, is recommended as the primary add-on therapy for patients who fail to reach LDL-C goals with maximally tolerated statins. When added to statin therapy, ezetimibe resulted in incremental lowering of LDL-C levels and improved cardiovascular outcomes [3]. Bile acid sequestrants are often the preferred lipid-lowering agents for women of childbearing age, pregnant patients, and nursing mothers, because they are not absorbed systemically. However, their use remains limited by gastrointestinal complaints and drug-drug interactions. The 2026 recommendations include an expanded role for bempedoic acid, an adenosine triphosphate (ATP)-citrate lyase inhibitor that decreased the rate of cardiovascular events when used for primary and secondary prevention in high-risk individuals [4]. Bempedoic acid, administered alone or combined with ezetimibe, has emerged as a key non-statin therapy that can help statin-intolerant patients achieve lower LDL-C goals. Injectable proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have demonstrated potent LDL-C lowering effects and are recommended as add-on therapy for primary and secondary prevention in individuals with a very high risk of ASCVD events. Inclisiran, a small-interfering ribonucleic acid-based PCSK9i, is recommended for individuals with clinical ASCVD or heterozygous familial hypercholesterolemia (HeFH) who cannot achieve LDL-C goals on maximally tolerated statins. Inclisiran has demonstrated LDL-C reductions ranging from 48% to 52% [5,6] and is currently under investigation in several clinical trials, to determine whether the LDL-C lowering achieved with this medication translates into improved cardiovascular outcomes.

Bempedoic Acid Receives Multiple Class I Recommendations

Bempedoic acid is a prodrug that requires activation by a specific enzyme, very long-chain acyl-CoA synthetase-1 (ACSVL1), which is exclusively present in the liver and absent in skeletal muscle, making it an ideal option for individuals who discontinue statins due to myotoxicity. In statin-intolerant patients with hypercholesterolemia, bempedoic acid lowered LDL-C levels by a mean of 26.5% compared with placebo and achieved nearly a 40% reduction in LDL-C levels when combined with ezetimibe [7]. When added to a maximally tolerated statin, bempedoic acid decreased LDL-C levels by an additional 17% to 18% [8]. Therapy was generally well tolerated in this challenging-to-treat patient population. In the 2026 guidelines, bempedoic acid is recommended as a lipid-lowering therapy, alone or in combination with other agents, for statin-intolerant individuals who fall in several high-risk categories:

• In adults with clinical ASCVD who experience statin-attributed muscle symptoms on the recommended intensity of statin therapy and cannot achieve recommended treatment goals, bempedoic acid may be added to a lower-dose statin (if tolerated) to reduce risk for ASCVD (class I)
• Initiation of bempedoic acid and/or ezetimibe is recommended for adults with diabetes who have statin-attributed side effects (class I)
• In adults with severe hypercholesterolemia, with or without clinical ASCVD, who are treated with maximally tolerated statin therapy, bempedoic acid may be added to achieve optimal LDL-C goals (class I)
• Adding bempedoic acid, with or without ezetimibe, may also be considered for achieving LDL-C goals <55 mg/dL and non–high density lipoprotein cholesterol (HDL-C) goals <85 mg/dL in adults with clinical ASCVD who are at very high risk on maximally tolerated statin therapy, and LDL-C targets <70 mg/dL and non–HDL-C targets <100 mg/dL in those with ASCVD who are not at very high risk on statin therapy (class IIa)
• Bempedoic acid may be added to intensified statin therapy in adults with subclinical atherosclerosis, as well as in adults at high (≥10%) 10-year estimated risk for ASCVD on maximally tolerated statin therapy who cannot achieve LDL-C goals <70 mg/dL and non–HDL-C goals <100 mg/dL (class IIa).

Recent advancements in non-statin therapies have expanded the range of options available for the primary prevention of ASCVD and adverse cardiovascular events in high-risk individuals. Yet, these medications are often underutilized in clinical practice due to clinical inertia and misconceptions regarding their role and efficacy.

“We are not going to get there with statins alone,” said Ann Marie Navar, MD, PhD, associate professor at UT Southwestern Medical Center, in Dallas, Texas and a member of the writing committee for the updated guidelines. “Even ezetimibe, which is cheap and generic and easy [to prescribe], is still not used to the degree that it needs to be to get our patients to goal. I think the key is to educate our colleagues on combination therapy and work on messaging to patients that, if you are starting at an LDL cholesterol [level] that is 160 mg/dL and your goal is 55 mg/dL, it is going to take a couple of steps to get there. The only way we are going to do that is by increasing the utilization of non-statins, starting with ezetimibe and continuing on to the novel non-statins, [including] bempedoic acid and PCSK9 inhibitors. Without greater uptake of [those therapies], we are not going to get our patients to goal.” Patient and provider education can increase the uptake of these therapies, both in combination with statins and as monotherapy in statin-intolerant patients, with the potential to achieve more effective reductions in lipoprotein levels and prevention of cardiovascular disease.

References:

1. Blumenthal R, Morris P, 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. JACC null2026, 0 (0). https://www.jacc.org/doi/10.1016/j.jacc.2025.11.016
2. Kamanu C, Karalis DG. The Role of Non-Statin Lipid Lowering Therapies to Reduce ASCVD Events in Primary Prevention. Curr Atheroscler Rep 2025 Apr 2;27(1):46.
3. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387–97
4. Nicholls SJ, Nelson AJ, Lincoff AM, et al. Impact of Bempedoic Acid on Total Cardiovascular Events: A Prespecified Analysis of the CLEAR Outcomes Randomized Clinical Trial. JAMA Cardiol 2024;9(3):245–253.
5. Ray KK, Troquay RPT, Visseren FLJ, et al. Long-term efficacy and safety of inclisiran in patients withhigh cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. Lancet Diabetes Endocrinol 2023;11:109–119.
6. Ray KK, Wright RS, Kallend D, et al; ORION-10 and ORION-11 Investigators. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med 2020 Apr 16;382(16):1507-1519.
7. Laufs U, Ballantyne CM, Banach M, et al. Efficacy and safety of bempedoic acid in patients not receiving statins in phase 3 clinical trials. J Clin Lipidol 2022;16(3):286-297.
8. Ruscica M, Sirtori CR, Carugo S, et al. Bempedoic Acid: for Whom and When. Curr Atheroscler Rep 2022;24(10):791-801.

Access the full 2026 ACC/AHA Joint Committee Guideline on the Management of Dyslipidemia here.