Conference Coverage

Non-Statin Lipid Therapies Advance ASCVD Risk Reduction: Insights from Leading Cardiologists

Anthony Calabro, MA

Key Highlights

  • Non-statin agents (including PCSK9 inhibitors, bempedoic acid, and emerging CETP inhibitors) offer effective low-density lipoprotein cholesterol (LDL-C) lowering for patients unable to achieve lipid goals with statins.
  • Evidence from major cardiovascular outcomes trials supports add-on or alternative therapy to reach LDL-C thresholds as low as < 55 mg/dL in very high–risk patients.
  • Combination approaches improve efficacy, safety, and adherence while addressing barriers such as intolerance and access.

Introduction

At a recent Practical Updates in Primary Care virtual series session1, Daniel E. Soffer, MD of the University of Pennsylvania and Seth S. Martin, MD, MHS of Johns Hopkins University reviewed current and emerging non-statin lipid-lowering strategies. Their session emphasized evidence-based pathways for optimizing atherosclerotic cardiovascular disease (ASCVD) prevention through advanced lipid management.

Presentation Findings

The presentation underscored that low-density lipoprotein cholesterol (LDL-C) is the key modifiable driver of plaque formation and cardiovascular risk. Data from a meta-analysis of 26 randomized trials2 demonstrated that each 1 mmol/L (~38 mg/dL) reduction in LDL-C reduces major vascular events by 22%.

Beyond statins, the experts highlighted several proven and novel agents:

  • Ezetimibe, which provides modest incremental LDL-C reduction.
  • PCSK9 inhibitors (alirocumab, evolocumab), shown in FOURIER3 and ODYSSEY4 Outcomes to lower LDL-C by ~60% and cut major events by 15%
  • Inclisiran, an siRNA therapy offering twice-yearly dosing with sustained LDL-C reduction
  • Bempedoic acid, evaluated in the CLEAR Outcomes trial of 13,970 statin-intolerant patients, reduced LDL-C by 21.7% and major adverse CV events by 13%.5
  • Obicetrapib, a CETP inhibitor currently under investigation, achieved a 35% LDL-C reduction in the BROADWAY trial6 and ~45% when combined with ezetimibe in the TANDEM trial.7

Updated American Heart Association/American College of Cardiology8,9 and National Lipid Association guidelines10 recommend thresholds of < 70 mg/dL for high-risk and < 55 mg/dL for very high-risk patients. Evidence from FOURIER-OLE11 showed continued safety and benefit with “lower for longer” LDL-C exposure

Clinical Implications

Clinicians are urged to individualize therapy based on risk, tolerance, efficacy, and cost. Non-statin therapies play a central role in both primary and secondary prevention, particularly for those with familial hypercholesterolemia, statin intolerance, or residual elevated LDL-C despite maximal therapy.

Dr Martin’s research emphasized precision lipid assessment, noting that standard Friedewald calculations can underestimate LDL-C at low levels, leading to undertreatment. Advanced equations, such as the Martin/Hopkins method, improve accuracy and treatment decisions. Combination approaches—such as statins plus ezetimibe or PCSK9 inhibitors, and oral regimens like bempedoic acid plus ezetimibe—enable more patients to reach evidence-based goals safely and sustainably.

Expert Commentary

“There is no apparent lower safety limit for LDL-C, and lower levels are associated with better outcomes,” said Dr Martin, professor of cardiology at Johns Hopkins University.

Dr Soffer added, “Addressing barriers—such as risk perception, misinformation, and access—is essential for implementing optimal lipid-lowering strategies in clinical practice.”

Conclusion

The evolving landscape of lipid management underscores that non-statin therapies are no longer niche options but essential tools for comprehensive ASCVD prevention. Clinicians should leverage combination regimens and emerging agents to achieve aggressive yet safe LDL-C targets, ultimately improving long-term cardiovascular outcomes.

References:

  1. Soffer DE, Martin SS. Enhancing cardiovascular health through lipid management: non-statin therapeutics for effective risk reduction. Presented at: Practical Updates in Primary Care; November 5, 2025. https://www.hmpglobalevents.com/pupc-2025.
  2. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681. doi:10.1016/S0140-6736(10)61350-5
  3. Sabatine MS, Giugliano RP, Keech AC, et al; FOURIER Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722.
  4. Schwartz GG, Steg PG, Szarek M, et al; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097-2107.
  5. 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(14):1353-1364.
  6. Nicholls SJ, Nelson AJ, Ditmarsch M, et al. Safety and efficacy of obicetrapib in patients at high cardiovascular risk (BROADWAY trial). N Engl J Med. Published online May 7 2025. doi:10.1056/NEJMoa2415820.
  7. Sarraju A, Brennan D, Hayden K, et al. Fixed-dose combination of obicetrapib and ezetimibe for LDL-cholesterol reduction (TANDEM trial). Lancet. Published online May 7 2025. doi:10.1016/S0140-6736(25)00721-4.
  8. 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. Circulation. 2019;139(25):e1082-e1143
  9. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk. J Am Coll Cardiol. 2022;80(14):1366-1418
  10. Soffer DE, Jacobson TA, Bays HE, et al. Lipid measurements in the management of cardiovascular diseases: Practical recommendations from the National Lipid Association writing group. J Clin Lipidol. 2024;18(5):e647-e663
  11. Gaba P, Giugliano RP, Sabatine MS, et al. Evolocumab in patients with atherosclerotic cardiovascular disease: extended follow-up from the FOURIER-OLE study. Circulation. 2023;147(16):1192-1203.