The Role of Lipid Lowering Therapy and Achieving Optimal LDL Levels

The association between elevated LDL levels and cardiovascular adverse events has been well established and the effects of lipid lowering therapies have demonstrable favorable effects on coronary plaque morphologies. The YELLOW III Trial (Effect of Evolocumab on Coronary Plaque Characteristics in Stable Coronary Artery Disease: a Multimodality Imaging Study) which focused on the effect of Evolocumab on plaque morphology in stable patients on maximal statin therapy. The study was presented by Dr. Annapoorna S. Kini, an interventional cardiologist at Mount Sinai Hospital New York and principal investigator of this trial at the American College of Cardiology meeting in New Orleans ton March 4-6th, 2023. The YELLOW III trial is part of a trilogy of studies that began 12 years ago, addressing lipid-lowering therapy and plaque formation.

In the pilot, the Yellow I Trial [Reduction in Yellow Plaque by Aggressive Lipid Lowering Therapy], the objective focused on the impact of short-term intensive statin therapy on intracoronary plaque lipid content [1]. FFR (Fractional Flow Reserve), IVUS (Intravascular Ultrasound), and NIRS (Near-Infrared Spectroscopy) were used to analyze obstructive lesions. This trial randomized patients into standard statin therapy, which are Simvastin, Pravastatin, Lovastatin, Atorvastin, Fluvastatin [7], and those taking a high intensity statin, Rosuvastatin 40 mg for 6-8 weeks. This study concluded that even short-term statin use reduces the lipid content of obstructive lesions.

In the follow-up study, the YELLOW II Trial [Intracoronary Imaging, Cholesterol Efflux, and Transcriptomes After Intensive Statin Treatment], investigators sought to understand what happens to plaque morphology or, in other words, “How does the cholesterol plaque come out?” [4]. Participants were treated with Rosuvastatin. This study analyzed participants’ genetic and transcriptomic changes. Optical Coherence Tomography (OCT) was utilized to better understand plaque morphological changes with statin exposure and the relationship between the lipid core and fibrous cap of coronary plaques [3]. OCT was also able to demonstrate changes in LDL, HDL, apo A-I, and macrophage functionality [2].  Patients experienced increased fibrous cap stabilization, and cholesterol efflux; CRP and other inflammatory markers decreased.

The current guidelines for secondary prevention now recommend a goal of LDL of 55 mg/dl [8]. For select patients, statin therapy and other adjunctive therapies are insufficient to adequately reduce LDL to suitable levels but can possibly be reduced with PCSK9 inhibitors such as Evolocumab which was the rational for the YELLOW III trial. The trial ultimately enrolled 110 patients. Participants enrolled had non-obstructive lesions and were given Evolocumab for 26 weeks. Participants with fibroatheroma saw a reduction from 48 % to 13%, showing a total 35 % reduction [5]. NIRS measurements and the total LDL also decreased [1].

Upon reflecting on the efficacy of the aggressive lipid-lowering therapy, Dr. Kini posed the question, “As Cardiologists, when will we be able to start prescribing aggressive lipid therapy such as Evolucumab? Moreover, how does a provider determine which patient receives either a statin therapy or a PCSK9 inhibitor? [1]” To better address this issue, Dr. Kini hopes to present a genetic analysis to help identify which patients will benefit from directly taking Evolocumab and which patients could remain on statin therapy.

Dr. Kini emphasizes there is more work to be done in this space. She looks to do a deeper study into transcriptional genomics to determine which patients will benefit from either therapy.

Chelsea Tweneboah is a medical student St. George’s University and served as a CardioNerds Conference Scholar for the American College of Cardiology 2023 Scientific Sessions.


  1. ACC 23: Effect of Evolocumab on Coronary Plaque Morphology: The YELLOW III Study, 2023.
  2. YELLOW III Study | Effects of PCSK9 Inhibitors on Coronary Plaque | Dr. Annapoorna Kini, 2023.
  3. “Changes in Plaque Lipid Content After Short-Term Intensive Versus Standard Statin Therapy | Elsevier Enhanced Reader.” Accessed March 9, 2023.
  4. “Intracoronary Imaging, Cholesterol Efflux, and Transcriptomes After Intensive Statin Treatment | Elsevier Enhanced Reader.” Accessed March 9, 2023.
  5. com. “Stable CAD Plaque Morphology Improved by PCSK9 Inhibitors: YELLOW III,” March 4, 2023.
  6. HCP Live. “YELLOW III Study Improves Understanding of Evolocumab in CAD Treatment,” March 5, 2023. .
  7. Sizar, Omeed, Swapnil Khare, Radia T. Jamil, and Raja Talati. “Statin Medications.” In StatPearls. Treasure Island (FL): StatPearls Publishing, 2022.
  8. US Preventive Services Task Force, Carol M. Mangione, Michael J. Barry, Wanda K. Nicholson, Michael Cabana, David Chelmow, Tumaini Rucker Coker, et al. “Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: US Preventive Services Task Force Recommendation Statement.” JAMA 328, no. 8 (August 23, 2022): 746.