LAUSR

To review randomized interventional clinical and imaging trials that support lower targeted atherogenic lipoprotein cholesterol goals in “extreme” and “very high” atherosclerotic cardiovascular disease (ASCVD) risk settings. Major atherosclerotic cardiovascular event (MACE) prevention among the highest risk patients with ASCVD requires aggressive management of global risks, including lowering of the fundamental atherogenic apolipoprotein B-associated lipoprotein cholesterol particles [i.e., triglyceride-rich lipoprotein remnant cholesterol, low-density lipoprotein cholesterol (LDL-C), and lipoprotein(a)]. LDL-C has been the long-time focus of imaging studies and randomized clinical trials (RCTs). The 2004 adult treatment panel (ATP-III) update recognized that the long-standing targeted LDL-C goal of < 100 mg/dL potentially fostered substantial undertreatment of the very highest coronary heart disease (CHD) risk individuals and was lowered to < 70 mg/dL as an “optional” goal for “very high” 10-year CHD [CHD death + myocardial infarction (MI)] risk exceeding 20%. This evidence-based guideline change was supported by the observed benefits demonstrated in the high-risk primary and secondary prevention populations in the Heart Protection Study (HPS), the acute coronary syndrome (ACS) population in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 trial (PROVE-IT), and the secondary prevention population in the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) intravascular ultrasound (IVUS) study. Subsequent national and international guidelines maintained a targeted LDL-C goal < 70 mg/dL, or a threshold for management of > 70 mg/dL for patients with CHD, CHD risk equivalency, or ASCVD. Subgroup or meta-analyses of several RCTs, IVUS imaging studies, and the ACS population in IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) supported the evidence-based 2017 American Association Clinical Endocrinologist (AACE) guideline change establishing a targeted LDL-C goal < 55 mg/dL, non-HDL-C < 80 mg/dl, and apolipoprotein B (apo B) < 70 mg/dL for patients at “Extreme” ASCVD risk, i.e., 10-year 3-point-MACE-composite (CV death, non-fatal MI, or ischemic stroke) risk exceeding 30%. Moreover, with no recognized lower-limit-associated intolerance or safety issues, even more intensive lowering of atherogenic cholesterol levels is supported by the following evidence base: (1) analysis of eight high-intensity statin-based prospective secondary prevention IVUS atheroma volume regression trials; (2) a distribution analysis of on-treatment, ezetimibe and background-statin, of the very low LDL-C levels reached and CVD event risk in the IMPROVE-IT ACS population; (3) the secondary prevention Global Assessment of Pl\aque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) on background-statin; and (4) the secondary prevention population of Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER). By example, in FOURIER, the population on background-statin at a baseline median 92 mg/dL achieved median LDL-C level of 30 mg/dL and non-HDL-C to < 65 mg/dl, and apo B to < 50 mg/dL, and subgroup and post hoc analyses all demonstrated additional ASCVD event reduction benefits as LDL-C was further reduced. The level of ASCVD risk determines the degree, urgency, and persistence in global risk management, including fundamental atherogenic lipoprotein cholesterol particle lowering. “Extreme” risk patients may require extremely low targeted LDL-C, non-HDL-C and apo B goals; such efforts, implied by more recent interventional trials and analyses, are aimed at maximal atheroma plaque regression, stabilization, and MACE event reduction with the aspiration of improved quality lifespan.