From: Are PCSK9 Inhibitors the Next Breakthrough in the Cardiovascular Field? J Am Coll Cardiol. 2015;65(24):2638-2651. doi:10.1016/j.jacc.2015.05.001 Figure Legend: SREBP-2 in hepatocytes regulates transcription of several lipids and proteins, including the low-density lipoprotein receptor (LDL-R) and proprotein convertase subtilisin/kexin type 9 (PCSK9) (step 1). PCSK9 is processed in the endoplasmic reticulum into a mature form (step 2) and undergoes packaging by the Golgi apparatus (as does the LDL-R) before being secreted (step 3). The LDL-R binds circulating low-density lipoprotein cholesterol (LDL-C) (step 4), and the pair is internalized in endosomes, where LDL-C can be shuttled for other use. Meanwhile, the LDL-R recirculates to the cell surface (step 5) up to 150 times, removing additional LDL-C from the circulation. PCSK9 regulates the number of LDL-R by binding to and internalizing the LDL-R (step 6), escorting it to its destruction in the lysosome (step 7). This does not permit the LDL-R to recirculate. Several methods to interfere with the function of PCSK9 are shown by the letters within red octagons. Small interfering ribonucleic acids (siRNAs) (A) can block transcription of PCSK9 messenger ribonucleic acid, whereas small molecular inhibitors (B) can disrupt the processing of PCSK9—both approaches reduce the production of functional PCSK9. Two extracellular approaches to inhibit PCSK9 function include monoclonal antibodies (MoAbs) (C) and adnectins (D) that prevent binding of PCSK9 to the LDL-R. SREBP = sterol-binding regulatory element-binding transcription factor. Date of download: 6/1/2016 Copyright © The American College of Cardiology. All rights reserved.

From: Are PCSK9 Inhibitors the Next Breakthrough in the Cardiovascular Field? J Am Coll Cardiol. 2015;65(24):2638-2651. doi:10.1016/j.jacc.2015.05.001 Figure Legend: Rates of composite adjudicated cardiovascular events in the ODYSSEY OUTCOMES (left) and OSLER (Open-Label Study of Long-Term Evaluation Against LDL-C) 1 and 2 (right) trials. In the ODYSSEY OUTCOME trial, the post-hoc cardiovascular endpoint was a composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, and unstable angina requiring hospitalization, assessed after an average follow-up of 65 weeks. In the OSLER trials, the pre-specified cardiovascular endpoint was a composite of death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and heart failure requiring hospitalization, assessed after an average follow-up of 11.1 months. Hazard ratios (HRs) are derived from analyses of Kaplan-Meier event rates. PCSK9 = proprotein convertase subtilisin/kexin type 9; SOC = standard of care. Date of download: 6/1/2016 Copyright © The American College of Cardiology. All rights reserved.

From: Are PCSK9 Inhibitors the Next Breakthrough in the Cardiovascular Field? J Am Coll Cardiol. 2015;65(24):2638-2651. doi:10.1016/j.jacc.2015.05.001 Figure Legend: (A) Alirocumab. (B) Evolocumab. (C) Bococizumab.*75 mg subcutaneous (SC) every other week with titration (as necessary) to 150 mg SC every other week, if low-density lipoprotein cholesterol (LDL-C) ≥50 mg/dl (1.29 mmol/l). ACS = acute coronary syndrome(s); CHD = coronary heart disease; CHF = congestive heart failure; CV = cardiovascular; F/U = follow-up; LVEF = left ventricular ejection fraction; MI = myocardial infarction; NCEP-ATP III = National Cholesterol Education Panel Adult Treatment Panel 3; PAD = peripheral arterial disease; pts = patients; Q2W = every other week; Q4W = every 4 weeks; Rx = treatment; SC = subcutaneous; TIA = transient ischemic attack; TLC = therapeutic lifestyle changes; UA = unstable angina. Date of download: 6/1/2016 Copyright © The American College of Cardiology. All rights reserved.

From: Are PCSK9 Inhibitors the Next Breakthrough in the Cardiovascular Field? J Am Coll Cardiol. 2015;65(24):2638-2651. doi:10.1016/j.jacc.2015.05.001 Figure Legend: In the LAPLACE-TIMI 57 (LDL-C Assessment with Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy-Thrombolysis In Myocardial Infarction 57) trial, the mean LDL-C among stable, high-risk patients with hypercholesterolemia was 123 mg/dl, a value that is similar to the average reported in several surveys of the U.S. general population (23). With administration of 140 mg every 2 weeks of evolocumab, the average LDL-C was reduced to a mean of 47 mg/dl, with >90% of patients achieving an LDL-C <70 mg/dl. The majority of patients thus achieved an LDL-C of 25 to 60 mg/dl, a range labeled as physiological for humans by Brown and Goldstein in their 1985 Nobel Lecture. HDL-C = high-density lipoprotein cholesterol; revasc = revascularization; other abbreviations as in Figures 1 and 2. Date of download: 6/1/2016 Copyright © The American College of Cardiology. All rights reserved.