RVX-208 affects epigenetics by inhibiting bromodomain and extraterminal (BET) proteins from binding to their natural ligand, acetyl-lysine marks on histone tails and thereby modulates gene activity. In SUSTAIN and ASSURE phase IIb trials of CVD patients (n=499), giving 200 mg/d of RVX-208 orally lead a 55% relative risk reduction in major adverse cardiovascular events (MACE) vs. placebo. This marked reduction in MACE is unlikely due to RVX-208’s modest induction of ApoA-I/HDL, thus prompting studies of RVX-208 for its benefits beyond lipids. Methods included microarray surveys of human whole blood (WB) or primary hepatocytes (PH) exposed to RVX-208. Cytokines were assayed in U937 macrophage and peripheral blood mononuclear cells (PBMC) exposed to RVX-208. Plasma samples from phase IIb patients were measured using SOMAScan proteomic analysis. Results of the microarray studies using WB showed a potential anti-atherogenic effect of RVX-208 because it suppressed activity of 37/46 pro-atherogenic while inducing 8/18 anti-atherogenic genes. Additionally, RVX-208 had potential anti-thrombotic properties by affecting 18 genes related to platelet function (e.g. downregulation of CD64 and thrombospondin 1). RVX-208 had anti-inflammatory effects on the expression of >25 cytokines including downregulation of MCP-1, osteopontin and PARC genes. The suppression of these 3 genes by RVX-208 was evident in not only WB but also in the LPS stimulated U937 and/or PBMCs. Whether these in vitro findings extended into patients were examined by SOMAScan showing lower levels of osteopontin and PARC protein in plasma of treated patients. Furthermore, a key marker of inflammation RANTES was markedly lowered in treated patients. Why RVX-208 may affect genes connected to CVD was explored by exposing PH to RVX-208. These studies showed a 25% reduction in levels of mRNA encoding flavin mono-oxygenase-3 (FMO3), an enzyme that produces trimethylamine oxide (TMAO) a metabolite which predicts CVD risk. In summary, RVX-208 inhibits BET proteins to impact cellular epigenetics that in turn affects expression of genes with known roles in CVD. This activity may underlie RVX-208’s anti-atherogenic, -thrombotic and –inflammatory effects in reducing MACE observed in clinical trials.