Objectives This study evaluated the effect of p38 mitogen-activated protein kinase (p38MAPK) inhibitor, BMS-582949, on atherosclerotic plaque inflammation, using (18)FDG-PET imaging. p38MAPK is an important element of inflammatory pathways in atherothrombosis and its inhibition may lead to reduced inflammation within atherosclerotic plaques. Methods Subjects with documented atherosclerosis (n = 72) on stable low-dose statin therapy and having at least one lesion with active atherosclerotic plaque inflammation in either aorta or carotid arteries were randomized to BMS-582949 (100 mg once daily), placebo, or atorvastatin (80 mg once daily), for 12 weeks. Arterial inflammation was assessed using (18)FDG-PET/CT imaging of the carotid arteries and aorta. Uptake of arterial (18)FDG was assessed as target-to-background ratio (TBR): 1) as a mean of all slices of the index vessel, and 2) within active slices of all vessels (AS: which includes only slices with significant inflammation (TBR ≥ 1.6) at the baseline). Results Treatment with BMS-582949 did not reduce arterial inflammation relative to placebo, (ΔTBR index: 0.10 [95% CI: -0.11, 0.30], p = 0.34; ΔTBR AS: -0.01 [-0.31, 0.28], p = 0.93) or hs-CRP (median %ΔCRP [IQR]: 33.83% [153.91] vs. 16.71% [133.45], p = 0.61). In contrast, relative to placebo, statin intensification was associated with significant reduction of hs-CRP (%ΔCRP [IQR]: -17.44% [54.68] vs. 16.71% [133.45], p = 0.04) and arterial inflammation in active slices (ΔTBRAS = -0.24 [95% CI: -0.46, -0.01], p = 0.04). Conclusions The findings of this study demonstrates that in stable atherosclerosis, 12 weeks of treatment with BMS-582949 did not reduce arterial inflammation or hs-CRP compared to placebo, whereas intensification of statin therapy significantly decreased arterial inflammation.
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