Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis

Abstract

Objectives: This study sought to determine the effects of a p38 mitogen-activated protein kinase inhibitor, losmapimod, on vascular inflammation, by (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography imaging.

Background: The p38 mitogen-activated protein kinase cascade plays an important role in the initiation and progression of inflammatory diseases, including atherosclerosis.

Methods: Patients with atherosclerosis on stable statin therapy (n = 99) were randomized to receive losmapimod 7.5 mg once daily (lower dose [LD]), twice daily (higher dose [HD]) or placebo for 84 days. Vascular inflammation was assessed by FDG positron emission tomography/computed tomography imaging of the carotid arteries and aorta; analyses focused on the index vessel (the artery with the highest average maximum tissue-to-background ratio [TBR] at baseline). Serum inflammatory biomarkers and FDG uptake in visceral and subcutaneous fat were also measured.

Results: The primary endpoint, change from baseline in average TBR across all segments in the index vessel, was not significantly different between HD and placebo (ΔTBR: -0.04 [95% confidence interval [CI]: -0.14 to +0.06], p = 0.452) or LD and placebo (ΔTBR: -0.02 [95% CI: -0.11 to +0.06], p = 0.579). However, there was a statistically significant reduction in average TBR in active segments (TBR ≥1.6) (HD vs. placebo: ΔTBR: -0.10 [95% CI: -0.19 to -0.02], p = 0.0125; LD vs. placebo: ΔTBR: -0.10 [95% CI: -0.18 to -0.02], p = 0.0194). The probability of a segment being active was also significantly reduced for HD when compared with placebo (OR: 0.57 [95% CI: 0.41 to 0.81], p = 0.002). Within the HD group, reductions were observed in placebo-corrected inflammatory biomarkers including high-sensitivity C-reactive protein (% reduction: -28% [95% CI: -46 to -5], p = 0.023) as well as FDG uptake in visceral fat (ΔSUV: -0.05 [95% CI: -0.09 to -0.01], p = 0.018), but not subcutaneous fat.

Conclusions: Despite nonsignificant changes for the primary endpoint of average vessel TBR, HD losmapimod reduced vascular inflammation in the most inflamed regions, concurrent with a reduction in inflammatory biomarkers and FDG uptake in visceral fat. These results suggest a systemic anti-inflammatory effect. (A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging; NCT00633022).