Context: Metabolic syndrome (MS) is characterized by low-grade inflammation and confers an increased risk for cardiovascular disease. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) reduce cardiovascular events in MS patients. There is a paucity of data examining the effect of statins on inflammation in MS.
Objective: We aimed to test the effect of simvastatin (40 mg/d) compared with placebo on biomarkers of inflammation [high-sensitivity C-reactive protein (hsCRP) and monocytic cytokines TNF, IL-6, and IL-1] in MS subjects.
Design and patients: We conducted a randomized, double-blind, placebo-controlled study at the University of California, Davis, Medical Center.
Participants: Participants were subjects with MS.
Intervention: Simvastatin (40 mg/d) or placebo was administered for 8 wk.
Methods and results: The hsCRP levels were assayed using a high-sensitivity immunoassay. Monocyte cytokines were assayed by ELISA after activation with lipopolysaccharide. Simvastatin therapy significantly decreased hsCRP levels in MS subjects compared with placebo (P < 0.0005) and resulted in a significant reduction in plasma and lipopolysaccharide-activated monocytic release of IL-6 and TNF (P < 0.025). Simvastatin therapy significantly decreased nuclear factor-kappaB and increased Akt activity in MS subjects compared with placebo. To gain mechanistic insights, human monocytes were pretreated with lovastatin with and without mevalonate or a phosphatidyl-3-kinase inhibitor or Rho kinase inhibitor. Lovastatin significantly decreased Rho kinase and nuclear factor-kappaB activity, significantly increased Akt activity, and resulted in decreased monocyte IL-6 levels; these effects were reversed with mevalonate and geranylgeranyl pyrophosphate, indicating direct effects of statins on protein prenylation.
Conclusions: Thus, we show a direct antiinflammatory effect of simvastatin therapy in MS. These findings could partly explain the benefit of statin therapy in these patients.