Reversing Vascular Dysfunction in Rheumatoid Arthritis: Improved Augmentation Index but Not Endothelial Function With Peroxisome Proliferator–Activated Receptor γ Agonist Therapy

OBJECTIVE: To examine the hypothesis that improving insulin sensitivity improves vascular function in rheumatoid arthritis (RA). METHODS: We performed a 20-week, single center, randomized, double-blind, placebo-controlled crossover study. Patients with RA (n = 34) with moderate disease activity who were receiving stable disease-modifying antirheumatic drug therapy were randomized to drug sequence, receiving either pioglitazone 45 mg/day or matching placebo for 8 weeks, followed by a 4-week washout period and the alternative treatment for 8 weeks. We measured changes in vascular stiffness (augmentation index and aortic pulse wave velocity [PWV]), endothelial function (reactive hyperemia index), and blood pressure. High-sensitivity C-reactive protein levels and the homeostatic model assessment of insulin resistance were also measured. The treatment effect of pioglitazone on outcomes was analyzed using linear mixed-effects models. RESULTS: Pioglitazone treatment resulted in a change in augmentation index of -4.7% units (95% confidence interval [95% CI] -7.9, -1.5) (P = 0.004) and in diastolic blood pressure of -3.0 mm Hg (95% CI -5.7, -0.2) (P = 0.03), but did not significantly change aortic PWV (P = 0.33) or reactive hyperemia index (P = 0.46). The improvements in augmentation index and diastolic blood pressure were not mediated by the effect of pioglitazone on insulin resistance or inflammation. CONCLUSION: Our findings indicate that pioglitazone improves some indices of vascular function, including augmentation index and diastolic blood pressure, in patients with RA. This is not mediated by improved insulin sensitivity.