Reversing vascular dysfunction in rheumatoid arthritis: PPAR-γ agonist therapy improves augmentation index but not endothelial function Michelle J Ormseth, MD 1 , Annette M Oeser, BS, MLAS 1,2 , Andrew Cunningham, MBChB 2 , Aihua Bian, MPH 3 , Ayumi Shintani, PhD, MPH 3 , Joseph Solus, PhD 1 , S Bobo Tanner, MD 1 , and C Michael Stein, MBChB 1,2 1 Division of Rheumatology, Department of Medicine, Vanderbilt University, Nashville, TN 2 Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, TN 3 Department of Biostatistics, Vanderbilt University, Nashville, TN Abstract Objective—To examine the hypothesis that improving insulin sensitivity would improve 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) and moderate disease activity on stable disease modifying anti-rheumatic drug therapy were randomized to drug sequence, receiving either pioglitazone 45mg daily or matching placebo for 8 weeks, followed by a 4-week washout period and the alternative treatment for 8 weeks. We measured change in vascular stiffness (augmentation index and aortic pulse wave velocity), endothelial function (reactive hyperemia index), and blood pressure. High sensitivity C-reactive protein (CRP), and the homeostatic model assessment of insulin resistance (HOMA) were also measured. The treatment effect of pioglitazone on outcomes was analyzed using linear mixed effect models. Results—Pioglitazone reduced augmentation index by −4.7% units (95% CI, −7.9, −1.5% units) P=0.004 and diastolic blood pressure by −3.0 mmHg (−5.7, −0.2 mmHg) P=0.03, but did not change aortic pulse wave velocity (P=0.33), or reactive hyperemia index (P=0.46) significantly. The improvements in augmentation index and diastolic blood pressure were not mediated by pioglitazone's effect on insulin resistance or inflammation. Conclusion—Pioglitazone improved some indices of vascular function, including augmentation index and diastolic blood pressure, in patients with RA; this was not mediated by improved insulin sensitivity. Address for correspondence: Michelle J Ormseth, MD, 1161 21 st Avenue South, T-3113 MCN, Nashville, TN 37232-2681, Telephone: 615-322-4746, Fax: 615-322-6248, michelle.ormseth@vanderbilt.edu. This trial is registered with ClinicalTrials.gov, # NCT00763139. Disclosures: None NIH Public Access Author Manuscript Arthritis Rheumatol. Author manuscript; available in PMC 2015 September 01. Published in final edited form as: Arthritis Rheumatol. 2014 September ; 66(9): 2331–2338. doi:10.1002/art.38686. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript