Peroxisome proliferator activated receptor-γ agonist pioglitazone improves vascular and metabolic dysfunction in systemic lupus erythematosus.

Premature cardiovascular events in systemic lupus erythematosus (SLE) contribute to morbidity and mortality, with no effective preventive strategies described to date. Immune dysregulation and metabolic disturbances appear to play prominent roles in the induction of vascular disease in SLE. The peroxisome proliferator activated receptor-gamma agonist pioglitazone (PGZ suppresses vascular damage and immune dysregulation in murine lupus and improves endothelial dysfunction in other inflammatory diseases. We hypothesised that PGZ could improve vascular dysfunction and cardiometabolic parameters in SLE. Eighty SLE subjects with mild to severe disease activity were randomised to a sequence of PGZ followed by placebo for 3 months, or vice versa, in a double-blind, cross-over design with a 2-month wash-out period. Primary endpoints were parameters of endothelial function and arterial inflammation, measured by multimodal assessments. Additional outcome measures of disease activity, neutrophil dysregulation, metabolic disturbances and gene expression studies were performed. Seventy-two subjects completed the study. PGZ was associated with a significant reduction in Cardio-Ankle Vascular Index (a measure of arterial stiffness) compared with placebo. Various metabolic parameters improved with PGZ, including insulin resistance and lipoprotein profiles. Circulating neutrophil extracellular trap levels also significantly decreased with PGZ compared with placebo. Most adverse events experienced while on PGZ were mild and resolved with reduction in PGZ dose. PGZ was well tolerated and induced significant improvement in vascular stiffness and cardiometabolic parameters in SLE. The results suggest that PGZ should be further explored as a modulator of cardiovascular disease risk in SLE. NCT02338999.

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Competing interests: Pfizer Inc. provided the drug and placebo. No financial support from the industry. NNM reported: Grants or contracts: AbbVie, Celgene, Janssen Pharmaceuticals, Inc, Novartis, AstraZeneca. Consulting fees: Amgen, Eli Lilly, Leo Pharma. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Board of the American Society for Preventive Cardiology, Board of National Psoriasis Foundation, Board of International Federation of Psoriatic Disease. DET reported: Royalties or licenses: Yearly royalties for sales of 'The Lupus Encyclopedia: A comprehensive guide for patients and families', Johns Hopkins University Press,Yearly royalties for sales of 'The Lupus Encyclopedia: A comprehensive guide for patients and families'. Consulting fees: GSK, participated in a paid group discussion that went over data of the BLISS-BELIEVE study. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Exagen, GSK, Aurinia, AstraZeneca. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Sjogren’s Foundation, Unpaid: Chair of the National Board. Stock: Aurinia. Other financial or non-financial interests: AstraZeneca, On a monograph about anifrolumab; paid. GSK, In a video discussing patient experiences, paidNIAMS has collaborative research agreements with Pfizer, Bristol Myers Squibb and Astra Zeneca.