The Peroxisome Proliferator-Activated Receptor-γ (PPAR) Agonist Pioglitazone Improves Vascular and Metabolic Dysfunction in Patients with Systemic Lupus Erythematosus (SLE)

Sarfaraz Hasni¹, Yenealem Temesgen-Oyelakin², Michael Davis³, Sarthak Gupta⁴, Elaine Poncio⁵, Mohammad Naqi¹, Xinghao Wang⁶, Christopher Oliveira⁷, Dillon Claybaugh¹, Amit Dey¹, Shajia Lu¹, Philip Carlucci⁸, Zerai Manna¹, Yinghui Shi¹, Isabel Ochoa⁵, Donald Thomas⁹, Theo Heller¹⁰, Massimo Gadina¹¹, Jun Chu⁴, Monica Purmalek¹, Xiaobai Li¹², Martin Playford¹³, Nehal Mehta¹³ and Mariana Kaplan¹, ¹National Institutes of Health, Bethesda, MD, ²National Institutes of Health (NIH), Bethesda, MD, ³NIAMS, Bethesda, MD, ⁴National Institutes of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, ⁵NIH/NIAMS, Bethesda, MD, ⁶NIAMS/NIH, Bethesda, MD, ⁷National Institutes of Health (NIH), Vienna, VA, ⁸New York University School of Medicine, New York, NY, ⁹Arthritis and Pain Associates of Prince George's County, Silver Spring, MD, ¹⁰NIDDK/National Institutes of Health, Bethesda, MD, ¹¹National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, ¹²Clinical Center, National Institutes of Health, Bethesda, MD, ¹³NHLBI/National Institutes of Health, Bethesda, MD

Meeting: ACR Convergence 2021

Keywords: Cardiovascular, clinical trial, risk factors, Systemic lupus erythematosus (SLE)

Session Information

Date: Tuesday, November 9, 2021

Title: SLE – Treatment Poster (1732–1772)

Session Type: Poster Session D

Session Time: 8:30AM-10:30AM

Background/Purpose: Premature cardiovascular events in SLE are associated with significant mortality and morbidity with no effective treatments described to date. Both immune dysregulation characteristics of SLE and metabolic disturbances appear to play a prominent role in the induction of vascular disease. In previous studies, the peroxisome proliferator-activated receptor (PPAR) agonist pioglitazone (PGZ) suppressed lupus phenotype, immune dysregulation, organ damage and vasculopathy in murine lupus. In human lupus peripheral blood mononuclear cells (PBMCs), in vitro PGZ modified T cell-specific responses and suppressed effector function. We hypothesized that PGZ could improve markers of vascular dysfunction and improve cardiometabolic parameters in SLE.

Methods: Eighty SLE subjects with mild to severe disease activity (SLEDAI 2K score between 4-20) were randomized to a sequence of PGZ (titrated up to 45 mg/day)followed by placebo for 3 months, or vice versa, in a 1:1 allocation ratio in a double-blind cross-over design with a 2 month wash out period. The primary endpoints were parameters of vascular endothelial function as measured by non-invasive multimodal vascular function studies. In a subset of patients, arterial inflammation was assessed by fluorodeoxyglucose positron emission tomography CT (FDG PET/CT). Additional outcome measures of disease activity, metabolic disturbances, adverse events (AEs), and gene expression studies were performed.

Results: A total of 72 subjects completed the study. The use of PGZ was associated with a decrease of 0.322±0.75 (mean±SD) in cardio ankle vascular index (CAVI) values compared to the placebo (0.02±0.65, p=0.005). Metabolic parameters also improved with PGZ, including the homeostasis model assessment of insulin resistance (HOMA2 IR) (p=0.0003), HDL-C (p=0.008), HDL particle size and number (p=< 0.0001; p=0.0009, respectively), and triglycerides (p=0.005). There were 249 predominantly mild adverse events (AE), 52.61% on PGZ and 47.39% on placebo. Most of the AEs experienced while on PGZ were related to fluid retention and mild transaminitis, which resolved with reduction in PGZ dose.

Conclusion: PGZ was well tolerated in SLE subjects with mild to severe disease activity. There was a significant improvement in vascular stiffness as well as improved cardiometabolic parameters. The results suggest that PGZ should be further explored as a modulator of cardiovascular disease risk in non-diabetic SLE patients.

Disclosures: S. Hasni, None; Y. Temesgen-Oyelakin, None; M. Davis, None; S. Gupta, None; E. Poncio, None; M. Naqi, None; X. Wang, None; C. Oliveira, None; D. Claybaugh, None; A. Dey, None; S. Lu, None; P. Carlucci, None; Z. Manna, None; Y. Shi, None; I. Ochoa, None; D. Thomas, Progentec, 1, GlaxoSmithKline, 6, Aurinia, 6, Exagen, 6; T. Heller, None; M. Gadina, None; J. Chu, None; M. Purmalek, None; X. Li, None; M. Playford, None; N. Mehta, NIH, 5, Astra Zeneca, 5, Celgene/Amgen, 5, Novartis, 5, Abbvie, 5, Abcentra, 1, 5, Janssen, 5, NPF, 1, 5; M. Kaplan, None.

To cite this abstract in AMA style:

Hasni S, Temesgen-Oyelakin Y, Davis M, Gupta S, Poncio E, Naqi M, Wang X, Oliveira C, Claybaugh D, Dey A, Lu S, Carlucci P, Manna Z, Shi Y, Ochoa I, Thomas D, Heller T, Gadina M, Chu J, Purmalek M, Li X, Playford M, Mehta N, Kaplan M. The Peroxisome Proliferator-Activated Receptor-γ (PPAR) Agonist Pioglitazone Improves Vascular and Metabolic Dysfunction in Patients with Systemic Lupus Erythematosus (SLE) [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/the-peroxisome-proliferator-activated-receptor-%ce%b3-ppar-agonist-pioglitazone-improves-vascular-and-metabolic-dysfunction-in-patients-with-systemic-lupus-erythematosus-sle/. Accessed .

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