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

Abstract

Objectives: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Trial registration number: NCT02338999.

Keywords: cardiovascular diseases; lipids; systemic lupus erythematosus.

Conflict of interest statement

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.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Consolidated Standards of Reporting Trials Flow Diagram. A total of 88 subjects were screened for the trial, with 80 subjects randomised to sequence AB (PGZ-wash-out-placebo N=39) or sequence BA (Placebo-wash-out-PGZ N=41). A total of 72 subjects completed all phases of the clinical trial. #Withdrew due to travel n=1; withdrew voluntarily due to AE (pruritus and increased urinary frequency) n=2; and lost to follow-up n=1. †Withdrawn due to SLE flare n=2. *Subject withdrew voluntarily due to weight gain n=2. AEs, adverse events; SLE, systemic lupus erythematosus.

Figure 2

PGZ improves vascular stiffness in SLE. Mean Cardio-Ankle Vascular Index (CAVI) average of right and left side in subjects randomised to sequence AB (N=39; PGZ-wash-out-placebo) and sequence BA (N=41; placebo-wash-out-PGZ). The CAVI values decreased by 0.32 points (95% CI 0.10 to 0.54, p=0.005) in the pioglitazone group compared with the placebo. All data presented as mean+SD. **p≤0.01.

Figure 3

PGZ improves lipoprotein profiles in SLE. (A) Mean circulating HDL in subjects randomised to sequence AB (N=39; PGZ-wash-out-placebo) and sequence BA (N=41; placebo-wash-out-PGZ). The serum HDL levels increased by 4.72 mg/dL (95% CI: (1.27 to 8.18) with PGZ compared with placebo, with return to baseline by the end of wash-out period; p=0.008. (B) Mean circulating small LDL particles (s-LDLP) in subjects randomised to sequence AB (N=39; PGZ-wash-out-placebo) and sequence BA (N=41; placebo-wash-out-PGZ). The serum s-LDLP levels redcued by −254.76 (95% CI −354.13 to −155.39) with PGZ compared with placebo; p

Figure 4

PGZ reduces serum alanine and improves insulin resistance in SLE. (A) Mean circulating serum alanine levels in subjects randomised to sequence AB (N=39; PGZ-wash-out-placebo) and sequence BA (N=41; placebo-wash-out-PGZ). The serum alanine levels redcued by −33.35 (95% CI (−51.29 to −15.4), with PGZ compared with placebo; p=0.0004. (B) Mean homoeostasis model assessment of IR (HOMA2-IR) in subjects randomised to sequence AB (N=39; PGZ-wash-out-placebo) and sequence BA (N=41; placebo-wash-out-PGZ). HOMA IR levels decreased by −0.23 (95% CI (−0.35 to −0.1), p=0.0003), respectively PGZ a compared with placebo. (C) Mean serum insulin levels in subjects randomised to sequence AB (N=39; PGZ-wash-out-placebo) and sequence BA (N=41; placebo-wash-out-PGZ). Overall, the serum insulin levels decresased by-3.77 (95% CI (−6.22 to –1.31), p=0.003) with the use of pioglitazone as compared with placebo. All data presented as mean+SD; **p≤0.01; ***p≤0.001. PGZ, pioglitazone; SLE, systemic lupus erythematosus.