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Published on: January 31, 2022
Peroxisome proliferator activated receptor-γ agonist pioglitazone improves vascular and metabolic dysfunction in
Sarfaraz Hasni1, Yenealem Temesgen-Oyelakin2, Michael Davis2
1Lupus Clinical Trials Unit, Office of the Clinical Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA sarfaraz.hasni@nih.gov.
Insights
Pioglitazone significantly improved vascular stiffness and cardiometabolic parameters in systemic lupus erythematosus (SLE) patients. This study suggests pioglitazone may help reduce cardiovascular disease risk in SLE.
Area of Science:
- Cardiovascular disease research
- Immunology
- Metabolic disorders
Background:
- Premature cardiovascular events are a major concern in systemic lupus erythematosus (SLE).
- Immune dysregulation and metabolic disturbances contribute to vascular disease in SLE.
- Pioglitazone (PGZ) shows potential in animal models and other inflammatory diseases.
Purpose of the Study:
- To investigate the efficacy of pioglitazone (PGZ) in improving vascular dysfunction and cardiometabolic parameters in SLE patients.
- To assess PGZ's impact on endothelial function, arterial inflammation, and related biomarkers.
- To evaluate the safety and tolerability of PGZ in SLE subjects.
Main Methods:
- A double-blind, placebo-controlled, cross-over study involving 80 SLE patients.
- Subjects received either PGZ or placebo for 3 months, followed by a 2-month wash-out period.
- Primary endpoints included endothelial function and arterial stiffness; secondary endpoints covered disease activity, metabolic parameters, and neutrophil function.
Main Results:
- Pioglitazone significantly reduced the Cardio-Ankle Vascular Index, indicating improved arterial stiffness.
- Metabolic parameters, including insulin resistance and lipoprotein profiles, showed improvement with PGZ.
- Circulating neutrophil extracellular trap levels decreased significantly with PGZ treatment.
Conclusions:
- Pioglitazone was well-tolerated and demonstrated significant improvements in vascular stiffness and cardiometabolic health in SLE patients.
- These findings suggest pioglitazone warrants further investigation as a therapeutic agent for cardiovascular disease risk modulation in SLE.
- Further research is recommended to explore PGZ's role in managing SLE-associated cardiovascular complications.
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.
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