medwireNews: Pioglitazone, a peroxisome proliferator activated receptor-γ agonist, is associated with improvements in vascular stiffness and various cardiometabolic parameters in patients with systemic lupus erythematosus (SLE), show study findings.
“These results have implications in using non-immunosuppressive therapy that could decrease CVD [cardiovascular disease] risk in patients with SLE,” say the study authors, led by Sarfaraz Hasni (National Institutes of Health, Bethesda, Maryland, USA).
They explain in the Annals of the Rheumatic Diseases: “While the underlying mechanisms of premature CVD in SLE are not well defined, immune dysregulation coupled with cardiometabolic dysfunction are considered key drivers.”
For their phase 1/2 study, the researchers randomly assigned 80 individuals, aged an average of 46 years (87.5% women), to receive pioglitazone (titrated from 30 mg/day up to 45 mg after the first week) or placebo for 3 months, before crossing over to the alternate treatment for a further 3 months with a 2-month washout period in between. The participants had mild-to-moderate disease activity, with an average SLEDAI 2K score of 5.1 points.
Arterial stiffness, measured by Cardio-Ankle Vascular Index at baseline, was approximately 7 points on average, which was “significantly higher than the reference value for age and gender-matched healthy volunteers,” the researchers point out. However, this was significantly decreased by an average of 0.32 points more with pioglitazone treatment than placebo.
Other measures of vascular stiffness, such as pulse wave velocity and reactive hyperemia index, did not significantly improve with pioglitazone, a discrepancy the team says supports “the need for multimodal measurements of vascular function to better understand how different vascular territories are affected in SLE.”
Various metabolic parameters also improved with pioglitazone versus placebo, including a significantly greater increase overall in mean high-density lipoprotein (HDL) of 4.72 mg/dL, a significant 0.28 nm greater increase in mean HDL particle size, and a 1.84 µmol/L greater decrease in mean HDL particle number. There was also a superior overall reduction in average triglyceride levels and triglyceride-rich proteins, of 18.09 mg/dL and 16.03 mg/dL, respectively, as well as a switch from small low-density lipoprotein particle size to less atherogenic larger ones.
The team reports a significantly greater reduction in alanine with pioglitazone versus placebo and improved insulin sensitivity due to a drop in serum insulin without a decrease in serum glucose.
Pioglitazone was well tolerated with 249 adverse events occurring at a similar rate with pioglitazone (52.6%) and placebo (47.4%). The majority of events were mild and resolved without intervention and there were no fractures or new cases of hematuria or bladder cancer.
The researchers comment that the study was not designed or powered to look at the effects of pioglitazone on disease activity, but they note that it remained stable during the study and levels of complement C4 “increased significantly” when patients were taking pioglitazone, “indicating some potential role in normalizing biomarkers of disease activity in SLE.”
There was a “putative immunomodulatory effect on dysregulated neutrophil biology,” as evidenced by a significant reduction in neutrophil extracellular trap levels, but otherwise no modification of interferon-stimulating genes or other immune-related parameters, they add.
“It is possible that the impact of [pioglitazone] on vascular function in SLE is not related to immune regulation but, rather, to modifications on metabolic parameters known to have significant impact on vascular disease,” Hasni and colleagues conclude.
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