Glitazone Drug May Cut Lupus Heart Risk

A way to reduce cardiovascular (CV) risk in people with systemic lupus erythematosus (SLE) without interfering with immune mechanisms could be near at hand, results of a clinical trial suggested

In a study involving 80 SLE patients, 3 months of treatment with pioglitazone (Actos) led to improvement in markers of vascular stiffness and cardiometabolic parameters (e.g., serum lipoproteins), relative to treatment with placebo, according to Sarfaraz Hasni, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland, and colleagues.

CV events are a leading contributor to reduced life expectancy and increased morbidity in SLE, the researchers noted in Annals of the Rheumatic Diseases. “As such, finding interventions that can modulate lupus vasculopathy, modify cardiometabolic risk and not further immunosuppress these patients is an area of great need in this disease,” they wrote.

They chose pioglitazone, a peroxisome proliferator activated receptor-gamma (PPAR-γ) agonist, for the trial because earlier studies in humans and animal models had indicated that this class of drug inhibits atherogenesis and inflammatory processes. Some research had found particularly that patients with rheumatoid arthritis — another autoimmune condition that comes with increased rates of CV disease — showed improvement in disease activity and vascular function with pioglitazone treatment.

The trial was structured such that participants served as their own controls, receiving 3 months of pioglitazone (30 mg/day titrated up to 45 mg/day if tolerated) or placebo, then crossing over to the other treatment for another 3 months, with a 2-month washout period in between.

Vascular stiffness was assessed with the Cardio-Ankle Vascular Index (CAVI). Other vascular health markers evaluated in the trial included pulse wave velocity, the Reactive Hyperemia Index, and vessel inflammation as seen in FDG-PET scans.

Participants had been living with lupus for a mean of 13 years. Their mean age was 46 and nearly 90% were women; 40% were Hispanic, 23% were white, and 22% were Black. Scores on the SLE Disease Activity Index-2K averaged 5.1 at enrollment.

Not all the results fell in line with the investigators’ hypothesis that pioglitazone would improve vascular function. Neither pulse wave velocity, Reactive Hyperaemia Index, nor PET-detected inflammation showed any differences between treatments. Only vascular stiffness as measured with CAVI showed clear improvement with the active drug — decreasing by 0.32 points more than during placebo treatment (95% CI -0.10 to -0.54). “CAVI values reverted to baseline during the washout period and while subjects were on placebo,” Hasni and colleagues reported.

As would be expected, pioglitazone treatment led to increases in HDL cholesterol levels and particle size while LDL particle size decreased; triglyceride levels also fell. Measures of insulin resistance also improved.

And as the researchers said they hoped, there was no effect on interferon-stimulating genes with pioglitazone. On the other hand, the active treatment reduced levels of neutrophil extracellular traps, structures that aid in innate immune responses but become part of the pathology in a number of autoimmune diseases including lupus. Hasni and colleagues cited research indicating that these structures “blunt the anti-atherogenic function” of HDL cholesterol. Infections were more common during the placebo periods than during pioglitazone treatment.

Pioglitazone was “well tolerated” during the study, the researchers wrote; adverse effects were similar to those typically seen with short-term treatment.

One limitation of the study was that, if pioglitazone became standard therapy in lupus, it would likely be given for much longer periods. Hasni and colleagues pointed out that some of the drug’s more serious risks only become apparent with chronic dosing, and thus could not be examined in the current trial. (Pioglitazone’s label includes a boxed warning about new-onset and exacerbated heart failure, and cautions about other risks including liver injury and bladder cancer.) The researchers called for further studies, perhaps with “newer generation drugs,” to further delineate the benefits and safety aspects of their novel approach.