Effect of Pioglitazone in Combination with Moderate Dose Statin on Atherosclerotic Inflammation: Randomized Controlled Clinical Trial Using Serial FDG-PET/CT

Background and Objectives: Non-statin therapy plus lower intensity statin might be an alternative in patients with coronary artery disease (CAD). A recent data suggested an anti-inflammatory therapy can reduce recurrent cardiovascular events and pioglitazone is also an intriguing inflammatory-modulating agent. However, limited data exist on whether pioglitazone on top of statins further attenuates plaque inflammation. Methods: Statin-$na\ddot{i}ve$ patients with stable CAD and carotid plaques of ${\geq}3mm$ were randomly prescribed moderate dose atorvastatin (20 mg/day), or moderate dose atorvastatin plus pioglitazone (30 mg/day) for 3 months. The primary endpoint was the change in the arterial inflammation of the carotid artery measured by $^{18}F$-fluorodeoxyglucose positron emission tomography/computed tomography ($^{18}F$-FDG-PET/CT) during 3 months. Results: Of the 41 randomized patients, 33 underwent an evaluation by fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT; 17 atorvastatin plus pioglitazone and 16 atorvastatin patients). The addition of pioglitazone significantly improved the insulin sensitivity and increased the high-density lipoprotein cholesterol after 3 months. Although a reduction in the (FDG) uptake by pioglitazone on top of atorvastatin in carotid arteries with plaque showed marginally statistical significance in the entire patient group (atorvastatin plus pioglitazone; $-0.10{\pm}0.07$ and atorvastatin $-0.06{\pm}0.04$, p=0.058), pioglitazone showed a further reduction of the fluorodeoxyglucose (FDG) uptake among patients who had a baseline FDG uptake above the median (atorvastatin plus pioglitazone; $-0.14{\pm}0.04$ and atorvastatin $-0.03{\pm}0.03$, p<0.001). Conclusions: Pioglitazone demonstrated marginally significant anti-inflammatory effects in addition to moderate dose atorvastatin. This may have been due to the lack of power of the study. However, pioglitazone may have an anti-inflammatory effect in those patients with high plaque inflammation (Trial registry at ClinicalTrials.gov, NCT01341730).