Since their first discovery as antiglycemic drugs in 1990, glitazones have gained interest as potential pharmacological targets for other disorders. They have multiple DNA-mediated effects that make them potential antifibrotic agents. Atheroma represents an important biologic model of fibrotic pathology, comprising diseases such as liver cirrhosis, pulmonary vascular disease, pulmonary fibrosis, and finally age-related male infertility and androgen decline due to under-studied vascular and atherosclerotic changes within the testicular tissue [21]. The potential regenerative therapeutic ability of pioglitazone on atheroma regression will be useful to patients with coronary or cerebrovascular diseases, as well give hope to diseased patients suffering from the aforementioned disorders [22,23,24].
In our study, we have examined the role of pioglitazone as an antidiabetic agent for the induction of atheroma regression in diabetic patients, which was demonstrated in six series comprising a total of 1180 patients who received pioglitazone vs. other antidiabetic agents. Our study has proved a statistically significant difference between pioglitazone and other alternative therapies, namely glimepiride and gliclazide, in decreasing CIMT as shown in Fig. 1. This superior effect could not be proved on AV by IVUS as shown in Fig. 2.
IMT is the earliest lesion to develop in the context of atherosclerosis, which could explain why pioglitazone has an effect on CIMT rather than atheroma volume. An established atheroma can be more resistant to any antifibrotic treatment, thus needing more time to achieve palpable results. Two out of the three studies that assessed the effect of pioglitazone had a relatively short duration, namely Ogasawara et al. and Nakayama et al. [7, 10]. More effect could have been achieved if the period of the clinical trial would have been extended [25].
The exact mechanisms by which pioglitazone reverse atheroma and fibrosis are not completely understood.
In our study, pioglitazone achieved no superior effect compared to other antidiabetic agents in the control of hyperglycemia or in reducing LDL lipoproteins. This suggests that pioglitazone operates through other mechanisms to allow for the regression of atherosclerosis.
Endothelial cell (EC) dysfunction stands as a cornerstone in the pathogenesis of atherosclerosis. The function of ECs might be compromised by increased shear stress, dyslipidemia, inflammation, and many other factors [26]. The disturbed function of ECs might induce the release of different injurious agents such as transforming growth factor (TGF), fibroblast growth factor (FGF), and vascular cell adhesion molecule (VCAM). These key players and other molecular targets can be directly downregulated by the epigenetic mechanisms exerted by pioglitazone [26, 27].
Furthermore, the correlation between pioglitazone use and HDL levels suggests that it is through an HDL-mediated mechanism that pioglitazone is able to achieve changes in atheroma volume and carotid intimal media thickness. This finding is supported by other studies which found a strong association between elevated non-HDL levels and other body mass parameters with CIMT in particular [18]. The study suggests that atherosclerotic pathology and its progression is more so factored by CIMT rather than plaque burden, and that this effect is mediated by cholesterol levels [18]. Through its antiatherogenic effects, by means of a reverse cholesterol transport pathway, elevated levels of HDL are an established method to decrease the risk of cardiovascular injury. The search for new and effective drugs for this purpose continues, and of particular interest are drugs that can increase endogenous levels of HDL, such as pioglitazone, rather than the use of exogenous substances that only mimic the effect of HDL [19]. Kardassis and colleagues showed that glitazones can improve the expression of HDL genes which go in agreement with our findings [28].
Decreased HDL levels are an established part of every level of atheroma pathophysiology whereby the mechanisms of (1) inhibiting monocyte adhesion to endothelial cells at sites of plaque formation, (2) promoting NO production which suppresses proliferation of the plaque, (3) promoting fibrinolysis, and (4) preventing intra-plaque hemorrhage and many other pleiotropic effects are lost in the setting of decreased HDL levels [19].
