In this study, we found that glimepiride significantly suppressed the plasma levels of eotaxin, FGF-2 and toxic AGE, and showed a trend to reduce those of fractalkine, sCD40L, MIP-β, VEGF and sRAGE, and to increase the levels of G-CSF and GM-CSF.
Sulfonylureas may increase the risk of cardiovascular events in patients with type 2 diabetes . However, glimepiride seems to have fewer unfavorable cardiovascular effects compared to other sulfonylureas. Glimepiride upregulated eNOS activity and inhibit NF-kB activation in human umbilical vein endothelial cells . In open-chest dogs, intracoronary infusion of glibenclamide, gliclazide and glimepiride all reduced coronary blood flow, increased coronary resistance, depressed the mechanical activity of the heart, enhanced myocardial O2-extraction, reduced the serum potassium level and induced a moderate endocardial ST-segment elevation, but glimepiride to a significantly less extent than glibenclamide and gliclazide . Likely underlying the favorable cardiovascular effects of glimepiride are its induction of ischemic preconditioning, suppression of ventricular tachycardia and lowering of the blood pressure, unlike other sulfonylureas [17–19]. Unfortunately, these effects has previously been shown only in animal experiments. Therefore, in this study, we provided the first demonstration of the clinical effects of glimepiride in humans. Previous reports revealed that glimepiride and rosiglitazon reduced the levels of hsCRP, AGEs , lipoprotein, homocyctein and plasminogen activator inhibitor-1  increased adiponectin  in T2DM. Recently phase 3 trial of empagliflozin, SGLT2 inhibitor, versus glimepiride as add-on to metformin in T2DM patients are being performed . However, the study about exenatide, GLP-1 agonist, versus glimepiride added to metformin revealed that glimepiride reduced hsCRP and increased adiponectin although exenatide did with great extent . Moreover, glimepiride could not prevent the atherosclerosis of carotid intima-media thickness  and coronary atherosclerosis  compared with pioglitazone.
AGEs are oxidative products formed from the reaction between carbohydrates and a free amino group of proteins, which are provoked by reactive species and are greatly accelerated in response to the hyperglycemia and oxidative stress that occur in diabetic subjects . Since the AGEs activate nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), transcription factors, which upregulates the expression of genes involved in vascular injury and endothelial dysfunction, in microvascular endothelial cells and induce angiogenesis, lowing the AGEs may contribute to ameliorating diabetic vasculopathy [20, 28–30]. The serum levels of toxic AGE were inversely associated with the number of endothelial progenitor cells in apparently healthy subjects . The reduction in toxic AGE and sRAGE by glimepiride in our present study, therefore, the results may suggest that glimepiride have a potential benefit for repairing the vascular injury and stop angiogenesis in diabetic patients.
In this study, there was a trend toward an increase in the level of G-CSF and GM-CSF after the administration of glimepiride for 24 weeks, suggesting that glimepiride has effects on angiogenesis, which is a pivotal mechanism that influences several physiological and pathological processes, including wound healing, because GM-CSF is known to induce bone marrow precursors to protect against the development of diabetes and to induce wound healing in diabetic mice [32–34]. In our study, the plasma levels of FGF-2 and VEGF were also reduced after the administration of glimepiride. FGF-2 is a potent mitogen in endothelial cells and smooth muscle cells that is released after endothelial injury  and is capable of inducing smooth muscle cell migration and proliferation, leading to neointima formation [36, 37]. The plasma FGF-2 level is low or undetectable in healthy subjects , but increases in microalbuminuric adult type 2 diabetic patients.
Both FGF-2 and VEGF are considered to be key factors in the angiogenic response [39, 40], and induce increased vascular permeability. The vascular hyperpermeability and increased blood flow caused by elevated tissue glucose and sorbitol levels can be blocked by neutralizing monoclonal and polyclonal antibodies directed against VEGF , suggesting that a sorbitol pathway-linked increase in VEGF may be involved in the hemodynamic changes and loss of endothelial cell barrier integrity induced by diabetes. Increased glucose induces the production of VEGF and FGF-2 to promote angiogenesis, and to protect against tissue injury. In our study, however, glimepiride reduced the plasma levels of VEGF and FGF-2.
We believe that the results of treatment may depend on the decreased induction of cytokines resulting from the glycemic improvement or via the pleiotropic effects of the drug. It was previously reported that patients with type 1 diabetes showed higher concentrations of plasma GM-CSF, soluble CD40, soluble CD40 ligand, MIP-β , and that the acute effect of clamped hyperglycemia increased the urinary excretion of eotaxin, FGF-2, GM-CSF, TNF-α and soluble CD40 ligand in patients with type 1 diabetes. Based on these results, our data supplements the favorable cardiovascular effects of glimepiride, which is in contrast to the unfavorable cardiac effects of other sulfonylureas.
In our study, the level of eotaxin also decreased after glimepiride treatment. Eotaxin is a potent eosinophil chemoattractant that is a member of the CC chemokine subfamily of inflammatory and immunoregulatory cytokines. Although the role of eotaxin in diabetes is still being elucidates, it is thought to be substantially involved in the development of the disease in patients with type 1 diabetes . Moreover, in patients with type 2 diabetes, insulin infusion reduced the levels of eotaxin and MCP-1 , and the eosinophil count is also related to albumin excretion in males . Although the role of eotaxin in diabetes is still unclear, the protein sequence of human eotaxin is 66% identical to that of human MCP-1. Therefore, the decrease in eotaxin by glimepiride may reflect its potent anti-diabetic properties.
This was a preliminary single-arm study that was designed to evaluate only six months of treatment in a small number of subjects. Glimepiride is already widely used anti-diabetic drug and it is hard to avoid the use of glimepiride in the control group for 6 months in real clinical world when randomized placebo-control group is performed. Therefore, we performed a single-arm study as preliminary report.
In this study, we confirmed that glimepiride may have angiogenic properties. However, we did not evaluate the effects of the treatment on diabetic retinopathy because there were no patients with diabetic retinopathy in our group. Therefore, future studies will be needed to determine whether glimepiride can ameliorate or prevent diabetic complications including macro- and microagiopathies.
We also did not elucidate whether these phenomenona depended specifically on the glycemic control or were affected by other feature of glimepiride. However, we confirmed that these results did not correlate with the lowering of the blood glucose level or the level of HbA1c. Therefore, these results may depend on the unique features of the drug itself.