Abstract
Purpose :
Dipeptidyl peptidase-4 inhibitors (DPP-4is) are a class of oral hypoglycemic agents used to treat type 2 diabetes. We aimed to investigate the effect of DPP-4is on conjunctival scarring after trabeculectomy, i.e., glaucoma filtering surgery. We used clinical data and an in vitro model based on inducing human Tenon’s fibroblast (HTF) fibrosis with transforming growth factor-β (TGF-β).
Methods :
We retrospectively reviewed the medical records of 41 eyes of 35 patients with diabetic neovascular glaucoma (NVG) who underwent initial trabeculectomy. Surgical success was compared in patients who received DPP-4is as part of treatment for diabetes (n=23) and those who did not (n=18). Elastica-Masson staining and DPP-4 immunostaining were performed on Tenon’s tissue samples obtained from primary open-angle glaucoma patients during trabeculectomy. We further assessed the antifibrotic effects of linagliptin (a DPP-4i) with quantitative real-time PCR for fibrotic markers, including α-SMA, Col1α1, and FN1; a scratch assay; and a collagen gel contraction assay using primary cultured HTFs treated with TGF-β1 and linagliptin. We used Western blotting to assess the ratio of phosphorylated Smad2/3 to Smad2/3 in the presence of linagliptin.
Results :
A Kaplan–Meier survival analysis showed that the surgical success rate was higher in patients treated with DPP-4is (P=0.017, log-rank test). A Cox proportional hazards model demonstrated that the use of DPP-4is was an independent contributor to surgical success after adjustment for other potential prognostic factors, i.e., age and preoperative IOP (RR=0.29, P=0.021). Elastica-Masson staining and DPP-4 immunostaining revealed that the tissue samples with scarring showed increased collagen and DPP-4 expression compared to the samples without scarring. The in vitro experiments showed that linagliptin treatment suppressed the increase in the level of markers for fibrotic HTFs induced by TGF-β1. In addition, linagliptin treatment inhibited TGF-β–induced cell migration and gel contraction and attenuated the phosphorylation of Smad2/3, which is a canonical pathway for TGF-β signaling.
Conclusions :
Our study demonstrates the potential effect of DPP-4is for maintaining bleb function after trabeculectomy in patients with diabetes and NVG. We also found that a member of the DPP-4i family, linagliptin, prevented fibrotic changes in HTFs by suppressing TGF-β/Smad signaling.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.