Impact of Sitagliptin on Endometrial Mesenchymal Stem-Like Progenitor Cells: A Randomised, Double-Blind Placebo-Controlled Feasibility Trial

Abstract

Background: Recurrent pregnancy loss (RPL) is associated with the loss of endometrial mesenchymal stem-like progenitor cells (eMSC). DPP4 inhibitors may increase homing and engraftment of bone marrow-derived cells to sites of tissue injury by preventing inactivation of stromal cell-derived factor-1α, a potent chemoattractant. Aims: To assess the effect of the DPP4 inhibitor sitagliptin on eMSC in women with RPL, to evaluate the impact on endometrial decidualization, and to assess the feasibility of a full-scale clinical trial. Methods: A double-blind, randomised, placebo-controlled feasibility trial on women aged 18 to 42 years with a history of 3 or more consecutive pregnancy losses, regular ovulatory menstrual cycles, and no contraindications to sitagliptin. Thirty-eighty subjects were randomised to either 100 mg sitagliptin daily for 3 consecutive cycles or identical placebo capsules. Computer generated, permuted block randomisation was used to allocate treatment packs. The primary outcome measure was the posttreatment eMSC count, assessed by colony forming unit (CFU) assays, in midluteal biopsies. Secondary outcome measures were change in CFU count before and after placebo or sitagliptin treatment, endometrial thickness, study acceptability, and subsequent pregnancy outcome within 12 months following the study. Tissue samples were subjected to explorative investigations. Findings: CFU counts following sitagliptin were higher compared to placebo when adjusted for baseline CFU counts and age (RR:1.52, 95%CI:1.32-1.75, P<0.01). The CFU count increased 1.68-fold in the sitagliptin group and 1.08-fold in the placebo group. The trial was acceptable and drug compliance high. were no serious adverse events. Explorative investigations showed that sitagliptin inhibits the expression of DIO2, a marker gene of senescent decidual cells. Interpretation: Sitagliptin increases eMSCs and decreases decidual senescence. A large-scale clinical trial evaluating the impact of preconception sitagliptin treatment on pregnancy outcome in RPL is feasible and warranted. Trial Registration: EU Clinical Trials Register no. 2016-001120-54. Funding Statement: The study was sponsored by UHCW NHS Trust and funded by Tommy’s baby charity (registered charity 1060508/ SC039280, Great Britain). R.F. received funding from Juntendo University, Japan. Declaration of Interests: The authors stated: There are no conflicts of interests. Ethics Approval Statement: The SIMPLANT study was approved by the Medicines and Healthcare Regulatory Authority (MHRA), the National Health Service Research Ethics Committee South Central-Hampshire B (16/SC/0229) and Research, Development and Innovation (RD&I) office at University Hospitals Coventry and Warwickshire (UHCW) National Health Service (NHS) Trust.