Anti-DPP4 monoclonal antibody, clone CC69

The cell dose in umbilical cord blood units is a major determinant for the outcome of hematopoietic cell transplantation. Prostaglandin analogs and dipeptidylpeptidase-4 (DPP4/CD26)-inhibitors enhance the ability of hematopoietic stem cells (HSCs) to reconstitute hematopoiesis. Here we explored the synergism between treprostinil, a stable prostaglandin agonist, and the DPP4/CD26-inhibitor vildagliptin. The combination of treprostinil and forskolin caused a modest but statistically significant increase in the surface levels of DPP4/CD26 on hematopoietic stem and progenitor cells (HSPCs) derived from murine bone and human cord blood. Their migration towards stromal cell-derived factor-1 (SDF-1/CXCL12) was enhanced, if they were pretreated with treprostinil and forskolin, and further augmented by vildagliptin. Administration of vildagliptin rescued 25% of lethally irradiated recipient mice injected with a limiting number of untreated HSPCs, but 90 to 100% of recipients injected with HSPCs preincubated with treprostinil and forskolin. The efficacy of vildagliptin surpassed that of treprostinil (60% rescue). Surprisingly, concomitant administration of vildagliptin and treprostinil resulted in poor survival of recipients indicating mutual antagonism, which was recapitulated when homing of and colony formation by HSPCs were assessed. These observations of regimen-dependent synergism and antagonism of treprostinil and vildagliptin are of translational relevance for the design of clinical trials. Key messages Pretreatment with treprostinil increases surface levels of DPP4/CD26 in HSPCs. Vildagliptin enhances in vitro migration of pretreated HSPCs. Vildagliptin enhances in vivo homing and engraftment of pretreated HSPCs. Unexpected mutual antagonism in vivo by concomitant administration of vildagliptin and treprostinil.

Diabetes mellitus type 2 is a metabolic disease increasing cardiovascular risk. At the same time, the patients with type 2 diabetes are at a greater risk of cardiovascular events, heart failure and chronic renal disease. This review summarizes clinical trials from UKPDS, DCCT and ACCORD till the most recent trials for the new antidiabetics focused on a cardiovascular safety - DPP4 inhibitors, SGLT2 inhibitors and GLP-1 analogues. The overview discusses the particular cardiovascular outcomes, comorbidities and potential renal benefits from the treatment. All new antidiabetic agents were non-inferior with respect to primary cardiovascular outcome, thus proved the cardiovascular safety. Moreover, some of the latest studies with GLP-1 agonists and SGLT2 inhibitors proved cardiovascular protectivity and led to a lower rate of cardiovascular events. These findings resulted in changes in the Guidelines of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). The SGLT2 inhibitors and GLP-1 agonists should be preferred in the group of patients with type 2 diabetes with established cardiovascular or renal disease with respect to new evidence.