Despite the beneficial effect of DPP4i on glucose levels , the high number of substrates of the DPP-4  raise the question whether one substrate (or more) would have negative effects to undermine the beneficial effects of glucose lowering in diabetes patients. Such an effect was documented by Jackson et al. [13, 14], who showed that treatment with Sitagliptin increased the renovascular effects of angiotensin II. This was attributed to enhanced effect of peptide YY1-36, one of the substrate of the DPP-4 enzyme. The clinical singnificance of this finding is unknown, however, tbe majority of the substrates are peptides with little or no cardiovascular effect .
The main effect of DPP4i is associated with GLP-1. Altough there are no randomized clinical studies on the effect of GLP-1 on cadiovascular disease, treatment with GLP-1 analogues may be associated with improved status of cardiovascular risk factors such as hypertension and body weight [15–17]. Besides the effects on CVD risk factors, GLP-1 was found to have a beneficial effect on infarct size in animal models , as well as among diabetes patients undergoing CABG surgery, where the untreated group required inotropic and vasoactive infusions more frequently compared to those treated with GLP-1 . Altough the number of studies evaluating the effects of DPP4i on CVD are limited, a beneficial effect of DPP4i treatment on blood pressure was observed in a study of non diabetic population . However, the magnitude of blood pressure reduction was minimal. Additional effects on atherosclerosis were found in a model of LDL receptor knockout mice, as well as in APOE knockout model, where DPP4i was associated with less atherosclerosis. The effect is attributed to reduced monocyte assocaited inflammation  and augmented effect of GLP-1 in macrophages and endothelial cells .
Besides the effect of DPP4i on CVD risk factors and atherosclerosis, an interesting and recent finding was the effect of DPP4i on endothelial progenitor cells (EPCs). Circulating EPCs, originating from the bone marrow, have the ability to differentiate into endothelial cells, and by that play a key role in vasculogenesis . In the cardiovascular system, the amount of circulating EPCs predicts the occurrence of cardiovascular events and death from cardiovascular causes . Fadini et al. showed recently that DPP4i enhances the level of circulating EPCs .
Our study showed a beneficial association between pre-treatment with DPP4i and short-term cardiovascular outcomes among patients admitted with acute coronary syndrome. Alongside the history of CHF and age, chronic treatment with Sitagliptin, the only DPP4i given in our study population, was associated with a better KILLIP class on admission and reduced rates of 30-day MACE. Similar results were reported recently by Engel et al., which showed reduced incidence of CVD endpoints among diabetes patients treated with Sitagliptin compared to ones treated with sulphonyl-urea . Moreoever, we documented additional lower rates of in-hospital complications (i.e. acute renal failure and pulmonary edema) with DPP4i treatment. This can be a random finding due to the small number of events, but it may also represent possible additional effects of DPP4 inhibition, such as the effect on endothelial dysfunction and inflammation .
It shoud be noted that Sitagliptin was the only DPP4 inhibitor that was presscribed in our dataset. Despite the similar mechanism of action, DPP4 inhibitors are not necessarily identical, and have pharmaco-dynamic and pharmaco-kinetic properties . This was also shown to have clinical ramifications in a recent study, which showed that the mean amplitude of glycemic excursions, highest blood glucose level after supper, and hyperglycemia after breakfast were significantly lower with vildagliptin BID compared to once daily sitagliptin . This question should be answered with randomized controlled trials that would be published in the near future.
As all retrospective analysis, one cannot conclude a direct effect of DPP4i on cardiovascular events, and only the on-going randomized studies could give a direct answer to this question. The small sample size in the DPP4i group and the fact that treatment duration was not recorded may increase the chances that the findings are accidental and could be randome. the In addition, our survey was not designed to be a study for diabetics, and therefore the status of the disease, the rate of control as well as the duration are not available.
In conclusion, our data from ACSIS 2010 suggest that pre-treatment with DPP4i may be associated with a lower risk of in hospital complications and 30-day MACE among patients presenting with acute coronary syndrome. These findings suggest a possible role for DPP4i in appropriately selected high-risk patients with diabetes mellitus.