Background Newer antidiabetic drugs, i.e., dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may exert distinct cardiovascular effects. We sought to explore their impact on vascular function. Methods Published literature was systematically searched up to January 2018 for clinical studies assessing the effects of DPP-4 inhibitors, GLP-1 RAs, and SGLT-2 inhibitors on endothelial function and arterial stiffness, assessed by flow-mediated dilation (FMD) of the brachial artery and pulse wave velocity (PWV), respectively. For each eligible study, we used the mean difference (MD) with 95% confidence intervals (CIs) for FMD and PWV. The pooled MD for FMD and PWV were calculated by using a random-effect model. The presence of heterogeneity among studies was evaluated by the I2 statistic. Results A total of 26 eligible studies (n = 668 patients) were included in the present meta-analysis. Among newer antidiabetic drugs, only SGLT-2 inhibitors significantly improved FMD (pooled MD 1.14%, 95% CI: 0.18 to 1.73, p = 0.016), but not DPP-4 inhibitors (pooled MD = 0.86%, 95% CI: -0.15 to 1.86, p = 0.095) or GLP-1 RA (pooled MD = 2.37%, 95% CI: -0.51 to 5.25, p = 0.107). Both GLP-1 RA (pooled MD = −1.97, 95% CI: -2.65 to -1.30, p < 0.001) and, to a lesser extent, DPP-4 inhibitors (pooled MD = -0.18, 95% CI: -0.30 to -0.07, p = 0.002) significantly decreased PWV. Conclusions Newer antidiabetic drugs differentially affect endothelial function and arterial stiffness, as assessed by FMD and PWV, respectively. These findings could explain the distinct effects of these drugs on cardiovascular risk of patients with type 2 diabetes.

: We systematically reviewed the literature regarding the impact of dipeptidyl peptidase-4 inhibitors (DPP-4i) on vascular function, including endothelial function and arterial stiffness (predictors of atherosclerosis progression and cardiovascular disease) in patients with type 2 diabetes mellitus (T2DM). We searched PubMed in order to identify clinical trials that investigated the effect of DPP-4i on vascular function in patients with T2DM when compared with placebo. Although 168 articles were initially found, only 6 studies (total 324 patients) investigated the effect of DPP-4i, especially linagliptin and sitagliptin, satisfied the inclusion criteria. Linagliptin enhanced endothelial function and exerted a slight beneficial effect on arterial wall properties. Sitagliptin seems to have a neutral effect on these variables. The currently available limited evidence suggests a beneficial effect of DPP-4i, especially linagliptin, on vascular function in patients with T2DM.

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Background Patients with type 2 diabetes mellitus (T2DM) are at higher risk for thrombotic events. Platelet function may be used to assess prothrombotic state in patients with cardiovascular disease. Purpose We aimed to investigate whether the administration of novel antidiabetic agents influence platelet function in TDM2 patients. Patients and methods We 60 enrolled consecutive patients with T2DM, on stable antidiabetic therapy, who did not achieve therapeutic targets. Subjects were assessed to receive an additional anti-diabetic agent; dipeptidyl peptidase-4 inhibitor (DPP4i, n=14), glucagon like peptide-1 receptor agonist (GLP1RA, n=24), sodium/glucose cotransporter-2 inhibitor (SGLT2i, n=22). Platelet reactivity was measured with PFA-200 collagen/epinephrine (c-EPI) and PFA-200 collagen/ADP (c-ADP) closure time. Glycosylated hemoglobin (HbA1c), c-EPI and c-ADP were assessed at baseline and 3 months after treatment intensification. Results There was no difference between the study groups regarding gender, age, hypertension, dyslipidemia, smoking, Hba1c and CADP or CEPI (p=NS for all) at baseline. All groups achieved better glycemic control in terms of HbA1c values between baseline and follow-up (for DPP4i: 7.4±0.2% vs 6.7±0.2%, for GLP1RA: 8.3±0.2% vs 6.9±0.1%, for SGLT2i: 7.5±0.1% vs 6.7±0.1% and for insulin 9.8±0.5% vs 7.7±0.4%, p<0.001 for all). After a 3 month-period, treatment intensification with these novel agents did not influence c-EPI and c-ADP values [155.4±6.64 sec vs 152.9±8.28 sec (p=0.678) and 106.6±4.30 sec vs 106.8±3.93 sec (p=0.955) respectively] in whole population. In subgroup analysis, for patients off antiplatelet treatment (n=31), c-EPI was significantly decreased from 148.4±8.5 to 129.8±13.9 sec (p=0.036), but not c-ADP (from 105.4±5.3 to 99.3±4.9 sec, p=0.094). In patients who did receive antiplatelets (n=37), c-EPI and c-ADP were not significantly changed (c-EPI 163.1±10.9 to 179.6±13.9 sec p=0.201 and c-ADP from 106.6±8.2 sec to 114.6±7.3 sec, p=0.318) respectively. Conclusion Antiplatelet treatment prevents thrombotic risk in T2DM patients receiving novel antidiabetics. The effects of novel antidiabetics on platelet reactivity -as well as any distinct class properties- merits further investigation. Acknowledgement/Funding None

Background Arterial stiffness flags increased cardiovascular disease risk in type 2 diabetes mellitus (T2DM) patients. There is limited data on how novel anti-diabetic agents affect arterial stiffness. Purpose To investigate the effects of novel anti-diabetic agents on arterial stiffness in T2DM patients. Patients and methods We enrolled 64 consecutive patients under stable antidiabetic therapy who did not achieve therapeutic targets. Subjects were assessed to receive an additional antidiabetic agent to optimize glucose control; dipeptidyl peptidase-4 inhibitor (DPP4i, n=14), glucagon like peptide-1 receptor agonist (GLP1RA, n=21), sodium/glucose cotransporter-2 inhibitor (SGLT2i, n=21) or long-acting insulin (n=8). Glycosylated hemoglobin (HbA1c) as well as carotid-femoral pulse wave velocity (PWV) and augmentation index (Alx) were measured (as indices of arterial stiffness) were measured at baseline and 3 months after treatment intensification. Results There were no differences between the study groups in traditional risk factors, or baseline HbA1c, PWV and Alx levels (p=NS for all). All groups achieved better glycemic control in terms of HbA1c values between baseline and follow-up (for DPP4i: 7.4±0.2% vs 6.7±0.2%, for GLP1RA: 8.3±0.2% vs 6.9±0.1%, for SGLT2i: 7.5±0.1% vs 6.7±0.1% and for insulin 9.8±0.5% vs 7.7±0.4%, p<0.001 for all). PWV decreased from 10.0±0.84 to 9.1±0.43 m/sec (p=0.092) in the DPP4i group, from 11.7±0.72 to 10.2±0.74 m/sec (p<0.001) in the GLP1RA group, from 1.3±0.54 to 9.6±0.59 m/sec (p=0.001) in the SGLT2i group and from 11.6±1.04 to 11.1±1.02 m/sec (p=0.219) in the insulin group. Alx was also decreased from 34.2±1.89 to 31.5±2.17% (p=0.023) in the DPP4i group, from 29.1±1.52 to 25.6±2.09% (p<0.001) in the GLP1RA group, from 29.9±1.44 to 24.2±1.48% (p<0.001) in SGLT2i group, and from 28.2±2.33 to 26.2±1.64% (p=0.153) in insulin group. Conclusions These preliminary data provide evidence that treatment intensification -particularly with GLP1RA, and SGLT2i- benefits vascular properties, a finding which could partly explain the positive findings of recent randomized clinical trails in this field. Acknowledgement/Funding None

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