The effects of empagliflozin, a SGLT2 inhibitor, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk, were examined in EMPA-REG OUTCOME [23]. remain unknown, it has been hypothesized that metformin stimulates GLP-1 secretion directly and/or indirectly and prolongs the half-life of GLP-1, and that metformin may potentiate the glucose-lowering effects of GLP-1 by increasing target tissue sensitivity to GLP-1 [8]. Open in a separate window Figure 1 Glucose-lowering effects of metformin. A Significant Influence of Glycemic Variability (GV) on Microvascular and Macrovascular Complications in Patients With Diabetes With the spread of continuous glucose monitoring (CGM), glycemic GV is attracting attention. Emerging evidence suggests that GV contributes to adverse clinical outcome in patients with diabetes [9]. A recent meta-analysis assessing GV has shown associations of GV with microvascular and macrovascular complications and mortality in type 1 and type 2 diabetes [10]. Proposed mechanisms for GV-induced adverse vascular outcomes include increased oxidative stress and enhanced expression of proteins involved in vascular pathology [11]. A Dose-Dependent Effect of Metformin on GV Although various mechanisms have been suggested as metformin-mediated glucose-lowering, it remains unknown which of these mechanisms plays a crucial role at various daily doses of metformin. Our previous [12] and present study using CGM demonstrated that metformin improved GV in a dose-dependent manner (Fig. 2). Open in a separate window AS2521780 Figure 2 Effects of dose of metformin and combination of metformin with vildagliptin (DPP4 inhibitor) on glycemic variability, in a 55-year-old type 2 diabetic woman with body mass index of 29.2 kg/m2. The Effect of Combination of Dipeptidyl Peptidase 4 (DPP4) Inhibitors With Metformin on GV The present study using CGM showed that the combination of DPP4 inhibitor with metformin improved GV (Fig. 2). Effects of combination of metformin with incretin-related drugs (DPP4 inhibitors, GLP-1 analogs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors on GV were shown in Table 1 [13-19]. The combination of metformin with incretin-related drugs significantly improved GV as compared with the combination of metformin with other drugs. The combination of metformin with dapagliflozin (SGLT2 inhibitor) also significantly improved GV as compared with the combination of dapagliflozin with insulin. Table 1 Effects of Combination of Metformin With Incretin-Related Drugs (DPP4 Inhibitors, GLP-1 Analogs) and SGLT2 Inhibitors AS2521780 on Glycemic Variability thead th align=”left” rowspan=”1″ colspan=”1″ /th th align=”left” rowspan=”1″ colspan=”1″ Effective combination therapy /th th align=”left” rowspan=”1″ colspan=”1″ Improvement of glycemic variability /th th align=”left” rowspan=”1″ colspan=”1″ Comparative combination therapy /th /thead Takahashi et al. [13]Metformin (750 mg) + linagliptin (5 mg) Metformin (1,500 mg) monotherapyKim et al. [14]Metformin + vildagliptin Metformin + glimepirideKim et al. [15]Metformin ( 1,000 mg) + vildagliptin (100 mg) Rabbit Polyclonal to SGCA Metformin ( 1,000 mg) + pioglitazone (15 mg)Kim et al. [16]Metformin + sitagliptin (100 mg) Metformin + glimepiride (2 mg)Frias et al. [17]Metformin ( 1,500 mg) + once-weekly exenatide (2 mg) Metformin ( 1,500 mg) + placeboMa et al. [18]Metformin + liraglutide Metformin + NPH insulinHenry et al. [19]Metformin ( 1,500 mg) + dapagliflozin (10 mg) Insulin ( 30 units) + dapagliflozin (10 mg) Open in a separate window Many Participants Had Been Taking Metformin in the Trials of New Anti-Diabetic Drugs That Showed Excellent Cardiovascular Outcomes The cardiovascular effect of AS2521780 semaglutide, AS2521780 a GLP-1 AS2521780 analog with an extended half-life of approximately 1 week, in type 2 diabetes was examined in SUSTAIN-6 [20]. In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo. The cardiovascular effect of liraglutide, a GLP-1 analog,.