In summary, ΔFMD was significantly improved after 12 weeks of treatment in both the sitagliptin and voglibose groups, and there was no significant difference in ΔFMD between the two groups.
Alpha GI improves postprandial endothelial dysfunction in patients with type 2 diabetes ,. We showed that not only voglibose, an alpha GI, but also sitagliptin, a DPP-4 inhibitor, improves endothelial function as assessed by FMD in patients with type 2 diabetes. The impact of a DPP-4 inhibitor on endothelial dysfunction in patients with type 2 diabetes is controversial. A recent study showed that sitagliptin improved endothelial dysfunction assessed by the reactive hyperemia arterial tonometry index (RHI) after 6 months of treatment in patients with diabetes and coronary artery disease . We also showed that sitagliptin improved endothelial dysfunction assessed by another method, FMD. A prospective observational single arm trial also showed that the treatment with sitagliptin for 12 weeks increased FMD in patients with type 2 diabetes . Here, we conducted a randomized prospective multicenter study in patients with type 2 diabetes and revealed improvement of FMD after the 12-week treatment with sitagliptin. In contrast, another short-term study showed that DPP-4 inhibitors, including sitagliptin or alogliptin, attenuated endothelial function as evaluated by FMD after 6 weeks of treatment in patients with diabetes . Furthermore, voglibose, an alpha GI, did not affect FMD in the study. Therefore, short-term treatment with either DPP-4 inhibitors or alpha GI does not ameliorate endothelial dysfunction in patients with diabetes. Our study showed that 12-week treatment with either sitagliptin or voglibose ameliorated endothelial function. Thus, at least 12 weeks of treatment is needed to improve endothelial function.
The STOP-NIDDM trial showed that an alpha GI reduces the risk of cardiovascular events in patients with IGT . DPP-4 inhibitors are also expected to have beneficial cardiovascular effects ,. However, two recent trials with DPP-4 inhibitors, SAVOR-TIMI 53 and EXAMINE trials, showed that saxagliptin and alogliptin did not increase or decrease ischemic events in patients with type 2 diabetes ,. These trials demonstrated the safety of DPP-4 inhibitors but did not demonstrate cardiovascular benefits. Patients at high risk patients for cardiovascular disease were enrolled in those studies. In the SAVOR-TIMI 53 trial, about 78% of the patients had established cardiovascular disease, and the EXAMINE trial consisted of patients with acute coronary syndrome. Mean HbA1c levels were about 8.0 in patients of those studies. Our study included relatively low-risk patients. Only about 25% of the patients in our study had established cardiovascular diseases. Mean HbA1c levels were about 7.0. ΔFMD was significantly improved after 12 weeks of treatment in both the sitagliptin and voglibose groups in our study. The clinical implication of this study is the demonstration of beneficial effects of both sitagliptin and voglibose on endothelial dysfunction in low-risk and mild-risk patients with type 2 diabetes. Therefore, sitagliptin and voglibose might have cardiovascular benefits in low-risk and mild-risk patients with type 2 diabetes. Further studies are needed to clarify the long-term benefits for cardiovascular disease .
Iwamoto et al. reported that once-daily sitagliptin monotherapy (50 mg/day) showed greater efficacy and better tolerability than did thrice-daily voglibose (0.6 mg/day) over 12 weeks in Japanese patients with type 2 diabetes , but there was no significant difference in changes in HbA1c between the sitagliptin (50 mg/day) and voglibose (0.6 mg/day) groups in our study. Mean HbA1c levels at baseline in the former study and our study were about 7.8 and 7.0, respectively. Lower HbA1c at baseline in our study might have had an influence on changes in HbA1c levels. Sitagliptin tended to increase GLP-1 levels after 12 weeks of treatment, but there was no significant difference in changes in GIP and GLP-1 between the two groups in this study. These results might be because of the small sample size.
Matsubara et al. reported that treatment with sitagliptin for 6 months improved endothelial dysfunction along with a decrease in hs-CRP in patients with coronary artery disease and uncontrolled diabetes . Lipid profiles and eGFR did not change after treatment with sitagliptin in that study as well as in our study. Our study showed no significant difference in changes in hs-CRP after treatment with sitagliptin. Furthermore, Sakamoto et al. reported that sitagliptin improved blood pressure and lipid profiles in patients with type 2 diabetes . These different results might be due to the small sample size, short-term treatment or study in low risk patients with type 2 diabetes.
Fadini et al. reported that sitagliptin increased circulating EPCs in type 2 diabetic patients with concomitant upregulation of stromal-derived factor-1α (SDF-1α) . SDF-1α is a chemokine that stimulates bone marrow mobilization of EPCs and is one of the substrates of DPP-4. We also showed that sitagliptin significantly increased circulating CD34, but voglibose did not increase CD34. Therefore, this is an ancillary effect of sitagliptin and it is independent from blood glucose levels. Liao et al. reported that the number of EPCs was an independent risk factor for FMD . Thus, this effect might be favorable for the preservation of endothelial function in the future. Further long-term studies are needed to clarify this point.
A recent study revealed that alogliptin, a DPP-4 inhibitor, did not increase the frequency of serious adverse events, including hypoglycemia, cancer, pancreatitis, and initiation of dialysis in patients with type 2 diabetes who had a recent acute coronary syndrome . A pooled analysis of 25 randomized clinical trials did not indicate that treatment with sitagliptin increases cardiovascular risk in patients with type 2 diabetes mellitus . Our study also showed that sitagliptin did not cause serious adverse events. Thus, DPP-4 inhibitors may be safe drugs for patients with type 2 diabetes.
The first limitation of this study was the small sizes of the groups. The second was heterogeneity of the population in this study. The age range was quite wide in our study. The third limitation was that our study was a short-term study. Our findings need to be confirmed in a large cohort of patients with type 2 diabetes and with a long period.
In conclusion, sitagliptin improves endothelial dysfunction just as well as voglibose in patients with type 2 diabetes. Furthermore, sitagliptin increases the level of circulating CD34. Sitagliptin has protective effects on endothelial function without adverse events. These effects have potential favorable cardiovascular implications for patients with type 2 diabetes.