Effect of Saxagliptin on Endothelial Function in Patients with Type 2 Diabetes : A Prospective Multicenter Study

The dipeptidyl peptidase-4 inhibitor saxagliptin is a widely used antihyperglycemic agent in patients with type 2 diabetes. The purpose of this study was to evaluate the effects of saxagliptin on endothelial function in patients with type 2 diabetes. This was a prospective, multicenter, interventional study. A total of 34 patients with type 2 diabetes were enrolled at four university hospitals in Japan. Treatment of patients was initially started with saxagliptin at a dose of 5 mg daily. Assessment of endothelial function assessed by flow-mediated vasodilation (FMD) and measurement of stromal cell-derived factor-1α (SDF-1α) were conducted at baseline and at 3 months after treatment with saxagliptin. A total of 31 patients with type 2 diabetes were included in the analysis. Saxagliptin significantly increased FMD from 3.1 ± 3.1% to 4.2 ± 2.4% (P = 0.032) and significantly decreased total cholesterol from 190 ± 24 mg/dL to 181 ± 25 mg/dL (P = 0.002), glucose from 160 ± 53 mg/dL to 133 ± 25 mg/dL (P < 0.001), HbA1c from 7.5 ± 0.6% to 7.0 ± 0.6% (P < 0.001), urine albumin-to-creatinine ratio from 63.8 ± 134.2 mg/g to 40.9 ± 83.0 mg/g (P = 0.043), and total SDF-1α from 2108 ± 243 pg/mL to 1284 ± 345 pg/mL (P < 0.001). These findings suggest that saxagliptin is effective for improving endothelial function

Diagnostic Criteria of FMD and NID

Background - Diagnostic criteria of flow-mediated vasodilation (FMD), an index of endothelial function, and nitroglycerin-induced vasodilation (NID), an index of vascular smooth muscle function, of the brachial artery have not been established. The purpose of this study was to propose diagnostic criteria of FMD and NID for normal endothelial function and normal vascular smooth muscle function. Methods and Results - We investigated the cutoff values of FMD and NID in subjects with (risk group) and those without cardiovascular risk factors or cardiovascular diseases (no-risk group) in 7277 Japanese subjects (mean age 51.4±10.8 years) from the Flow-Mediated Dilation Japan study and the Flow-Mediated Dilatation Japan Registry study for analysis of the cutoff value of FMD and in 1764 Japanese subjects (62.2±16.1 years) from the registry of Hiroshima University Hospital for analysis of the cutoff value of NID. Receiver-operator characteristic curve analysis of FMD to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of FMD to diagnose subjects in the no-risk group was 7.1%. Receiver-operator characteristic curve analysis of NID to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of NID to diagnose subjects in the no-risk group was 15.6%. Conclusions - We propose that the cutoff value for normal endothelial function assessed by FMD of the brachial artery is 7.1% and that the cutoff value for normal vascular smooth muscle function assessed by NID of the brachial artery is 15.6% in Japanese subjects

男性における非常に高いHDL-Cレベルと内皮機能障害との関係

広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

Low Levels of Low-Density Lipoprotein Cholesterol and Endothelial Function in Subjects without Lipid-Lowering Therapy

An elevation of serum low-density lipoprotein cholesterol (LDL-C) levels has been associated with endothelial dysfunction in statin na&iuml;ve subjects. However, there is no information on endothelial function in subjects with extremely low levels of LDL-C. The purpose of the present study was to determine the relationship of LDL-C levels, especially low levels of LDL-C, with endothelial function. Endothelial function assessed by flow-mediated vasodilation (FMD) measurement and LDL-C levels were evaluated in 7120 subjects without lipid-lowering therapy. We divided the subjects into five groups by LDL-C levels: &lt;70 mg/dL, 70&ndash;99 mg/dL, 100&ndash;119 md/dL, 120&ndash;139 mg/dL, and &ge;140 mg/dL. FMD values were significantly smaller in subjects with LDL-C levels of &ge;140 mg/dL than in those with LDL-C levels of 70&ndash;99 mg/dL and 100&ndash;119 mg/dL (p &lt; 0.001 and p = 0.004, respectively). The FMD values in the LDL-C of &lt;70 mg/dL group were not significantly different from those in the other groups. To evaluate the relationship of extremely low LDL-C levels with endothelial function, we divided the subjects with LDL-C of &lt;70 mg/dL into those with LDL-C levels of &lt;50 mg/dL and 50&ndash;69 mg/dL. FMD values were similar in the LDL-C &lt;50 mg/dL group and &ge;50 mg/dL group in the propensity score-matched population (p = 0.570). A significant benefit was not found in subjects with low LDL-C levels from the aspect of endothelial function

Inconvenient relationship of haemoglobin A1c level with endothelial function in type 2 diabetes in a cross-sectional study

Objective The aim of this study was to determine the relationship of haemoglobin A1c (HbA1c) level with flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) in patients with type 2 diabetes.Design Cross-sectional study.Setting 22 university hospitals and affiliated clinics in Japan.Participants 1215 patients with type 2 diabetes including 349 patients not taking antidiabetic drugs.Measures We evaluated FMD and HbA1c level. All patients were divided into four groups based on HbA1c level: &lt;6.5%, 6.5%–6.9%, 7.0%–7.9% and ≥8.0%.Results An inverted U-shaped pattern of association between HbA1c level and FMD was observed at the peak of HbA1c of about 7%. FMD was significantly smaller in the HbA1c &lt;6.5% group than in the HbA1c 6.5%–6.9% group and HbA1c 7.0%–7.9% group (p&lt;0.001 and p&lt;0.001), and FMD values were similar in the HbA1c &lt;6.5% group and HbA1c ≥8.0% group. There were no significant differences in NID values among the four groups. After adjustments for confounding factors, FMD was significantly smaller in the HbA1c &lt;6.5% group than in the HbA1c 6.5%–6.9% and HbA1c 7.0%–7.9% group (p=0.002 and p=0.04). In patients not taking antidiabetic drugs, FMD was also significantly smaller in the HbA1c &lt;6.5% group than in the HbA1c 6.5%–6.9% group and HbA1c 7.0%–7.9% group (p&lt;0.001 and p=0.02), and there were no significant differences in NID values among the four groups.Conclusions These findings suggest that there is an inverted U-shaped pattern of association between FMD and HbA1c and that a low HbA1c level of &lt;6.5% is associated with endothelial dysfunction.Trial registration number UMIN000012950, UMIN000012951, UMIN000012952 and UMIN000003409

TGs and CV Events

Background: Circulating triglyceride (TG) levels are a current focus as a residual risk for cardiovascular (CV) events. We evaluated the relationship between circulating TG levels and future CV events in patients with coronary artery disease (CAD) who were treated with conventional therapy. Methods and Results: We analyzed data for 652 patients who were enrolled in the FMD-J Study A. We investigated the associations between serum TG levels and first major CV events (death from CV cause, nonfatal acute coronary syndrome (ACS), nonfatal stroke, and CAD) for a 3-year follow-up period. Patients were divided into 4 groups based on serum TG level: low-normal (<100 mg/dL), high-normal (100–149 mg/dL), borderline hypertriglyceridemia (150–199 mg/dL), and moderate hypertriglyceridemia (≥200 mg/dL). During a median follow-up period of 46.6 months, 14 patients died (9 from CV causes), 16 had nonfatal ACS, 6 had nonfatal stroke, and 54 had CAD. The Kaplan-Meier curves for first major CV event among the 4 groups were significantly different (P=0.04). After adjustment for various confounders, serum TG level ≥100 mg/dL were significantly associated with an increased risk of first major CV events compared with serum TG level <100 mg/dL. Conclusions: Serum TG level may be a surrogate marker for predicting CV events in patients with CAD