Sitagliptin versus mitiglinide switched from mealtime dosing of a rapid-acting insulin analog in patients with type 2 diabetes: a randomized, parallel-group study.

PURPOSE: We determined the feasibility of substituting sitagliptin or mitiglinide for bolus insulin injection therapy in patients with type 2 diabetes. METHODS: 60 patients with type 2 diabetes were enrolled and randomized to switch from mealtime dosing of a rapid-acting insulin analog to either sitagliptin or mitiglinide for 16 weeks. RESULTS: Body weight, body mass index, and waist circumference decreased significantly in both groups at the end of the study. Mitiglinide significantly increased fasting plasma glucose (FPG) levels at the end of the study from 146.5±36.3 to 168.0±38.8 mg/dL, whereas sitagliptin did not affect FPG. Glycated hemoglobin (HbA1c) and 1,5-anhydroglucitol increased significantly in both groups. The C peptide immunoreactivity (CPR) responses after arginine were diminished in both groups. γ-GTP and triglycerides increased, and high-density lipoprotein cholesterol and adiponectin decreased, in the sitagliptin group, but not in the mitiglinide group. Mean Diabetes Treatment Satisfaction Questionnaire scores improved significantly in both groups. Patients whose mean total daily doses of rapid-acting insulin analog were 16.6 and 17.8 units were switched to sitagliptin and mitiglinide, respectively, without a change in the HbA1c level. Total insulin doses/body weight predicted changes in HbA1c only in the sitagliptin group, but not in the mitiglinide group. Use of >0.27 IU/kg of a rapid-acting insulin analog predicted an increase in HbA1c after switching to sitagliptin. The CPR index (CPI) was also a predictor for a change in HbA1c in the sitagliptin group, but not in the mitiglinide group; patients with a CPI<1.4 developed a worse HbA1c after switching to sitagliptin. CONCLUSIONS: Sitagliptin may predominantly act on FPG, whereas mitiglinide may act on postprandial plasma glucose to achieve glycemic control after switching from a bolus insulin regimen. Additional therapy to sitagliptin or mitiglinide is clearly required to obtain equivalent glycemic control in patients using a higher dose of insulin. TRIAL REGISTRATION NUMBER: (UMIN 000007051).

Renoprotective effects of atorvastatin compared with pravastatin on progression of early diabetic nephropathy.

INTRODUCTION: Several studies have shown that statins suppress the progression of diabetic nephropathy. However, few reports have directly compared the renoprotective effects between potent and conventional statins. MATERIALS AND METHODS: Patients with diabetic nephropathy, selected as those with a serum creatinine level of 0.9-1.5 mg/dL and simultaneously having either microalbuminuria or positive proteinuria, were randomly assigned to one of three groups: a conventional diet therapy group, a group given 10 mg of pravastatin and a group given 10 mg of atorvastatin. Renal function was evaluated before and after a 12-month period of therapy. RESULTS: The atorvastatin group had a significant decrease in low-density lipoprotein cholesterol at 3 months and thereafter compared with the other groups. The urinary albumin-to-creatinine ratio significantly decreased in the atorvastatin group; the degree of this decrease was significantly greater than that in the diet therapy group. The kidney function estimated with cystatin C (CysC) and the estimated glomerular filtration rate calculated from CysC were significantly preserved in the atorvastatin group compared with the pravastatin group. In a multivariate regression analysis, the use of atorvastatin was the only explanatory variable for the changes in CysC; this was independent of changes in low-density lipoprotein cholesterol. CONCLUSIONS: Atorvastatin is more effective than pravastatin for the prevention of increase in CysC, and this renoprotective effect was considered to a result of the pleiotropic effect of atorvastatin independent of its lipid-lowering effect. This study was registered with UMIN (no. UMIN 000001774).

Cross talk of tumor necrosis factor-alpha and the renin-angiotensin system in tumor necrosis factor-alpha-induced plasminogen activator inhibitor-1 production from hepatocytes.

Tumor necrosis factor (TNF)-alpha and local activation of the renin-angiotensin system may contribute to insulin resistance and atherosclerosis. In this study, we investigated the involvement of these mediators in the liver. We found that the gene expression of renin-angiotensin system components, together with that of plasminogen activator inhibitor (PAI)-1, is upregulated in the liver of patients with obesity and type 2 diabetes. We next examined the role of the renin-angiotensin system on TNF-alpha-induced PAI-1 production in the nonmalignant human hepatocyte cell line THLE-5b. THLE-5b cells expressed genes encoding renin-angiotensin system components including angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin type 1 (AT(1)) receptor. ACE, angiotensinogen, and angiotensin AT(1) receptor mRNA expression were upregulated time-dependently by TNF-alpha. Moreover, angiotensin AT(1) receptor antagonist dose-dependently inhibited TNF-alpha-induced PAI-1 production. Interestingly, high-dose olmesartan, but not candesartan, reduced the increased expression of the angiotensin AT(1) receptor. These results suggest that TNF-alpha and the local renin-angiotensin system coordinately stimulate PAI-1 production in hepatocytes. Selective angiotensin AT(1) receptor antagonists inhibit both TNF-alpha- and angiotensin II-induced PAI-1 production in hepatocytes, suggesting a cross talk between both systems.