Takehiro Kawata

Clinical Significance of Urinary Liver-Type Fatty Acid Binding Protein in Diabetic Nephropathy of Type 2 Diabetic Patients

OBJECTIVE Urinary liver-type fatty acid–binding protein (L-FABP) is a promising indicator of tubular but not glomerular damage. The aim of this study was to evaluate the clinical usefulness of urinary L-FABP as a prognostic biomarker in impaired diabetic nephropathy in type 2 diabetes. RESEARCH DESIGN AND METHODS This investigation involved a cross-sectional and longitudinal analysis of the relationship between urinary L-FABP levels and progressive nephropathy. Urinary L-FABP was measured with enzyme-linked immunosorbent assay. In the cross-sectional analysis, the association of urinary L-FABP, with the severity of diabetic nephropathy, was investigated in 140 patients with type 2 diabetes and in 412 healthy control subjects. Of the patients in the former study, 104 have been followed for 4 years. The progression of diabetic nephropathy was defined as progressive albuminuria, end-stage renal disease, or induction of hemodialysis. RESULTS Urinary L-FABP levels were progressively increased in subjects with normo-, micro-, or macroalbuminuria and further increased in patients with end-stage renal disease. In the longitudinal analysis, high urinary L-FABP levels were associated with the increase in albuminuria, progression to end-stage renal disease, or induction of hemodialysis. This was particularly demonstrated in the subgroup of patients without renal dysfunction (n = 59), where high urinary L-FABP levels were associated with the progression of diabetic nephropathy. CONCLUSIONS Urinary L-FABP accurately reflected the severity of diabetic nephropathy in type 2 diabetes, and its level was high in the patients with normoalbuminuria. Moreover, higher urinary L-FABP was a risk factor for progression of diabetic nephropathy.

Pleiotropic Effects of Sitagliptin in the Treatment of Type 2 Diabetes Mellitus Patients

Background Sitagliptin is a DPP-4 inhibitor that became available for use in Japan three years ago. This study was conducted to identify the pleiotropic effects of sitagliptin other than blood glucose lowering in Japanese type 2 diabetes mellitus patients. Methods A retrospective, observational study of 940 type 2 diabetes mellitus patients was conducted. The primary outcome measures were HbA1c, blood pressure, and lipid profiles measured at 0, 4, and 12 weeks of sitagliptin therapy. Results After 12 weeks of sitagliptin treatment, compared with baseline, HbA1c decreased 0.64% ± 0.86%; systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased significantly; and serum creatinine (Cr) and uric acid (UA) levels were mildly but significantly elevated. A correlation analysis of the changes in systolic blood pressure, diastolic blood pressure, creatinine, and uric acid (ΔSBP, ΔDBP, ΔCr, ΔUA) from baseline to 12 weeks showed significant negative correlations between ΔSBP and ΔCr, ΔSBP and ΔUA, and ΔDBP and ΔCr. Total cholesterol and postprandial triglycerides were significantly decreased at both 4 and 12 weeks. Alkaline phosphatase (ALP) decreased significantly, and there was a significant positive correlation between changes in ALP and HbA1c. Conclusions Sitagliptin seems to be effective not only in lowering blood glucose but also in lowering blood pressure, lipid, and ALP levels. Sitagliptin appears to contribute to a Na-diuretic action due to GLP-1.

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

(J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00221.x, 2012)

Evaluation of whole-abdominal fat volume by 700-slice CT scanning and comparison with the umbilical fat area anthropometric indices

SUMMARY BACKGROUND The fat area at the umbilical region on CT scans is widely used to identify visceral obesity. However, whether it precisely represents the abdominal visceral fat volume is uncertain, because of technical difficulty in evaluating whole-abdominal visceral fat volume. In this study, we compared the whole-abdominal visceral fat and subcutaneous fat volumes with the visceral fat area at the umbilical region and anthropometric indices. METHODS The study population consisted of 131 Japanese diabetic and non-diabetic subjects (72 males and 59 females) who underwent anthropometric measurements (height, weight, waist circumference, and hip circumference) and CT scanning from the top of the liver to the pelvic floor (about 700 slices) to analyze the whole-abdominal and umbilical contents of visceral and subcutaneous fat. RESULTS The visceral fat volume of the male group was 1.3-fold higher than that of the female group, while the subcutaneous fat volume of the female group was 1.3-fold higher than that of the male group. The visceral fat area at the umbilical region was strongly correlated with visceral fat volume (r = 0.921 in males and 0.931 in females). Both visceral and subcutaneous fat volumes were strongly correlated with the waist circumference (r = 0.768 and 0.809 in males and 0.744 and 0.803 in females), but not with the BMI or waist/hip ratio. CONCLUSION The visceral fat area at the umbilical region is an optimal indicator for whole-abdominal visceral fat volume, and the waist circumference is the anthropometric index that reflects visceral obesity more closely than BMI or the waist/hip ratio.

Safety and efficacy of adding sitagliptin to insulin in patients with type 2 diabetes: The ASSIST-K study

We retrospectively studied more than 1000 patients with type 2 diabetes attending 36 Japanese clinics to investigate the efficacy and safety of adding sitagliptin to various insulin regimens. We found that the treatment with add-on sitagliptin for 6-months was effective, irrespective of the type or dose of concomitant insulin.

Comparison of the hypoglycemic effect of sitagliptin versus the combination of mitiglinide and voglibose in drug-naïve Japanese patients with type 2 diabetes

Objective: The postprandial glucose (PPG) level is reduced by α-GIs, glinides and DPP4Is through different pharmacological actions. The aim of this study was to compare the effect of sitagliptin (S) versus that of the combination of mitiglinide and voglibose (M+V) on markers of glycemic control. Research design and methods: A randomized cross-over trial was performed in 20 patients with drug-naïve type 2 diabetes. The patients were randomized to receive S (50 mg/day) or M+V (1 tablet 3 times daily). Treatment was continued for 8 weeks, after which they were switched to the other regimen and treated for another 8 weeks. At baseline, after the first regimen, and after the second regimen, a meal test was performed. Main outcome measures: The markers of glycemic control were examined. Results: Reduction of glucose excursion was significantly greater with M+V than with S. HbA1c did not change with either regimen. However, 1,5-anhydroglucitol showed a significant increase from baseline with both regimens (7.9 ± 4.3 μg/ml at baseline vs. 10.6 ± 5.5 with S, p < 0.05 and 15.1 ± 6.2 with M+V, p < 0.01). Compared with baseline, glycoalbumin was significantly reduced by M+V, but not S (19.6 ± 2.9% at baseline vs. 17.3 ± 3.8% with M+V, p < 0.05). Conclusion: M+V achieved better control of PPG excursion than S.

Factors Influencing Changes in Hemoglobin A1c and Body Weight During Treatment of Type 2 Diabetes With Ipragliflozin: Interim Analysis of the ASSIGN-K Study

Background Ipragliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor that blocks glucose reabsorption in the proximal tubules. SGLT2 inhibitors are expected to be effective in patients with insulin resistance and obesity, but it is important to select treatment according to patient background factors that minimizes the risk of adverse events. There have been a limited number of investigations into the relationship between the clinical efficacy (reducing hemoglobin A1c (HbA1c) and body weight (BW)) or safety of SGLT2 inhibitors and patient characteristics. Methods ASSIGN-K is an investigator-initiated, multicenter, prospective observational study examining the efficacy and safety of ipragliflozin (50 - 100 mg/day for 52 weeks) in Japanese patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with HbA1c ≥ 6.0% (National Glycohemoglobin Standardization Program) despite diet and exercise therapy or diet and exercise plus antidiabetic drug therapy. We conducted an interim analysis of the relationship between changes in HbA1c or BW and characteristics in patients who had been on treatment for more than 12 weeks. Results In 257 patients completing 12 weeks of treatment, HbA1c decreased significantly from 8.23% to 7.55% (-0.68%, P < 0.01). The change in HbA1c after 12 weeks was -0.17%, -0.33%, and -1.16% when baseline HbA1c was < 7%, 7% to < 8%, and ≥ 8%, respectively (P < 0.05, P < 0.01, and P < 0.01, respectively), and -1.30%, -0.62%, and -0.62% when baseline body mass index (BMI) was < 25, 25 to < 30, and ≥ 30, respectively (all P < 0.01). Stratified analysis showed that age, gender, or BMI did not have a significant influence on the improvement in HbA1c. Multiple regression analysis showed that reduction in HbA1c was greater as baseline HbA1c increased and the duration of diabetes decreased. A higher baseline HbA1c was associated with less weight loss. Conclusions Ipragliflozin significantly improved HbA1c in patients with T2DM. HbA1c improved more when baseline HbA1c was higher and the duration of diabetes was shorter, suggesting that current treatment policies for diabetes could be re-examined.

Is a Switch From Insulin Therapy to Liraglutide Possible in Japanese Type 2 Diabetes Mellitus Patients

Background To evaluate the efficacy of switching from insulin to the GLP-1 receptor agonist liraglutide in type 2 diabetes mellitus patients. Methods The subjects were 231 outpatients with type 2 diabetes mellitus being treated with liraglutide for the first time. For 161 patients, liraglutide was continued for 24 weeks (continuation group), and for 70 patients, liraglutide was discontinued before 24 weeks (discontinuation group). Fasting and postprandial blood glucose levels, HbA1c, body weight, and insulin dose were evaluated before the switch to liraglutide (baseline) and at 12 and 24 weeks of administration. Trends in HbA1c and weight were compared at 12 and 24 weeks of administration. Multiple regression analyses were conducted to identify clinical factors predicting a successful switch to liraglutide. Results Multiple regression analysis with ΔHbA1c as the dependent variable in the continuation group indicated that HbA1c at 12 weeks of administration decreased with higher baseline HbA1c and increased with higher baseline daily insulin doses. Multiple regression analysis with Δweight as the dependent variable indicated that Δweight at 24 weeks of liraglutide administration was higher with higher baseline daily insulin doses and longer duration of diabetes. Based on the area under the receiver operating characteristic curve, cut-off values of 19 units for daily insulin dose and nine years for duration of diabetes were identified. Conclusions Switching from insulin to liraglutide therapy is possible for carefully selected patients. Daily insulin dosage and duration of insulin therapy appear to be clinically useful indicators for the efficacy of liraglutide therapy.

Factors Predicting Therapeutic Efficacy of Combination Treatment With Sitagliptin and Insulin in Type 2 Diabetic Patients: The ASSIST-K Study.

Background It is unclear whether dipeptidyl peptidase-4 inhibitors decrease hemoglobin A1c (HbA1c) in a glucose-dependent manner in patients on insulin therapy who have impaired insulin secretion. This study investigated factors influencing the efficacy of sitagliptin when used concomitantly with insulin to treat type 2 diabetes mellitus (T2DM) in the real-world setting. Methods A retrospective study was conducted of 1,004 T2DM patients at 36 Japanese clinics associated with the Diabetes Task Force of the Kanagawa Physicians Association. Eligible patients had been on insulin for at least 6 months, with a baseline HbA1c of 7.0% (53 mmol/mol) or higher. Baseline characteristics and laboratory data from 495 patients were subjected to multiple regression analysis to identify factors influencing the change of HbA1c. Results Most patients (n = 809) received sitagliptin at a dose of 50 mg. In the 1,004 patients, HbA1c decreased by 0.74% (6 mmol/mol) and body weight increased by 0.1 kg after 6 months of combination therapy. Multiple regression analysis showed that a higher baseline HbA1c, older age, and lower body mass index influenced the change of HbA1c after 6 months. Hypoglycemic symptoms occurred in 7.4%, but none were severe. Conclusions These results emphasize the importance of a higher HbA1c at the commencement of sitagliptin therapy in patients on insulin. Glucose-dependent suppression of glucagon secretion by sitagliptin may be useful in patients with impaired insulin secretion. Sitagliptin can be used concomitantly with insulin irrespective of the insulin regimen, duration of insulin treatment, and concomitant medications.

Dietary survey in Japanese patients with type 2 diabetes and the influence of dietary carbohydrate on glycated hemoglobin: The Sleep and Food Registry in Kanagawa study

The present study investigated the relationship between the macronutrient energy ratio, dietary carbohydrate and glycated hemoglobin levels in Japanese patients with type 2 diabetes, to generate a potential optimal dietary intake of macronutrients for such patients.