Ikuro Matsuba

Antibodies to GAD in Japanese diabetic patients: a multicenter study.

We determined the prevalence of antibodies to glutamic acid decarboxylase (anti-GAD) in Japanese diabetic patients. Anti-GAD were detected by RIP Anti-GAD Hoechst, which is a new sensitive radioimmunoassay (RIA) kit using purified pig brain GAD as the antigen. One thousand nine hundred Japanese patients were collected by the Study Group for Antibodies to GAD. The prevalence of anti-GAD in the subjects of this study was: 35.4% (326/921) in all patients with IDDM, 50.3% (96/191) in patients with IDDM less than 1-year duration, 4.3% (29/680) in NIDDM, 37.9% (39/103) in slowly progressive IDDM, 10.5% (4/38) in gestational diabetes mellitus, 0% (0/27) in impaired glucose tolerance, 4.8% (6/124) in the school children with glycosuria, 2.1% (1/47) in the relatives of IDDM and 5.0% (1/20) in neurological diseases without diabetes. The prevalence in normal subjects was 2.2% (7/323). Anti-GAD are frequently detected by the RIA kit in patients with IDDM of short duration and this assay may be useful for population screening for IDDM and for better understanding of its pathogenesis.

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)

The status of glycemic control by general practitioners and specialists for diabetes in Japan: a cross-sectional survey of 15,652 patients with diabetes mellitus.

To determine the status of diabetes care by general practitioners and diabetes specialists in Japan, we conducted a nation-wide cross-sectional survey. We asked 8112 clinics and hospitals randomly, from throughout Japan, to participate in this study and 721 facilities agreed. A total of 15,652 patients aged from 15 to 97 with type 1 and type 2 diabetes were enrolled. Of these, 14,560 (93.0%) and 1092 (7.0%) patients were cared for by general practitioners and diabetes specialists, respectively. HbA1c levels were measured by a latex agglutination method, and age, height, body weight, type of diabetes and treatment modality were obtained from each patient. Mean HbA1c level for all patients treated by general practitioners was significantly lower than for those treated by the diabetes specialists (6.8+/-1.2% vs. 7.0+/-1.2%, p=0.0002). Mean HbA1c level for patients without insulin therapy was lower than for those treated with insulin, irrespective of caring physician. The proportion of patients treated with insulin therapy by diabetes specialists was higher (17.7%) than that by general practitioners (6.5%). This study showed that average HbA1c levels in Japanese patients treated by either general practitioners or specialists was acceptable, regardless of study limitations or bias.

Factors Associated With Reduced Efficacy of Sitagliptin Therapy: Analysis of 93 Patients With Type 2 Diabetes Treated for 1.5 Years or Longer

Background Several studies have shown the effectiveness of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for type 2 diabetes, with a hypoglycemic effect being demonstrated both when it is administered alone or in combination with other oral antidiabetic agents. However, there are few reports about its long-term efficacy, although medications for diabetes need to be effective over the long term. This study (as part of ASSET-K) aimed to investigate the efficacy and safety of sitagliptin when it was administered for 1.5 years or longer, and to explore factors associated with reduction of the therapeutic response. Methods Out of 375 patients treated with sitagliptin (50 mg/day) at Kanamori Diabetes Clinic between December 2009 and March 2012, 133 could be followed up for 72 weeks without interruption. After excluding 40 patients in whom the dosage and/or types of concomitant medications were modified during that period, the remaining 93 were included in this analysis. Clinical indices, such as blood glucose, HbA1c, and body weight, were investigated retrospectively. Compliance with diet and exercise therapy at 48 weeks was checked by a questionnaire. Results In the 93 patients analyzed (sitagliptin monotherapy, n = 9; combination therapy, n = 77; and switching from an alpha-glucosidase inhibitor or glinide, n = 7), hemoglobin A1c (HbA1c) showed a significant decrease after 24 weeks (7.70 ± 0.73% at baseline vs. 6.90 ± 0.55% at 24 weeks), but then showed a slight increase at 48 weeks. HbA1c was subsequently maintained in the same range with no significant changes until 72 weeks. A positive correlation was noted between the changes of HbA1c and body weight from 24 to 48 weeks. Compliance with diet and exercise therapy was worse in patients showing a ≥ 0.3% increase of HbA1c (n = 37) from 24 to 48 weeks than in the others (n = 56). Multiple logistic regression analysis showed that both factors were independent determinants of the increase of HbA1c from 24 weeks onward. Conclusions Sitagliptin showed good efficacy and safety when administered for 18 months as both monotherapy and combination therapy. Inadequate compliance with diet/exercise therapy and weight again may be associated with an increase of HbA1c over time during treatment with sitagliptin.

Factors influencing the durability of the glucose-lowering effect of sitagliptin combined with a sulfonylurea.

We analyzed the changes of glycemic control over 12 months and the factors influencing blood glucose in 162 Japanese patients with type 2 diabetes having inadequate glycemic control despite sulfonylurea‐based therapy who received add‐on sitagliptin. Hemoglobin A1c (HbA1c) decreased significantly after 4 weeks of treatment, and this improvement was maintained for 1 year, although HbA1c was slightly higher in week 52 than in week 24. Comparison of the patients showing a ≥0.4% increase of HbA1c between weeks 24 and 52 (n = 57) with the others (n = 105) showed a significant difference in the change of bodyweight, as well as the dose of glibenclamide (both P < 0.01). Although combined therapy with sitagliptin and a sulfonylurea seems to be effective for at least 1 year, blood glucose levels are more likely to increase again in patients who show greater weight gain after 24 weeks of treatment and those receiving a higher dose of glibenclamide.

Secretory units of islets in transplantation index is a useful clinical marker to evaluate the efficacy of sitagliptin in treatment of type 2 diabetes mellitus

We carried out a retrospective analysis of 40 Japanese patients with type 2 diabetes mellitus who received sitagliptin. Glycated hemoglobin (HbA1c) and fasting plasma glucose were significantly decreased from 7.53 ± 0.65% and 155.2 ± 29.4 mg/dL at baseline to 6.80 ± 0.60% (P < 0.01) and 131.2 ± 22.3 mg/dL (P < 0.01) at week 20, respectively. β‐Cell function was evaluated by the secretory units of islets in transplantation (SUIT) index, which was significantly increased from 28.5 ± 14.0 at baseline to 38.6 ± 17.0 at week 20 (P < 0.01). Multivariate analysis was carried out between ΔHbA1c and several parameters (age, the duration of diabetes, body mass index, triglyceride [TG], C‐peptide [CPR], ΔCPR, HbA1c [baseline] and ΔSUIT), which showed HbA1c (baseline; β = 0.580, P < 0.001) and ΔSUIT (β = 0.308, P < 0.05) as significant independent determinants of ΔHbA1c. These two variables explained 53% of the variance in HbA1c response. These results suggest that SUIT index can be a clinical marker for the efficacy of sitagliptin in treatment of diabetes mellitus. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00109.x, 2011)

Fasting insulin levels and metabolic risk factors in type 2 diabetic patients at the first visit in Japan: a 10-year, nationwide, observational study (JDDM 28).

OBJECTIVE To investigate the relationship between fasting insulin levels and metabolic risk factors (MRFs) in type 2 diabetic patients at the first clinic/hospital visit in Japan over the years 2000 to 2009. RESEARCH DESIGN AND METHODS In total, 4,798 drug-naive Japanese patients with type 2 diabetes were registered on their first clinic/hospital visits. Conventional clinical factors and fasting insulin levels were observed at baseline within the Japan Diabetes Clinical Data Management (JDDM) study between consecutive 2-year groups. Multiple linear regression analysis was performed using a model in which the dependent variable was fasting insulin values using various clinical explanatory variables. RESULTS Fasting insulin levels were found to be decreasing from 2000 to 2009. Multiple linear regression analysis with the fasting insulin levels as the dependent variable showed that waist circumference (WC), BMI, mean blood pressure, triglycerides, and HDL cholesterol were significant, with WC and BMI as the main factors. ANCOVA after adjustment for age and fasting plasma glucose clearly shows the decreasing trend in fasting insulin levels and the increasing trend in BMI. CONCLUSIONS During the 10-year observation period, the decreasing trend in fasting insulin was related to the slight increase in WC/BMI in type 2 diabetes. Low pancreatic β-cell reserve on top of a lifestyle background might be dependent on an increase in MRFs.

Long-term efficacy and safety of sitagliptin in the treatment of Japanese Type 2 diabetes (ASSET-K1) to a target of HbA1c<7%

Background: Few studies have investigated the factors related to improvement and maintenance of glycemic control with sitagliptin in Type 2 diabetes (T2D) patients. Aim: To identify factors contributing to reaching and maintaining glycated hemoglobin (HbA1c) <7% with sitagliptin in Japanese T2D patients. Subjects and methods: This study included 1327 patients who were: taking sitagliptin as monotherapy; switched to sitagliptin; or taking sitagliptin in combination therapy. At baseline and 1, 3, 6, and 12 months after starting sitagliptin, weight, body mass index (BMI), HbA1c, fasting plasma glucose (FPG), and post-prandial plasma glucose (PPG) were measured. The subjects were divided into a group that achieved HbA1c<7% at 12 months, a poor control group(HbA1c≥8% at 12 months), and a discontinued group. Multiple regression analysis was performed to identify factors contributing to long-term control and maintenance with sitagliptin treatment. Results: HbA1c decreased significantly from 8.0% at baseline to 7.3%, but weight was unchanged. FPG and PPG improved significantly. The HbA1c<7% group had a significantly higher age and a significantly lower BMI at baseline than the HbA1c≥8% group and the discontinued group. On multivariate regression analysis, baseline HbA1c, baseline BMI, and Δbody weight after 12 months were significantly related to HbA1c reduction. The most common adverse event was hypoglycemia, and the most common adverse event responsible for discontinuation was constipation. Conclusions: HbA1c<7.0% was achieved in 31 % of T2D patients who had poor control with conventional treatment. Weight management is important for maintaining good long-term control with sitagliptin.

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.