Self-reported rate of eating is significantly associated with body mass index in Japanese patients with type 2 diabetes. Japan Diabetes Clinical Data Management Study Group (JDDM26).

We examined whether the rate of eating was associated with the body mass index and glycemic control status in Japanese patients with type 2 diabetes (50% women, mean±SD age 59.4±7.5 years). Rapid eating was significantly associated with body mass index (p=0.047). The body mass index of those who reported eating quickly was 0.8 kg/m² higher than in individuals who reported eating at medium speed even after adjustment for known confounders. No significant association was observed between the rate of eating and HbA(1c). Our findings suggest an association between self-reported rapid eating and an elevated body mass index in patients with type 2 diabetes.

Patient characteristics associated with improvement in glycemic control following addition of an oral antidiabetic drug to DPP-4 inhibitor monotherapy in Japanese patients with type 2 diabetes mellitus (JDDM 60).

AIMS: The current study evaluated patient demographics and clinical characteristics that associated with HbA1c reduction following addition of one oral antidiabetic drug (OAD) to DPP4i monotherapy. METHODS: A retrospective study was conducted using CoDiC database. Adult T2DM patients treated with sitagliptin monotherapy for ≥ 6 months and adding one OAD were extracted. Association between patient characteristics at the time of add-on OAD and following HbA1c reduction was assessed. RESULTS: Of 444 included patients, mean age was 62 years and 33% were female. All add-on OAD classes demonstrated further HbA1c reduction (p < 0.05). The majority received biguanide (BG; 61%) or sulfonylurea (SU; 25%) add-on therapy. BG and SU groups showed a significant association between higher baseline HbA1c categories and greater HbA1c reductions (BG: - 0.24 to - 1.75%, p < 0.0001; SU: - 0.15 to - 2.11%, p < 0.0001). Lower HDL-cholesterol/higher non-HDL-cholesterol (BG), male gender (SU), and lower SBP (SU) were associated with larger HbA1c reductions. The results for baseline HbA1c (BG and SU) and gender (SU) were also confirmed by multivariate analysis. CONCLUSION: The majority of Japanese T2DM patients on sitagliptin monotherapy who require an add-on OAD utilized BG or SU. There were 2 determinants of glycemic response: baseline HbA1c with BG and SU and gender with SU during add-on OAD therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00514-5.

Association of a SNP in the IAPP gene and hyperglycemia on ß-cell dysfunction in type 2 diabetes: the Toon Genome Study.

OBJECTIVE: In type 2 diabetes, the significant pathological change in pancreatic islets is amyloid deposits. Its major component is islet amyloid polypeptide (IAPP). The objective of this study was to evaluate the possibility that the effect of the IAPP genotype on ß-cell dysfunction in type 2 diabetes is modified by variations in plasma glucose levels. METHODS: Participants from the Toon Genome Study underwent a 75 g OGTT for the diagnosis of glucose tolerance and the evaluation of insulin secretion. We examined the effect of a SNP, rs77397980, on ß-cell function by analyzing an interaction (statistics) between the IAPP genotype and AUC glucose. RESULTS: The ratio of the C-allele carriers was essentially the same among subjects with normal glucose tolerance, impaired glucose tolerance and diabetes. In subjects with diabetes, along with an increase in AUC glucose, fasting insulin remained constant in the T/T homozygotes and appeared to decrease in the C-allele carriers. A homeostasis model assessment (HOMA)-IR appeared to be increased in the former and decreased in the latter. In subjects with diabetes stratified into cases with higher AUC glucose than the median, fasting insulin and HOMA-IR were lower in the C-allele carriers than in the T/T homozygotes. An interaction between the IAPP genotype and AUC glucose was indicated in the effect on HOMA-IR. CONCLUSIONS: The possibility that the association between IAPP genotype and basal insulin level is modified by variation in plasma glucose, resulting in a decreased basal insulin in type 2 diabetes, cannot be excluded. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00523-4.

Trends in glycemic control in patients with insulin therapy compared with non-insulin or no drugs in type 2 diabetes in Japan: a long-term view of real-world treatment between 2002 and 2018 (JDDM 66).

INTRODUCTION: We investigated trends in the proportion of diabetes treatment and glycemic control, which may be altered by recent advances in insulin and non-insulin drugs, in Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A serial cross-sectional study was performed using a multicenter large-population database from the Japan Diabetes Clinical Data Management study group. Patients with type 2 diabetes who attended clinics belonging to the study group between 2002 and 2018 were included to examine trends in glycated hemoglobin A1c (HbA1c) by treatment group using multivariable non-linear regression model. RESULTS: The proportion of patients with insulin only decreased from 15.0% to 3.6%, patients with insulin+non-insulin drugs increased from 8.1% to 15.1%, patients with non-insulin drugs increased from 50.8% to 67.0%, and those with no drugs decreased from 26.1% to 14.4% from 2002 to 2018, respectively. The HbA1c levels of each group, except for no drugs, continued to decrease until 2014 (unadjusted mean HbA1c (%) from 2002 to 2014: from 7.89 to 7.45 for insulin only, from 8.09 to 7.63 for insulin+non-insulin, and from 7.51 to 6.98 for non-insulin) and remained unchanged thereafter. Among insulin-treated patients, use of human insulin decreased, use of long-acting analog insulin increased, and concomitant use of non-insulin drugs increased (from 35.1% in 2002 to 80.9% in 2018), which included increased use of dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists, and the persistently high use of metformin. CONCLUSIONS: During the past two decades, combined use of insulin and non-insulin drugs increased and glycemic control improved and leveled off after 2014 in Japanese patients with type 2 diabetes. Further studies of the trend in association with age and factors related to metabolic syndrome are necessary to investigate strategies aiming at personalized medicine in diabetes care.

Improved insulin sensitivity with sodium-glucose cotransporter 2 inhibitor treatment in a patient with slowly progressive type 1 diabetes mellitus with metabolic syndrome: a case report.

We herein report the clinical course of a 56-year-old Japanese patient with slowly progressive type 1 diabetes mellitus, metabolic syndrome, non-alcoholic fatty liver disease, and severe insulin resistance. The patient's intravenous glucose tolerance test indicated marked reductions in insulin sensitivity and endogenous insulin secretion. Accordingly, administration of ipragliflozin l-proline, a sodium-glucose cotransporter 2 inhibitor, promoted improvements in insulin sensitivity and blood glucose levels, as well as a decrease in visceral fat, improvement in dyslipidemia, and decrease in hepatic lipid content, suggesting the potential efficacy of sodium-glucose cotransporter 2 inhibitors for obese patients with type 1 diabetes mellitus exhibiting insulin resistance.

Combination of disease duration-to-age at diagnosis and hemoglobin A1c-to-serum C-peptide reactivity ratios predicts patient response to glucose-lowering medication in type 2 diabetes: A retrospective cohort study across Japan (JDDM59).

AIMS/INTRODUCTION: Knowing the collective clinical factors that determine patient response to glucose-lowering medication would be beneficial in the treatment of type 2 diabetes. We carried out a retrospective cohort study to explore the combination of clinical factors involved in its therapeutic efficacy. MATERIALS AND METHODS: The results of cohort studies retrieved using the CoDiC® database across Japan from January 2005 to July 2018 were analyzed based on criterion that using insulin therapy indicates severe type 2 diabetes. RESULTS: A logistic regression analysis showed that age at diagnosis, disease duration, hemoglobin A1c (HbA1c) and serum C-peptide reactivity (CPR) at medication commencement were associated with the probability of insulin treatment. Receiver operating characteristic curve showed that these clinical factors predicted insulin treatment positivity with an area under the curve of >0.600. The area under the curve increased to 0.674 and 0.720 for the disease duration-to-age at diagnosis ratio and HbA1c-to-CPR ratio, respectively. Furthermore, area under the curve increased to 0.727 and 0.750 in the indices (duration-to-age ratio at diagnosis × 43 + HbA1c) and (duration-to-age ration at diagnosis × 21 + HbA1c-to-CPR ratio), respectively. After stratification to three groups according to the indices, monthly HbA1c levels during 6 months of treatment were higher in the upper one-third than in the lower one-third of patients, and many patients did not achieve the target HbA1c level (53 mmol/mol) in the upper one-third, although greater than fourfold more patients were administered insulin in the upper one-third. CONCLUSIONS: The combination of disease duration-to-age at diagnosis and HbA1c-to-CPR ratios is a collective risk factor that predicts response to the medications.

Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus.

OBJECTIVE: We tested the hypothesis that insulin therapy rather than sulfonylurea (SU) treatment is preferable to reverse or preserve beta-cell function among patients with slowly progressive insulin-dependent (type 1) diabetes (SPIDDM) or latent autoimmune diabetes in adults. METHODS: This multicenter, randomized, nonblinded clinical study screened 4089 non-insulin-dependent diabetic patients for glutamic acid decarboxylase autoantibodies (GADAb). Sixty GADAb-positive non-insulin-requiring diabetic patients with a 5-yr duration or shorter of diabetes were assigned to either the SU group (n = 30) or the insulin group (n = 30). Serum C-peptide responses to annual oral glucose tolerance tests were followed up for a mean of 57 months. The primary endpoint was an insulin-dependent state defined by the sum of serum C-peptide values during the oral glucose tolerance test (SigmaC-peptide) less than 4 ng/ml (1.32 nmol/liter). RESULTS: The progression rate to an insulin-dependent state in the insulin group (three of 30, 10%) was lower than that in the SU group (13 of 30, 43%; P = 0.003, log-rank). Longitudinal analysis demonstrated that SigmaC-peptide values were better preserved in the insulin group than in the SU group. Multiple regression analysis demonstrated that insulin treatment, a preserved C-peptide response, and a low GADAb titer at entry were independent factors in preventing progression to an insulin-dependent state. Subgroup analysis suggested that insulin intervention was highly effective for SPIDDM patients with high GADAb titers [> or =10 U/ml (180 World Health Organization U/ml)] and preserved beta-cell function [SigmaC-peptide > or = 10 ng/ml (3.31 nmol/liter)] at entry. No severe hypoglycemic episodes occurred during the study. CONCLUSIONS: Insulin intervention to preserve beta-cell function is effective and safe for patients with SPIDDM or latent autoimmune diabetes in adults.

Predictors of glycemic control in Japanese subjects with type 2 diabetes mellitus.

The purpose of this study was to investigate which pathophysiological and demographic characteristics of Japanese subjects with type 2 diabetes mellitus were associated with poor glycemic control and to propose a statistical model for predicting their glycemic control. A total of 220 subjects with type 2 diabetes mellitus were enrolled in this study. Frequently sampled intravenous glucose tolerance test was performed to determine the first-phase C-peptide secretion rate (CS1) and insulin sensitivity index. Multiple regression analysis in a stepwise manner was carried out to identify independent regulators of glycemic control. Upon stepwise linear regression analysis with hemoglobin A1c as a dependent parameter, fasting plasma glucose concentration (FPG), CS1, and onset age remained as predictors, explaining 41.0% of glycemic control. The young-onset group (onset age < or =48 years) had significantly higher hemoglobin A1c than the old-onset group (onset age >48 years) (P = .0148), although the present age was significantly older in the old-onset group; and there were no significant differences in duration of diabetes, treatment, body mass index, FPG, fasting insulin level, homeostasis model assessment of insulin resistance, CS1, and log(insulin sensitivity index) between them. Worsening factors of glycemic control in Japanese subjects with type 2 diabetes mellitus were elevated FPG, impaired first-phase insulin secretion, and young age of onset of the disease. Because glycemic control in the subjects with young-onset diabetes tends to be worse, early and aggressive intervention should be required for those with young-onset diabetes to prevent long-term complications.

IAPP/amylin and ß-cell failure: implication of the risk factors of type 2 diabetes.

In type 2 diabetes (T2D), the most significant pathological change in pancreatic islets is amyloid deposits, of which a major component is islet amyloid polypeptide (IAPP), also called amylin. IAPP is expressed in ß-cells and co-secreted with insulin. Together with the inhibitory effects of synthetic human IAPP (hIAPP) on insulin secretion, our studies, using hIAPP transgenic mice, in which glucose-stimulated insulin secretion was moderately reduced without amyloid deposit, and hIAPP gene-transfected ß-cell lines, in which insulin secretion was markedly impaired without amyloid, predicted that soluble hIAPP-related molecules would exert cytotoxicity on ß-cells. Human IAPP is one of the most aggregation-prone peptides that interact with cell membranes. While it is widely reported that soluble hIAPP oligomers promote cytotoxicity, this is still a hypothesis since the mechanisms are not yet fully defined. Several hIAPP transgenic mouse models did not develop diabetes; however, in models with backgrounds characterized for diabetic phenotypes, ß-cell function and glucose tolerance did worsen, compared to those in non-transgenic models with similar backgrounds. Together with these findings, many studies on metabolic and molecular disorders induced by risk factors of T2D suggest that in T2D subjects, toxic IAPP oligomers accumulate in ß-cells, impair their function, and reduce mass through disruption of cell membranes, resulting in ß-cell failure. IAPP might be central to ß-cell failure in T2D. Anti-amyloid aggregation therapeutics will be developed to create treatments with more durable and beneficial effects on ß-cell function.

Correction to: IAPP/amylin and ß­cell failure: implication of the risk factors of type 2 diabetes.

[This corrects the article DOI: 10.1007/s13340-018-0347-1.].

Serum resistin level is associated with insulin sensitivity in Japanese patients with type 2 diabetes mellitus.

Impaired insulin secretion and decreased insulin sensitivity are the main pathophysiologic features responsible for development of hyperglycemia in type 2 diabetes mellitus. Insulin resistance is often associated with increased adipose tissue mass. To examine which variables influence insulin sensitivity, we compared metabolic parameters, serum resistin, leptin, and adiponectin concentrations to the insulin sensitivity, obtained by frequently sampled intravenous glucose tolerance test using the minimal model analysis, in 113 Japanese patients with type 2 diabetes mellitus. Duration of diabetes, fasting plasma glucose, fasting insulin, homeostasis model assessment of insulin resistance index, and serum resistin concentration were significantly higher in the insulin-resistant subgroup compared with the insulin-sensitive subgroup and correlated with insulin sensitivity. Stepwise regression analysis also identified these parameters as independent regulators of insulin sensitivity. The present study reconfirmed that fasting insulin level or homeostasis model assessment of insulin resistance would be a surrogate measure of insulin resistance and demonstrated that insulin resistance increases progressively after the onset of overt diabetes and that the serum resistin level is associated with insulin sensitivity, suggesting that resistin plays an important role in the development of insulin resistance in Japanese patients with type 2 diabetes mellitus.

The Arg121Trp variant in PAX4 gene is associated with beta-cell dysfunction in Japanese subjects with type 2 diabetes mellitus.

Mutations in PAX4, a transcription factor involved in the beta-cell differentiation, could predispose to the development of type 2 diabetes mellitus. To clarify the role of PAX4 Arg121Trp mutation on the development of type 2 diabetes mellitus, we try to determine the clinical phenotype in diabetic subjects with this mutation. Study subjects consisted of 793 type 2 diabetic patients and 318 control subjects. Genotyping for Arg121Trp polymorphism was performed by Invader assay. Clinical phenotype was determined in diabetic subjects including 20 Trp121 carriers and 142 wild-type subjects using a combination of 2-compartment model of C-peptide kinetics and minimal model analysis during intravenous glucose tolerance test. We detected 3 Trp/Trp, 51 Arg/Trp, and 739 Arg/Arg in diabetic subjects, and 16 Arg/Trp and 302 Arg/Arg in control subjects. The frequency of Trp121 allele was 3.59% and 2.51% in diabetic and control groups, respectively (P = .19). Rate of insulin users was higher in Trp121 carriers compared with the wild-type group (42.5% vs 25.0%, P = .0046). First-phase C-peptide secretion was significantly decreased in the diabetic subjects with Trp121 allele compared with the patients with wild type (P = .0048), whereas there were no significant differences in insulin sensitivity and glucose effectiveness between the groups. Arg121Trp mutation in PAX4 gene could be associated with beta-cell dysfunction in Japanese subjects with type 2 diabetes mellitus.

Actual usage and clinical effectiveness of insulin preparations in patients with Type 1 diabetes mellitus in Japan: CoDiC-based analysis of clinical data obtained at multiple institutions (JDDM 3).

To clarify the actual usage of insulin preparations and their effectiveness on glycaemic control in patients with Type 1 diabetes mellitus in Japan, we analyzed clinical data collected via CoDiC, an electronic system for diabetes data collection and management, at 28 institutes. Of 18,470 diabetic patients registered with CoDiC in June, 2003, 12,279 patients were being treated with insulin preparations and/or oral hypoglycemic agents, with 861 of these patients having Type 1 diabetes mellitus and 11,418 patients having Type 2 diabetes. Three analytical surveys were carried out with the Type 1 diabetes patients. Study I: Cross-sectional survey on the treatment in 2002. Six hundred and thirteen patients received intensive conventional insulin treatment (ICT). The number of patients receiving rapid-acting insulin analogue (RA) was greater than that of patients receiving regular insulin (R). Serum CPR was lower in the patients with ICT than in the patients with conventional insulin treatment (CT). Study II: Survey on the changes in the actual usage and clinical effectiveness of insulin preparations, based on the data input in 2001 and 2002. The number of patients with ICT using RA insulin markedly increased. Study III: Analysis of the participants' clinical course over the 18-month period of the study from the time of first consultation. The dose of insulin increased during the term. The average HbA1c level fell drastically and reached to 7.5% over the first 9 months of the study and then remained between a range of 7.5% and 8% for the rest of the study period. In conclusion, ICT is actively performed and the RA insulin analogues are widely used in Type 1 diabetic patients in Japan. Basal-bolus therapy should be used to treat Type 1 diabetic patients with postprandial serum CPR of less than 0.5 ng/ml. It is difficult to obtain the ideal glycaemic control in Type 1 diabetic patients with the currently available insulin preparations.

The status of diabetes control and antidiabetic drug therapy in Japan--a cross-sectional survey of 17,000 patients with diabetes mellitus (JDDM 1).

The number of diabetic patients has been increasing in Japan and consequently diabetic complications are the most important target to be prevented through improving glycemic control. In order to describe the glycemic control status and treatment of diabetic patients by specialists in Japan over three years, from 2000 to 2002, we examined HbA1c, other laboratory data and the modality of drug therapy in the study population, 8170 in 2000, 11,831 in 2001, and 16,934 in 2002. Patients were registered at clinics and hospitals that were members of the Japan Diabetes Clinical Data Management Study Group (JDDM). HbA1c levels, other laboratory data, and details of drug therapy were collected and analyzed using SPSS and MS Access. The mean HbA1c levels were essentially unchanged during the study periods, ranging from 7.9% to 7.8%, and from 7.1% to 7.0%, in type 1 and type 2 diabetic patients, respectively. In type 2 diabetes, the frequency of oral hypoglycemic agents (OHA) use increased from 44.9% to 51.4%, while the use of diet-only therapy decreased from 29.9% to 25.4% over the study period. Although the systolic blood pressure was slightly above target, the mean blood pressure and the mean lipid profile were mostly within the treatment goals set by the Japan Diabetes Society. This first report from a large scale study of the daily management of diabetes in Japan revealed that the average HbA1c level was superior to most of the results reported from other countries. Nonetheless, 66% of the patients still had HbA1c levels and half of the patients had other laboratory parameters including blood pressure and lipid profile that were greater than those recommended by the Japan Diabetes Society. The nature of diabetes drug therapy in Japan has gradually changed as new drugs have appeared in the market.

Relationship between kidney function decline and initial risk factors for the progression of diabetic kidney disease: a retrospective analysis of 91 Japanese patients with type 2 diabetes.

BACKGROUND: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) in Japan. The clinical course and factors related to the progression of DKD to ESRD are important issues when treating patients with DKD. METHODS: Ninety-one type 2 diabetic patients with DKD that had progressed from chronic kidney disease (CKD) stages G1-3 on their initial clinical visit to ESRD were enrolled. The decline in the estimated glomerular filtration rate (eGFR) was analyzed and the initial clinical factors that influenced the decline rate were explored. RESULTS: There was a linear decline in eGFR before progression to ESRD, with a median annual decline rate (∆eGFR) of 9.2 mL/min/1.73 m2. In all patients, a history of coronary artery disease and increased levels of initial eGFR and high-density lipoprotein cholesterol (HDL-C) were positive predictors of log ∆eGFR, whereas age, history of cerebral infarction (CI), and an increased level of serum albumin were negative predictors of log ∆eGFR. In patients with CKD stages G1-2 on their first visit, male sex and increased diastolic blood pressure were positive predictors. In patients with CKD stage G3 on their first visit, an increased level of LDL-C was a positive predictor, whereas a history of CI and an increased level of serum total bilirubin (TBil) were negative predictors. CONCLUSION: In addition to the common risk factors, initial eGFR, HDL-C, and TBil were identified as novel risk factors for ESRD. These risk factors may differ between patients with early and advanced stages of CKD.

Relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetic patients (JDDM38).

AIMS/INTRODUCTION: We carried out an observational cohort study to examine the relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetics. MATERIALS AND METHODS: We analyzed the CoDiC(®) database of the Japan Diabetes Data Management Study Group across 67 institutions in Japan. In a total of 3,698 drug-naïve patients who were initiated with metformin, dipeptidyl peptidase-4 inhibitor (DPP-4i) or sulfonylurea (SU) from 2007 to 2012, we evaluated body mass index (BMI) and hemoglobin A1c (HbA1c). The patients were stratified according to their clinical features, and matched using a propensity score to adjust for baseline factors. RESULTS: HbA1c was reduced with all drugs, with the largest effect elicited by DPP-4i and the smallest by SU (P = 0.00). HbA1c increased with SU after 6 months in the patients stratified by an age-of-onset of <50 years (P = 0.00). BMI increased with SU in the patients stratified by a BMI of <25 (P = 0.00), and decreased with metformin in the patients with a BMI >25 (P = 0.00). The reduction in HbA1c was larger in patients with HbA1c of ≥8%, compared with that in patients with HbA1c of <8% (P = 0.00). HbA1c during the study period was higher in patients who were added to or swapped with other drug(s), than in patients continued on the original drug (P = 0.00). CONCLUSIONS: The effect on bodyweight and glycemic control differed among metformin, DPP-4i and SU, and the difference was associated with clinical features.

Fulminant type 1 diabetes: a nationwide survey in Japan.

OBJECTIVE: To describe the clinical and immunologic characteristics of fulminant type 1 diabetes, a novel subtype of type 1 diabetes, we conducted a nationwide survey. RESEARCH DESIGN AND METHODS: History and laboratory data, including islet-related autoantibodies, were examined in 222 patients with fulminant and nonfulminant type 1 diabetes in our hospitals in addition to another 118 patients with fulminant type 1 diabetes located outside our hospitals in Japan. RESULTS: In our hospitals, of the 222 patients studied, 43 (19.4%) were diagnosed with fulminant type 1 diabetes, 137 (61.7%) were classified as having autoimmune type 1 diabetes, and 42 were type 1 diabetic subjects who were not fulminant and did not have anti-islet antibodies. An additional 118 fulminant patients outside our hospitals were enrolled, making a total of 161 fulminant type 1 diabetic subjects (83 male and 78 female subjects; 14 children/adolescents and 147 adults) identified from all over Japan. (In 2000, the average incidence was three cases per month.) Flu-like symptoms and pregnancy were more frequently observed in the fulminant than in the autoimmune group (P < 0.001). In the fulminant patients, 4.8% were positive for anti-GAD antibodies and none were positive for anti-islet antigen 2 antibodies. CONCLUSIONS: Fulminant type 1 diabetes is a distinct subtype and accounts for approximately 20% of the ketosis-onset type 1 diabetes cases in Japan. Flu-like symptoms are characteristic of disease onset. Metabolic derangement is more severe in this subtype than in autoimmune type 1 diabetes.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with alpha-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on metformin or pioglitazone alone (Study for an Ultimate Combination Therapy to Control Diabetes with Sitagliptin-1): A multicenter, randomized, open-label, non-inferiority trial.

AIMS/INTRODUCTION: To assess the efficacy and safety of sitagliptin compared with α-glucosidase inhibitors in Japanese patients with type 2 diabetes inadequately controlled by metformin or pioglitazone alone. MATERIALS AND METHODS: In the present multicenter, randomized, open-label, parallel-group, active-controlled, non-inferiority trial, 119 patients aged 20-79 years with type 2 diabetes who had glycated hemoglobin 6.9-8.8% on stable metformin (500-1,500 mg/day) or pioglitazone (15-30 mg/day) alone were randomly assigned (1:1) to receive the addition of sitagliptin (50 mg/day) or an α-glucosidase inhibitor (0.6 mg/day voglibose or 150 mg/day miglitol) for 24 weeks. The primary end-point was change in glycated hemoglobin from baseline to week 12. All data were analyzed according to the intention-to-treat principle. RESULTS: After 12 weeks, reductions in adjusted mean glycated hemoglobin from baseline were -0.70% in sitagliptin and -0.21% in the α-glucosidase inhibitor groups respectively; between-group difference was -0.49% (95% confidence interval -0.66 to -0.32, P < 0.0001), meeting the predefined non-inferiority criterion (0.25%) and showing statistical significance. This statistical significance also continued after 24 weeks. Although sitagliptin did not affect bodyweight, α-glucosidase inhibitors decreased bodyweight significantly from baseline (-0.39 kg; P = 0.0079). Gastrointestinal disorders were significantly lower with sitagliptin than with an α-glucosidase inhibitor (6 [10.3%] patients vs 23 [39.7%]; P = 0.0003). Minor hypoglycemia occurred in two patients (3.5%) in each group. CONCLUSIONS: Sitagliptin showed greater efficacy and better tolerability than an α-glucosidase inhibitor when added to stable doses of metformin or pioglitazone. These findings support the use of sitagliptin in Japanese patients with type 2 diabetes inadequately controlled by insulin-sensitizing agents. This trial was registered with UMIN (no. 000004675).

Multicenter prevention trial of slowly progressive type 1 diabetes with small dose of insulin (the Tokyo study): preliminary report.

In 1996, we designed a randomized multicenter study to assess the effects of small doses of insulin on beta cell failure in slowly progressive type 1 diabetes (the Tokyo Study). We report here the preliminary results of this study. Glutamic acid decarboxylase 65 antibody (GADA)-positive patients were randomly divided into 2 groups: one group received insulin (Ins group), the other a sulfonylurea (SU group). Fifty-four patients (24 Ins group, 30 SU group) were analyzed at the end of a 4-year period. All patients underwent a 75 g oral-glucose test (O-GTT) every 6-12 months. The insulin-dependent stage was defined based on an integrated value of serum C-peptide levels on O-GTT ( summation operator CPR; sum of CPR at 0, 30, 60, 90, and 120 min) below 4.0 ng/mL. The summation operator CPR in the SU group decreased progressively from 22.0 +/- 10.6 to 11.3 +/- 7.5 ng/mL over the 48-month period (p < 0.001 vs. baseline). The summation operator CPR in the Ins group was unchanged. Among the SU group, 30% of subjects (9/30) progressed to IDDM, while 8.3% of Ins group subjects (2/24) progressed to IDDM (p = 0.087). With regard to the subjects who had a preserved C-peptide response ( summation operator CPR >/= 10 ng/mL), the proportion of SU group subjects who progressed to IDDM was significantly higher than that of the Ins group (7/28, 25% vs. 0/21, 0%, p = 0.015). Among subjects with a high GADA titer (>/=0 U/mL), 9/14 (64.3%) of the SU group, but only 2/16 (12.5%) of the Ins group, developed IDDM (p = 0.0068). As to those with a high GADA titer and a preserved C-peptide response, SU group subjects progressed to IDDM (7/12, 58.3%) more frequently than Ins group subjects (0/14, 0%) (p = 0.0012). In summary, our results suggest that small doses of insulin effectively prevent beta cell failure in slowly progressive type 1 diabetes. We recommend avoiding SU treatment and instead administering insulin to NIDDM patients with high GADA titer.

Insulin intervention to preserve beta cells in slowly progressive insulin-dependent (type 1) diabetes mellitus.

Slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) is characterized by (1) late age of onset, with initial features of NIDDM and subsequent progression to insulin-dependent stage; (2) high predictive value of autoantibodies against glutamic acid decarboxylase (GADAb) and islet cell antibodies (ICA) for progression of beta cell failure; (3) less predominant T cell response, which may attack and eventually destroy beta-cells in affected pancreas. These findings may suggest a rationale for intervention to prevent slowly progressive beta cell dysfunction in this type of diabetes. We identified three independent risk factors for progression of beta cell failure in SPIDDM: (1) sulfonylurea treatment; (2) ICA-positive periods; and (3) initial body weight. We hypothesized that removal of the risk factors for further progression of beta cell dysfunction will have beneficial effects on intervention strategy in treating SPIDDM. In our pilot study, we used a small dose of insulin instead of sulfonylurea in the early stage of treatment of patients with SPIDDM. Insulin-treated SPIDDM patients had a sustained C peptide response (CPR), while most of sulfonylurea-treated patients progressed to an insulin-dependent state. We organized a randomized multicenter clinical trial to study early treatment to prevent the progression of beta cell dysfunction in SPIDDM (the Tokyo Study). It was demonstrated that early intervention with insulin therapy is an effective treatment modality in the early stage of SPIDDM patients who had preserved beta cell function at entry (integrated value of serum C peptide values at 0, 30, 60, 90, and 120 minutes; Sigma CPR >or= 10 ng/mL) and high GADAb (>10 U/mL). Preventive insulin treatment was ineffective in the patients who had diminished insulin reserve at entry (Sigma CPR < 10 ng/mL). Insulin intervention to preserve beta cell dysfunction in SPIDDM is effective and safe in patients with preserved beta cell function and high GADAb titers at the initiation of insulin.