Japanese Type 2 Diabetes Mellitus Patients Research Articles

Thirty-Year Trends in the Prevalence and Severity of Diabetic Retinopathy at the First Visit in Patients with Untreated Type 2 Diabetes Mellitus

ABSTRACT Purpose Although the rate of diabetic retinopathy (DR)-related blindness has decreased in developed countries in recent years, the reasons for this decrease have remained unclear. The prevalence/severity trends of DR at the first visit in patients with untreated type 2 diabetes mellitus (T2DM) patients seen between the1986s and 2018s were assessed. Methods A total of 1979 Japanese T2DM patients diagnosed between 1986 and 2018 were divided into four groups by the decade of their first visit: the 1986 years (1986–1987), the 1996 years (1996–1997), the 2006 years (2006–2008), the 2016 years (2016–2018). The DR prevalence/severity trends were assessed. Results A significant decrease in the rate of prevalence of DR from the 1986s to 2016s was observed among previously untreated T2DM patients visiting our hospital for the first time (1986s: 25.5%; 1996s: 26.2%; 2006s: 22.2%; and 2016s: 15.6%). The prevalence was significantly higher in females (30.2%) than in males (21.3%). Although the severity trend of DR did not differ significantly among the four measurement years, the rate of simple DR was the highest in the 2016s. Conclusion We found, for the first time, a significant decrease in the rate of prevalence of DR from the 1986s to 2016s in patients with untreated T2DM visiting our hospital for the first time. A decrease in the rate of DR prevalence could explain, at least in part, the observed reduction in the rate of blindness in patients with T2DM.

Retrospective Study of IDegLira, a New Fixed-Ratio Combination, in Japanese Patients With Type 2 Diabetes Mellitus: Analysis of Background Factors Affecting Effectiveness After 6 Months of Treatment.

The aim of the study was to provide real-world data on the effectiveness and safety of a new fixed-ratio combination, insulin degludec/liraglutide (IDegLira) injection in Japanese patients with type 2 diabetes mellitus (T2DM). The primary endpoint was the change in glycated hemoglobin (HbA1c) level 6 months after the introduction of IDegLira. We also examined the rate of achievement of target HbA1c 7% and the individualized HbA1c targets set for each patient. Baseline characteristics associated with the change in HbA1c were also assessed. Seventy-five patients with T2DM were included in the analysis. After the initiation of IDegLira, HbA1c decreased significantly from baseline with a change of -1.81% (baseline 9.61% and at 6 months 7.80%; P < 0.001). At baseline, the achievement rate of 7% HbA1c was 2.67% (n = 2), which increased to 36.0% (n = 27) after 6 months of IDegLira introduction (P < 0.05). The attainment rate of individualized HbA1c targets, which were set considering each patient's characteristics, improved from 2.67% (n = 2) to 49.3% (n = 37) (P < 0.001). Regardless of sex, body mass index, estimated glomerular filtration rate, duration of diabetes, or history of glucagon-like peptide-1 receptor agonist use, IDegLira significantly reduced HbA1c, but a higher C-peptide index was associated with a greater reduction in HbA1c. In this study, initiation of IDegLira in a real-world clinical setting was beneficial in lowering HbA1c in Japanese T2DM patients with inadequate glycemic control with existing therapy.

Higher Iron Intake Is Independently Associated with Obesity in Younger Japanese Type-2 Diabetes Mellitus Patients.

We aimed to analyze the association between dietary iron intake and obesity assessed by BMI after adjustment for nutrient intake (macronutrients and fiber) and food groups. The study design was cross-sectional. Patients with type-2 diabetes (n = 1567; 63.1% males; mean age 62.3 ± 11.6 years) were included in the study. To assess diet, consumption of typical food groups was determined by a food frequency questionnaire. Obesity was defined as BMI ≥ 25 kg/m2. We performed a binary regression analysis between quartiles of iron intake and obesity by quartiles of age group. A direct linear association was found for the highest quartile of iron intake and obesity in the younger age group of 30 to 54 years (OR = 3.641, 95% CI = 1.020–12.990; p trend = 0.011). Multivariate analysis using food groups as opposed to nutrients revealed a positive trend for obesity in the younger age group after adjusting for lifestyle factors, energy intake and bean and vegetable intake (p trend = 0.023). In all participants, an inverse association was observed before adjustment by vegetable intake (OR = 0.453, 95% CI = 0.300–0.684; p trend = 0.001). Higher iron intake was associated with obesity independent of macronutrient and fiber intake but only in the youngest quartile of age group examined.

Cross sectional study on proportion of sulfonylureas among various oral antidiabetic drugs using for Japanese patients with type 2 diabetes, analyzed from NSAID Study-2.

We aimed to investigate the certainty of using sulfonylureas in Japanese patients with type 2 diabetes mellitus (T2DM) by analyzing data from the 2018 Nationwide Survey on Actual Intervention for T2DM by Japanese Practitioners (NSAID Study). Of the 6525 and 1545 participants in the NSAID Study under the care of general practitioners (GP) and diabetes specialists (SP), respectively, we included 5423 (83.1%) and 1058 (68.5%) patients who were treated with only oral antidiabetic drugs (OADs) by GPs and SPs, respectively, in the analysis. Among the seven OAD classes in monotherapy, sulfonylureas were the third and fifth most prescribed OADs by GPs (7.1%) and SPs (6.4%), respectively. Sulfonylurea usage increased with combination therapy. Glimepiride was the most commonly prescribed sulfonylurea. Patients who used sulfonylureas had higher hemoglobin A1c (HbA1c) levels and lower body mass indices (BMIs) than patients who did not use sulfonylureas. The results of this study clearly demonstrated that, among the OADs, sulfonylureas were not frequently used in monotherapy, although the opportunity of using sulfonylurea increased with the number of OADs prescribed in combination therapies by both GPs and SPs in Japan. Moreover, low-dose glimepiride was the most-prescribed sulfonylurea for Japanese T2DM patients, especially for those who were lean and had higher HbA1c levels.

THE BODY MASS INDEX INFLUENCES THE ACHIEVEMENT RATIO OF TARGET BLOOD PRESSURE BY SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS IN JAPANESE TYPE 2 DIABETES PATIENTS WITH CKD

Objective: Some large clinical trials using sodium-glucose cotransporter 2 inhibitor (SGLT2i) revealed the superiority in the renal outcome in type 2 diabetes mellitus (T2DM) patients. We already reported that the decrease in blood pressure (BP) was closely related to the renoprotective effects and SGLT2i was useful for the BP management in T2DM patients. The aim of this study is to clarify how body mass index (BMI; kg/m2) influence the achievement ratio of target BP by using SGLT2i in Japanese T2DM patients. Design and method: We retrospectively assessed 447 patients with Japanese T2DM patients with chronic kidney disease (CKD) who underwent SGLT2i treatment for more than 1 year and whose BP at office was uncontrolled (&lt;130/80mmHg) before SGLT2i treatment. We set the endpoint that was the achievement of target BP at office (&lt;130/80mmHg) after SGLT2i treatment. From ROC curve analysis, the estimated optimal cutoff value for BMI as a marker for the endpoint was 29.For comparative analyses, we performed the cohort model of patients with BMI &gt; 29 at baseline or those with BMI &lt;29, that was used propensity score–matching methods with the following algorithm: 1:1 nearest neighbor match with a ±0.047 caliper and no replacement. Results: The comparison of 130 propensity-matched patients in each group were performed. The incidence of the achievement of target BP after treatment was significantly higher in patients with BMI&lt;29 at baseline than in those with BMI &gt; 29 (n = 44 [33.8%] and n = 27 [20.8%], respectively, p = 0.018). The mean arterial pressure after SGLT2i treatment was significantly lower in patients with BMI&lt;29, compared with those with BMI &gt; 29 (94.5 ± 9.4 and 98.5 ± 10.0 mmHg, respectively, p = 0.002). From the analysis of mean prevalence of incidence of the endpoint depending on the quintiles of all patients, there was a significant difference between the two groups (p = 0.017) and the OR for the endpoint was 0.538 (95%CI,0.332, 0.873, p = 0.012, Mantel-Haenszel method) in patients with BMI&lt;29. Conclusions: The BMI influenced the achievement ratio of target BP in Japanese T2DM patients with CKD. Further study should be performed to clarify the relation between obesity and BP lowering effects by SGLT2i treatment.

Benefit of Early Add-on of Linagliptin to Insulin in Japanese Patients With Type 2 Diabetes Mellitus: Randomized-Controlled Open-Label Trial (TRUST2).

This trial was conducted to assess the long-term safety, efficacy, and benefit of early add-on of linagliptin to insulin in patients with type 2 diabetes mellitus (T2DM). This trial enrolled 246 subjects. The subjects were randomized to the linagliptin group or the control group and were observed for 156weeks. After week 16, subjects in the control group were also allowed to add linagliptin to evaluate the benefit of early add-on of linagliptin to insulin. The primary end point was a change in HbA1c from baseline to week 16. Secondary end points included fasting plasma glucose, daily insulin dose, and frequency of adverse events. HbA1c and fasting plasma glucose levels significantly decreased from baseline to week 16 in the linagliptin group compared with the control group. The significant improvement in HbA1c continued until week 52. The daily insulin dose significantly decreased in the linagliptin group compared with the control group. The frequency of hypoglycemia and adverse events was comparable in both groups. Add-on of linagliptin to insulin was tolerated, improved glycemic control, and reduced the daily insulin dose. This study demonstrates the long-term safety, efficacy and benefit of early add-on of linagliptin to insulin in Japanese T2DM patients.

Comparison of Patient-Led and Physician-Led Insulin Titration in Japanese Type 2 Diabetes Mellitus Patients Based on Treatment Distress, Satisfaction, and Self-Efficacy: The COMMIT-Patient Study.

IntroductionIn Japan, patient-led insulin titration is rare in type 2 diabetes mellitus (T2DM) patients. Few studies have compared the effects of patient-led versus physician-led insulin titration on patient-reported outcomes in Japanese T2DM patients. This study aimed to compare the effects of patient-led and physician-led insulin titration in Japanese insulin-naïve T2DM patients on safety, glycemic control, and patient-reported outcomes (emotional distress, treatment satisfaction, and self-efficacy).MethodsUltimately, 125 insulin-naïve Japanese T2DM patients were randomly assigned to either a patient-led insulin self-titration group or a physician-led insulin titration group and monitored for 24 weeks. The primary endpoint was a change in emotional distress as measured using the Problem Areas in Diabetes scale (PAID). Secondary endpoints included treatment satisfaction, as measured with the Diabetes Treatment Satisfaction Questionnaire (DTSQ), self-efficacy as measured using the Insulin Therapy Self-Efficacy Scale (ITSS), glycated hemoglobin (HbA1c) levels, fasting plasma glucose levels, body weight, insulin daily dose, and frequency of hypoglycemia.ResultsThere was no significant difference between the groups in PAID and DTSQ scores. The results for the primary endpoint should be interpreted taking account that the sample size for the power calculation was not reached. ITSS scores were significantly higher in the patient-led self-titration group. HbA1c and fasting plasma glucose levels were significantly decreased in both groups, but the decrease was significantly larger in the patient-led self-titration group. Although the insulin daily dose was significantly higher in the patient-led self-titration group, severe hypoglycemia did not occur in either group, and the frequency of hypoglycemia was similar in both groups.ConclusionSelf-measurement of blood glucose and self-titration of insulin enhanced the patients’ self-efficacy without compromising their emotional distress or treatment satisfaction. Also, insulin self-titration was found to be safe and effective; it resulted in better glycemic control without severe hypoglycemia.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) (registration number: UMIN000020316).Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-020-00995-8.

Abstract 13289: Incidence of Heart Failure Hospital Admissions Among Type 2 Diabetes Mellitus Patients and the Potential Impact of SGLT2 Inhibitors in Japan: A Population-based Study From the Shizuoka Kokuho Database

Introduction: Recent large-scale clinical trials have shown that the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduces the risk of cardiovascular (CV) events, particularly heart failure (HF) hospitalizations, in type 2 diabetes mellitus (T2DM) patients with established CV disease. We aimed to assess (1) the incidence of HF admissions, and (2) the potential reduction in HF admissions with the further introduction of SGLT2i, in a contemporary large administrative claims database in Japan. Methods: We selected patients aged ≥40 years, without previous HF diagnosis, who newly initiated oral antidiabetics in Shizuoka Kokuho Database between 2013 and 2018. We estimated the 5-year cumulative incidence of hospitalization for HF, myocardial infarction (MI), and stroke, treating death as a competing risk. Among the subgroup of patients with laboratory data, we identified patients meeting the inclusion criteria for EMPA-REG OUTCOME (EMPA-REG) or DECLARE-TIMI 58 (DECLARE) regarding HbA1c, eGFR, and CV disease. We estimated the number of events that can be reduced if they benefited the same risk reduction from the trials. Results: Among 23,340 oral antidiabetic drug initiators (46.0% women, 21.9% ≥75 years old) included, 2.6% were initiated on SGLT2i. The 5-year cumulative incidences of hospitalization for HF, MI, and stroke were 5.4% (95% confidence interval: 4.9-5.9%), 1.9% (1.7-2.2%), and 6.1% (5.7-6.6%), respectively. Among 6192 patients with laboratory data, 651 (10.5%) and 2680 (43.3%) patients met the EMPA-REG-like and DECLARE-like criteria, respectively (Figure). The 5-year cumulative incidence among the 2849 patients meeting either of the criteria was estimated to decrease from 97.1 to 75.2 events via 75% adoption of SGLT2i. Conclusion: The burden of HF among Japanese T2DM patients was high, almost equivalent to stroke. Increased use of SGLT2i among patients with high CV risk may significantly reduce its disease burden.

Effectiveness and safety of insulin glargine 300 unit/mL in Japanese type 2 diabetes mellitus patients: a 12-month post-marketing surveillance study (X-STAR study)

ABSTRACT Background With limited real-world insulin glargine 300 unit/mL (Gla-300) data available, we assessed the effectiveness and safety of Gla-300 in the Japanese type 2 diabetes mellitus (T2DM) population. Research design and methods X-STAR was a prospective, observational, 12-month post-marketing study of Gla-300 from 2015 to 2018. T2DM patients received Gla-300 as the first insulin (insulin-naïve) or after treatment with another type of insulin (insulin-experienced). Results We identified 1,227 insulin-naïve and 3,394 insulin-experienced patients. Insulin-naïve group increased the Gla-300 starting dose by 2.80 U/day during 12 months (7.49 to 10.29 U/day). Mean HbA1c reduced by 1.99% (9.82 to 7.83%), and 28.4% showed HbA1c < 7.0%. Insulin-experienced group had a baseline insulin dose of 14.86 U/day, which increased by 0.73 U/day. Mean HbA1c reduced by 0.18% (7.99 to 7.81%), and 24.6% showed HbA1c < 7.0%. Adverse drug reactions occurred in 3.42% (insulin-naïve) and 4.45% (insulin-experienced); symptomatic hypoglycemia (2.93% and 3.86%, respectively) was the most common in both groups. Conclusions Gla-300, in clinical practice, provides an effective and safe therapy as HbA1c was reduced/maintained in insulin-naïve/experienced Japanese T2DM patients without new safety signal. This study provides insights into the current Japanese clinical practices where insulin use is delayed and conservative despite relatively low HbA1c achievement.

512-P: The Concomitant Insulin Treatment with Sodium–Glucose Cotransporter 2 Inhibitors Influenced the Renal Composite Outcome in Japanese Type 2 Diabetes Patients with Chronic Kidney Disease

Background and Aim: Some large clinical trials using SGLT2 inhibitor revealed the superiority in the renal outcome in patients with type 2 diabetes mellitus (T2DM) patients. We already reported that SGLT2 inhibitor improved urinary albumin-creatinine ratio at baseline (ACR) in Japanese T2DM patients with CKD and revealed some factors that influence to the renoprotective effects of SGLT2 inhibitor. The aim of this study is to clarify how the concomitant insulin treatment with SGLT2 inhibitor influence the renal composite outcome. Research Design and Methods: We retrospectively assessed 624 patients with Japanese T2DM patients with CKD who underwent SGLT2 inhibitor treatment for more than 1 year. We set the renal composite endpoint that was the progression of the stage of albuminuria or the decrease in eGFR by ≥15% per year. For comparative analyses, we performed the cohort model of patients with or without insulin treatment that was used propensity score (PS) matching methods. The PS matching was using the following algorithm: 1:1 nearest neighbor match with a ±0.04 caliper and no replacement. Further, all patients were stratified into quintiles based on the corresponding PS and included in the analyses. Results: The comparison of 149 PS-matched patients in each group were performed. The incidence of renal composite outcome was significantly higher in patients with insulin treatment than without it (n=23[15.4%] and n=10[6.7%], respectively, p=0.033). The results from the analysis depending on the quintiles of all patients by the Mantel-Haenszel method, there was a significant difference between the two groups (p=0.021) and the odds ratio for the renal composite outcome was 2.09 (95%CI,1.15, 3.80, p=0.016) in patients with insulin treatment. Conclusion: The concomitant insulin treatment with SGLT2 inhibitor influenced the renal composite outcome in Japanese T2DM patients with CKD. Disclosure K. Kobayashi: None. M. Toyoda: None. H. Sakai: None. K. Tamura: Research Support; Self; AstraZeneca K.K., Ono Pharmaceutical Co., Ltd. Speaker’s Bureau; Self; AstraZeneca K.K., Ono Pharmaceutical Co., Ltd. N. Hatori: None.

Cardiovascular safety and effectiveness of vildagliptin in patients with type 2 diabetes mellitus: a 3-year, large-scale post-marketing surveillance in Japan

ABSTRACTObjectives: The dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin is indicated for type 2 diabetes mellitus (T2DM). However, the long-term safety, effectiveness, and clinical relationship with cardiovascular events of vildagliptin have not been evaluated in Japan.Methods: The authors conducted post-marketing surveillance (PMS) to evaluate the safety and effectiveness of vildagliptin in more than 3000 Japanese T2DM patients for up to 3 years. Main assessments included demographics, major adverse cardiovascular events (MACE), adverse events (AEs), adverse drug reactions (ADRs), and glycated hemoglobin (HbA1c).Results: In this PMS, 3831 patients (775 sites) were registered in April 2010 − April 2012. The safety analysis population comprised 3769 patients; 2085 patients were aged ≥65 years, and 240, 411, and 114 had renal impairment, hepatic impairment, and heart failure, respectively. The median treatment duration was 2.7 years. The incidence of MACE was 6.04 cases/1000 person-years, mostly attributable to cerebrovascular events (4.27 cases/1000 person-years). The AE and ADR incidences were 26.0% and 5.3%, respectively. The incidence of hypoglycemia was 0.6%. No significant changes in body weight occurred and mean change in HbA1c from baseline at final assessment was −0.74 ± 1.41% (p < 0.0001).Conclusions: In real-world clinical settings, vildagliptin was well tolerated, with similar profiles as previously reported.

Safety and efficacy of vildagliptin: 52-week post-marketing surveillance of Japanese patients with type 2 diabetes in combination with other oral antidiabetics and insulin

ABSTRACT Background: Vildagliptin is a dipeptidyl peptidase-4 inhibitor that reduces glycemia in patients with type 2 diabetes mellitus (T2DM). When approved in 2013, data on vildagliptin combined with >750 mg/day metformin in Japanese patients were limited. There is a need to confirm the safety and efficacy of vildagliptin in combination with oral antidiabetic drugs (OADs). Research design and methods: This 52-week post-marketing surveillance (PMS) observational study in Japanese T2DM patients evaluated the safety and efficacy of vildagliptin in combination with OADs including high-dose metformin or insulin but excluding combination with sulfonylureas alone. Results: During this survey of 3006 Japanese T2DM patients, 13.61% of patients experienced adverse events (AEs) and 2.20% reported a serious AE (SAE). The frequency of AEs/SAEs was similar when in combination with biguanides (12.93%/1.46%), metformin ≥1000 mg/day (12.92%/1.22%), metformin <1000 mg/day (12.62%/1.54%), thiazolidine derivatives (16.71%/2.86%), α-glucosidase inhibitors (13.18%/1.90%), rapid-acting insulin secretagogues (glinides) (20.41%/5.71%), or insulin (15.87%/2.47%). The mean ± SD changes from baseline at endpoint in glycated hemoglobin and fasting blood glucose were −0.76 ± 1.27% and −23.3 ± 57.3 mg/dL, respectively, and these changes were consistent, regardless of concomitant OAD. Conclusions: Long-term vildagliptin combination therapy is safe and effective in Japanese T2DM patients in real-world settings.

1217-P: The Kidney Effects of the SGLT2 Inhibitors on the Japanese Type 2 Diabetes Mellitus Patients with Chronic Kidney Disease

Background: In some large-scale clinical trials, the administration of sodium glucose co-transporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) has revealed pronounced and consistently beneficial renal outcome. However, it is unclear whether long term SGLT2i administration led to similar results in Japanese T2DM patients. Objective: To elucidate the renal effects of long term SGLT2i administration in Japanese T2DM patients with chronic kidney disease (CKD). Method: Data from T2DM patients with CKD who were visiting members of Kanagawa Physicians Association and being administered SGLT2i for more than 1 year were used. Result: We analyzed 753 patients. Six SGLT2i types were used with median administration period of 33.0 months. The mean albumin-to-creatinine ratio (ACR) significantly decreased from 36.0 to 27.5 (mg/gCr, p&amp;lt;0.01). Based on intensity, the mean ACR value significantly decreased from 72.1 to 54.8 in microalbuminuric patients (n=288) and from 625.1 to 414.1 in macroalbuminuric patients (n=58) (p&amp;lt;0.01); however, it did not change in normoalbuminuric patients (n=275). Multiple linear regression analysis revealed that the localized ACR baseline value, change (Δ) in systolic and diastolic BP, and ΔHbA1c were independently correlated with ΔACR; values of these regression coefficients were -0.21, 0.01, 0.01, and 0.08, respectively (p&amp;lt;0.01). The eGFR decreased from 77.5±22.2 to 72.7±22.4 mL/min/1.73 m2 (p&amp;lt;0.01). The localized ACR baseline value, ΔBW, age, baseline eGFR, treatment duration, and baseline diastolic BP were independently correlated with ΔeGFR; the regression coefficients were -1.35, -0.42, -0.24, -0.23,-0.11, and -0.08, respectively (p&amp;lt;0.01). Conclusion: This study confirmed that the improvement of ACR was also observed in the real world; however, eGFR gradually decreased after long term SGLT2i administration. The relationship between background factors should be further discussed in future. Disclosure K. Kobayashi: None. M. Toyoda: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Medtronic Japan Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. N. Hatori: None. H. Sakai: None. T. Furuki: None. K. Tamura: Advisory Panel; Self; AstraZeneca. Research Support; Self; AstraZeneca, Ono Pharmaceutical Co., Ltd. Speaker's Bureau; Self; AstraZeneca, Ono Pharmaceutical Co., Ltd. M. Miyakawa: None.

Relationship of patient background with macro- and microvascular complications: a 2-year post-marketing surveillance of vildagliptin in nearly 20,000 Japanese diabetic patients

ABSTRACTBackground: Vildagliptin is indicated for type 2 diabetes mellitus (T2DM); however, the onset and exacerbation of diabetic complications in Japanese T2DM patients treated with vildagliptin is unknown.Research design and methods: This 2-year post-marketing surveillance (PMS) assessed the real-world safety and efficacy of vildagliptin therapy in 19,218 Japanese T2DM patients. The relationship between the incidence of macro- and microvascular complications with patient characteristics and changes in glycemic control (HbA1c) were evaluated.Results: The incidences of macro- and microvascular diseases were 1.14% and 3.09%, respectively. Patients with HbA1c ≥8.4% had a higher odds ratio (OR) for micro- and macrovascular disease (OR: 2.02 and 1.90) compared with patients with HbA1c <6.9%. Patient characteristics (OR, 95% CI) associated with macrovascular disease were age (1.04, 1.01–1.07) and a history of macrovascular disease (3.38, 1.98–5.75). Microvascular disease was associated with a final HbA1c level ≥7.0% (1.48, 1.11–1.98) and previous diabetic nephropathy (1.42, 1.05–1.93). The mean (SD) HbA1c decreased from 7.89% (1.46%) to 7.05% (0.99%) after 24 months.Conclusions: Vildagliptin elicited no increases/exacerbations of diabetic complications; this PMS suggested that the incidence of diabetic complications tends to be low in subjects with good HbA1c control.

Low resting energy expenditure in postmenopausal Japanese women with type 2 diabetes mellitus.

Resting energy expenditure (REE) is an important tool in nutrition management, especially in type 2 diabetes mellitus (T2DM). The predicted REE (pREE) was reported to be inaccurate, compared with measured REE (mREE) in Japanese T2DM patients. Despite the accuracy of REE, measured via indirect calorimetry (mREE), the technique is demanding. This study evaluated the associated clinical factors of the difference between pREE and mREE in Japanese patients with T2DM. Forty-nine Japanese patients with T2DM but no severe complications (32 men and 17 women) were enrolled. mREE was determined via indirect calorimetry. Participants average age was 56.3 ± 11.0years, body mass index was 25.2 ± 3.6kg/m2, and HbA1c was 9.6 ± 1.6%. The mean mREE was 1099 ± 212kcal/day. Age, body mass index, hemoglobin, and uric acid levels were all associated with mREE by simple regression; of these, body weight was the significant factor in the multiple regression analysis. When the patients were divided into tertiles, the average mREE values were lower than the pREE values for each group. The difference between mREE and pREE was largest in the lowest value group, whose subjects were mostly women aged over 50years. This group of women showed significantly lower mREE (904 ± 121kcal) in comparison with men in the same age group, with 26% overestimation of pREE, even when the equation that yielded the closest mREE value was used. The previously reported pREE overestimates mREE in Japanese patients with T2DM, especially in postmenopausal women.

Gut microbiota disorders cause type 2 diabetes mellitus and homeostatic disturbances in gut-related metabolism in Japanese subjects

Few studies have investigated the host-microbe metabolic axis in people with type 2 diabetes mellitus (T2DM). This study aimed to determine and compare the nutrient intakes and metabolic markers and to elucidate the relationships among these factors in Japanese T2DM patients and control individuals. Fifty-nine Japanese T2DM patients and 59 matched healthy control individuals participated in this study. We examined the differences regarding the participants’ dietary habits, microbiota, and fecal short-chain fatty acids, and analyzed the relationships between the gut microbiota and blood metabolic markers in the T2DM patients and the control subjects. The T2DM patients consumed more carbohydrates, and had lower fecal propionate and butyrate concentrations, larger fecal populations of Bifidobacterium spp. and bacteria of the order Lactobacillales, and smaller fecal Bacteroides spp. populations than the control individuals. In the T2DM patients, the level of Bifidobacterium spp. correlated negatively with the carbohydrate intake and the level of bacteria of the order Lactobacillales correlated negatively with the protein intake. T2DM patients have gut dysbiosis that may contribute to disease onset and influence its prognosis. Furthermore, homeostatic disturbances in the gut-related metabolism may underlie the pathogenesis of T2DM.

Rationale and Design of the STOP-OB Study for Evaluating the Effects of Tofogliflozin and Glimepiride on Fat Deposition in Type 2 Diabetes Patients Treated with Metformin/DPP-4 Inhibitor Dual Therapy.

BackgroundThe global pandemic of type 2 diabetes mellitus (T2DM) is an enormous clinical and socioeconomic burden. Biguanides and DPP-4 inhibitors (DPP-4i) are the most commonly used therapies in Japanese T2DM patients. When glycemic control is not adequate despite combination of these drugs, there is no consensus on the next step drug. Systematic reviews and meta-analyses of previous trials have indicated that glycemic control with triple combination therapies yields similar results. Thus, beneficial effects on cardiovascular risk factors may be important. The present study was designed to evaluate body fat percentage and several insulin resistance parameters after addition of tofogliflozin or glimepiride to the regimens of patients being treated with metformin and a DPP-4 inhibitor but failing to attain adequate blood glucose control.MethodsSodium glucose cotransporter-2 inhibitor, tofogliflozin versus glimepiride, comparative trial in patients with type 2 diabetes on body composition is an ongoing, multicenter, prospective, randomized, open-label, parallel-group trial. T2DM patients treated with metformin/DPP-4 inhibitor dual therapy have been recruited and randomly assigned to 20 mg/day tofogliflozin (n = 32) or 0.5 mg/day glimepiride (n = 32) groups, with either of these drugs being added to pre-existing regimens for 24 weeks.Planned OutcomesThe primary endpoint is the change in body fat percentage from baseline to 24 weeks. The secondary outcomes are changes in body composition other than fat percentage, body weight, parameters related to glycemic control and β-cell function, parameters related to lipids and arteriosclerosis, parameters related to liver function, parameters related to diabetic nephropathy, and uric acid levels. Safety parameters will also be analyzed. This is the first trial comparing the effects and safety of adding an SGLT2i and a sulfonylurea as the third-line oral agent to metformin/DPP-4i dual therapy. The results will provide valuable information for choosing third-line oral agents.Trial RegistrationUMIN000026161.FundingKowa Co. Ltd. and Kowa Pharmaceutical Co. Ltd., Tokyo, Japan.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0491-4) contains supplementary material, which is available to authorized users.

Albuminuria Increases All-Cause Mortality in Japanese Patients with Type 2 Diabetes Mellitus.

Previous studies have reported that diabetic kidney disease is associated with cardiovascular events and death. Little is known about the independent association of albuminuria and estimated glomerular filtration rate (eGFR), with mortality in Asian patients with type 2 diabetes mellitus (T2DM) without renal failure. We conducted a historical cohort study to clarify this issue in Japanese patients with T2DM. In this study, we recruited 385 patients with T2DM, who never had chronic renal failure (eGFR < 30 mL/min/1.73 m2 at baseline) and malignant diseases. With the end point of all-cause mortality, Cox regression analysis was performed. During the observational period of 7 years, 54 patients died. Cox regression analysis adjusted for confounding factors such as age, duration of diabetes, body mass index, and HbA1c, and showed that urinary albumin level was significantly associated with the mortality [hazard ratio (HR) = 1.32, 95% confidence interval (CI) = 1.03–1.70 per standard deviation (SD) increase, p = 0.031]. After additional adjustment for eGFR, the association remained significant (HR = 1.32, 95% CI = 1.02–1.70 per SD increase, p = 0.033). On the other hand, eGFR was not associated with the mortality. The present study showed that higher urinary albumin was associated with increased all-cause mortality in T2DM, independently of eGFR. These findings suggest that, regardless of eGFR, albuminuria is important for the increased risk of mortality in Japanese T2DM patients without chronic renal failure (eGFR < 30 mL/min/1.73 m2). However, because of several limitations, further large-scale longitudinal studies are necessary to confirm the present study.

The Postprandial C-peptide–to–Glucose Ratio Correlated with Beta-Cell Function in Japanese Patients with Type 2 Diabetes Mellitus

The onset of type 2 diabetes mellitus(T2DM) is based on the insulin resistance and decreasing of insulin secretion. Residual β-cell function is a key factor in achieving optimal glycemic control in patients with type 2 diabetes. Glucagon induces insulin secretion by direcdtly stimulating β-cells, therefore glucagon stimulaton test(GST) is a reliable marker for β-cell function. Fasting C-peptide(CPR)-index(CPR[ng/ml] to glucose[mg/dl] ratio x100; F-CPRI) is used as a marker of insulin secretion. We evaluated the efficacy of postprandial CPR to glucose ratio(P-CPRI) as a tool for evaluating β-cell function. Japanese T2DM patients with inadequte glycemic control(HbA1c&amp;gt;7.0%) were enrolled in the study(n=333, insulin therapy =217). HbA1c, fasting CPR and glucose were measured, and F-CPRI was calculated. Postprandial(120 min after breakfast) CPR and glucose were measured, and P-CPRI was calculated. For the GST, CPR was determinated before and 6 min after 1mg of glucagon injection. GSTδCPR(CPR[6 min] - CPR[0 min]) was calculated. Factors correlated with GSTδCPR were analyzed using simple and multiple stepwise regression analysis. P value&amp;lt;0.was defined as statistically different. F-CPR-index, P-CPR-index and GSTδCPR were 1.42±0.85, 2.26±1.59 and 1.85±1.15, respectively. Simple regression analysis showed that GSTδCPR was significantly correlated with age, height, body weight(BW), BMI, gender, duration of diabetes, diebetic retinopathy, diabetic nephropathy, insulin therapy, F-CPRI and P-CPRI. Multiple stepwise regression analysis revealed that independent factors contributing to GSTδCPR were BW(β=0.331, p&amp;lt;0.001), P-CPRI(β=0.451, p&amp;lt;0.001), duration of diabetes(β= -0.104, p=0.025), diabetic retinopathy(β= -0.127, p=0.004), DPP-4 inhibitor(β= -0.089, p=0.036) and biguanide(β= -0.144, p=0.001). Our date demonstrated that P-CPRI was valuable in assessing β-cell function and can help clinicians in clinical practice. Disclosure Y. Matsuhashi: None. S. Chikazawa: None. H. Nakayama: None. M. Murabayashi: None. S. Mizushiri: None. S. Osonoi: None. K. Takahashi: None. H. Otaka: None. M. Yanagimachi: None. H. Murakami: None. M. Daimon: None.

Dapagliflozin significantly reduced liver fat accumulation associated with a decrease in abdominal subcutaneous fat in patients with inadequately controlled type 2 diabetes mellitus

AimsWe examined dapagliflozin-induced changes in liver fat accumulation. MethodsWe prospectively recruited Japanese patients with inadequately controlled type 2 diabetes mellitus (T2DM) [hemoglobin A1c (HbA1c) >7.0%]. Dapagliflozin (5 mg/day) or non-sodium glucose cotransporter 2 inhibitors (SGLT2i) was added to the patients’ treatment regimen for 6 months. Changes in liver fat accumulation were assessed by the liver-to-spleen (L/S) attenuation ratio using abdominal computed tomography (CT). ResultsThis study enrolled 55 Japanese T2DM patients. The L/S ratio significantly increased in the dapagliflozin group compared with the non-SGLT2i group. Abdominal subcutaneous fat area (SFA), visceral fat area, total fat area assessed by abdominal CT, aspartate aminotransferase, alanine aminotransferase (ALT), and γ-glutamyl transpeptidase decreased significantly only in the dapagliflozin group. Changes in the L/S ratio showed a significant negative relationship with changes in abdominal SFA, ALT, and non-esterified fatty acid. In sub-group analyses of non-insulin users, hepatic insulin extraction was assessed by the plasma C-peptide-to-insulin ratio, which was significantly increased in the dapagliflozin group but not in the non-SGLT2i group. ConclusionIn patients with inadequately controlled T2DM, additional dapagliflozin-treatment significantly reduced the liver fat accumulation associated with a decrease in abdominal SFA.