Effect of dapagliflozin on 24-hour glycemic variables in Japanese patients with type 2 diabetes mellitus receiving basal insulin supported oral therapy (DBOT): a multicenter, randomized, open-label, parallel-group study.

INTRODUCTION: This study aimed to evaluate the impacts of dapagliflozin on 24-hour glucose variability and diabetes-related biochemical variables in Japanese patients with type 2 diabetes who had received basal insulin supported oral therapy (BOT). RESEARCH DESIGN AND METHODS: Changes in mean daily blood glucose level before and after 48-72 hours of add-on or no add-on of dapagliflozin (primary end point) and diabetes-related biochemical variables and major safety variables during the 12 weeks (secondary end point) were evaluated in the multicenter, randomized, two-arm, open-label, parallel-group comparison study. RESULTS: Among 36 participants, 18 were included in the no add-on group and 18 were included in the dapagliflozin add-on group. Age, gender, and body mass index were comparable between the groups. There were no changes in continuous glucose monitoring metrics in the no add-on group. In the dapagliflozin add-on group, mean glucose (183-156 mg/dL, p=0.001), maximum glucose (300-253, p<0.01), and SD glucose (57-45, p<0.05) decreased. Time in range increased (p<0.05), while time above the range decreased in the dapagliflozin add-on group but not in the no add-on group. After 12-week treatment with dapagliflozin add-on, 8-hydroxy-2'-deoxyguanosine (8OHdG), as well as hemoglobin A1c (HbA1c), decreased. CONCLUSIONS: This study showed that the mean daily blood glucose and other daily glucose profiles were amended after 48-72 hours of dapagliflozin add-on in Japanese patients with type 2 diabetes who received BOT. The diabetes-related biochemical variables such as HbA1c and urinary 8OHdG were also obtained during the 12 weeks of dapagliflozin add-on without major adverse events. A preferable 24-hour glucose profile in 'time in ranges' and an improvement in reactive oxygen species by dapagliflozin warrant us to evaluate these benefits in larger clinical studies. TRIAL REGISTRATION NUMBER: UMIN000019457.

High FIB4 index is an independent risk factor of diabetic kidney disease in type 2 diabetes.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) may be linked to development of chronic kidney diseases (CKD). The FIB4 index, a noninvasive liver fibrosis score, has been reported to predict CKD in non-diabetic patients, but there are no reports yet in diabetic cases. Therefore, we evaluated the prognostic impact of FIB4 index on the risk of developing diabetic kidney disease (DKD) in Japanese patients with type 2 diabetes in a retrospective cohort study. We assessed patients with type 2 diabetes with an eGFR ≥ 60 mL/min/1.73 m2 and without dipstick positive proteinuria (≥ 1 +) at their first visit to our department. Participants were divided into two groups based on the FIB4 index at their first visit: FIB4 index > 1.3 and FIB4 index ≤ 1.3. The primary endpoint was defined as a decrease in eGFR < 60 mL/min/1.73 m2 or the onset of proteinuria during the course of treatment. The average age of all 584 type 2 diabetic participants (360 [61.6%] men) was 55 ± 11 years. There were 187 patients in the FIB4 index group > 1.3 (32.0%) and the median observation period was 6.0 (3.8-11.0) years. Kaplan-Meier survival analysis indicated that the risks of developing DKD, eGFR < 60 and proteinuria were all higher in FIB4 index > 1.3 patients than in FIB4 ≤ 1.3 patients. In the Cox regression analysis, an FIB4 index > 1.3 was a significant predictor for onset of DKD (HR 1.54, 95% CI 1.15-2.08) and proteinuria (HR 1.55, 95% CI 1.08-2.23), but not for an eGFR < 60 (HR 1.14, 95% CI 0.79-1.99). To the best of our knowledge, this is the first study to demonstrate that an FIB4 index > 1.3 has a prognostic impact on the development of CKD and proteinuria in type 2 diabetic patients. This warrants further investigation of the prognostic impact of the development of DKD or proteinuria.

Fast walking is a preventive factor against new-onset diabetes mellitus in a large cohort from a Japanese general population.

Based on questionnaires from 197,825 non-diabetic participants in a large Japanese cohort, we determined impact of (1) habit of exercise, (2) habit of active physical activity (PA) and (3) walking pace on new-onset of type 2 diabetes mellitus. Unadjusted and multivariable-adjusted logistic regression models were used to determine the odds ratio of new-onset diabetes mellitus incidence in a 3-year follow-up. There were two major findings. First, habits of exercise and active PA were positively associated with incidence of diabetes mellitus. Second, fast walking, even after adjusting for multiple covariates, was associated with low incidence of diabetes mellitus. In the subgroup analysis, the association was also observed in participants aged ≥ 65 years, in men, and in those with a body mass index ≥ 25. Results suggest that fast walking is a simple and independent preventive factor for new-onset of diabetes mellitus in the health check-up and guidance system in Japan. Future studies may be warranted to verify whether interventions involving walking pace can reduce the onset of diabetes in a nation-wide scale.

Factors Associated with Risk of Diabetic Complications in Novel Cluster-Based Diabetes Subgroups: A Japanese Retrospective Cohort Study.

Diabetes is a complex and heterogeneous disease, making the prediction of the risks of diabetic complications challenging. Novel adult-onset diabetes subgroups have been studied using cluster analysis, but its application in East Asians remains unclear. We conducted a retrospective cohort study to elucidate the clinical utility of cluster-based subgroup analysis in the Japanese population. Cluster analysis based on anti-glutamate decarboxylase antibody (GAD antibody) levels, age at diagnosis, body mass index (BMI), hemoglobin A1c (A1c), and homeostatic model assessment 2 estimates of ß-cell function and insulin resistance was performed in 1520 diabetic patients. The risk of developing diabetic complications was analyzed using Kaplan-Meier analysis and the Cox proportional hazards model. By cluster analysis, we identified five distinct subgroups of adult-onset diabetes in the Japanese population. The risk of diabetic complications varied greatly among the clusters. Patients with severe autoimmune diabetes or severe insulin deficiency diabetes were at an increased risk of diabetic retinopathy, and those with severe insulin resistant diabetes (SIRD) had the highest risk of developing diabetic kidney disease (DKD). After adjusting for uncorrectable and correctable risk factors, SIRD was found to be an independent risk factor for DKD. In conclusion, we identified five subgroups of adult-onset diabetes and the risk factors for diabetic complications in the Japanese population. This new classification system can be effective in predicting the risk of diabetic complications and for providing optimal treatment.

Walking Speed is the Sole Determinant Criterion of Sarcopenia of Mild Cognitive Impairment in Japanese Elderly Patients with Type 2 Diabetes Mellitus.

Diabetes mellitus is a risk factor for mild cognitive impairment (MCI) and dementia. However, how the clinical characteristics of MCI patients with type 2 diabetes mellitus are linked to sarcopenia and/or its criteria remain to be elucidated. Japanese patients with type 2 diabetes mellitus were categorized into the MCI group for MoCA-J (the Japanese version of the Montreal cognitive assessment) score <26, and into the non-MCI group for MoCA-J ≥26. Sarcopenia was defined by a low skeletal mass index along with low muscle strength (handgrip strength) or low physical performance (walking speed <1.0 m/s). Univariate and multivariate-adjusted odds ratio models were used to determine the independent contributors for MoCA-J <26. Among 438 participants, 221 (50.5%) and 217 (49.5%) comprised the non-MCI and MCI groups, respectively. In the MCI group, age (61 ± 12 vs. 71 ± 10 years, p < 0.01) and duration of diabetes mellitus (14 ± 9 vs. 17 ± 9 years, p < 0.01) were higher than those in the non-MCI group. Patients in the MCI group exhibited lower hand grip strength, walking speed, and skeletal mass index, but higher prevalence of sarcopenia. Only walking speed (rather than muscle loss or muscle weakness) was found to be an independent determinant of MCI after adjusting for multiple factors, such as age, gender, body mass index (BMI), duration of diabetes mellitus, hypertension, dyslipidemia, smoking, drinking, estimated glomerular filtration rate (eGFR), HbA1c, and history of coronary heart diseases and stroke. In subgroup analysis, a group consisting of male patients aged ≥65 years, with BMI <25, showed a significant OR for walking speed. This study showed that slow walking speed is a sole determinant criterion of sarcopenia of MCI in patients with type 2 diabetes mellitus. It was suggested that walking speed is an important factor in the prediction and prevention of MCI development in patients with diabetes mellitus.

Burden of Undiagnosed Type 2 Diabetes in Diabetic Kidney Disease: A Japanese Retrospective Cohort Study.

The risk of developing diabetic kidney disease (DKD) in patients with undiagnosed diabetes mellitus (UD) has never been evaluated. We studied the burden of UD on the risk of developing DKD in the Japanese population in a single-center retrospective cohort study. The patients with type 2 diabetes mellitus, but without DKD (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or proteinuria), were recruited from January 2018 to January 2019; medical records were scrutinized retrospectively from January 2003 until May 2019. The individuals, with diabetes that could not be denied based on past and current records, comprised the undiagnosed diabetes (UD) group whereas those with confirmed diagnosis comprised the diagnosed diabetes (DD) group. The group differences were tested using a Kaplan-Meier curve and Cox proportional hazards model. Among the 408 participants, 164 (40.2%) and 244 (59.8%) comprised the DD and UD groups, respectively. The baseline parameters, including age, male gender, and BMI were comparable between the groups, but the plasma glucose, HbA1c levels, and diabetic retinopathy prevalence were higher in the UD group. The risk of developing DKD (log rank test, p < 0.001), an eGFR of < 60 mL/min/1.73 m2 (p = 0.001) and proteinuria (p = 0.007) were also higher in the UD group. The unadjusted and adjusted hazard ratios for DKD were 1.760 ((95% CI: 1.323-2.341), p < 0.001) and 1.566 ((95% CI: 1.159-2.115), p = 0.003), respectively, for the UD group. In conclusion, this is the first report showing that UD is a strong risk factor for DKD. The notion that a longer duration of untreated diabetes mellitus is involved strongly in the risk of developing DKD warrants the need for the identification and monitoring of UD patients.

Secondary analyses to assess the profound effects of empagliflozin on endothelial function in patients with type 2 diabetes and established cardiovascular diseases: The placebo-controlled double-blind randomized effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi-center placebo-controlled double-blind randomized trial.

AIMS/INTRODUCTION: Recent clinical trials on sodium-glucose cotransporter 2 inhibitors showed improved outcomes in patients with type 2 diabetes at a high risk of cardiovascular events. However, the underlying effects on endothelial function remain unclear. MATERIALS AND METHODS: The effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi-center placebo-controlled double-blind randomized (EMBLEM) trial in patients with type 2 diabetes and cardiovascular disease showed empagliflozin treatment for 24 weeks had no effect on peripheral endothelial function measured by reactive hyperemia peripheral arterial tonometry. This post-hoc analysis of the EMBLEM trial included a detailed evaluation of the effects of empagliflozin on peripheral endothelial function in order to elucidate the clinical characteristics of responders or non-responders to treatment. RESULTS: Of the 47 patients randomized into the empagliflozin group, 21 (44.7%) showed an increase in the reactive hyperemia index (RHI) after 24 weeks of intervention, with no apparent difference in the clinical characteristics between patients whose RHI either increased (at least >0) or did not increase. There was also no obvious difference between the treatment groups in the proportion of patients who had a clinically meaningful change (≥15%) in log-transformed RHI. No correlation was found between changes in RHI and clinical variables, such as vital signs and laboratory parameters. CONCLUSIONS: Treatment with empagliflozin for 24 weeks in patients with type 2 diabetes and cardiovascular disease did not affect peripheral endothelial function, and was not related to changes in clinical variables, including glycemic parameters. These findings suggest that the actions of sodium-glucose cotransporter 2 inhibitors other than direct improvement in peripheral endothelial function were responsible, at least in the early phase, for the clinical benefits found in recent cardiovascular outcome trials.

Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by systemic metabolic abnormalities and the development of micro- and macrovascular complications, resulting in a shortened life expectancy. A recent cardiovascular (CV) safety trial, the EMPA-REG OUTCOME trial, showed that empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, markedly reduced CV death and all-cause mortality and hospitalization for heart failure in patients with T2DM and established CV disease (CVD). SGLT2 inhibitors are known to not only decrease plasma glucose levels, but also favorably modulate a wide range of metabolic and hemodynamic disorders related to CV pathways. Although some experimental studies revealed a beneficial effect of SGLT2 inhibitors on atherosclerosis, there is a paucity of clinical data showing that they can slow the progression of atherosclerosis in patients with T2DM. Therefore, the EMBLEM trial was designed to investigate whether empagliflozin treatment can improve endothelial function, which plays a pivotal role in the pathogenesis of atherosclerosis, in patients with T2DM and established CVD. METHODS: The EMBLEM trial is an ongoing, prospective, multicenter, placebo-controlled double-blind randomized, investigator-initiated clinical trial in Japan. A total of 110 participants with T2DM (HbA1c range 6.0-10.0%) and with established CVD will be randomized (1:1) to receive either empagliflozin 10 mg once daily or a placebo. The primary endpoint of the trial is change in the reactive hyperemia (RH)-peripheral arterial tonometry-derived RH index at 24 weeks from baseline. For comparison of treatment effects between the treatment groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for the following allocation factors: HbA1c (<7.0 or ≥7.0%), age (<65 or ≥65 years), systolic blood pressure (<140 or ≥140 mmHg), and current smoking status (nonsmoker or smoker). Key secondary endpoints include the change from baseline for other vascular-related markers such as arterial stiffness, sympathetic nervous activity, and parameters of cardiac and renal function. Importantly, serious adverse effects independently on the causal relationship to the trial drugs and protocol will be also evaluated throughout the trial period. DISCUSSION: EMBLEM is the first trial to assess the effect of empagliflozin on endothelial function in patients with T2DM and established CVD. Additionally, mechanisms associating empagliflozin-mediated actions with endothelial function and other CV markers will be evaluated. Thus, the trial is designed to elucidate potential mechanisms by which empagliflozin protects CV systems and improves CV outcomes. Trial registration Unique Trial Number, UMIN000024502 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000028197 ).

The effects of liraglutide on both hypereosinophilic insulin allergy and the characteristics of anti-insulin antibodies in type 2 diabetes mellitus: a case report.

BACKGROUND: Liraglutide is one of the glucagon-like peptide-1 analogs; there are only a few reports of liraglutide being used for the treatment of insulin allergy. Furthermore, anti-insulin immunoglobulin G antibodies are occasionally detected in patients with diabetes. Hence, we report a case in which switching to liraglutide therapy ameliorated both the symptoms of insulin allergy with hypereosinophilia and the characteristics of insulin antibodies in a patient with type 2 diabetes mellitus. CASE PRESENTATION: We present the case of a 70-year-old Japanese man with type 2 diabetes who developed insulin allergy with hypereosinophilia. Anti-insulin antibodies, high glycated hemoglobin levels (approximately 12 %), and high serum insulin levels were detected. Because a change in his insulin treatment was inefficient, treatment with liraglutide to protect residual insulin secretion was started, resulting in improvements in his insulin allergy, serum glycated hemoglobin, insulin, and eosinophil levels. Scatchard plots revealed decreased binding capacity and increased affinity constant for high affinity sites of anti-insulin antibodies. CONCLUSIONS: Liraglutide might be useful for treating insulin allergy and anti-insulin antibodies in patients with type 2 diabetes.