Effect of Combination Therapy of Canagliflozin Added to Teneligliptin Monotherapy in Japanese Subjects with Type 2 Diabetes Mellitus: A Retrospective Study.

Recently, dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been very often used in subjects with type 2 diabetes mellitus (T2DM). In addition, combination drugs of both inhibitors have attracted much attention in aspects of its cost-effectiveness and improvement of patients' adherence. However, it is still poorly understood which factors are related to the efficacy of SGLT2 inhibitors as add-on therapy to DPP-4 inhibitors. Therefore, we aimed to elucidate in which type of individuals and/or under which conditions canagliflozin as add-on therapy to teneligliptin could exert more beneficial effects on glycemic control and/or renal protection. We retrospectively analyzed 56 Japanese subjects with T2DM in the real-world clinical practice. Three months after starting the combination therapy, the change of HbA1c (ΔHbA1c) was strongly related to HbA1c levels at baseline. As expected, serum glucagon level was increased after starting the combination therapy. Interestingly, however, the change of glucagon levels (Δglucagon) was not related to HbA1c levels at baseline, ΔHbA1c, and other parameters, which indicated that the increase of glucagon did not clinically affect the effectiveness of combination therapy. In addition, the change of urinary albumin excretion (ΔUAE) was negatively correlated with systolic blood pressure and HbA1c levels at baseline and positively correlated with the change of systolic blood pressure (ΔsBP) in univariate analysis. Furthermore, in multivariate analysis, only ΔsBP was the independent factor associated with ΔUAE. Taken together, canagliflozin as add-on therapy to teneligliptin improves glycemic control in a Δglucagon-independent manner and reduces UAE in a ΔsBP-dependent manner in Japanese subjects with T2DM.

Comparison of the effects of three kinds of glucose-lowering drugs on non-alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, open-label, three-arm, active control study.

AIMS/INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is often observed in individuals with type 2 diabetes mellitus, and it is known that the presence of type 2 diabetes mellitus leads to the aggravation of NAFLD. The aim of this study was to compare the possible effects of three kinds of oral hypoglycemic agents on NAFLD in individuals with type 2 diabetes mellitus. MATERIALS AND METHODS: We carried out a prospective clinical trial (a randomized and open-label study) in patients with type 2 diabetes mellitus and NAFLD. A total of 98 patients were randomly allocated either to the dapagliflozin (n = 32), pioglitazone (n = 33) or glimepiride (n = 33) group, and the patients took these drugs for 28 weeks. The primary end-point was the change of the liver-to-spleen ratio on abdominal computed tomography. RESULTS: There was no difference in baseline clinical characteristics among the three groups. Dapagliflozin, pioglitazone and glimepiride ameliorated hyperglycemia similarly. Bodyweight and visceral fat area were significantly decreased only in the dapagliflozin group. Serum adiponectin levels were markedly increased in the pioglitazone group compared with the other two groups. Dapagliflozin and pioglitazone, but not glimepiride, significantly increased the liver-to-spleen ratio, and the effects of dapagliflozin and pioglitazone on the liver-to-spleen ratio were comparable. CONCLUSIONS: The present study showed that the decrease of visceral fat area and the increase of adiponectin level contributed to the improvement of NAFLD in patients with type 2 diabetes mellitus. Furthermore, dapagliflozin and pioglitazone exerted equivalent beneficial effects on NAFLD in patients with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action.

Impact of physical activity and sedentary time on glycated hemoglobin levels and body composition: Cross-sectional study using outpatient clinical data of Japanese patients with type 2 diabetes.

AIMS/INTRODUCTION: This study examined the association among sedentary time (ST), physical activity (PA), glycated hemoglobin and body composition in Japanese type 2 diabetes patients. MATERIALS AND METHODS: Patients with type 2 diabetes who visited the outpatient clinic at Kawasaki Medical School Hospital, Okayama, Japan, comprised the study's participants. Self-administered International Physical Activity Questionnaire short forms were obtained and analyzed for 1,053 patients, including 158 patients for whom waist circumference and visceral fat accumulation were measured. From the questionnaire, three categorical data (low, moderate, high) and continuous data (METs/h/week) regarding PA and ST (min/day), respectively, were obtained. RESULTS: The patients categorized as having low PA had significantly higher body mass index than those categorized as having high levels, after adjustment was made for confounders. Continuous data of PA were negatively associated with waist circumference and visceral fat accumulation. ST was positively associated with body mass index. After dividing the participants into four groups according to medians of ST and PA, the following categories were established: long ST and low PA, long ST but high PA, short ST but low PA and short ST and high PA. In terms of body mass index, short ST and high PA measured significantly lower than long ST and low PA. For waist circumference and visceral fat accumulation, short ST but low PA and short ST and high PA measured significantly lower than long ST and low PA and long ST but high. CONCLUSIONS: These results imply that the combination of avoiding sedentary behavior and increasing PA might be important in the prevention bodyweight gain and in the avoidance of central obesity, respectively, in Japanese type 2 diabetes patients.

Idiopathic and isolated adrenocorticotropic hormone deficiency presenting as continuous epigastric discomfort without symptoms of hypoglycemia: a case report.

BACKGROUND: Isolated adrenocorticotropic hormone deficiency is one kind of hypopituitarism and is triggered by various diseases including autoimmune disorder and/or autoimmune hypophysitis. Adrenocorticotropic hormone deficiency brings out various serious symptoms such as severe hypoglycemia, hypotensive shock, and disturbance of consciousness. CASE PRESENTATION: Here we report a case of 65-year-old Japanese man who developed idiopathic and isolated adrenocorticotropic hormone deficiency. He had continued epigastric comfort without any symptom of hypoglycemia or any autoimmune abnormality. Since he continued to complain of mild epigastric discomfort and general malaise, he was misdiagnosed as having functional dyspepsia and a depression state and took medicine for them for several months. Infection markers and several antibodies which we examined were all negative. An abdominal computed tomography scan showed no mass in adrenal tissue; contrast magnetic resonance imaging of his brain showed that pituitary size was within normal range, and pituitary gland deep dyeing delay and/or deeply stained deficit were not observed. However, in a corticotropin-releasing hormone load test, response of adrenocorticotropic hormone and cortisol was poor after corticotropin-releasing hormone loading, and in growth hormone-releasing peptide 2 load test, adrenocorticotropic hormone response was poor, suggesting the presence of adrenocorticotropic hormone deficiency. Therefore, we started treatment with hydrocortisone, and his various symptoms were soon mitigated. CONCLUSIONS: We should bear in mind the possibility of adrenocorticotropic hormone deficiency even when patients complain of epigastric discomfort or general malaise alone.

Eicosapentaenoic acid/arachidonic acid ratio and weight loss during hospitalization for glycemic control among overweight Japanese patients with type 2 diabetes: a retrospective observational study.

BACKGROUND: The study aimed to examine the relationship between levels of serum eicosapentaenoic acid (EPA), arachidonic acid (AA), as well as EPA/AA ratio and weight loss during hospitalization in participants considered to be overweight, with type 2 diabetes. METHODS: The study participants included 142 patients who were hospitalized for treatment of type 2 diabetes. We divided the participants into two groups depending on the achievenemt in reduction of bodyweight 3% or more during hospitalization and examined the relationship between serum levels of EPA and AA, as well as ratio of EPA/AA on admission and effectiveness of weight loss under strict dietary therapy during hospitalization, using Cox proportional hazard models. RESULTS: After adjustment was made for several confounders, the hazard ratio of effective weight loss for logarithmical serum EPA was 1.59 (95% CI 1.02-2.49, P = 0.04) and for logarithmical EPA/AA ratio 1.64 (1.03-2.61, P = 0.04), whereas the hazard ratio for effective weight loss for logarithmical serum AA was 1.11 (0.45-2.78, P = 0.82). In addition, after dividing EPA/AA ratio and serum EPA into quartiles based on participant number, the hazard ratio for the highest quartile of EPA/AA ratio was 2.33 (1.14-4.77, P = 0.02), and for the highest quartile of serum EPA 1.60 (0.80-3.19, P = 0.18) compared with the lowest quartile. CONCLUSION: These results suggest the possibility that EPA is involved in bodyweight change under a caloric-restriction regimen. In addition, EPA/AA ratio was found to be a better predictor of medical intervention for weight loss among overweight patients with type 2 diabetes, compared with serum EPA level.

Effect of mild exercise on glycemic and bodyweight control in Japanese type 2 diabetes patients: A retrospective analysis.

We retrospectively evaluated the effects of mild physical exercise (P) in a routine clinical setting on glycemic and bodyweight control in Japanese type 2 diabetes patients with and without individualized nutritional therapy (D). We analyzed 49 patients who participated in P that measured 2.5 metabolic equivalents and was held once every 2 weeks, compared with 83 non-participant controls, followed over a period of approximately 1.6 years. With a Cox model, the adjusted hazard ratio for improved glycated hemoglobin by numerical count of P was 1.03 (95% confidence interval [CI] 1.00-1.07; P = 0.025). Among four categories - with neither P nor D, only P, only D, and both P and D - the hazard ratios for reduced body mass index were 1.0, 0.87 (95% CI 0.46-1.67), 0.58 (95% CI 0.25-1.30) and 2.17 (95% CI 1.03-4.59), respectively. Even mild physical exercise contributed to glycemic control. The combination of P and D exerted beneficial effects on bodyweight control.

Verification of Kumamoto Declaration 2013 and Glycemic Targets for Elderly Patients with Diabetes in Japan for prevention of diabetic complications: A retrospective longitudinal study using outpatient clinical data.

AIMS/INTRODUCTION: The present study examined the association between the onset of micro- and macroangiopathy in type 2 diabetes mellitus patients and levels of glycated hemoglobin (HbA1c) described in the Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013 or those indicated in the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with Diabetes. MATERIALS AND METHODS: Patients with type 2 diabetes mellitus who visited the outpatient clinic at Kawasaki Medical School Hospital between 2000 and 2016 and received follow up for >2 years were eligible for the present study. Two datasets, comprising 2,424 or 3,316 patients without micro- or macroangiopathy at the start of follow up, were used, respectively. The Cox model was used in two categories of patients, younger and elderly, with the dividing line set at the age of 65 years. RESULTS: For the prevention of microangiopathy, in all patients, there was found to be no advantage in controlling HbA1c at a level of <6.0% based on the categories in the Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013, and there was found to be a disadvantage in maintaining HbA1c ≥8.5% based on the categories in the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with Diabetes guideline. For the prevention of macroangiopathy in younger patients, there seemed to be an advantage in maintaining HbA1c within the range of 6.0-6.9% and <7.0% based on the Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013 and the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with Diabetes, respectively. CONCLUSIONS: In all type 2 diabetes mellitus patients, average HbA1c should be maintained <7.0% to prevent microangiopathy. However, in elderly patients, no optimal target for preventing macroangiopathy was found, in contrast to the younger patients in the present study.

Efficacy and Safety of Switching from Insulin Glargine 100 U/mL to the Same Dose of Glargine 300 U/mL in Japanese Type 1 and 2 Diabetes Patients: A Retrospective Analysis.

Objective Insulin glargine [300 U/mL (Gla-300)] achieved better glycemic control and reduced the risk of hypoglycemia in comparison to glargine [100 U/mL; (Gla-100)] in phase 3 trials. This is the first study to retrospectively evaluate the efficacy and safety of Gla-300 in Japanese type 1 and 2 diabetes patients in a routine clinical setting. Methods We analyzed 20 type 1 diabetes patients and 62 type 2 diabetes patients who switched from Gla-100 to the same dose of Gla-300. Sixty type 2 diabetes patients who continued the use of Gla-100 during the study were included as controls. Results At three months after switching, the HbA1c levels were decreased in the patients with type 1 diabetes, but not to a significant extent. In the type 2 diabetes patients, the HbA1c levels were significantly decreased after switching (p<0.01). In contrast, there was no change in the HbA1c levels of the type 2 diabetes patients who continued the use of Gla-100 over the same period. The BMI values of the type 1 diabetes patients tended to decrease (p=0.06) and there was a significant decrease in the BMI values of the type 2 diabetes patients (p<0.05). There was no change in the BMI values of the type 2 diabetes patients who continued the use of Gla-100. The rates of hypoglycemia and adverse events did not change during the follow-up period. Conclusion In the clinical setting, switching from Gla-100 to the same dose of Gla-300 had a favorable effect on glycemic control and body weight control in Japanese type 1 and type 2 diabetes patients, without any increase in adverse events; however, a prospective study should be performed to confirm these findings.

Switching from low-dose thiazide diuretics to sodium-glucose cotransporter 2 inhibitor improves various metabolic parameters without affecting blood pressure in patients with type 2 diabetes and hypertension.

AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors function to increase urinary glucose excretion and improve glycemic control in individuals with type 2 diabetes mellitus. SGLT2 inhibitors, as well as diuretics, increase urinary volume, which leads to the reduction of blood pressure. The aim of the present study was to compare the effects of SGLT2 inhibitor and thiazide diuretic on blood pressure, metabolic parameters and body mass composition. MATERIALS AND METHODS: A total of 31 participants were enrolled in the present study. We switched from thiazide diuretics to an SGLT2 inhibitor, ipragliflozin, in participants with type 2 diabetes and hypertension whose blood pressure was controlled with thiazide diuretics. Three months after the switch, we evaluated the effects of such switching on blood pressure, various metabolic parameters and body mass composition. RESULTS: There was no significant difference in blood pressure from baseline to 3 months later. However, glycated hemoglobin, fasting plasma glucose and uric acid were significantly decreased after the switch. Body mass index and visceral fat area were also significantly reduced after the switch. Furthermore, urinary albumin excretion was also significantly decreased after the switch. CONCLUSIONS: Switching from thiazide diuretic to an SGLT2 inhibitor, ipragliflozin, markedly improved various metabolic parameters and body mass composition without affecting blood pressure in participants with type 2 diabetes and hypertension.

Werner Syndrome and Diabetes Mellitus Accompanied by Adrenal Cortex Cancer.

Werner syndrome is a rare genetic disease characterized by progeria, diabetes mellitus, cataracts and various types of malignancy. However, there are few reports showing adrenal cortex cancer in subjects with Werner syndrome. We herein report an extremely rare case of Werner syndrome accompanied by adrenal cortex cancer. Based on the data obtained from blood samples, computed tomography, magnetic resonance imaging and 131I adosterol scintigraphy, we diagnosed this subject with adrenal cortex cancer and Cushing's syndrome. Since the prognosis of adrenal cancer is very poor, we should be aware of the possibility of adrenal cancer occurring in subjects with Werner syndrome.

Dramatic mitigation of bone pain after phosphorus replacement therapy in a subject with FGF23-related hypophosphatemic osteomalacia.

INTRODUCTION: Fibroblast growth factor 23 (FGF23) is secreted from bone and suppresses the absorption of phosphorus in renal proximal tubule and in intestinal tract. Therefore, the increase of serum FGF23 levels leads to hypophosphatemic situations. Tumor-induced osteomalacia is often induced by various tumors, but it is often difficult to identify the localization of tumor, because most of the FGF23-producing tumors are small and could be observed in any part of the body. CASE DESCRIPTION: Here we report a case of elderly female subject with FGF23-related hypophosphatemic osteomalacia who repeatedly experienced severe bone pain and fragility fracture in various parts of the body. Although we failed to identify the localization of tumor in this subject even with various examination, after starting phosphorus replacement therapy with relatively small amounts of calcium phosphate (1.5 g/day) (phosphorus content: 270 mg), hypophosphatemia was ameliorated and repeated bone pain was dramatically mitigated without any surgical operation. DISCUSSION AND EVALUATION: Even when we fail to identify the localization of tumor in subjects with FGF23-related hypophosphatemic osteomalacia, phosphorus replacement therapy for hypophosphatemia could reduce the bone pain. CONCLUSIONS: We should be aware of the possibility that phosphorus replacement therapy exert marked beneficial effects for the reduction of bone pain in subjects with FGF23-related hypophosphatemic osteomalacia even when we fail to identify tumor localization.