Effects of Elobixibat in Patients with Diabetes and Concomitant Chronic Constipation: an 8-week, Prospective, Single-center, Single-arm Study.

AIMS: To evaluate the efficacy and safety of elobixibat in patients with diabetes and concomitant chronic constipation. METHODS: This was a single-center, single-arm study. Thirty-three patients with diabetes and chronic constipation, as defined by the Rome IV criteria, were treated with elobixibat (10 mg/day) for 8 weeks. Patients recorded stool properties, including spontaneous bowel movements (SBMs) and stool consistency, according to the Bristol Stool Form Scale (BSFS). Quality of life for constipation was evaluated with the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL). RESULTS: Of the 33 eligible patients, 30 completed the study. Elobixibat significantly increased the median (interquartile range) frequency of SBMs per week, from 5.0 (3.0-7.0) at baseline to 6.0 (4.0-7.0] at week 8 (p = 0.030). After 8 weeks, the BSFS score approached 4; the score for normal stool consistency and the JPAC-QOL score significantly improved from 1.05 ± 0.40 at baseline to 0.94 ± 0.53 (p = 0.048); and glycated albumin and serum lipid profiles significantly improved. Stratified analysis revealed that SBMs increased especially in patients with low SBM frequency, in particular in women, older adults, patients without overweight, patients with a long duration of constipation, and patients with diabetic neuropathy. No serious adverse events occurred. CONCLUSIONS: Among patients with diabetes who met the Rome IV criteria for constipation, elobixibat was effective, especially in those with few SBMs at baseline. Improvements in lipid profiles could be an advantage of elobixibat compared with other laxatives. CLINICAL TRIAL REGISTRY: Japan Registry of Clinical Trials registration number: jRCTs031190092.

Correlation between blood ketones and exhaled acetone measured with a semiconducting gas sensor.

Breath acetone (BrAce) has been reported to be useful for monitoring the pathophysiology of patients with diabetes. However, devices that measure BrAce are expensive, complex and uncommon. The FM-001, originally designed to monitor a marker of weight loss in healthy people, is a device for measuring BrAce. The FM-001 is a loading semiconducting gas sensor that is a simple and reusable device. The aim of this study was to evaluate the correlation between blood total ketone bodies (TKB) and BrAce measured with the FM-001 in patients with diabetes. Furthermore, through evaluation of that correlation, we sought to detect patients at high risk of developing diabetic ketoacidosis (DKA). Thirty-five participants (age 52 [40-57], T2DM 32, T1DM 3) were enrolled. Scatter plots and linear regression lines relating BrAce to TKB and the correlation coefficients were calculated. Receiver-operating characteristic analysis was performed to determine the cut-off for predicting patients prone to DKA. The results showed that BrAce strongly correlates with TKB (R= 0.828), and the correlation was stronger in patients whose serum C-peptide was not low. The optimal BrAce cut-off for predicting risk of developing DKA was 3400 ppb (AUC 0.924, sensitivity 73.3%, specificity 100%), which corresponds to a TKB ⩾ 1000µmol l-1. BrAce also weakly correlated with free fatty acid. Thus, BrAce levels measured with the FM-001 strongly correlate with TKB, even in patients with diabetes. This suggests the FM-001 is a simple and potentially useful method for detecting diabetic ketosis. (UMIN-ID: UMIN000038086).

A retrospective cohort study for the treatment of Asian diabetic ketoacidosis: optimizing initial doses of insulin.

AIM: An insulin dose of 0.1 U/kg/h recommended by Western guidelines occasionally induces a precipitous decreasing blood glucose in Asian diabetic ketoacidosis (DKA). It is known that clinical factors, such as insulin sensitivity, differ between Asians and Americans/Europeans. We investigated how treatment options affect the time to DKA resolution to determine the optimal treatment for Asian DKA patients. METHODS: This was a retrospective cohort study from a single institution in Japan. A total of 34 adult DKA patients were observed. Baseline characteristics and treatment-related parameters were compared between patients whose DKA was resolved within 18 h and those in which it was not. RESULTS: Significant differences were observed in the initial insulin dose (mean [standard deviation]: 0.053 [0.021] versus 0.031 [0.014] U/kg/h; P = 0.003) and the baseline ß-hydroxybutyrate (7.2 [3.2] versus 9.9 [2.6] mmol/L; P = 0.024) and HCO 3 - levels (11.2 [4.1] versus 7.7 [3.1] mmol/L; P = 0.014). Multivariable logistic regression analysis revealed that the initial insulin dose was significantly associated with early resolution of DKA and was independent of basal conditions. Receiver operating characteristic curve analysis indicated that the optimal cut-off point for the initial insulin dose was 0.051 U/kg/h. With an initial insulin dose of 0.051 U/kg/h or higher, early resolution of DKA was obtained in 92.9% of patients. CONCLUSION: An initial insulin dose of more than 0.05 U/kg/h provides an early resolution of DKA in Asian patients. Lower insulin doses significantly delay resolution. These results provide practical information for acute phase treatment of Asian DKA.

Development of a simple prediction model for adrenal crisis diagnosis.

To develop a prediction model for adrenal crisis (AC) diagnosis among individuals with adrenal insufficiency that relies on the values of routinely measured clinical parameters, for application in standard clinical practice. We retrospectively analysed data from five referral centres in Japan. Multivariate binary logistic regression was used to identify independent predictors of AC, and receiver operating characteristic curve analysis was used to determine their optimal cut-off points. The analysis included data from 54 patients with 90 AC events. Logistic regression revealed that serum sodium and C-reactive protein (CRP) levels were independent predictors of AC. Serum sodium levels < 137 mEq/L had a sensitivity of 71.1% and specificity of 95.6%. CRP levels > 1.3 mg/dL had a sensitivity of 84.4% and specificity of 94.9%. In combination, serum sodium levels < 137 mEq/L or CRP levels > 1.3 mg/dL for AC diagnosis had sensitivity and specificity values of 97.8% and 94.4%, respectively. The combined use of serum sodium and CRP levels had high sensitivity and specificity, and can be used for AC screening in standard clinical practice. The model can assist in identifying AC among high-risk individuals. A larger prospective study is needed to validate these results.

Clinical and biochemical outcomes after adrenalectomy and medical treatment in patients with unilateral primary aldosteronism.

OBJECTIVES: Current clinical guidelines of primary aldosteronism recommend adrenalectomy (AdX) for unilateral primary aldosteronism based on the studies showing the potential superiority of AdX over the medical treatment. However, since most medically treated cases consisted of bilateral primary aldosteronism and all surgically treated cases consisted of unilateral primary aldosteronism, the different subtype of primary aldosteronism could be a bias for their effects. This study compared the effects of AdX and medical therapy in patients with unilateral primary aldosteronism confirmed by adrenal vein sampling. METHODS: Of the 339 patients with unilateral primary aldosteronism in the Japan Primary Pldosteronism Study data base, unilateral AdX and treatment with mineral corticoid receptor antagonists (MRAs) was done in 276 patients (AdX group) and in 63 patients (MRAs group), respectively. The effects were compared by the clinical (improvement of blood pressure) and biochemical outcomes (improvement of hypokalemia). RESULTS: At baseline, use of potassium replacement, plasma aldosterone concentration, aldosterone-to-renin ratio, estimated glomerular filtration rate, and prevalence of adrenal mass on imaging were higher in the AdX group than in the MRAs group. At 6 months after commencement of specific treatment for primary aldosteronism, clinical outcome and biochemical outcome in the AdX group were superior than those in the MRAs group. The difference of the outcome between the two groups were the case even after adjusting for the different clinical backgrounds in the two groups before the specific treatment. CONCLUSION: Our study provides evidence that AdX is the first choice of treatment in the patients with unilateral primary aldosteronism in terms of clinical and biochemical outcome.

Efficacy and safety of thrice-weekly insulin degludec in elderly patients with type 2 diabetes assessed by continuous glucose monitoring.

As life expectancy becomes longer in Japan, there has been an increase of elderly patients with type 2 diabetes who need insulin therapy but cannot perform self-injection due to dementia or other conditions. Therefore, the aim of this study was to investigate the efficacy and safety of thrice-weekly insulin degludec therapy in elderly patients with poorly controlled diabetes. The subjects were 22 hospitalized elderly Japanese patients with type 2 diabetes who had difficulty with self-injection. After becoming stable on once-daily insulin degludec treatment, they were assigned to continue once-daily injection (OD group) or were switched to thrice-weekly injection (TW group) for one week. In the TW group, insulin degludec (IDeg) was injected at twice the OD dose before lunch on Monday, Wednesday, and Friday. Glycemic control was assessed by continuous glucose monitoring (CGM) over 7 days. The mean 7-day glucose level (131±25 mg/dL with OD vs. 152±30 mg/dL with TW, p=0.11) and the mean 7-day standard deviation (32±10 mg/dL with OD vs. 36±14 mg/dL with TW, p=0.45) did not differ significantly between the two groups. The percent duration of glucose <70 mg/dL (2.4±3.1% with OD vs. 1.3±2.5% with TW, p=0.39) and glucose >200 mg/dL (7.2±12.1% with OD vs. 15.6±18.0% with TW, p=0.22) over 7 days also showed no significant differences between the two groups. In conclusion, thrice-weekly IDeg provided by a visiting nurse could be a practical option for elderly diabetic patients who have difficulty performing self-injection of insulin.

Proposed cut-off value of the intrahepatic lipid content for metabolically normal persons assessed by proton magnetic resonance spectroscopy in a Japanese population.

AIMS: To determine the threshold intrahepatic lipid (IHL) content separating metabolically normal from abnormal in a Japanese population based on proton magnetic resonance spectroscopy ((1)H-MRS). METHODS: A total of 305 Japanese subjects aged 20-69years were investigated. The subjects underwent general examination, blood tests, and (1)H-MRS of the liver after an overnight fast. They completed a questionnaire about daily drinking habits and their daily alcohol intake was calculated. RESULTS: The median IHL content was 4.7% in men and 1.7% in women, and it increased along with the number of features of metabolic syndrome (MetS). The optimum IHL cut-off value for separating normal subjects from those with at least one feature of MetS was 6.5% in men (AUC of ROC: 0.727, 95%-CI: 0.649-0.804) and 1.8% in women (0.765, 0.685-0.844). Alcohol intake was not correlated with the IHL content according to multiple logistic regression analysis. CONCLUSION: This study demonstrated a close association of IHL with features of MetS and identified IHL content cut-off values for metabolic normality in Japanese subjects.

Proposed cut-off values of the waist circumference for metabolic syndrome based on visceral fat volume in a Japanese population.

AIM/INTRODUCTION: Waist circumference (WC) is the most important parameter for diagnosis of metabolic syndrome. The present study was carried out to obtain optimal WC cut-off values for diagnosis of metabolic syndrome in a Japanese population based on the measurement of total intra-abdominal visceral fat volume (VFV), which could be expected to reflect visceral obesity more precisely than visceral fat area. MATERIALS AND METHODS: A total of 405 Japanese persons undergoing health screening were investigated. visceral fat volume was calculated from the data in 700-800 computed tomography slices from the top of the liver to the floor of the pelvic cavity. Then, receiver operating characteristic analysis was used to determine the cut-off value of the VFV/height ratio. Subsequently, the corresponding WC value was obtained by linear regression analysis. RESULTS: The cut-off value of the VFV/height ratio was 2,317 cm(3) /m in men and 1,425 cm(3) /m in women. The sensitivity and specificity of the ratio were 52.9 and 86.4% in men vs 63.4 and 82.2% in women, respectively. The corresponding cut-off value of WC was 86.0 cm in men and 80.9 cm in women. CONCLUSIONS: The proposed cut-off values of WC for metabolic syndrome are 85 cm in Japanese men and 80 cm in Japanese women.

Effect of sitagliptin on intrahepatic lipid content and body fat in patients with type 2 diabetes.

AIMS: To evaluate the effect of the DPP-4 inhibitor sitagliptin on intrahepatic lipid (IHL) content and body fat in overweight Japanese patients with type 2 diabetes. METHODS: A prospective, 24-week, single-center, open-label comparative study enrolled 20 Japanese patients with type 2 diabetes (male: 11, female: 9) with a BMI≥25 kg/m(2) or fatty liver. Subjects were randomly assigned to receive treatment with sitagliptin (25 mg titrated up to 50 mg: S) or glimepiride (0.5 mg titrated up to 1 mg: G). After starting each treatment, IHL and total fat mass were evaluated by (1)H-magnetic resonance spectroscopy ((1)H-MRS) and dual energy X-ray absorptiometry (DEXA), respectively at baseline and at 12 weeks and 24 weeks. RESULTS: After 24 weeks, HbA1c levels showed a similar significant decrease in both groups from 7.2 (7.0, 7.5) to 6.6 (6.4, 6.8)%, (54 (53, 56) to 48(47, 49) mmol/mol) with S and 7.3(6.8, 7.4) to 6.6 (6.3, 6.7)%, (55 (51, 56) to 48 (46, 49) mmol/mol) with G, median (interquartile range), p<0.05 vs. baseline, with no significant differences between the two groups. The IHL and total body fat mass were decreased in S group from 24.5(18.9, 36.6) to 20.5 (14.6, 28.5)% (p=0.009) and 22.5 (20.6, 33.7) to 21.6 (19.7, 32.4)kg (p=0.028), respectively, but not in G group. CONCLUSIONS: Our findings indicate that sitagliptin and glimepiride achieved similar glycemic control, but only sitagliptin reduced IHL and total body fat (UMIN: 000013356).