Validation study of case-identifying algorithms for severe hypoglycemia using hospital administrative data in Japan.

OBJECTIVE: The purpose of this study was to evaluate the performance of algorithms for identifying cases of severe hypoglycemia in Japanese hospital administrative data. METHODS: This was a multicenter, retrospective, observational study conducted at 3 acute-care hospitals in Japan. The study population included patients aged ≥18 years with diabetes who had an outpatient visit or hospital admission for possible hypoglycemia. Possible cases of severe hypoglycemia were identified using health insurance claims data and Diagnosis Procedure Combination data. Sixty-one algorithms using combinations of diagnostic codes and prescription of high concentration (≥20% mass/volume) injectable glucose were used to define severe hypoglycemia. Independent manual chart reviews by 2 physicians at each hospital were used as the reference standard. Algorithm validity was evaluated using standard performance metrics. RESULTS: In total, 336 possible cases of severe hypoglycemia were identified, and 260 were consecutively sampled for validation. The best performing algorithms included 6 algorithms that had sensitivity ≥0.75, and 6 algorithms that had positive predictive values ≥0.75 with sensitivity ≥0.30. The best-performing algorithm with sensitivity ≥0.75 included any diagnoses for possible hypoglycemia or prescription of high-concentration glucose but excluded suspected diagnoses (sensitivity: 0.986 [95% confidence interval 0.959-1.013]; positive predictive value: 0.345 [0.280-0.410]). Restricting the algorithm definition to those with both a diagnosis of possible hypoglycemia and a prescription of high-concentration glucose improved the performance of the algorithm to correctly classify cases as severe hypoglycemia but lowered sensitivity (sensitivity: 0.375 [0.263-0.487]; positive predictive value: 0.771 [0.632-0.911]). CONCLUSION: The case-identifying algorithms in this study showed moderate positive predictive value and sensitivity for identification of severe hypoglycemia in Japanese healthcare data and can be employed by future pharmacoepidemiological studies using Japanese hospital administrative databases.

Breadfruit (Artocarpus altilis): Processing, nutritional quality, and food applications.

Breadfruit is an underutilized but highly nutritive crop containing complex carbohydrates while being low in fat. It is also a good source of essential amino acids (leucine, isoleucine, and valine). With a better understanding of breadfruit's morphology, its potential as a global solution to food security has been gaining popularity. Breadfruit has been forecasted to have a larger amount of suitable cultivable land area compared to major crops such as rice and wheat, making its cultivation more desirable. Due to its highly perishable nature, good post-harvesting and post-processing practices are essential to extend the shelf life of breadfruit for global transportation and consumption. This paper aims to provide a comprehensive review on various processing methods of flour and starch, nutritional significance and new food applications of this novel food staple. In this review, the effects of the different processing and post-processing methods of breadfruit flour and starch have been described, and the nutritional composition and application of breadfruit flour as an ingredient replacer in various food applications have been discussed. It is vital to understand the processing and post-processing methods of breadfruit flour to enhance its shelf-life, physicochemical and functional properties. Furthermore, a compilation of novel food applications has been done to promote its use in the food industry. In conclusion, breadfruit flour and starch are highly versatile for use in numerous food products with added health benefits.

Safety and effectiveness of dulaglutide 0.75 mg in Japanese patients with type 2 diabetes in real-world clinical practice: 36 month post-marketing observational study.

AIMS/INTRODUCTION: This study evaluated the safety and effectiveness of dulaglutide in patients with type 2 diabetes in the real-world setting in Japan. MATERIALS AND METHODS: This prospective, observational post-marketing surveillance study was conducted for 36 months (July 2016 to July 2021) in Japan. Investigators reported data via an electronic data capture system. Data were analyzed by overall population and age group (<65, ≥65 to <75, and ≥75 years). RESULTS: The analysis population (N = 3,136) included 1,538 (49.04%), 869 (27.71%), and 729 (23.25%) patients aged <65 years, ≥65 to <75 years, and ≥75 years, respectively. Overall, 231 patients (7.37%) experienced ≥1 adverse drug reactions, with the highest frequency in the ≥75 years group. The most common adverse drug reactions were gastrointestinal disorders (n = 106; 3.38%). Severe hypoglycemia (n = 4; 0.13%), major adverse cardiovascular events (n = 4; 0.13%), and acute pancreatitis (n = 1; 0.03%) were uncommon. The mean glycated hemoglobin and bodyweight were reduced from baseline by -0.76% and -1.6 kg, respectively (last observation carried forward). The rate of dulaglutide continuation at 36 months was 58.03% overall and 59.43%, 63.13%, and 48.88% in the <65, ≥65 to <75, and ≥75 years groups, respectively. A factor analysis showed age ≥65 years was associated with a greater incidence of gastrointestinal adverse drug reactions as well as larger reductions in glycated hemoglobin and bodyweight. CONCLUSIONS: The current real-world data are in accordance with clinical trial findings and further confirm the safety and effectiveness of dulaglutide for elderly patients, whose numbers were limited in the clinical trials.

Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial.

BACKGROUND: Due to potential ethnic differences in the pathophysiology of type 2 diabetes, new therapeutics need to be evaluated in Japanese patients. We aimed to assess the safety and glycaemic efficacy of tirzepatide as an add-on treatment in Japanese patients with type 2 diabetes who had inadequate glycaemic control with stable doses of various oral antihyperglycaemic monotherapies. METHODS: This multicentre, open-label, parallel-group, randomised, phase 3 trial was conducted at 34 medical research centres and hospitals in Japan. Eligible participants were aged 20 years or older with inadequately controlled (HbA1c ≥7·0% to <11·0%) type 2 diabetes and were receiving oral antihyperglycaemic monotherapy (sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinedione, glinides, or SGLT2 inhibitors) for at least 3 months (stable dose for ≥8 weeks before screening), had a BMI of 23 kg/m2 or higher, and stable bodyweight (±5%) for at least 3 months before screening. After a 2-week screening and 2-week lead-in period, all participants were randomly assigned (1:1:1) to receive 5, 10, or 15 mg of tirzepatide, administered once per week subcutaneously for 52 weeks followed by a 4 week safety follow-up period, using a computer-generated random sequence and interactive web response system, stratified by oral antihyperglycaemic medication group. All participants started receiving 2·5 mg tirzepatide and doses were escalated by 2·5 mg every 4 weeks until the assigned dose was reached. The primary endpoint was safety and tolerability during 52 weeks of treatment, assessed as incidence of treatment-emergent adverse events in the modified intention-to-treat (mITT) population. This trial is registered with ClinicalTrials.gov, NCT03861039. FINDINGS: Between March 30, 2019, and Feb 16, 2021, with recruitment and enrolment continuing until Feb 4, 2020, 484 participants were assessed for eligibility and 443 were randomly assigned to receive at least one dose of tirzepatide (148 [33%] in the 5 mg group, 147 [33%] in the 10 mg group, and 148 [33%] in the 15 mg group). 398 (90%) participants completed the study and treatment. Most participants (343 [77%] of 443) had at least one treatment-emergent adverse event. Treatment-emergent adverse events were more frequent in the tirzepatide 15 mg group (125 [84%] of 148) than the 5 mg (109 [74%] of 148) and 10 mg groups (109 [74%] of 147). The most frequent treatment-emergent adverse events with tirzepatide were mild or moderate nasopharyngitis (75 [17%]), nausea (74 [17%]), constipation (54 [12%]), diarrhoea (51 [12%]), and decreased appetite (44 [10%]). At week 52, mean changes from baseline in bodyweight were -3·8 kg (SE 0·5; -5·1% reduction) in the 5 mg group, -7·5 kg (0·5; -10·1% reduction) in the 10 mg group, and -10·2 kg (0·5; -13·2% reduction) in the 15 mg group. Least squares mean HbA1c at baseline reduced from 8·5% (SE 0·1) to 6·0% (0·1) in the 5 mg tirzepatide group, from 8·6% (0·1) to 5·6% (0·1) in the 10 mg group, and from 8·6% (0·1) to 5·6% (0·1) in the 15 mg group at week 52. No adjudication-confirmed deaths were reported. INTERPRETATION: Tirzepatide was well tolerated as an add-on to oral antihyperglycaemic monotherapy in Japanese participants with type 2 diabetes and showed improvement in glycaemic control and bodyweight, irrespective of background oral antihyperglycaemic medication. Tirzepatide is a potential new treatment option for Japanese patients with type 2 diabetes that is inadequately controlled with single oral antihyperglycaemic medication. FUNDING: Eli Lilly and Company. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Utilization of glucagon-like peptide-1 receptor agonists and changes in clinical characteristics in patients with type 2 diabetes by chronic kidney disease stage in Japan: A descriptive observational study using a nationwide electronic medical records database.

AIM: To describe the utilization of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and changes in clinical characteristics before and after GLP-1 RA initiation in patients with type 2 diabetes (T2D) by chronic kidney disease (CKD) stage. MATERIALS AND METHODS: In this retrospective descriptive study using a nationwide electronic medical records database in Japan, we included patients with GLP-1 RA prescriptions from June 2010 to October 2019. Clinical characteristics at GLP-1 RA initiation, persistence proportion, and changes in clinical measurements after GLP-1 RA initiation were described for all patients and by CKD stage, defined by baseline estimated glomerular filtration rate (eGFR). RESULTS: We included 8049 patients. During the study period, the proportion of patients with T2D initiating GLP-1 RAs increased from 1.5% in 2010 to 3.3% in 2019. Also, the mean (95% confidence interval) of baseline age and eGFR ranged from 58.6 (56.7-60.4) to 66.3 (65.5-67.2) years and from 72.9 (68.0-77.9) to 64.0 (62.2-65.8) mL/min/1.73m2 , respectively. The persistence proportion at 12 months was 49.5% overall, 37.8% in T2D patients with CKD with a baseline eGFR of less than 30 mL/min/1.73m2 , and 34.6% in those undergoing dialysis. The rate of deterioration in renal function reduced after GLP-1 RA initiation. CONCLUSIONS: The utilization of GLP-1 RAs has been increasing over the past decade, and GLP-1 RAs have been used in patients with limited treatment options, such as the elderly or those with CKD. In T2D patients with CKD, the persistence proportion of GLP-1 RAs was not low, and the renal dysfunction may be moderated by GLP-1 RA initiation.

Safety and effectiveness of empagliflozin in Japanese patients with type 2 diabetes: interim analysis from a post-marketing surveillance study.

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are effective treatments for type 2 diabetes mellitus (T2DM). We present the interim findings of an ongoing post-marketing surveillance (PMS) study in Japanese patients with T2DM receiving empagliflozin.Research design and methods: This 3-year, prospective, observational, multicenter PMS evaluated the safety and effectiveness of empagliflozin in Japanese clinical practice. Patients with T2DM who had not been treated with empagliflozin before enrollment were eligible. Assessments, including the primary endpoint of incidence of adverse drug reactions (ADRs), were based on electronic case report forms (eCRF).Results: Of 8,180 registered patients from 1,103 sites, 7,618 patients had an eCRF including a follow-up visit and were treated (mean age, 58.8 years; 10.5% aged ≥75 years; 63.2% male; mean HbA1c, 8.01%; 41.8% with HbA1c ≥8.0%; 24.8% and 61.8% with at least mild hepatic and renal impairment, respectively). Mean treatment duration was 98.4 weeks; 644 (8.5%) patients had ≥1 ADR, including 8.5% of patients aged ≥75 years. Hypoglycemia, urinary tract infection, genital infections, volume depletion, diabetic ketoacidosis, and lower limb amputation occurred in 0.28%, 0.62%, 0.53%, 0.33%, 0%, and 0.03% of patients, respectively.Conclusions: The reported ADRs were consistent with the known safety profile of empagliflozin.Trial registration: ClinicalTrials.gov identifier: NCT02489942.

Cost-effectiveness Analysis of Empagliflozin in Japan Based on Results From the Asian subpopulation in the EMPA-REG OUTCOME Trial.

PURPOSE: The goal of this study was to assess the cost-effectiveness of empagliflozin in Japan based on the Asian subpopulation in the EMPA-REG OUTCOME trial. METHODS: The trial has shown a reduction in the risk for cardiovascular (CV) and renal events with empagliflozin in patients with type 2 diabetes mellitus and established CV disease. A cost-effectiveness analysis based on the overall population of the EMPA-REG OUTCOME trial was reported previously by using a lifetime discrete event simulation model. The same modeling frame was adapted to evaluate the cost-effectiveness of treatment with empagliflozin added to standard of care (SoC) compared with SoC alone in Japan. The time to relevant clinical events and the hazard ratios were derived from an Asian subpopulation in the EMPA-REG OUTCOME trial. The costs for each event were estimated from a Japanese medical claims database. Direct medical costs, life expectancy, and quality-adjusted life years (QALYs) were calculated from the public health care perspective. FINDINGS: Treatment with empagliflozin was estimated to increase life expectancy by 6.2 years and 2.7 QALYs, whereas total cost increased by 1,115,475 yen compared with treatment with SoC alone. The incremental cost-effectiveness ratio was 415,849 yen/QALY. In the sensitivity analysis, there was no case that was in excess of the reference value of the incremental cost-effectiveness ratio in the pilot introduction for price revision in Japan (ie, 5 million yen/QALY). IMPLICATIONS: Based on the Asian subpopulation in the EMPA-REG OUTCOME trial, our results suggest that empagliflozin added to SoC is highly cost-effective compared with SoC alone in Japan.

The impact of a low glycaemic index (GI) diet on simultaneous measurements of blood glucose and fat oxidation: A whole body calorimetric study.

OBJECTIVE: Low glycaemic index (GI) foods are known to minimize large fluctuations in blood glucose levels and have been suggested to increase fat oxidation. The objective of this study was to simultaneously investigate glucose excursion and substrate oxidation in a whole body calorimetre when Chinese male subjects were provided a low or high GI meal. MATERIALS/METHODS: In a randomized, controlled crossover non blind design, 12 healthy Chinese male adults (BMI 21.8 ± 1.3 kgm-2) attended two sessions consisting of either four low or high glycaemic meals (LGI vs HGI). Breakfast, lunch and snack were consumed in a whole body calorimetre while dinner was consumed at home. Daily changes in glycaemic response (GR) and postprandial GR responses were measured using a continuous glucose monitoring system. The GR was further calculated to obtain the incremental area under the curve (iAUC) for glucose concentrations. Glycaemic variability was calculated as mean amplitude of glycaemic excursion (MAGE). Substrate oxidation was calculated by measuring respiratory quotient and urine nitrogen excretion. RESULTS: After LGI meals in the whole body calorimetre, iAUC for glucose (P = 0.008) was lower compared to the HGI session. The HGI treatment produced a significantly greater MAGE than the LGI treatment over the 24 hour period (P < 0.001). Additionally, higher fat oxidation and lower carbohydrate oxidation were observed following breakfast and lunch when comparing LGI to HGI (P < 0.05). CONCLUSIONS: Consumption of LGI meals was capable of attenuating 24-hour blood glucose profiles and decreasing postprandial glucose excursions in healthy Asian males. Additionally, LGI mixed meals were able to promote fat oxidation over carbohydrate oxidation when compared to HGI mixed meals. The consumption of low GI meals may be a strategic approach in improving overall glycaemia and increasing fat oxidation in Asians consuming a high carbohydrate diet.

Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins.

BACKGROUND: There exists a subpopulation of T2DM in whom first-line doses of statin are insufficient for optimally reducing LDL-C, representing a major risk of CVD. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles leading to residual risks. METHODS: Lipid changes were assessed in a randomized, multicenter, 12-week, open-label study comparing a high-potency statin (10mg of atorvastatin or 1mg of pitavastatin) plus ezetimibe (EAT: n = 53) with a double dose of statin (20mg of atorvastatin or 2mg of pitavastatin) (DST: n = 56) in DM subjects who had failed to achieve the optimal LDL-C targets. Lipid variables were compared with a primary focus on LDL-C and with secondary focuses on the percentage of patients who reached the LDL-C targets and changes in the levels of RLP-C (remnant like particle cholesterol) and sd-LDL-C, two characteristic atherogenic risks of DM. RESULTS: The reduction of LDL-C (%), the primary endpoint, differed significantly between the two groups (-24.6 in EAT vs. -10.9 in DST). In the analyses of the secondary endpoints, EAT treatment brought about significantly larger reductions in sd-LDL-C (-20.5 vs. -3.7) and RLP-C (-19.7 vs. +5.5). In total, 89.4% of the patients receiving EAT reached the optimized treatment goal compared to 51.0% of the patients receiving DST. The changes in TC (-16.3 vs. -6.3) and non-HDL-C (-20.7 vs. -8.3) differed significantly between the two groups. CONCLUSION: Ezetimibe added to high-potency statin (10 mg of atorvastatin or 1 mg of pitavastatin) was more effective than the intensified-dose statin (20 mg of atorvastatin or 2 mg of pitavastatin) treatment not only in helping T2DM patients attain more LDL-C reduction, but also in improving their atherogenic lipid profiles, including their levels of sd-LDL-C and RLP-C. We thus recommend the addition of ezetimibe to high-potency statin as a first line strategy for T2DM patients with insufficient statin response. TRIAL REGISTRATION: The UMIN Clinical Trials Registry UMIN000002593.

Glycaemic index and glycaemic load of selected popular foods consumed in Southeast Asia.

The objective of the present study was to determine the glycaemic index (GI) and glycaemic load (GL) values of standard portion sizes of Southeast Asian traditional foods. A total of fifteen popular Southeast Asian foods were evaluated. Of these foods, three were soft drinks, while the other twelve were solid foods commonly consumed in this region. In total, forty-seven healthy participants (eighteen males and twenty-nine females) volunteered to consume either glucose at least twice or one of the fifteen test foods after a 10-12 h overnight fast. Blood glucose concentrations were analysed before consumption of the test food, and 15, 30, 45, 60, 90 and 120 min after food consumption, using capillary blood samples. The GI value of each test food was calculated by expressing the incremental area under the blood glucose response curve (IAUC) value of the test food as a percentage of each participant's average IAUC value, with glucose as the reference food. Among the fifteen foods tested, six belonged to low-GI foods (Ice Green Tea, Beehoon, Pandan Waffle, Curry Puff, Youtiao and Kaya Butter Toast), three belonged to medium-GI foods (Barley Drink, Char Siew Pau and Nasi Lemak), and the other six belonged to high-GI foods (Ice Lemon Tea, Chinese Carrot Cake, Chinese Yam Cake, Chee Cheong Fun, Lo Mai Gai and Pink Rice Cake). The GI and GL values of these traditional foods provide valuable information to consumers, researchers and dietitians on the optimal food choice for glycaemic control. Moreover, our dataset provides GI values of fifteen foods that were not previously tested extensively, and it presents values of foods commonly consumed in Southeast Asia.

The impact of eating methods on eating rate and glycemic response in healthy adults.

Singapore is an island state that is composed of three major ethnic groups, namely Chinese, Malay and Indian. Its inhabitants consume food either using chopsticks (Chinese), fingers (Malay and Indian) or spoon (Chinese, Malay and Indian). Previous work by our group showed that the degree of mastication significantly influenced the glycemic response. The degree of mastication in turn may depend on the eating method as the amount of food taken per mouthful and chewing time differs between eating methods. Eleven healthy volunteers came in on six non-consecutive days to the laboratory and evaluated three methods of eating white rice (spoon, chopsticks and fingers) once and the reference food (glucose solution) three times in a random order. Their glycemic response (GR) was measured for the subsequent 120 min. Mastication parameters were determined using surface electrode electromyography. The GR to white rice eating with chopsticks was significantly lower than spoon. The GI of eating rice with chopsticks was 68 which is significantly lower than eating with spoon (GI=81). However there were no differences between fingers and spoon, and between fingers and chopsticks either in GR 120 min or GI. The inter-individual number of mouthful, number of chews per mouthful, chewing time per mouthful and the total time taken to consume the whole portion of rice were significantly different between spoon and chopsticks groups. Significant correlations between the number of mouthful to take the entire portion of rice and amount of rice per mouthful during mastication and the GR were observed for eating rice with spoon and chopsticks, but not for fingers. The results suggest that individual differences in number of mouthful and amount of rice per mouthful may be two of the causes for inter-individual differences in the GR between spoon and chopsticks. The present study suggests that eating rice with different feeding tools has different chewing times and amount of food taken per mouthful and then alters the GI of the rice.

A Case of Rathke's Cleft Cyst Associated with Transient Central Adrenal Insufficiency and Masked Diabetes Insipidus.

A 73-year-old woman admitted to our hospital because of headache, poor appetite, malaise, weight loss, and vomiting was found to have central adrenal insufficiency and thyrotoxicosis due to silent thyroiditis. Polyuria developed after replacement with glucocorticoid (masked diabetes insipidus), which was controlled with nasal administration of desmopressin. Magnetic resonance imaging of the brain showed a large cystic pituitary mass (18 × 18 × 12 mm) extending suprasellarly to the optic chiasm. Transsphenoidal surgery revealed that the pituitary tumor was Rathke's cleft cyst. Following surgery, replacement with neither glucocorticoid nor desmopressin was needed any more. Therefore, it is suggested that Rathke's cleft cyst is responsible for the masked diabetes insipidus and the central insufficiency. Furthermore, it is speculated that thyrotoxicosis with painless thyroiditis might induce changes from subclinical adrenal insufficiency to transiently overt insufficiency.

[Criteria of obesity and obesity disease in Japan].

In this paper, we review the definition and the criteria of obesity and obesity disease in Japan. Obesity is defined for the subjects who are more than 25kg/m2 of body mass index (BMI). When such subjects have any diseases associated with obesity, they are diagnosed as obesity disease by the criteria decided in Japan Society for the Study of Obesity. According to the guideline for treatment and management of obesity disease 2006, obesity diseases are classified in two types of the following; one type is based on the qualitative changes of adipocytes (obesity disease with predominantly visceral fat or, so called, a type of metabolic syndrome), and the other is done on the quantative changes (obesity disease with predominantly subcutaneous fat). Obesity diseases with predominantly visceral fat are associated with diabetes mellitus, dyslipidemia, hypertension, and so far. On the other hand, obesity diseases with predominantly subcutaneous fat tend to induce osteoarthritis, obstructive sleep apnea syndrome (OSAS), and so far.

Circulating levels of ganglioside GM3 in metabolic syndrome: A pilot study.

BACKGROUND: Insulin resistance is a characteristic feature of metabolic syndrome. Ganglioside GM3 [α-Neu5Ac-(2-3)-ß-Gal-(1-4)-ß-Glc-(1-1)-ceramide] may impair insulin sensitivity in adipose tissue. We investigated the relationship between serum GM3 levels and adiposity indices, as well as between serum GM3 levels and metabolic risk variables. METHODS: Study 1: we assessed serum GM3 levels in normal subjects and in patients with hyperglycemia and/or hyperlipidemia (HL). Study 2: we investigated the relationship between serum GM3 levels and metabolic risk variables in patients with type 2 diabetes. RESULTS: Study 1: serum GM3 levels were higher in hyperglycemic patients (1.4-fold), hyperlipidemic patients (1.4-fold) and hyperglycemic patients with hyperlipidemia (1.6-fold), than in normal subjects. Study 2: serum GM3 levels were significantly increased in type 2 diabetic patients with severe obesity (visceral fat area (VFA) >200 cm(2), BMI > 30). The GM3 level was positively correlated with LDL-c (0.403, p = 0.012) in type 2 diabetes mellitus, but not affected by blood pressure. In addition, the high levels of small dense LDL (>10 mg/dL) were associated with the elevation of GM3. CONCLUSIONS: Serum GM3 levels was affected by glucose and lipid metabolism abnormalities and by visceral obesity. GM3 may be a useful marker for severity of metabolic syndrome.