Therapy-Related Satisfaction and Quality of Life for Japanese People with Diabetes Using Rapid-Acting Insulin Analogs: A Web-Based Survey.

INTRODUCTION: People with diabetes require insulin to regulate blood glucose (BG); rapid-acting insulin analogs (RAIA) represent one approach for BG management. New fast-acting RAIA administered at the start of a meal suppress postprandial BG better than conventional RAIA. New RAIA are expected to confer higher treatment satisfaction and improved quality of life (QOL) than conventional RAIA. METHODS: This cross-sectional, web-based survey in Japan (November 2022) included people with diabetes (type 1/2), aged ≥ 18 years, registered in the Rakuten Insight Diabetes Panel, using new and/or conventional RAIA. RAIA-specific satisfaction was evaluated by questions on RAIA use (scores: 1 [not at all satisfied]; 7 [very satisfied]) and QOL by the Diabetes Therapy-Related (DTR)-QOL questionnaire (scores: 0-100, 100 = best) for the whole population (primary endpoint) and for new versus conventional RAIA users (secondary endpoint). Multiple regression models were used to compare new versus conventional RAIA users. RESULTS: The analysis population comprised 217 people with diabetes (new RAIA, n = 109; conventional RAIA, n = 108). Mean (standard deviation) RAIA-specific satisfaction scores ranged from 5.1 (1.2) to 5.4 (1.2); DTR-QOL total score was 51.6 (20.4). RAIA satisfaction scores were numerically higher for new versus conventional RAIA users; no difference in DTR-QOL total score was observed. DTR-QOL satisfaction with treatment domain score was significantly higher in new versus conventional RAIA users (least squares mean difference [standard error]: 7.3 [3.1]; 95% confidence interval: 1.2, 13.4; P = 0.0197). RAIA-specific satisfaction was higher among patients who discussed BG sufficiently with their doctor versus those who did not. CONCLUSIONS: New RAIA users have greater treatment satisfaction than conventional RAIA users. QOL was similar among new and conventional RAIA users, except for satisfaction with treatment, which was significantly higher among new RAIA users. Detailed explanations from the doctor to the person with diabetes about the relationship between new RAIA and BG status are essential. A graphical plain language summary is available with this article.

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.

Long-term Efficacy and Safety of Ultra Rapid Lispro in Japanese Patients With Type 1 Diabetes: Subpopulation Analysis of the 52-Week PRONTO-T1D Study.

INTRODUCTION: The PRONTO-T1D study evaluated the efficacy and safety of ultra rapid lispro (URLi) versus lispro in adults with type 1 diabetes mellitus. After 26 weeks of treatment, mealtime and postmeal URLi provided effective and comparable glycemic control in a prespecified subpopulation analysis of Japanese patients from PRONTO-T1D. We present the results of a 52-week study which evaluated the long-term efficacy and safety of URLi in Japanese patients. METHODS: After an 8-week lead-in period to optimize basal insulin treatment, Japanese patients were randomized to one of three treatment groups: the 52-week double-blind mealtime URLi (n = 62) or mealtime lispro (n = 59) group, respectively, or the 52-week open-label postmeal URLi (n = 46) group. RESULTS: At week 52, there were no statistically significant differences in change from baseline in hemoglobin A1c (HbA1c) between Japanese patients on URLi and those on lispro; the least-squares mean (LSM) treatment difference was 0.04% (95% confidence interval [CI] - 0.18, 0.25) between mealtime URLi and lispro, and 0.04% (95% CI - 0.19, 0.28) between postmeal URLi and mealtime lispro. No significant between-group differences were observed in the number of patients achieving the HbA1c target of < 7.0% (20.0, 30.5 and 16.3% of those on mealtime URLi, mealtime lispro and postmeal URLi, respectively). Daily average blood glucose levels in the 10-point self-monitored blood glucose profiles at week 52 were similar between treatments. However, compared with lispro, lower blood glucose levels were observed for the mealtime URLi group at the morning 1- and 2-h postmeal time points with LSM differences of - 32.7 mg/dL (- 1.82 mmol/L) (p = 0.005) and - 23.2 mg/dL (- 1.29 mmol/L) (p = 0.029), respectively. There were no significant treatment differences in the incidences of treatment-emergent adverse events, documented hypoglycemia and severe hypoglycemia; however, the rate of documented hypoglycemia was lower in the mealtime URLi arm compared with the lispro arm. CONCLUSIONS: Overall glycemic control and improved postprandial glucose via self-monitoring was maintained in Japanese patients following 52 weeks of treatment with URLi versus lispro, including postmeal URLi administration. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03214367.

Determinants and impact of physical impairment in patient-reported outcomes among older patients with type 2 diabetes mellitus in Japan.

OBJECTIVE: To investigate the predictive factors associated with physical impairment among older patients with type 2 diabetes mellitus (T2DM) in Japan and to examine the potential impact of physical impairment on patient-reported health outcomes in this population. METHODS: A cross-sectional analysis was conducted using patient-reported data from the 2012-2014 Japan National Health and Wellness Survey. Physical impairment was measured using the Physical Component Summary (PCS) score of the Short-Form 36-Item Health Survey (SF-36) three-component model (using Japanese norms). Older T2DM patients (≥65 years old; n = 1511) were dichotomized into physically impaired (PCS ≤ 25th percentile; n = 378) and non-physically impaired (PCS > 25th percentile; n = 1133). Work productivity (absenteeism, presenteeism and overall work impairment), activity impairment and healthcare resource utilization were compared between these groups. RESULTS: Age, female sex, low and high body mass index (BMI), diabetes-related complications, cardiovascular events, unawareness of having hypoglycemic events in the past 3 months, and lack of regular exercise were significant factors associated with physical impairment in multivariable analysis. The physically impaired group reported significantly more regular outpatient visits (13.48 vs. 10.16, respectively, p < .001), 1% or greater absenteeism (16.7% vs. 4.1%, p = .005), greater presenteeism (27.8% vs. 12.2%, p = .001), overall work impairment (30.0% vs. 13.0%, p = .001) and overall activity impairment (39.5% vs. 17.2%, p < .001) than the non-physically-impaired group after adjusting for covariates. CONCLUSIONS: This study identified age, BMI, diabetes-related comorbidities, history of cardiovascular events and lack of exercise as key predictors associated with physical impairment in older patients with T2DM in Japan, which predicted low work productivity as well as activity impairment. This study provides support that physical impairment in patients with T2DM may lead to low work productivity and activity impairment.Supplemental data for this article is available online at https://doi.org/10.1080/03007995.2020.1846170.

Ultra-Rapid Lispro Efficacy and Safety Compared to Humalog® in Japanese Patients with Type 1 Diabetes: PRONTO-T1D Subpopulation Analysis.

INTRODUCTION: We evaluated the efficacy and safety of ultra-rapid lispro (URLi) in comparison to lispro in a subgroup analysis of Japanese adults with type 1 diabetes mellitus from the phase 3 PRONTO-T1D trial. METHODS: After an 8-week lead-in to optimize basal insulin treatment, patients were randomized to 52-week double-blind mealtime URLi or lispro, or 26-week open-label postmeal URLi. The primary endpoint was change in hemoglobin A1c (HbA1c) from baseline (week 0) to week 26 between mealtime URLi and lispro. The multiplicity adjusted objectives were 1- and 2-h postprandial glucose (PPG) excursions after a meal test between mealtime URLi and lispro, and change in HbA1c from baseline to week 26 between postmeal URLi and mealtime lispro. RESULTS: This manuscript presents pre-specified exploratory analyses of 26-week data from Japanese patients randomized to double-blind URLi (n = 62) or lispro (n = 59), or open-label URLi (n = 46). Mean baseline HbA1c levels were 7.52% for mealtime URLi, 7.44% for lispro, and 7.51% for postmeal URLi at randomization. At week 26, the least squares mean (LSM) difference compared to lispro was 0.04% (95% confidence interval [CI] - 0.14 to 0.22) for mealtime URLi, and 0.16% (95% CI - 0.04 to 0.35) for postmeal URLi. In comparison to lispro, mealtime URLi resulted in statistically significantly lower 1- and 2-h PPG excursions during the mixed-meal tolerance test. LSM differences were - 40.5 mg/dL, 95% CI - 59.5 to 21.4 (- 2.25 mmol/L, 95% CI - 3.3 to - 1.2) for 1-h PPG excursions and - 51.7 mg/dL, 95% CI - 81.7 to - 21.8 (- 2.87 mmol/L, 95% CI - 4.5 to - 1.2) for 2-h PPG excursions at week 26. There were no significant treatment differences in rates of severe/overall hypoglycemia, or incidence of treatment-emergent adverse events. CONCLUSIONS: Mealtime and postmeal URLi provide effective and comparable glycemic control in Japanese patients. Mealtime URLi demonstrated more effective PPG control compared to lispro. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03214367.

Ultra-Rapid Lispro Efficacy and Safety Compared to Humalog® in Japanese Patients With Type 2 Diabetes: PRONTO-T2D Subpopulation Analysis.

INTRODUCTION: The aim of this study was to evaluate the efficacy and safety of ultra-rapid lispro (URLi) versus lispro in a subgroup analysis of Japanese adults with type 2 diabetes mellitus (T2DM) from the phase 3 PRONTO-T2D trial. METHODS: After an 8-week lead-in period during which patients transitioned to insulin lispro 3 times a day before main meals in association with basal insulin (glargine or degludec), the patients were randomized to 26 weeks of double-blind URLi or lispro injected immediately prior to meals. The primary endpoint was change in hemoglobin A1c (HbA1c) from baseline to week 26 between URLi and lispro. The multiplicity-adjusted objectives were 1- and 2-h postprandial glucose (PPG) excursions after a test meal and change in HbA1c from baseline to week 26 in the URLi and lispro groups. RESULTS: Results were obtained from prespecified exploratory analyses of 26-week data in Japanese patients randomized to receive URLi (n = 47) or lispro (n = 46). Mean baseline HbA1c levels significantly improved during the lead-in period to a baseline value of 7.50% and 7.60% in patients subsequently randomized to the URLi and lispro treatment groups, respectively. At week 26, the least squares mean (LSM) difference in HbAc1 between the URLi and lispro groups was 0.13% (95% confidence interval [CI] - 0.12 to 0.39) (1.4 mmol/mol, 95% CI - 1.3 to 4.2). Although there were no significant differences in PPG excursions at any time-point, numerically smaller PPG excursions were consistently observed from 30 min to 3 h during the mixed-meal tolerance test in patients on URLi compared to those on lispro. LSM differences in PPG excursions at week 26 were - 10.5 mg/dL (95% CI - 32.7 to 11.7) (- 0.58 mmol/L, 95% CI - 1.82 to 0.65) at 1 h and - 14.9 mg/dL (95% CI - 40.3 to 10.5) (- 0.83 mmol/L, 95% CI - 2.24 to 0.58) at 2 h. There were no significant differences between treatments in rates of severe/overall hypoglycemia or incidence of treatment-emergent adverse events. CONCLUSIONS: URLi administered as prandial insulin in combination with basal insulin provides effective glycemic control when administered immediately before a meal in Japanese patients with T2DM. URLi was well tolerated in this population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03214380.

Ultra-Rapid Lispro results in accelerated insulin lispro absorption and faster early insulin action in comparison with Humalog® in Japanese patients with type 1 diabetes.

AIMS/INTRODUCTION: Ultra-rapid lispro (URLi) is a novel ultra-rapid mealtime insulin. This study compared the pharmacokinetic and glucodynamic profiles, safety, and tolerability of URLi and lispro (Humalog® ) in Japanese patients with type 1 diabetes mellitus. MATERIALS AND METHODS: This was a phase I, single center, randomized, patient- and investigator-blind, two-period, cross-over study. A total of 31 patients received a single subcutaneous 15-U dose of URLi or lispro before undergoing a euglycemic clamp procedure. Primary pharmacokinetic endpoints were the time to early half-maximal drug concentration and the area under the concentration versus time curve from 0 to 30 min postdose. The glucodynamic endpoints were the time to early half-maximal glucose infusion rate before time to maximum glucose infusion rate, and the time to onset of insulin action. RESULTS: URLi showed accelerated insulin lispro absorption compared with lispro, as shown by a decrease of 56% (URLi: 10.2 min, lispro: 23.3 min; P < 0.0001) in the early half-maximal drug concentration, and a 2.4-fold increase in the area under the concentration versus time curve from 0 to 30 min (P < 0.0001). The duration of insulin lispro exposure was 88 min shorter after URLi administration compared with lispro. URLi reduced the early half-maximal glucose infusion rate before time to maximum glucose infusion rate and the time to onset of insulin action significantly compared with lispro. The glucose infused within the first 30 min of the clamp was 2.16-fold greater with URLi compared with lispro. There was no difference in total exposure or glucose infused between treatments. All treatment-emergent adverse events were mild/moderate in severity. CONCLUSIONS: In Japanese type 1 diabetes mellitus patients, URLi showed accelerated insulin lispro absorption, reduced late exposure, overall shorter duration and faster early insulin action compared with lispro.

Open-label, randomized study comparing basal insulin peglispro and insulin glargine, in combination with oral antihyperglycemic medications, in insulin-naïve Asian patients with type 2 diabetes.

INTRODUCTION: The present phase 3, randomized, open-label study compared the efficacy and safety of basal insulin peglispro with insulin glargine after 26 weeks of treatment when added to oral antihyperglycemic medications in insulin-naïve Asian patients with type 2 diabetes. MATERIALS AND METHODS: The primary objective was to show non-inferiority of the change in glycated hemoglobin from baseline to 26 weeks. RESULTS: At 26 weeks, insulin peglispro was non-inferior to glargine, meeting the primary objective. Patients receiving insulin peglispro (n = 192) showed a greater reduction in glycated hemoglobin from baseline compared with glargine (n = 196); -1.6 vs -1.4%, P = 0.005) and in fasting serum glucose (-61.2 vs -54.8 mg/dL, P = 0.02). A significantly higher proportion of patients receiving insulin peglispro achieved glycated hemoglobin <7% (57 vs 44%, P = 0.012). Insulin peglispro patients showed significantly less weight gain from baseline (1.1 vs 1.6 kg, P = 0.03). Relative rates (insulin peglispro/glargine) of total and nocturnal hypoglycemia through 26 weeks were 1.06 (P = 0.67) and 0.7 (P = 0.10), respectively. Significantly more insulin peglispro-treated patients experienced adverse events compared with glargine-treated patients (P = 0.042). Alanine aminotransferase and aspartate aminotransferase were significantly increased from baseline with insulin peglispro compared with glargine at week 26 (3.5 vs -4.6 IU/L and 2.8 vs -1.5 IU/L, respectively; P < 0.001). The incidence of injection site reactions was low and did not differ between the treatments. DISCUSSION: Insulin peglispro provided better glycemic control vs glargine with no differences in hypoglycemia and increased aminotransferases in insulin-naïve Asian patients with type 2 diabetes.

Insulin lispro 25/75 and insulin lispro 50/50 as starter insulin in Japanese patients with type 2 diabetes: subanalysis of the CLASSIFY randomized trial.

In Japan, premixed insulins are commonly used as starter insulin for type 2 diabetes. This subpopulation analysis assessed the efficacy and safety of twice-daily LM25 (25% insulin lispro/75% insulin lispro protamine) and LM50 (50% insulin lispro/50% insulin lispro protamine) as starter insulin in Japanese subjects, and compared these results with the whole-trial populations of East Asian subjects. In this subpopulation analysis of an open-label, phase 4, randomized trial (CLASSIFY), Japanese subjects received LM25 (n = 88) or LM50 (n = 84) twice-daily for 26 weeks. The primary outcome was change from baseline at Week 26 in glycated hemoglobin (HbA1c). Results for Japanese subjects were generally similar to those for the whole-trial population. Similar changes from baseline in HbA1c were observed for LM25 and LM50 groups (least squares [LS] mean difference [95% confidence interval] of LM25 - LM50 = 0.13 [-0.16, 0.41]%, 1.42 [-1.75, 4.48] mmol/mol, p = 0.388). More LM50-treated subjects than LM25-treated subjects achieved HbA1c targets of <7.0% (59.5% versus 43.2%; p = 0.034) or ≤6.5% (45.2% versus 28.4%; p = 0.027). The reduction in postprandial blood glucose concentrations after morning and evening meals was statistically significantly greater for LM50 than for LM25. The incidence of both hypoglycemia and treatment-emergent adverse events were similar between treatment groups. Both LM25 and LM50 twice daily appear to be effective and well tolerated as starter insulin, although LM50 might be more effective for Japanese type 2 diabetes patients.

Impact of diet on the efficacy of insulin lispro mix 25 and insulin lispro mix 50 as starter insulin in East Asian patients with type 2 diabetes: Subgroup analysis of the Comparison Between Low Mixed Insulin and Mid Mixed Insulin as Starter Insulin For Patients with Type 2 Diabetes Mellitus (CLASSIFY Study) randomized trial.

AIMS/INTRODUCTION: The pathophysiology of diabetes differs between Asian and Western patients in many ways, and diet is a primary contributor. The present study examined the effect of diet on the efficacy of 25% insulin lispro/75% insulin lispro protamine suspension (LM25) and 50% insulin lispro/50% insulin lispro protamine suspension (LM50) as starter insulin in Chinese and Japanese patients with type 2 diabetes and inadequate glycemic control with oral antidiabetic medication. MATERIALS AND METHODS: This was a predefined subgroup analysis of a phase 4, open-label, 26-week, parallel-arm, randomized (computer-generated random sequence) trial (21 January 2013 to 22 August 2014). Nutritional intake was assessed from food records kept by participants before study drug administration. Outcomes assessed were changes from baseline in self-monitored blood glucose, 1,5-anhydroglucitol and glycated hemoglobin. RESULTS: In total, 328 participants were randomized to receive twice-daily LM25 (n = 168) or LM50 (n = 160). Median daily nutritional intake (by weight and percentage of total energy) was 230.8 g of carbohydrate (54%), 56.5 g of fat (31%) and 66 g of protein (15%). Improvements in self-monitored blood glucose were significantly greater (P ≤ 0.028) in the LM50 group than in the LM25 group, regardless of nutritional intake. When carbohydrate (by weight or percentage energy) or fat (by weight) intake exceeded median levels, LM50 was significantly more efficacious than LM25 (P ≤ 0.026) in improving 1,5-anhydroglucitol and glycated hemoglobin. CONCLUSIONS: Glycemic control improved in both LM25 and LM50 groups, but LM50 was significantly more efficacious under certain dietary conditions, particularly with increased carbohydrate intake.

Efficacy and safety of growth hormone replacement therapy in Japanese adults with growth hormone deficiency: a post-marketing observational study.

This large-scale observational study examined the long-term effectiveness and safety of growth hormone (GH) replacement therapy for adult GH deficiency (GHD) in Japanese clinical practice using the Hypopituitary Control and Complications Study database. The study included 402 GHD patients for safety analyses and a subset of 209 patients (149 adult-onset and 60 childhood-onset GHD patients) who had not previously received GH replacement therapy for the efficacy analyses. Data on clinical, metabolic, quality of life (QoL) characteristics, and all adverse events (AEs) were collected at baseline (start of GH treatment), 6 months, 1 year and 2 years. Over the observation period, there were improvements from baseline in insulin-like growth factor-I standard deviation scores (P<0.001), although the changes in metabolic parameters were minimal. QoL (Short Form-36) Z-scores significantly increased from baseline in both onset-type groups for several subscale domains (P<0.05). A total of 145 (36.1%) patients experienced ≥1 AE. Common AEs were hyperlipidaemia (2.7%) and hyperinsulinaemia (2.2%). Some patients experienced recurrent hypothalamic/pituitary tumour (events per 1000 patient-years: 2.78), new benign (0.93), malignant tumour (10.28) or other new tumour (0.93), new diabetes mellitus (7.45), and new stroke (3.71). Seven patients died during the observation period. Our safety findings are inconclusive about the associations between GH replacement and AEs, although the incidence of diabetes mellitus and cardiovascular events are similar to those reported in the Japanese general population. In conclusion, the key beneficial effects of GH replacement therapy for GHD are observed in routine clinical practice in Japan.

CCAAT/enhancer binding protein alpha maintains the ability of insulin-stimulated GLUT4 translocation in 3T3-C2 fibroblastic cells.

In 3T3-L1 preadipocytes, hormonal induction causes adipose conversion and facilitates the expression of insulin-sensitive glucose transporter, GLUT4. Evidence has accumulated that, in 3T3-L1 preadipocytes, the formation of GLUT4 storage vesicle and its translocation to plasma membrane precede both lipid accumulation and expression of GLUT4 and C/EBPalpha, a key transcription factor for adipose differentiation. On the other hand, 3T3-C2 fibroblastic cells, a subline of 3T3-L1, follow adipogenic process till mitotic clonal expansion stage (2 days after hormonal induction), but do not proceed to terminal differentiation stage (8 days after the induction), resulting in a lack of adipose conversion and GLUT4 expression. Here we show that, when myc-tagged GLUT4 was retrovirally expressed in 3T3-C2 cells, insulin-stimulated GLUT4 translocation did occur on day 2 after the induction. On day 8 after the induction, however, neither GLUT4 translocation nor the expression of C/EBPalpha was observed. We also created 3T3-C2 cells stably expressing both myc-tagged GLUT4 and C/EBPalpha, demonstrating that co-expressed cells showed insulin-stimulated GLUT4 translocation on day 8 after the induction, as well as adipose conversion coupling with PPARgamma expression. Our results provide evidence that C/EBPalpha has the potential to maintain the ability of insulin-stimulated GLUT4 translocation in C/EBPalpha-deficient 3T3-C2 fibroblastic cells.