Efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes: A subgroup analysis by baseline variables in the PIONEER 9 and PIONEER 10 trials.

AIMS/INTRODUCTION: To assess the impact of baseline characteristics on the efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: In the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) 9 and 10 trials, Japanese patients were randomized to once-daily oral semaglutide (3, 7, or 14 mg) or a comparator (placebo or once-daily subcutaneous liraglutide 0.9 mg in PIONEER 9; once-weekly subcutaneous dulaglutide 0.75 mg in PIONEER 10) for 52 weeks, with 5 weeks of follow up. An exploratory analysis grouped patients in each trial according to baseline glycated hemoglobin (HbA1c ; ≤8.0, >8.0-≤9.0, or >9.0%), body mass index (<25, ≥25-<30, or ≥30 kg/m2 ) and, for PIONEER 10 only, by background medication (sulfonylurea, glinide, thiazolidinedione, α-glucosidase inhibitor, sodium-glucose cotransporter 2 inhibitor). Efficacy (changes from baseline to week 26 in HbA1c and bodyweight) and safety were assessed. RESULTS: Seven hundred and one patients were included (PIONEER 9: N = 243; PIONEER 10: N = 458). In both trials, HbA1c reductions increased as baseline HbA1c increased; there were no other apparent patterns between the variables investigated and HbA1c or bodyweight changes. There was one statistically significant subgroup interaction between baseline HbA1c and estimated treatment differences in bodyweight change for oral semaglutide 14 mg versus placebo in PIONEER 9 (P = 0.0286). Baseline HbA1c , baseline body mass index and background medication did not appear to affect the proportions of patients reporting adverse events. CONCLUSIONS: Oral semaglutide is effective across a range of baseline subgroups of Japanese patients with type 2 diabetes, with no unexpected safety findings.

Efficacy and safety of oral semaglutide by baseline age in Japanese patients with type 2 diabetes: A subgroup analysis of the PIONEER 9 and 10 Japan trials.

A post-hoc exploratory analysis of the PIONEER 9 and 10 trials evaluated the effect of baseline age (<65 and ≥65 years) on the efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes. In PIONEER 9 and 10, patients were randomized to once-daily oral semaglutide (3, 7 or 14 mg) or a comparator (placebo or once-daily subcutaneous liraglutide 0.9 mg [PIONEER 9]; once-weekly subcutaneous dulaglutide 0.75 mg [PIONEER 10]) for 52 weeks, with 5 weeks' follow-up. In total, 701 patients were included (PIONEER 9: N = 243; PIONEER 10: N = 458). Glycaemic efficacy of oral semaglutide was similar in Japanese patients aged <65 years compared with those ≥65 years, and there did not appear to be a clear pattern between age subgroup and body weight changes. Across treatment arms, adverse events generally occurred in greater proportions of patients aged ≥65 versus <65 years. There was generally a higher rate of premature trial product discontinuation because of adverse events in the older age group. These results indicate that oral semaglutide is efficacious in Japanese patients irrespective of age.

Efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes: A post hoc subgroup analysis of the PIONEER 1, 3, 4 and 8 trials.

AIMS: To evaluate, through exploratory post hoc subgroup analyses, the efficacy and safety of oral semaglutide versus comparators in Japanese patients enrolled in the global PIONEER 1, 3, 4 and 8 clinical trials. MATERIALS AND METHODS: Patients were randomized to once-daily oral semaglutide 3, 7 or 14 mg or comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg). Change from baseline in glycated haemoglobin (HbA1c) and body weight, and proportions of patients attaining HbA1c <7.0% (53 mmol/mol) and body weight loss ≥5%, were analysed at week 26 for all Japanese patients in each trial separately using the treatment policy estimand (regardless of treatment discontinuation or rescue medication use). Adverse events (AEs) were analysed descriptively. RESULTS: Reductions in HbA1c from baseline in Japanese patients were 1.0% to 1.2% (11.3 mmol/mol to 13.3 mmol/mol) and 1.4% to 1.7% (15.7 mmol/mol to 18.3 mmol/mol) for oral semaglutide 7 mg and 14 mg, respectively. HbA1c reductions were similar or greater than with comparators. Body weight reductions were 1.0% to 2.7% and 3.7% to 4.7% for oral semaglutide 7 mg and 14 mg, respectively, and were generally greater with oral semaglutide than comparators. As expected, the main class of AEs was gastrointestinal, and these AEs comprised most commonly mild-to-moderate constipation, nausea and diarrhoea. CONCLUSIONS: Oral semaglutide appears efficacious and well tolerated in Japanese patients across the type 2 diabetes spectrum.

Efficacy and safety of fast-acting insulin aspart versus insulin aspart in children and adolescents with type 1 diabetes from Japan.

The aim of this post-hoc subgroup analysis, which was based on data from the treat-to-target, 26-week, onset 7 trial, was to confirm the efficacy and safety of fast-acting insulin aspart (faster aspart) versus insulin aspart (IAsp), both in combination with basal insulin degludec, in children and adolescents from Japan with type 1 diabetes (T1D). Of the onset 7 trial population (1 to <18 years; N = 777), 66 participants from Japan (65 Asian and one non-Asian) were randomized to mealtime faster aspart (n = 24), post-meal faster aspart (n = 19), or IAsp (n = 23). Data for the subgroup from Japan were analysed descriptively. Change from baseline in hemoglobin A1c 26 weeks after randomization was 0.23%, 0.74%, and 0.39%, for mealtime faster aspart, post-meal faster aspart, and IAsp respectively. Change from baseline in 1-h post-prandial glucose increment (based on 8-point self-measured blood glucose profiles) showed numerical differences in favor of mealtime faster aspart versus IAsp at breakfast (-30.70 vs. -2.88 mg/dL) and over all meals (-18.21 vs. -5.55 mg/dL). There were no clinically relevant numerical differences between treatment arms in the overall rate of severe or blood glucose-confirmed hypoglycemia. At week 26, mean total insulin dose was 1.119 U/kg/day for mealtime faster aspart, 1.049 U/kg/day for post-meal faster aspart, and 1.037 U/kg/day for IAsp. In conclusion, in children and adolescents with T1D from Japan, mealtime and post-meal faster aspart with insulin degludec was efficacious in controlling glycemia without additional safety concerns versus IAsp.

Effect of Orally Administered Semaglutide Versus Dulaglutide on Diabetes-Related Quality of Life in Japanese Patients with Type 2 Diabetes: The PIONEER 10 Randomized, Active-Controlled Trial.

INTRODUCTION: In the randomized Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) 10 trial, once-daily orally administered semaglutide-the first oral glucagon-like peptide 1 receptor agonist (GLP-1RA)-was similarly tolerated with comparable (at 7 mg) or better (at 14 mg) efficacy versus the injectable GLP-1RA dulaglutide 0.75 mg. Health-related quality of life (HRQoL) in PIONEER 10 was assessed using the Japanese-specific Diabetes Therapy-Related Quality of Life (DTR-QoL) questionnaire. METHODS: The DTR-QoL comprises 29 questions, providing four domain and total scores. Answers were converted to a score between 0 and 100, with higher scores indicating greater HRQoL. Two estimands were prespecified: treatment policy (regardless of treatment discontinuation or rescue medication use) and trial product (assuming on treatment without rescue medication) in all randomized patients. Outcomes were assessed at weeks 26 and 52. RESULTS: Mean baseline DTR-QoL domain scores were similar between treatment arms and were generally lower (giving more scope for improvement) for "anxiety and dissatisfaction with treatment" (62.1-65.3) and "satisfaction with treatment" (53.9-57.9) than "burden on social activities and daily activities" (76.5-77.7) and "hypoglycemia" (83.5-88.2). Using the treatment policy estimand, orally administered semaglutide 7 and 14 mg improved HRQoL versus dulaglutide 0.75 mg for the total score (estimated mean change from baseline [CfB] 7.3 and 8.1 vs 3.3; estimated treatment difference [ETD] 3.9 and 4.8) and the "anxiety and dissatisfaction with treatment" domain (CfB 9.7 and 10.9 vs 3.7; ETD 6.0 and 7.2) at week 52. Orally administered semaglutide 14 mg improved the "satisfaction with treatment" domain versus dulaglutide 0.75 mg (CFB 13.8 vs 5.7; ETD 8.1). DTR-QoL scores for orally administered semaglutide tended to be more durable (sustained over time) than for dulaglutide. Outcomes for the trial product estimand were similar. CONCLUSION: Orally administered semaglutide 7 and 14 mg improved the patients' HRQoL measured by the Japanese-specific DTR-QoL instrument versus dulaglutide 0.75 mg at week 52. TRIAL REGISTRATION: ClinicalTrials.gov NCT03015220.

Efficacy and safety of fast-acting insulin aspart compared with insulin aspart in combination with insulin degludec in Japanese adults with type 1 diabetes: a subgroup analysis of the randomized onset 8 trial.

This study aimed to confirm the efficacy and safety of mealtime and post-meal fast-acting insulin aspart versus insulin aspart, both with basal insulin degludec, in Japanese patients with type 1 diabetes. This was a subgroup analysis of onset 8, a randomized multicenter, treat-to-target trial of mealtime fast-acting insulin aspart (subgroup n = 73), mealtime insulin aspart (n = 83), or open-label post-meal fast-acting insulin aspart (n = 89), all for 26 weeks. Change from baseline in HbA1c was considered the primary endpoint. After 26 weeks, the estimated treatment difference (ETD, 95% CI) for change from baseline in HbA1c between mealtime fast-acting insulin aspart or post-meal fast-acting insulin aspart vs. insulin aspart was 0.01% (-0.16;0.19) and 0.10% (-0.07;0.27), respectively. Following a standardized meal test, ETD for change from baseline in postprandial glucose (PPG) increment at 1 hour was -16.91 mg/dL (-32.15;-1.68) for mealtime fast-acting insulin aspart and 40.16 mg/dL (25.46;54.87) for post-meal fast-acting insulin aspart, both versus insulin aspart. Mean self-measured blood glucose 1-hour PPG increments also showed a trend towards improved PPG control with mealtime fast-acting insulin aspart versus insulin aspart. Rates of overall hypoglycemia (35.56, 37.72 and 38.75 per patient-year of exposure with mealtime fast-acting insulin aspart, post-meal fast-acting insulin aspart and insulin aspart, respectively) and meal-related hypoglycemia were similar between treatment arms. Consistent with findings of onset 8, this analysis confirmed mealtime and post-meal fast-acting insulin aspart provided effective HbA1c and PPG control versus insulin aspart, with similar safety profiles, in Japanese adults with type 1 diabetes.

Fast-acting insulin aspart versus insulin aspart in the setting of insulin degludec-treated type 1 diabetes: Efficacy and safety from a randomized double-blind trial.

AIM: To evaluate the efficacy and safety of mealtime or post-meal fast-acting insulin aspart (faster aspart) vs mealtime insulin aspart (IAsp), both in combination with insulin degludec, in participants with type 1 diabetes (T1D). METHODS: This multicentre, treat-to-target trial (Clinical trial registry: NCT02500706, ClinicalTrials.gov) randomized participants to double-blind mealtime faster aspart (n = 342) or IAsp (n = 342) or open-label post-meal faster aspart (n = 341). The primary endpoint was change from baseline in HbA1c 26 weeks post randomization. All available information, regardless of treatment discontinuation, was used for evaluation of the effect. RESULTS: Non-inferiority for the change from baseline in HbA1c was confirmed for mealtime and post-meal faster aspart vs IAsp (estimated treatment difference [ETD]: 95%CI, -0.02% [-0.11; 0.07] and 0.10% [0.004; 0.19], respectively). Mealtime faster aspart was superior to IAsp for 1-hour PPG increment using a meal test (ETD, -0.90 mmol/L [-1.36; -0.45]; P < 0.001). Self-monitored 1-hour PPG increment favoured faster aspart at breakfast (ETD, -0.58 mmol/L [-0.99; -0.17]; P = 0.006) and across all meals (-0.48 mmol/L [-0.74; -0.21]; P < 0.001). Safety profiles and overall rate of severe or blood glucose-confirmed hypoglycaemia were similar between treatments, but significantly less hypoglycaemia was seen 3 to 4 hours after meals with mealtime faster aspart. CONCLUSION: Mealtime and post-meal faster aspart in conjunction with insulin degludec provided effective glycaemic control compared with IAsp, with no increased safety risk. Mealtime faster aspart provided PPG control superior to that of IAsp.

Transarterial chemoembolization with miriplatin vs. epirubicin for unresectable hepatocellular carcinoma: a phase III randomized trial.

BACKGROUND: This prospective study investigated the superiority of transarterial chemoembolization (TACE) with miriplatin over TACE with epirubicin regarding overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC). METHODS: Patients with unresectable HCC were randomized 1:1 to receive TACE with miriplatin or epirubicin in lipiodol. The primary endpoint was OS; secondary endpoints were percentages of patients who achieved treatment effect (TE) 4 (100% necrotizing effect or tumor reduction), duration of time to TACE failure, and adverse events (AEs). OS was compared using a stratified log-rank test adjusted for clinical stage, Child-Pugh class, and institution. RESULTS: Of 257 patients enrolled from August 2008 to August 2010, 247 were analyzed for efficacy and toxicity (miriplatin, n = 124; epirubicin, n = 123). Baseline characteristics were well balanced between the two groups. Median OS times were 1111 days for miriplatin and 1127 days for epirubicin (adjusted hazard ratio 1.01, 95% confidence interval 0.73-1.40, P = 0.946). TE4 rates were 44.4% for miriplatin and 37.4% for epirubicin. Median times to TACE failure were 365.5 days for miriplatin and 414.0 days for epirubicin. AEs of grade 3 or higher, including elevated aspartate aminotransferase (miriplatin, 39.5%; epirubicin, 57.7%) and elevated alanine aminotransferase (miriplatin, 31.5%; epirubicin, 53.7%), were less frequent in the miriplatin than the epirubicin group. CONCLUSIONS: OS after TACE with miriplatin was not superior to that after TACE with epirubicin; however, hepatic AEs were less frequent with miriplatin. CLINICAL TRIAL REGISTRATION: JapicCTI-080632.