Long-term efficacy and safety of two doses of Norditropin® (somatropin) in Noonan syndrome: a 4-year randomized, double-blind, multicenter trial in Japanese patients.

This 4-year randomized, double-blind, multicenter trial (NCT01927861) investigated the long-term efficacy and safety of Norditropin® (NN-220; somatropin) in Japanese children with short stature due to Noonan syndrome. Pre-pubertal children with Noonan syndrome were randomized 1:1 to receive 0.033 mg/kg/day (n = 25, mean age 6.57 years) or 0.066 mg/kg/day (n = 26, mean age 6.06 years) GH. Height standard deviation score (SDS) change after 208 weeks from baseline was evaluated using an analysis of covariance model. Height SDS improved from -3.24 at baseline with a significantly greater increase (estimated mean [95% confidence interval]) with 0.066 vs. 0.033 mg/kg/day GH (1.84 [1.58; 2.10] vs. 0.85 [0.59; 1.12]; estimated mean difference 0.99 [0.62; 1.36]; p < 0.0001). The majority of treatment-emergent adverse events (TEAEs) were non-serious, mild and assessed as unlikely treatment-related. TEAE rates and frequencies of serious TEAEs were similar between groups. Three patients receiving 0.066 mg/kg/day were withdrawn; two due to TEAEs at days 1,041 and 1,289. Mean insulin-like growth factor-I SDS increased from -1.71 to -0.75 (0.033 mg/kg/day) and 0.57 (0.066 mg/kg/day) (statistically significant difference). In both groups, there were only minor glycosylated hemoglobin changes, similar oral glucose tolerance test insulin response increases and no clinically relevant changes in oral glucose tolerance test blood glucose, vital signs, electrocardiogram or transthoracic echocardiography. In conclusion, treatment with 0.033 and 0.066 mg/kg/day GH for 208 weeks improved height SDS in Japanese children with short stature due to Noonan syndrome with a significantly greater increase with 0.066 vs. 0.033 mg/kg/day GH and was well tolerated, with no new safety concerns.

Efficacy and safety of two doses of Norditropin® (somatropin) in short stature due to Noonan syndrome: a 2-year randomized, double-blind, multicenter trial in Japanese patients.

This randomized double-blind multicenter trial (NCT01927861) evaluated the growth-promoting effect and safety of Norditropin® (NN220; somatropin) in Japanese children with short stature due to Noonan syndrome. Prepubertal children aged 3-<11 years (boys) or 3-<10 years (girls) with Noonan syndrome were randomized to receive GH 0.033 mg/kg/day (n = 25, mean age 6.57 years, 11 females) or 0.066 mg/kg/day (n = 26, mean age 6.06 years, eight females) for 104 weeks. Change in height standard deviation score (HSDS) from baseline was analyzed based on an ANCOVA model. Baseline HSDS was -3.24. Estimated change in HSDS [95% CI] after 104 weeks' treatment was 0.84 [0.66, 1.02] and 1.47 [1.29, 1.64] for the lower and higher doses, respectively; estimated mean difference 0.63 [0.38, 0.88], p < 0.0001. Rates and patterns of adverse events (AEs) were similar between groups. Most were mild and reported as unlikely to be related to Norditropin®. There were no withdrawals due to AEs. Insulin-like growth factor-I SDS increased from -1.71 to -0.64 (0.033 mg/kg/day) and to 0.63 (0.066 mg/kg/day). HbA1c increased slightly (0.033 mg/kg/day: +0.14%; 0.066 mg/kg/day: +0.13%); glucose profiles were almost unchanged; insulin profiles increased in both groups in the oral glucose tolerance test. There were no clinically significant abnormal electrocardiogram or echocardiography findings. We conclude that Norditropin® at doses of 0.033 mg/kg/day or 0.066 mg/kg/day for 104 weeks increases height in Japanese children with short stature due to Noonan syndrome, with a favorable safety profile. The effect was greater with 0.066 mg/kg/day compared with 0.033 mg/kg/day.

Use of diabetes medications in adults with T2D and CVD in Japan: secondary analysis of the CAPTURE study.

Introduction: The CAPTURE study estimated the global prevalence of established cardiovascular disease (CVD) and characterized the usage of glucose-lowering agents (GLAs) in adults with type 2 diabetes (T2D) across 13 countries. The purpose of this secondary analysis of data from the Japanese sites within CAPTURE (NCT03786406, NCT03811288) was to provide data about medication usage stratified by CVD status among Japanese participants with T2D. Materials and methods: Data on GLA usage (including those with proven cardiovascular [CV] benefits) in Japanese participants with T2D managed in clinics or hospitals were collected and stratified by CVD subgroups. Results: There were 800 Japanese participants in the CAPTURE study (n = 502 [no CVD group], n = 298 [CVD group], n = 268 [atherosclerotic CVD subgroup]). Oral antidiabetic agents and insulin were used by 88.5% and 23.4%, respectively, of participants overall. Among participants with established CVD, dipeptidyl peptidase-4 inhibitors (65.1%) were most frequently used, followed by biguanides (50.7%) and insulins (26.2%). The pattern was similar among participants with atherosclerotic CVD. A lower proportion of participants in the CVD group used glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) with proven CV benefits versus the no CVD group (GLP-1 RAs: 7.0% vs. 8.6%; SGLT-2is: 13.4% vs. 19.1%). Conclusion: This analysis of the CAPTURE study provided a comprehensive overview of prescription patterns for the treatment of T2D in Japan. Use of GLAs with proven CV benefit was low, even in participants with established CVD, which was comparable to the findings from the global cohort. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00638-w.

Cardiovascular disease prevalence in adults with type 2 diabetes in Japan: results from the Japanese centers in the CAPTURE study.

Introduction: CAPTURE was a cross-sectional, non-interventional study (NCT03786406, NCT03811288) investigating the prevalence and characteristics of cardiovascular disease (CVD) in adults with type 2 diabetes (T2D) across 13 countries worldwide. Here we present the findings for Japan. Materials and methods: Data were collected from adults aged ≥ 20 years (aged ≥ 18 years in countries outside Japan) with T2D who were managed in clinics or hospitals in 2019. Standardized methodology was used for all countries. The prevalence of CVD and its subtypes was estimated, weighted by care setting (clinics versus hospitals). Results: Among participants from Japan (total: 800; clinics: 440; hospitals: 360), mean (standard deviation) age was 65.6 (11.2) years and glycated hemoglobin 7.2% (0.9). Sixty-seven percent of participants were male, 57.8% had diabetes duration > 10 years, 49.8% had body mass index ≥ 25 kg/m2 and 63.1% had hypertension. The weighted prevalences (95% confidence interval [CI]) of CVD and atherosclerotic CVD were 37.3% (34.2;40.3) and 33.5% (30.6;36.4), respectively. The prevalence (95% CI) of the most common subtypes of CVD was: carotid artery disease 20.5% (18.2;22.8), coronary heart disease 11.9% (9.7;14.1) and cerebrovascular disease 10.4% (8.3;12.5). Conclusions: These contemporary data from the CAPTURE study on CVD prevalence in adults with T2D in Japan show that approximately one in three adults with T2D had established CVD, which is comparable to the prevalence in the global study cohort. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-022-00612-y.

A randomized trial to investigate the efficacy and safety of once-daily liraglutide 1.8 mg in Japanese adults with type 2 diabetes exhibiting an inadequate response to liraglutide 0.9 mg.

AIMS/INTRODUCTION: The present trial compared the efficacy and safety of once-daily liraglutide 1.8 mg with liraglutide 0.9 mg in Japanese patients with type 2 diabetes to assess the incremental effects of liraglutide 1.8 mg in those who exhibited an inadequate response to 0.9 mg. MATERIALS AND METHODS: This 26-week randomized trial (NCT02505334) enrolled Japanese adults with type 2 diabetes across 47 sites in Japan. Participants with glycated hemoglobin (HbA1c ) 7.5-10.0% were included and those on insulin treatment were excluded. Participants discontinued pre-trial oral antidiabetic drug and initiated liraglutide 0.9 mg for a 12-week run-in period, after which those with HbA1c ≥7.0% (466) were randomized (1:1) to two treatment arms: continuing liraglutide 0.9 mg or dose escalation to 1.8 mg. The change from baseline in HbA1c (primary endpoint) and treatment-emergent adverse events (secondary endpoint) were measured at the end of 26 weeks. RESULTS: After 26 weeks of treatment, liraglutide 1.8 mg was more effective compared with 0.9 mg in lowering HbA1c levels, with an estimated treatment difference of -0.40% (95% confidence interval [CI] -0.55, -0.24; P < 0.0001). Liraglutide 1.8 mg was associated with significantly greater odds of participants reaching HbA1c <7.0% (estimated odds ratio [EOR] 3.87; 95% CI 2.12, 7.08; P < 0.0001) and ≤6.5% (EOR 3.78; 95% CI 1.36, 10.54; P = 0.0109) compared with 0.9 mg. Both doses were well tolerated. CONCLUSIONS: Liraglutide 1.8 mg had better efficacy in improving HbA1c levels after 26 weeks treatment vs 0.9 mg in Japanese patients, with both doses well tolerated.

Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a, randomised, controlled trial.

BACKGROUND: Given the unique phenotype of type 2 diabetes in Japanese patients, novel therapies such as oral semaglutide require evaluation in this population. PIONEER 9 aimed to assess the dose-response of oral semaglutide and to compare the efficacy and safety of oral semaglutide with placebo and a subcutaneous GLP-1 receptor agonist in a Japanese population. METHODS: PIONEER 9 was a 52-week, phase 2/3a, randomised, controlled trial done at 16 sites (clinics and university hospitals) in Japan. Japanese patients aged 20 years or older with uncontrolled type 2 diabetes managed by diet or exercise or with oral glucose-lowering drug monotherapy (washed out) were randomly assigned (1:1:1:1:1) to receive double-blind once-daily oral semaglutide (3 mg, 7 mg, or 14 mg) or placebo, or open-label subcutaneous once-daily liraglutide 0·9 mg. The primary endpoint was change in HbA1c from baseline to week 26 with the trial product (primary) estimand (which assumes all patients remained on trial product without rescue medication use) in all randomly assigned patients. This trial is registered with ClinicalTrials.gov, NCT03018028. FINDINGS: Between Jan 10, and July 11, 2017, 243 patients were randomly assigned to oral semaglutide 3 mg (n=49), 7 mg (n=49), or 14 mg (n=48), or placebo (n=49), or to liraglutide 0·9 mg (n=48). Changes in HbA1c from baseline (mean 8·2%) to week 26 were dose-dependent with oral semaglutide (mean change -1·1% [SE 0·1] for oral semaglutide 3 mg, -1·5% [0·1] for 7 mg, and -1·7% [0·1] for 14 mg), -0·1% (0·1) with placebo, and -1·4% (0·1) with liraglutide 0·9 mg. Estimated treatment differences for change in HbA1c compared with placebo were -1·1 percentage points (95% CI -1·4 to -0·8; p<0·0001) for oral semaglutide 3 mg, -1·5 percentage points (-1·7 to -1·2; p<0·0001) for oral semaglutide 7 mg, and -1·7 percentage points (-2·0 to -1·4; p<0·0001) for oral semaglutide 14 mg. Estimated treatment differences for change in HbA1c compared with liraglutide 0·9 mg were 0·3 percentage points (95% CI -0·0 to 0·6; p=0·0799) for oral semaglutide 3 mg, -0·1 percentage points (-0·4 to 0·2; p=0·3942) for oral semaglutide 7 mg, and -0·3 percentage points (-0·6 to -0·0; p=0·0272) for oral semaglutide 14 mg. Gastrointestinal events, predominantly of mild or moderate severity, were the most frequently reported class of adverse event with oral semaglutide: constipation was most common, occurring in five to six (10-13%) patients with oral semaglutide, three (6%) with placebo, and nine (19%) with liraglutide 0·9 mg. INTERPRETATION: This study showed that oral semaglutide provides significant reductions in HbA1c compared with placebo in a dose-dependent manner in Japanese patients with type 2 diabetes, and has a safety profile consistent with that of GLP-1 receptor agonists. FUNDING: Novo Nordisk.

Safety and efficacy of the combination of the glucagon-like peptide-1 receptor agonist liraglutide with an oral antidiabetic drug in Japanese patients with type 2 diabetes: Post-hoc analysis of a randomized, 52-week, open-label, parallel-group trial.

AIMS/INTRODUCTION: The aim of the present post-hoc analysis was to investigate the safety and efficacy of liraglutide in combination with one oral antidiabetic drug (OAD) across different OAD classes. MATERIALS AND METHODS: This was a post-hoc analysis using data from a 52-week, open-label, parallel-group trial, in which patients with type 2 diabetes inadequately controlled with a single OAD (α-glucosidase inhibitor, glinide, metformin or thiazolidinedione) were randomized to either pretrial OAD in combination with liraglutide 0.9 mg/day (liraglutide group) or pretrial OAD in combination with an additional OAD (additional OAD group). The primary outcome investigated in this post-hoc analysis was the incidence of adverse events. RESULTS: The proportions of patients experiencing adverse events across the different groups of pretrial OADs were comparable between liraglutide and additional OAD (α-glucosidase inhibitor 74.6 vs 70.0%; glinide 93.1 vs 87.1%; metformin 91.8 vs 87.1%; thiazolidinedione 86.2 vs 96.4%, respectively). Minor hypoglycemia was infrequent (seven episodes in two patients randomized to liraglutide, and two episodes in two patients randomized to additional OAD). The mean reduction in glycated hemoglobin appeared greater with liraglutide therapy, with the estimated mean treatment difference (95% confidence interval [CI]) for liraglutide vs additional OAD ranging from -0.14%, 95% CI: -0.48 to 0.21 (-1.5 mmol/mol, 95 CI: -5.2 to 2.3) to -0.44%, 95% CI:-0.79 to -0.09 (-4.8 mmol/mol, 95% CI: -8.6 to -1.0). CONCLUSIONS: The present analysis suggests that Japanese patients on OAD monotherapy might benefit from a greater improvement in glycemic control, without impacting tolerability, by combining their OAD with liraglutide rather than another OAD, regardless of which OAD monotherapy they are receiving.

Efficacy and safety of adding liraglutide to existing insulin regimens in Japanese patients with type 2 diabetes mellitus: A post-hoc analysis of a phase 3 randomized clinical trial.

AIMS/INTRODUCTION: To determine the efficacy and safety of adding liraglutide to three different insulin regimens in Japanese patients with type 2 diabetes mellitus. MATERIALS AND METHODS: In this post-hoc analysis, results from a 36-week, randomized, double-blind, placebo-controlled, parallel-group trial are reported. Individuals with type 2 diabetes mellitus were stratified according to their pre-trial insulin regimen (basal, basal-bolus and premix). The primary objective was to determine whether adding liraglutide (0.9 mg/day) to fixed-dose insulin therapy was superior vs fixed-dose insulin monotherapy, assessed by the effect on glycemic control after 16 weeks of treatment. RESULTS: The treatment effect on glycated hemoglobin reduction was independent of the pre-trial insulin regimen. Comparing liraglutide with a placebo, liraglutide was associated with glycated hemoglobin reduction in all insulin regimens, with placebo-corrected reductions at 16 weeks ranging from -1.45 to -1.17%, and maintained at 36 weeks. Liraglutide resulted in a greater reduction in mean plasma glucose obtained from seven-point self-monitoring, and greater proportions of patients achieved target glycated hemoglobin. With liraglutide, slightly higher proportions of patients receiving basal and basal-bolus insulin reported confirmed hypoglycemia from 0 to 16 weeks. CONCLUSIONS: The efficacy and safety of adding liraglutide to insulin therapy was confirmed, regardless of pre-trial insulin regimen.

Liraglutide is effective and well tolerated in combination with an oral antidiabetic drug in Japanese patients with type 2 diabetes: A randomized, 52-week, open-label, parallel-group trial.

INTRODUCTION: The safety and efficacy of liraglutide in combination with an oral antidiabetic drug (OAD) compared with combination of two OADs were assessed in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: This was a 52-week, open-label, parallel-group trial in which patients whose type 2 diabetes was inadequately controlled with a single OAD (glinide, metformin, α-glucosidase inhibitor or thiazolidinedione) were randomized 2:1 to either pretrial OAD in combination with liraglutide 0.9 mg/day (liraglutide group; n = 240) or pretrial OAD in combination with an additional OAD (additional OAD group; n = 120). The primary outcome measure was the incidence of adverse events (AEs). RESULTS: Overall, 86.3% of patients in the liraglutide group and 85.0% of patients in the additional OAD group experienced AEs; these were similar in nature and severity. Adverse event rates were 361 and 331 per 100 patient-years of exposure, respectively. Confirmed hypoglycemia was rare (seven episodes in two patients on liraglutide, and two in two patients on additional OAD). There were no reported pancreatitis events, and no unexpected safety signals were identified. Mean reductions in glycosylated hemoglobin were significantly greater in the liraglutide group than the additional OAD group [estimated mean treatment difference -0.27% (95% confidence interval (CI) -0.44, -0.09; P = 0.0026)]; reductions in mean fasting plasma glucose levels were also greater with liraglutide [estimated mean difference -5.47 mg/dL (-0.30 mmol/L; 95% CI: -10.83, -0.10; P = 0.0458)]. CONCLUSIONS: Liraglutide was well tolerated and effective as combination therapy with an OAD in Japanese patients with type 2 diabetes.

Combination therapy with liraglutide and insulin in Japanese patients with type 2 diabetes: A 36-week, randomized, double-blind, parallel-group trial.

AIMS/INTRODUCTION: To assess efficacy and safety of liraglutide in combination with insulin compared with insulin monotherapy in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: This was a 36-week, multicenter, double-blind, parallel-group trial, where patients on stable insulin therapy (basal/premixed/basal-bolus) were randomized 1:1 to additional liraglutide 0.9 mg/day (n = 127) or placebo (n = 130). The insulin dose was fixed for 16 weeks, and titrated based on self-measured plasma glucose thereafter. The primary end-point was change in glycosylated hemoglobin after 16 weeks. RESULTS: Superiority of liraglutide plus insulin versus insulin monotherapy was confirmed based on estimated mean difference in glycosylated hemoglobin after 16 weeks of -1.30% (-14 mmol/mol; 95% confidence interval -1.47 to -1.13 [-16, -12]; P < 0.0001). Statistical significance was maintained to week 36. More patients on liraglutide achieved a glycosylated hemoglobin target of <7.0% (<53 mmol/mol) at week 16 (estimated odds ratio 50.57; 95% confidence interval 16.59 to 154.16; P < 0.0001). Improvements in seven-point self-measured plasma glucose and fasting plasma glucose were significantly greater with liraglutide than the placebo at week 16. Insulin dose after 36 weeks was lower with liraglutide than the placebo (estimated treatment ratio: 0.82 [95% confidence interval 0.76-0.90; P < 0.0001]). Occurrence of adverse events was similar in the two groups (85.8 and 81.5%, respectively); most were mild in severity. There were no significant differences in the number of hypoglycemic episodes during the 36 weeks. CONCLUSIONS: Adding liraglutide to insulin results in superior glycemic control compared with insulin alone in Japanese patients with type 2 diabetes, and is generally well tolerated.