Safety and efficacy analyses across age and body mass index subgroups in East Asian participants with type 2 diabetes in the phase 3 tirzepatide studies (SURPASS programme).

AIM: To assess the safety and efficacy of tirzepatide in people of East Asian descent based on age and body mass index (BMI). MATERIALS AND METHODS: Data of participants enrolled in East Asian countries in the SURPASS-1, -3, -4, -5, J-mono and J-combo phase 3 clinical trials were included. Participants with type 2 diabetes with a baseline HbA1c of 7.0% up to 11.0% and a BMI of 23 kg/m2 or greater or 25 kg/m2 or greater were included. Participants treated with tirzepatide 5, 10 or 15 mg were evaluated to assess the safety and efficacy of tirzepatide in people of East Asian descent (94% from Japan) based on age (< 65 and ≥ 65 years) and BMI (< 25 and ≥ 25 kg/m2 ). Key safety and efficacy outcomes were assessed. RESULTS: At baseline, 73% of East Asian participants had a BMI of 25 kg/m2 or greater and 74% were younger than 65 years. At week 52, tirzepatide induced a similar dose-dependent reduction in HbA1c, waist circumference and BMI across subgroups. Across all BMI and age subgroups, mean absolute HbA1c reductions across the three doses ranged from 2.3% to 3.0%, and mean waist circumference reductions ranged from 4.3 to 9.8 cm. Improvements in absolute insulin sensitivity, assessed by homeostatic model assessment for insulin resistance, were greater in those with a baseline BMI of ≥ 25 kg/m2 . Improvements in lipid profiles were similar across subgroups. While the safety profile of tirzepatide was broadly similar across BMI and age subgroups, drug discontinuation because of adverse events was higher in participants with a baseline age of ≥ 65 years. CONCLUSIONS: This post hoc analysis showed that once-weekly tirzepatide had a similar safety and efficacy profile across BMI and age subgroups in East Asian participants.

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.

Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial.

BACKGROUND: As the disease progresses, many patients with type 2 diabetes have difficulty in reaching treatment goals. We aimed to assess the efficacy and safety of tirzepatide, a novel GIP and GLP-1 receptor agonist, compared with dulaglutide in Japanese patients with type 2 diabetes. METHODS: This multicentre, randomised, double-blind, parallel, active-controlled, phase 3 trial was conducted in 46 medical research centres and hospitals in Japan. Adults aged 20 years or older with type 2 diabetes who had discontinued oral antihyperglycaemic monotherapy or were treatment-naïve were included. Participants were randomly assigned (1:1:1:1) to receive tirzepatide (5, 10, or 15 mg) or dulaglutide (0·75 mg) once per week using a computer-generated random sequence with an Interactive Web Response System. Participants were stratified based on baseline HbA1c (≤8·5% or >8·5%), baseline BMI (<25 or ≥25 kg/m2), and washout of antidiabetic medication. Participants, investigators, and the sponsor were masked to treatment assignment. The starting dose of tirzepatide was 2·5 mg once per week for 4 weeks, which was then increased to 5 mg in the tirzepatide 5 mg treatment group. For the tirzepatide 10 and 15 mg treatment groups, increases by 2·5 mg occurred once every 4 weeks until the assigned dose was reached. The primary endpoint was mean change in HbA1c from baseline at week 52 measured in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03861052. FINDINGS: Between May 7, 2019, and March 31, 2021, 821 participants were assessed for study eligibility and 636 were randomly assigned to receive at least one dose of tirzepatide 5 mg (n=159), 10 mg (n=158), or 15 mg (n=160), or dulaglutide 0·75 mg (n=159). 615 (97%) participants completed the study and 21 (3%) discontinued. Participants had a mean age of 56·6 years (SD 10·3) and were mostly male (481 [76%]). At week 52, HbA1c decreased from baseline by a least squares mean of -2·4 (SE 0·1) for tirzepatide 5 mg, -2·6 (0·1) for tirzepatide 10 mg, -2·8 (0·1) for tirzepatide 15 mg, and -1·3 (0·1) for dulaglutide. Estimated mean treatment differences versus dulaglutide were -1·1 (95% CI -1·3 to -0·9) for tirzepatide 5 mg, -1·3 (-1·5 to -1·1) for tirzepatide 10 mg, and -1·5 (-1·71 to -1·4) for tirzepatide 15 mg (all p<0·0001). Tirzepatide was associated with dose-dependent reductions in bodyweight with a least square mean difference of -5·8 kg (SE 0·4; -7·8% reduction) for 5 mg, -8·5 kg (0·4; -11·0% reduction) for 10 mg, and -10·7 kg (0·4; -13·9% reduction) for 15 mg of tirzepatide compared with -0·5 kg (0·4; -0·7% reduction) for dulaglutide. The most common treatment-emergent adverse events were nausea (19 [12%] participants in the 5 mg group vs 31 [20%] in the 10 mg group vs 32 [20%] in the 15 mg group all receiving tirzepatide vs 12 (8%) in the group receiving dulaglutide), constipation (24 [15%] vs 28 [18%] vs 22 [14%] vs 17 [11%]), and nasopharyngitis (29 [18%] vs 25 [16%] vs 22 [14%] vs 26 [16%]). The most frequent adverse events were gastrointestinal (23 [4%] of 636). INTERPRETATION: Tirzepatide was superior compared with dulaglutide for glycaemic control and reduction in bodyweight. The safety profile of tirzepatide was consistent with that of GLP-1 receptor agonists, indicating a potential therapeutic use in Japanese patients with type 2 diabetes. FUNDING: Eli Lilly and Company. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Multinational Observational Study to Understand Insulin Treatment Intensification: Japanese Subgroup Analysis of the MOSAIc Study.

INTRODUCTION: MOSAIc was a multinational, non-interventional, prospective, observational cohort study designed to provide an understanding of the specific challenges associated with intensification of initial insulin therapy in patients with type 2 diabetes mellitus (T2DM). We present a sub-analysis of Japanese patients from MOSAIc, with data analyzed longitudinally over 2 years, to provide insight on how T2DM treatment is intensified. METHODS: Japanese patients with T2DM receiving any insulin therapy for at least 3 months were eligible for study inclusion. Baseline and clinical data were collected during an initial baseline visit and during four subsequent prospective visit windows (within ± 3 months) at 6, 12, 18, and 24 months. Treatment intensification was defined as addition of new insulin, increase in insulin dosage (1-unit change or 10% compared with the previous visit), increase in insulin injection frequency, and/or addition of non-insulin antihyperglycemic agents. RESULTS: Of 116 Japanese patients who completed the study, 50.0% (n = 58) received treatment intensification. Baseline characteristics of patients with treatment intensification included a longer duration of diabetes, higher incidence of baseline microvascular complications, and higher HbA1c compared to those without intensification. There was no significant difference in HbA1c change from baseline between the two groups at any post-baseline visit. Insulin intensification accounted for 61.2% of treatment changes, with non-insulin-related intensification accounting for 36.2% of treatment changes. An increase in insulin dose was the most frequent treatment change (51.7%), followed by the addition of new insulin (22.4%), and an increase in insulin injection frequency (6.9%). CONCLUSION: Real-world data from Japanese patients with T2DM who received treatment intensification showed that an increase in insulin dose and the addition of new insulin were the most frequent treatment intensification methods. HbA1c was maintained through 2 years of treatment. TRIAL REGISTRATION: NCT01400971, ClinicalTrials.gov.

A phase 1 multiple-ascending dose study of tirzepatide in Japanese participants with type 2 diabetes.

AIM: To investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of tirzepatide in Japanese participants with type 2 diabetes (T2D). METHODS: This phase 1, double-blind, placebo-controlled, parallel-dose, multiple-ascending dose study randomized participants to once-weekly subcutaneous tirzepatide or placebo. The tirzepatide treatment groups were: 5 mg (5 mg, weeks 1-8), 10 mg (2.5 mg, weeks 1-2; 5 mg, weeks 3-4; 10 mg, weeks 5-8), and 15 mg (5 mg, weeks 1-2; 10 mg, weeks 3-6; 15 mg, weeks 7-8). The primary outcome was tirzepatide safety and tolerability. RESULTS: Forty-eight participants were randomized. The most frequently reported treatment-emergent adverse events (AEs) were decreased appetite and gastrointestinal AEs, which were generally dose-dependent and mild in severity. The plasma tirzepatide concentration half-life was approximately 5 days. After 8 weeks of treatment, fasting plasma glucose decreased from baseline with tirzepatide versus placebo; the least squares (LS) mean decrease compared with placebo (95% confidence interval [CI]) was 52.7 (35.9-69.6), 69.1 (52.3-85.9), and 68.9 (53.2-84.6) mg/dL in the 5-, 10-, and 15-mg treatment groups, respectively (P < .0001 for all treatment groups). Tirzepatide also resulted in LS mean decreases from baseline versus placebo at 8 weeks in HbA1c up to 1.6% (95% CI 1.2%-1.9%; P < .0001 for all treatment groups) and body weight up to 6.6 kg (95% CI 5.3-7.9; P < .0001 for all treatment groups). CONCLUSIONS: All tirzepatide doses were well tolerated. The safety, tolerability, PK, and PD profiles of tirzepatide support further evaluation of once-weekly dosing in Japanese people with T2D.

Glucagon-Like Peptide-1 Receptor Agonist Utilization in Type 2 Diabetes in Japan: A Retrospective Database Analysis (JDDM 57).

INTRODUCTION: There are limited real-world data on the prescribing of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for patients with type 2 diabetes mellitus (T2DM). METHODS: This was a retrospective analysis of the CoDiC® database of the Japan Diabetes Clinical Data Management Study Group (JDDM). Demographic and clinical characteristics, concomitant treatment patterns, and GLP-1 RA treatment persistence or modification in patients with T2DM initiating GLP-1 RA therapy were evaluated. RESULTS: The analysis included 932 eligible patients with T2DM who had their first GLP-1 RA prescription (index date) between September 2016 and July 2018. Mean age was 63.8 years and 56.0% were male. Most patients had an index GLP-1 RA of dulaglutide (65.7%) or liraglutide (29.1%). Common comorbidities were obesity (58.7%), hypertension (54.7%), dyslipidemia (52.0%), retinopathy (11.3%), and nephropathy (10.2%). Mean hemoglobin A1c (HbA1c) levels decreased from 8.3 to 7.8% over 6 months after GLP-1 RA initiation, and the proportion of patients achieving HbA1c < 7.0% increased from 14.4% at index date to 22.9% at 6 months. Reductions occurred in mean body weight, body mass index, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and adjusted urinary albumin over 6 months. Antidiabetic medication use decreased after GLP-1 RA initiation, whereas non-antidiabetic medication prescribing showed little change. Index GLP-1 RA persistence rates were 80.5%, 66.2%, and 51.6% at 6, 12, and 18 months post-index, respectively, with a median persistence until discontinuation or switch of 600 days. Persistence rates at 6, 12, and 18 months post-index, respectively, were 81.9%, 70.7%, and 65.4% for dulaglutide and 79.7%, 60.0%, and 30.4% for liraglutide. CONCLUSION: The study shows real-world benefits of GLP-1 RA therapy for T2DM, including improvements in HbA1c, body weight, and blood lipid profile, and supports the high rates of long-term persistence previously reported with dulaglutide, the GLP-1 RA most commonly prescribed for T2DM in Japanese clinical practice.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are drugs that patients with type 2 diabetes mellitus (T2DM) take to help control their blood sugar levels. In Japan, the GLP-1 RAs that doctors can prescribe are dulaglutide, exenatide, liraglutide, and lixisenatide as of May 2020. We conducted a study of how GLP-1 RAs are used to treat patients with T2DM in Japanese real-world clinical practice. We used a large database of anonymous information from hospitals and clinics in Japan. Over 900 adult patients started their first GLP-1 RA treatment for T2DM between September 2016 and July 2018. Before these patients started GLP-1 RA treatment, many were overweight, had high blood pressure, and had abnormal levels of lipids in their blood. Six months after starting GLP-1 RA treatment, on average these patients had lower hemoglobin A1c (a measure of average blood sugar levels), lower body weight, and better blood lipid levels than before they started GLP-1 RA treatment. Dulaglutide was the most common GLP-1 RA prescribed, then liraglutide. After 6 months, most patients (four-fifths) continued to use their GLP-1 RA treatment without stopping or changing to another treatment. After 18 months, half of the patients were still using their GLP-1 RA. Two-thirds of patients on dulaglutide and one-third of patients on liraglutide continued the treatment after 18 months. This study shows that GLP-1 RAs can benefit patients with T2DM in real-world clinical practice. It also shows that patients may be able to take long-term dulaglutide treatment.

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.

Long-term safety and effectiveness of biosimilar insulin glargine in Japanese patients with diabetes mellitus in routine clinical practice: results of a post-marketing safety study.

Objective: To evaluate the long-term safety and effectiveness of biosimilar insulin glargine (GLY) in real-world clinical practice.Methods: This prospective, non-interventional, multicenter, observational, post-marketing safety study (PMSS) enrolled Japanese patients with type 1 or 2 diabetes mellitus (T1DM or T2DM) starting GLY therapy, and was required by Japanese Pharmaceutical Affairs Law mandating post-marketing safety surveillance to acquire safety and effectiveness data of biosimilar products. Data collected from the 12-month observation included patient characteristics, adverse events, and blood glucose control.Results: The study enrolled 141 patients with T1DM and 1104 patients with T2DM. Pre-study insulin was used by 94.1% of patients with T1DM and 75.0% with T2DM. 65.4% of patients with T1DM and 64.3% with T2DM switched from the reference product (GLY-switched), while 25.0% with T2DM were insulin-naive. Adverse events were reported by 5.7% and 8.5% in T1DM and T2DM, respectively. Similar incidences were reported in GLY-switched. Adverse events were reported by 10.7% in insulin-naive T2DM. Baseline mean hypoglycemic events/month were 1.8 and 0.1 in T1DM and T2DM, respectively: the mean change from baseline (CFB) was -1.2 (p = .066) and 0.0 (p = .915), respectively. Baseline mean HbA1c was 8.4% and 8.7% in T1DM and T2DM, respectively; the mean CFB was -0.5% (p < .001) and -0.9% (p < .001), respectively, and -1.5% (p < .001) in insulin-naive T2DM.Conclusions: This first long-term Japanese PMSS of GLY demonstrated adverse events, hypoglycemia, and glycemic control consistent with the known GLY profile for T1DM and T2DM patients, in routine clinical practice.

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.

A 1-year safety study of dulaglutide in Japanese patients with type 2 diabetes on a single oral hypoglycemic agent: an open-label, nonrandomized, phase 3 trial.

The goal of this study was to assess the safety and efficacy of 0.75 mg of dulaglutide, a once weekly glucagon-like peptide-1 receptor agonist, in Japanese patients with type 2 diabetes (T2D) on a single oral hypoglycemic agent (OHA). In this phase 3, nonrandomized, open-label, parallel-group, 52-week study, safety and efficacy of once weekly dulaglutide 0.75 mg were assessed in Japanese patients with T2D on a single OHA (sulfonylureas [SU], biguanides [BG], α-glucosidase inhibitors [AGI], thiazolidinedione [TZD], or glinides [GLN]). A total of 394 patients were treated with study drug, and 92.9% completed the 52-week treatment period. The most frequent treatment-emergent adverse events were nasopharyngitis and gastrointestinal disorders, including constipation, diarrhea, and nausea. Incidences of hypoglycemia varied across the combination therapy groups: incidence was greater in patients receiving SU compared with other combinations. No severe hypoglycemic episodes occurred during the study. Increases from baseline in pancreatic and total amylase, lipase, and pulse rate were observed in all 5 combination therapy groups. Significant reductions from baseline in HbA1c were observed in all 5 combination therapy groups (-1.57% to -1.69%, p < 0.001 for all). Mean body weight changes from baseline varied across the combination therapy groups: a significant increase was observed in combination with TZD, there were no significant changes in combination with SU or GLN, and significant reductions were observed in combination with BG or AGI. Once weekly dulaglutide 0.75 mg in combination with a single OHA was overall well tolerated and improved glycemic control in Japanese patients with T2D.

Monotherapy with the once weekly GLP-1 receptor agonist dulaglutide for 12 weeks in Japanese patients with type 2 diabetes: dose-dependent effects on glycaemic control in a randomised, double-blind, placebo-controlled study.

The aim of this study was to evaluate the dose-dependent effect of dulaglutide, a glucagon-like peptide-1 receptor agonist, on glycaemic control in Japanese patients with type 2 diabetes mellitus who were treated with diet/exercise or oral antidiabetic drug monotherapy. In this randomised, double-blind, placebo-controlled, parallel-group, 12-week study, patients received once weekly subcutaneous dulaglutide doses of 0.25, 0.5, or 0.75 mg (DU 0.25, DU 0.5, and DU 0.75, respectively) or placebo (n=36, 37, 35, and 37, respectively). The primary measure was change from baseline in glycated haemoglobin (HbA1c; %) at 12 weeks. Continuous variables were analysed using a mixed-effects model for repeated measures. Significant dose-dependent reductions in HbA1c were observed (least squares mean difference versus placebo [95% confidence interval]): DU 0.25=-0.72% (-0.95, -0.48), DU 0.5=-0.97% (-1.20, -0.73), and DU 0.75=-1.17% (-1.41, -0.93); p<0.001. Significant improvements in plasma glucose (PG), both fasting and average 7-point self-monitored blood glucose, were also observed with dulaglutide versus placebo (p<0.001). Dulaglutide was well-tolerated. Gastrointestinal adverse events (AEs) were more common in dulaglutide-treated patients, with nausea the most frequent (8 [5.5%]). Few dulaglutide-treated patients discontinued due to AEs (4 [3.7%]), and no serious AEs related to study medication occurred. Three patients (DU 0.5=1 and DU 0.75=2) reported asymptomatic hypoglycaemia (PG ≤70 mg/dL). The observed dose-dependent reduction in HbA1c and acceptable safety profile support further clinical development of dulaglutide for treatment of type 2 diabetes mellitus in Japan.

Efficacy and safety of stepwise introduction of insulin lispro mix 50 in Japanese patients with type 2 diabetes inadequately controlled by oral therapy.

The objective of this study was to evaluate the efficacy and safety of stepwise introduction of insulin lispro mix 50 (LM50) from once to 3 times daily in Japanese patients with type 2 diabetes mellitus inadequately controlled by oral therapy. This was a multicenter, open-label, non-randomized trial consisting of three 16-week periods (48 weeks total); all patients were given once-daily injections of LM50 in Period 1. The regimen was intensified to twice daily in Period 2, and 3 times daily in Period 3 if HbA1c was ≥ 6.9% before the start of the period. A total of 135 patients were enrolled, and 116 patients completed the study. Main baseline characteristics of enrolled patients were a mean age of 60.3 years, mean diabetes duration of 11.4 years, mean BMI of 25.2 kg/m(2), and mean HbA1c of 8.71%. The percentages of patients who achieved HbA1c levels <6.9% and <7.4% at endpoint were 18.5% (25/135 patients) and 52.6% (71/135 patients), respectively. Mean HbA1c decreased significantly from 8.70% to 7.44% (p<0.001). The incidence of hypoglycemic episodes over the treatment periods was 65.9% (89/135 patients); severe hypoglycemia occurred in 2.2% (3/135 patients). There were no other clinically significant safety issues related to the study drug. Stepwise introduction of LM50 from once to 3 times daily can be a safe, effective, and simple therapy for Japanese patients with type 2 diabetes mellitus inadequately controlled by oral therapy.

Tadalafil once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a randomized placebo- and tamsulosin-controlled 12-week study in Asian men.

OBJECTIVES: To examine the efficacy and safety of tadalafil in Asian men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. METHODS: Asian men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia were randomized to once-daily placebo (n=154), tadalafil 2.5 mg (n=151), tadalafil 5.0 mg (n=155) or tamsulosin 0.2 mg (active control, n=152) for 12 weeks. RESULTS: Total International Prostate Symptom Score least-squares mean changes from baseline to end-point significantly improved with tadalafil 2.5 mg (-4.8, P=0.003) and 5 mg (-4.7, P=0.004) versus placebo (-3.0). Significant improvement in the International Prostate Symptom Score versus placebo was observed earlier (week 2) for tadalafil 5.0 mg than for tadalafil 2.5 mg (week 8). Significant improvements (P<0.05) in both tadalafil groups versus placebo were observed for the International Prostate Symptom Score voiding subscore, International Prostate Symptom Score Quality of Life, and for Patient and Clinician Global Impressions of Improvement. Significant improvements versus placebo were observed in the International Prostate Symptom Score storage subscore for tadalafil 5.0 mg (-1.7, P=0.021), but not tadalafil 2.5 mg (-1.5, P=0.072). No significant improvements in benign prostatic hyperplasia Impact Index or improvements in peak urinary flow rates were observed with tadalafil 2.5 mg or 5.0 mg versus placebo. Tamsulosin treatment resulted in significant improvements versus placebo across all efficacy parameters, except for peak urinary flow rates. Safety results were consistent with the known tadalafil and tamsulosin safety profiles. CONCLUSIONS: Tadalafil once daily represents an effective and well tolerated medical treatment for Asian men presenting with lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

Safety of exenatide once weekly for 52 weeks in Japanese patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: An initial 26-week, randomized, open-label study compared the efficacy and safety of exenatide 10 mcg twice daily with exenatide 2 mg once weekly in Asian patients with type 2 diabetes who experienced inadequate glycemic control with oral antidiabetes medications. The aim of this study was to evaluate the safety of exenatide once weekly in Japanese patients, a subset of the initial patient population, who continued into this extension study for an additional 26 weeks of therapy on exenatide once weekly, followed by 10 weeks without exenatide once weekly. MATERIALS AND METHODS: Japanese patients initially assigned to exenatide twice daily (n = 62) switched to exenatide once weekly for the extended 26 weeks, and patients initially assigned to exenatide once weekly (n = 74) continued on this regimen for the remainder of the study (total treatment of 52 weeks). RESULTS: A total of 68% of patients reported one or more treatment-emergent adverse events during the extension period; the most common of these were nasopharyngitis (14%) and vomiting (6%). No major hypoglycemic episodes were reported. Improvements in glycated hemoglobin, fasting plasma glucose and postprandial glucose were maintained over 52 weeks of treatment. At week 52, bodyweight remained reduced from baseline. CONCLUSIONS: Exenatide once weekly added to oral antidiabetes medication was well tolerated in Japanese patients with type 2 diabetes, and was associated with glycemic control and weight loss through to 52 weeks, supporting the use of exenatide once weekly as an adjunctive treatment for type 2 diabetes in this patient population. The initial 26-week portion of this trial was registered with ClinicalTrials.gov (no. NCT00917267).

Effects of insulin changes on quality of life and glycemic control in Japanese patients with type 2 diabetes mellitus: The insulin-changing study intending to gain patients' insights into insulin treatment with patient-reported health outcomes in actual clinical treatments (INSIGHTs) study.

AIMS/INTRODUCTION: Our primary objective was to assess changes in quality of life (QOL) associated with changes in insulin regimen in patients with type 2 diabetes mellitus. Secondary objectives were to assess the reasons for and patterns of changes in insulin regimen, and the effects on glycemic control. MATERIALS AND METHODS: This 12-week, observational study included patients with type 2 diabetes mellitus (n = 625) who planned to change insulin regimen (type of insulin, injection device and/or number of injections). The primary outcome measure was a change from baseline in QOL assessed by the Insulin Therapy-Related (ITR) QOL questionnaire. The secondary outcome measures included change from baseline in plasma glycated hemoglobin (HbA1c) level, the reasons for and pattern of insulin regimen change, and change from baseline in QOL assessed by Diabetes Treatment Satisfaction Questionnaire (DTSQ). RESULTS: QOL did not worsen during the study. Improvements were seen in the ITR-QOL 'daily activities' subscale score (baseline: 12.7 ± 2.3; week 12: 12.9 ± 2.3; P = 0.038, n = 568) and the DTSQ 'perceived frequency of hyperglycemia' subscale score (baseline: 3.4 ± 1.6; week 12: 3.0 ± 1.7; P < 0.001, n = 573). Glycemic control improved, as evidenced by decreased plasma HbA1c levels (baseline: 8.21 ± 1.47%; week 12: 7.85 ± 1.31%; P < 0.001, n = 606). CONCLUSIONS: It was suggested that insulin regimen changes might improve glycemic control in Japanese patients with type 2 diabetes mellitus without worsening QOL. This trial was registered with ClinicalTrials.gov (no. NCT01055808).

Effects of propofol on left ventricular mechanoenergetics in the excised cross-circulated canine heart.

Although propofol is commonly used for general anesthesia, its direct effects on left ventricular (LV) contractility and energetics remain unknown. Accordingly, we studied the effects of intracoronary propofol on excised cross-circulated canine hearts using the framework of the Emax (a contractility index)-PVA (systolic pressure-volume area, a measure of total mechanical energy)-V(O2) (myocardial oxygen consumption per beat) relationship. We obtained 1) the V(O2)-PVA relationship of isovolumic contractions with varied LV volumes at a constant Emax, 2) the V(O2)-PVA relationship with varied LV volumes at a constant intracoronary concentration of propofol, and 3) the V(O2)-PVA relationship under increased intracoronary concentrations of either propofol or CaCl(2) at a constant LV volume to assess the cardiac mechanoenergetic effects of propofol. We found that propofol decreased Emax dose-dependently. The slope of the linear V(O2)-PVA relationship (oxygen cost of PVA) remained unchanged by propofol. The PVA-independent V(O2)-Emax relationship (oxygen cost of Emax) was the same for propofol and Ca(2+). In conclusion, propofol showed a direct negative inotropic effect on LV. At its clinical concentrations, decreases in contractility by propofol were relatively small. Propofol shows mechanoenergetic effects on the LV that are similar to those of Ca(2+) blockers or ß-antagonists-i.e., it exerts negative inotropic effects without changing the oxygen costs of Emax and PVA.

Efficacy and safety profile of exenatide once weekly compared with insulin once daily in Japanese patients with type 2 diabetes treated with oral antidiabetes drug(s): results from a 26-week, randomized, open-label, parallel-group, multicenter, noninferiority study.

BACKGROUND: Exenatide once weekly (QW) is an extended-release formulation of exenatide, a glucagon-like peptide-1 receptor agonist that reportedly improves glycemic control in patients with type 2 diabetes. OBJECTIVE: The goal of this study was to test the hypothesis that exenatide QW is noninferior to insulin glargine, as measured by change in glycosylated hemoglobin (HbA(1c)) from baseline to end point (week 26 [primary end point]) in Japanese patients with type 2 diabetes who have inadequate glycemic control with oral antidiabetes drugs. METHODS: In this open-label, parallel-group, multicenter, noninferiority registration study, patients were randomized (1:1) to add exenatide QW (2 mg) or once-daily insulin glargine (starting dose, 4 U) to their current oral antidiabetes drug treatment. The primary analysis was change in HbA(1c) from baseline to end point, evaluated by using a last-observation-carried-forward ANCOVA model, with a predefined noninferiority margin of 0.4%. Secondary analyses (a priori) included analysis of superiority for between-group comparisons of change in weight and the proportion of patients reaching HbA(1c) target levels of ≤7.0% or ≤6.5%. RESULTS: The baseline characteristics of the exenatide QW (215 patients) and insulin glargine (212 patients) treatment groups were similar: mean (SD) age, 57 (10) years and 56 (11) years, respectively; 66.0% and 69.8% male; mean HbA(1c), 8.5% (0.82%) and 8.5% (0.79%); and mean weight, 69.9 (13.2) kg and 71.0 (13.9) kg. Exenatide QW was statistically noninferior to insulin glargine for the change in HbA(1c) from baseline to end point (least squares mean difference, -0.43% [95% CI, -0.59 to -0.26]; P < 0.001), with the 95% CI upper limit less than the predefined noninferiority margin (0.4%). A significantly greater proportion of patients receiving exenatide QW compared with insulin glargine achieved HbA(1c) target levels of ≤7.0% (89 of 211 [42.2%] vs 44 of 210 [21.0%]) or ≤6.5% (44 of 214 [20.6%] vs 9 of 212 [4.2%]) at end point (P < 0.001 for both). Patient weight was reduced with exenatide QW compared with insulin glargine at end point (least squares mean difference, -2.01 kg [95% CI, -2.46 to -1.56]; P < 0.001). Exenatide QW was well tolerated, with a lower risk of hypoglycemia compared with insulin glargine but a higher incidence of injection-site induration. CONCLUSIONS: Exenatide QW was statistically noninferior to insulin glargine for the change in HbA(1c) from baseline to end point; these results suggest that exenatide QW may provide an effective alternative treatment for Japanese patients who require additional therapy to control their diabetes. ClinicalTrials.gov identifier: NCT00935532.

Tadalafil for the Treatment of Lower Urinary Tract Symptoms in Japanese Men with Benign Prostatic Hyperplasia: Results from a 12-week Placebo-controlled Dose-finding Study with a 42-week Open-label Extension.

OBJECTIVES: To examine the efficacy, safety, and dose response of tadalafil once daily in Japanese men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH-LUTS). METHODS: Men ≥45 years with moderate-to-severe BPH-LUTS were randomized to once-daily placebo (N = 140), tadalafil 2.5 mg (N = 142), or tadalafil 5.0 mg (N = 140), in a 12-week double-blind phase, followed by a 42-week, tadalafil 5.0 mg open-label extension (OLE) phase (N = 394). The primary outcome was total International Prostate Symptom Score (IPSS) change from baseline to last available observation in the double-blind phase. RESULTS: The least squares (LS) mean difference between placebo and tadalafil in total IPSS change from baseline was -0.7 (P = 0.201) and -1.1 (P = 0.062) for tadalafil 2.5 and 5 mg, respectively (ANCOVA; a dose-dependent improvement in placebo-adjusted total IPSS for tadalafil 5 mg versus 2.5 mg of 57%). Repeated-measures analyses identified a significant total IPSS change for tadalafil 5 mg (LS mean difference between placebo and tadalafil 5 mg: -1.2; P = 0.035), but not tadalafil 2.5 mg, at week 12. Significant improvements for tadalafil 5 mg were demonstrated (ANCOVA) for IPSS obstructive subscore (P = 0.033) and IPSS quality of life index (P = 0.022). Numerical improvements in IPSS scores were maintained over the OLE phase. Tadalafil was well tolerated with no unexpected adverse events. CONCLUSION: Tadalafil (5.0 mg) had a favorable benefit-to-risk profile, supporting further investigation of tadalafil (5.0 mg) in Japanese men with BPH-LUTS.

Improved glycemic control and reduced bodyweight with exenatide: A double-blind, randomized, phase 3 study in Japanese patients with suboptimally controlled type 2 diabetes over 24 weeks.

UNLABELLED: Aims/Introduction: To evaluate the efficacy and safety of the glucagon-like peptide-1 receptor agonist, exenatide, in Japanese patients with type 2 diabetes mellitus suboptimally controlled despite therapeutic doses of a sulfonylurea alone or combined with a biguanide or thiazolidinedione. MATERIALS AND METHODS: Patients were randomized to a placebo or exenatide, either 5 or 10 µg, given subcutaneously b.i.d. in addition to oral therapy. Patients randomized to 10 µg exenatide received 5 µg b.i.d. for the first 4 weeks, followed by 10 µg b.i.d. for the last 20 weeks. RESULTS: A total of 179 patients received the study drug and composed the full analysis set (n = 35, placebo; n = 72, exenatide 5 µg; n = 72, exenatide 10 µg; 68% male; 58 ± 10 years; body mass index 25.5 ± 4.1 kg/m(2); HbA1c 8.2 ± 0.9%; means ± standard deviations). Baseline to end-point (least-squares means ± standard errors) HbA1c changes (%) were -0.28 ± 0.15 (placebo), -1.34 ± 0.11 (exenatide 5 µg) and -1.62 ± 0.11 (exenatide 10 µg) (both P < 0.001, exenatide vs placebo). Baseline to end-point bodyweight changes (kg) were -0.47 ± 0.39 (placebo), -0.39 ± 0.28 (exenatide 5 µg) and -1.54 ± 0.27 (exenatide 10 µg; P = 0.026, exenatide 10 µg vs placebo). Nausea, generally mild to moderate, was reported in 8.6% (placebo), 25.0% (exenatide 5 µg) and 36.1% (exenatide 10 µg) of patients. Mild to moderate hypoglycemia was reported in 22.9% (placebo), 51.4% (exenatide 5 µg) and 58.3% (exenatide 10 µg) of patients. CONCLUSIONS: Over 24 weeks, exenatide vs the placebo improved glycemic control, reduced bodyweight (10 µg) and was well tolerated in Japanese patients with type 2 diabetes mellitus suboptimally controlled, despite oral therapy including a sulfonylurea. This trial was registered with ClinicalTrials.gov (no. NCT00577824). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00084.x, 2011).