Efficacy and Safety Evaluation of Human Growth Hormone Therapy in Patients with Idiopathic Short Stature in Korea - A Randomised Controlled Trial.

BACKGROUND: This trial evaluated the efficacy and safety of growth hormone (GH) therapy (Norditropin®; Novo Nordisk, Bagsværd, Denmark) in paediatric patients with idiopathic short stature (ISS) in Korea. METHODS: This was an open-label, parallel-group, multicentre, interventional trial (ClinicalTrials.gov identifier: NCT01778023). Pre-pubertal patients (mean age 6.2 years; height, 107.1 cm) were randomised 2:1 to 12 months' GH treatment (0.469 mg/kg/week; group A, n=36) or 6 months untreated followed by 6 months' GH treatment (group B, n=18). Safety analysis was based on adverse events (AEs) in all GH-treated patients. RESULTS: After 6 months, height velocity (Ht-V), change in both height standard deviation score (Ht-SDS) and insulin-like growth factor 1 (mean difference [95% confidence interval {CI}]: 5.15 cm/year [4.09, 6.21]; 0.57 [0.43, 0.71]; 164.56 ng/mL [112.04, 217.08], respectively; all p<0.0001) were greater in group A than in group B. Mean difference in Ht-V for 0-6 months versus 6-12 months was 2.80 cm/year (95% CI 1.55, 4.04) for group A and -4.60 cm/year (95% CI -6.12, -3.09; both p<0.0001) for group B. No unexpected AEs were reported. CONCLUSIONS: During the first 6 months, height was significantly increased in GH-treated patients versus untreated patients with ISS. Safety of GH was consistent with the known safety profile.

Self-Treated Hypoglycemia in Type 2 Diabetes Mellitus: Results from the Second Wave of an International Cross-Sectional Survey.

INTRODUCTION: The aim of this study was to assess the total frequency of self-treated hypoglycemia in type 2 diabetes mellitus patients using regimens including basal insulin analogs, and to describe the psychological impact and behavioral response to these events from the perspective of patients and prescribers (i.e., hospital specialists and primary care physicians). METHODS: The global attitude of patients and physicians 2 (GAPP2) survey was an online multinational, cross-sectional survey of patients with type 2 diabetes mellitus treated with basal insulin analogs, with or without bolus insulin. Prescribers directly involved in the care of these patients were also surveyed. Here, we report the results of the second wave of the GAPP2 survey, in which the primary variable of interest was self-treated hypoglycemia. RESULTS: A total of 855 patients and 1003 prescribers, from 7 countries, completed the survey. Overall, 28% of patients had experienced self-treated hypoglycemia during the previous 30 days, with two-thirds of events occurring during the day and one-third of events occurring nocturnally. Prescribers reported discussing events with 55% of patients over this period. Patients worried about self-treated hypoglycemia in a range of situations, and prescribers under-estimated this worry. Many patients who had experienced self-treated hypoglycemia in the last 30 days reported missing (19%), mistiming (7%), or reducing (7%) their basal insulin dose as a result. CONCLUSION: Self-treated hypoglycemia was relatively common in patients using basal insulin analogs, with or without bolus insulin. Whilst the frequency of hypoglycemia was greater during the daytime than at night, patients worried more about nocturnal events and this level of worry was under-estimated by physicians. Additional advice and support may be needed for both patients and prescribers, to reduce the frequency and impact of self-treated hypoglycemia. FUNDING: Novo Nordisk.

Safety, tolerability, and efficacy of insulin aspart in people with type 2 diabetes, as biphasic insulin aspart or with Basal insulin: findings from the multinational, non-interventional a1chieve study.

INTRODUCTION: The aim of the study was to investigate the clinical safety and effectiveness of starting insulin aspart (aspart) therapy in people with type 2 diabetes mellitus (T2DM) as a sub-analysis of the multinational, non-interventional A1chieve study. METHODS: Insulin-naïve and insulin-experienced people with T2DM in routine clinical care starting aspart alone at baseline and continuing aspart alone, changing to biphasic insulin aspart 30 (aspart premix) or adding a basal insulin by study end, were included. Safety, tolerability, and efficacy were evaluated over 24 weeks. RESULTS: Overall, 3,898 people started aspart at baseline. Of the 3,313 with 24-week data, 1,545 (46.6%) continued with aspart, 1,379 (41.6%) switched to aspart premix, and 214 (6.5%) added basal insulin, while the remainder switched to other regimens. No serious adverse drug reactions were reported. The proportion of participants reporting hypoglycemia decreased from baseline to week 24 in the aspart alone group (11.2% versus 4.1%, p < 0.001) and in the aspart + basal insulin group (13.1% versus 7.5%, p = 0.040), and was 3.7% at week 24 in the aspart premix group. The mean HbA1c decreased from baseline to week 24 (aspart: -2.1 ± 2.0% [-23 ± 22 mmol/mol], aspart premix: -2.3 ± 1.7% [-25 ± 19 mmol/mol], aspart + basal insulin: -2.0 ± 2.1% [-22 ± 23 mmol/mol]; p < 0.001). CONCLUSION: Insulin aspart therapy was well tolerated and was associated with improved glucose control over 24 weeks in people with T2DM.

Type 2 diabetes mellitus management and body mass index: experiences with initiating insulin detemir in the a1chieve study.

INTRODUCTION: This sub-analysis of the A1chieve study aimed to examine the safety and efficacy of insulin detemir (IDet) initiation over 24 weeks in relation to baseline body mass index (BMI) in people with type 2 diabetes mellitus (T2DM). METHODS: A1chieve was a 24-week non-interventional study to assess the safety and efficacy of insulin analogs in routine practice. This sub-analysis included insulin-naïve patients who initiated IDet therapy based on their physicians' decision. Patients were stratified according to baseline BMI (Group I, <25.0 kg/m(2); Group II, 25.0 to <30.0 kg/m(2); Group III, 30.0 to <35.0 kg/m(2); Group IV ≥35.0 kg/m(2)). Safety and efficacy variables were assessed over 24 weeks. RESULTS: Overall, 10,650 insulin-naïve patients were included (3,045 patients in Group I, 4,186 patients in Group II, 2,365 patients in Group III, and 1,054 patients in Group IV). Four serious adverse drug reactions (SADRs) were reported. From baseline to Week 24, there was no statistically significant difference in the proportion of patients reporting overall hypoglycemia in Group I (4.0% vs. 4.4%), while a significant decrease in Group II (4.8% vs. 4.0%, p = 0.0335) and significant increases in Groups III and IV (3.3% vs. 5.4% and 3.4% vs. 7.0%, respectively, p < 0.001) were noted. The mean body weight increased from baseline to Week 24 in Group I (60.7 ± 8.4 vs. 61.8 ± 8.5 kg) and reduced in Groups II, III, and IV (74.5 ± 9.2 vs. 74.2 ± 9.2 kg, 87.4 ± 10.3 vs. 86.0 ± 9.8 kg, and 102.2 ± 14.3 vs. 100.1 ± 14.2 kg, respectively; all p < 0.001). Significant improvements were noted in glycemic parameters, systolic blood pressure, and lipids over 24 weeks, irrespective of baseline BMI status. CONCLUSION: IDet therapy was associated with improved glycemic control and a low number of SADRs. Greater weight loss was observed with higher BMI.

Prevalence of diabetes complications in people with type 2 diabetes mellitus and its association with baseline characteristics in the multinational A1chieve study.

BACKGROUND: Current International Diabetes Federation guidelines recommend a target HbA1c <7.0%, but many people with diabetes worldwide find this difficult to achieve, increasing their risk of developing complications. This publication examines the prevalence of diabetes complications and its association with baseline characteristics in people with type 2 diabetes who participated in the A1chieve study. METHODS: A1chieve was a 24-week, multinational, open-label, observational study of 66,726 people with type 2 diabetes who had begun using biphasic insulin aspart 30, insulin aspart, or insulin detemir in routine clinical care. Participants were enrolled from 28 countries across four continents (Asia, Africa, Europe and South America). Baseline measurements of disease characteristics included: glycated haemoglobin (HbA1c), fasting (FPG) and post-prandial plasma glucose (PPG), high- and low-density lipoprotein cholesterol (H- or LDL-C), systolic blood pressure (SBP), and body mass index (BMI). Data on complications and use of vascular disease preventative drugs were collected. RESULTS: Complication rates were high (27.2% had macrovascular complications and 53.5% had microvascular complications), particularly in Russia, and use of vascular disease preventative drugs was lower than expected. Age, BMI, diabetes duration, LDL-C, and SBP were positively associated, and HDL-C negatively associated, with macro- and microvascular complications (all p < 0.05). HbA1c and FPG were negatively associated with macrovascular complications (both p < 0.05), which may be linked to the cross-sectional study design. CONCLUSIONS: These results suggest a worldwide failure to achieve glycaemic targets. Better diabetes management with earlier initiation and optimisation of insulin regimens (e.g., with insulin analogues in the A1chieve population) may reduce the prevalence of vascular complications, improve the lives of people with diabetes and reduce the burden on healthcare systems.

The effectiveness and safety of beginning insulin aspart together with basal insulin in people with type 2 diabetes in non-Western nations: results from the A1chieve observational study.

AIMS: The aim of this A1chieve sub-group analysis was to examine populations beginning insulin aspart together with any basal insulin, all ± oral glucose lowering drugs: insulin aspart added to existing basal insulin (n=519); switched from biphasic insulin (n=947); switched from NPH plus human meal-time insulins (n=586); and insulin-naïve begun with basal plus insulin aspart (n=1594). METHODS: A1chieve was a 24-week non-interventional study evaluating insulin analogues in 66,726 people with type 2 diabetes in routine clinical care in 28 non-Western countries. Major endpoints were analysed as change from baseline using Student's paired t-test. RESULTS: Baseline glycaemic control was poor (mean HbA1c: 9.4-10.1% [79-87 mmol/mol]). HbA1c, FPG and PPPG improved significantly from baseline in all groups (mean change from baseline in HbA1c: -2.8 to -1.8% [-31 to -20 mmol/mol]; FPG: -4.9 to -2.9 mmol/L; PPPG: -6.7 to -3.9 mmol/L; p<0.001 for all), resulting in a similar level of blood glucose control for all groups at study end. Unsurprisingly, hypoglycaemia rates increased in those starting insulin, but decreased in the other groups. Clinically significant improvements in serum lipids and quality of life occurred across all groups. CONCLUSIONS: These data support the use of basal plus prandial insulin regimens in routine clinical practice in people with type 2 diabetes with inadequate glycaemic control.

Safety and Effectiveness of Switching from a Basal-only to Biphasic Insulin Aspart 30 Insulin Regimen.

PURPOSE: This sub-analysis of the A1chieve study evaluated the safety and effectiveness of changing from a basal-only insulin regimen to biphasic insulin aspart 30. METHODS: A1chieve was an international, multicenter, prospective, open-label, non-interventional, 24-week study in people with type 2 diabetes mellitus starting/switching to therapy with biphasic insulin aspart 30, insulin detemir, or insulin aspart (alone/in combination) in routine clinical practice. This sub-analysis evaluated the safety and effectiveness of switching from basal insulin with either insulin glargine (GLA group) or insulin neutral protamine Hagedorn (NEU group) to biphasic insulin aspart 30. RESULTS: A total of 2,818 participants received biphasic insulin aspart 30 (1,395 in the GLA group and 1,423 in the NEU group). After 24 weeks of treatment, there were significant reductions in the proportion of patients with at least one hypoglycemia event: total [baseline vs. 24 weeks: 15.5% vs. 9.7% (p < 0.001) and 12.3% vs. 9.9% (p < 0.05), in NEU and GLA groups, respectively], major [2.5% vs. 0.08% (p < 0.001) and 1.2% vs. 0.08% (p < 0.001), in NEU and GLA groups, respectively] and nocturnal hypoglycemia [7.2% vs. 3.5% (p < 0.001) and 5.4% vs. 3.9% (p < 0.05), in NEU and GLA groups, respectively]. After 24 weeks of biphasic insulin aspart 30 there were statistically significant improvements from baseline in glycated hemoglobin, fasting plasma glucose, and post-prandial plasma glucose levels (p < 0.001) and in health-related quality of life (p < 0.001) in both groups. CONCLUSIONS: Biphasic insulin aspart 30 may benefit patients with poor glycemic control on basal insulin regimens who are seeking to change treatment.

Safety and effectiveness of insulin detemir in different age-groups in the a1chieve study.

INTRODUCTION: Diabetes therapy should balance glycemic control with risk of adverse events. This sub-analysis of the A1chieve study evaluated clinical safety and effectiveness of insulin detemir in different age-groups (≤40 years, >40-65 years, and >65 years) of insulin-experienced and insulin-naïve people with type 2 diabetes. METHODS: A1chieve was an international, open-label, non-interventional, 24-week study in 66,726 people with type 2 diabetes starting/switching to therapy with biphasic insulin aspart 30, insulin detemir or insulin aspart (alone/in combination) in routine clinical practice. This sub-analysis evaluated clinical safety and effectiveness in patients starting/switching to insulin detemir (±oral glucose-lowering drugs). RESULTS: In total, 15,241 patients were included in the sub-analysis. In all age-groups, the proportion of participants experiencing any, major or nocturnal hypoglycemia was significantly (all p < 0.05) reduced relative to baseline, except in insulin-naïve patients for any and nocturnal hypoglycemia, where there was a significant increase or no significant change in patients aged >65 years and >40-65 years, respectively, and no significant change in major hypoglycemia in insulin-naïve patients aged ≤40 years. Seven serious adverse drug reactions were reported. Body weight was significantly reduced in patients aged ≤40 years and >40-65 years and significantly increased in insulin-naïve patients aged >65 years at 24 weeks. At 24 weeks, glycated hemoglobin was reduced by 2.3%, 2.0%, and 1.8%, in the ≤40 years, >40-65 years, and >65 years age-groups, respectively (all p < 0.001). Fasting and post-prandial plasma glucose were significantly reduced and health-related quality of life (HRQoL) significantly improved across all patient cohorts (all p < 0.001). CONCLUSION: After 24-week treatment with insulin detemir, all age-groups of insulin-experienced and insulin-naïve patients had significantly improved glycemic control and HRQoL. The proportion of patients experiencing hypoglycemia was reduced in all age-groups but unchanged in insulin-naïve patients aged >40-65 years and increased in insulin-naïve patients aged >65 years. The safety and effectiveness of insulin detemir may benefit all age-groups.

Predictors of achieving HbA(1c) <7% and no hypoglycaemia 6 months after initiation of biphasic insulin aspart 30 in patients with type 2 diabetes in the IMPROVE study.

BACKGROUND: Early initiation of insulin therapy has widely been associated with numerous benefits, including improved glycaemic control and reduced long-term risk of developing microvascular diseases. Biphasic insulins offer a convenient option for insulin initiation, addressing both basal and postprandial insulin requirements with one injection, making them relatively simple for patients to dose. Development of biphasic insulin aspart (BIAsp) has further offered improved postprandial glycaemic control and lower rates of nocturnal and major hypoglycaemia than biphasic human insulin. METHODS: The safety and efficacy of the 30/70 rapid-acting/intermediate-acting formulation of BIAsp (BIAsp 30) in patients with type 2 diabetes was examined in the IMPROVE study, a 26-week, international, observational trial. In this subanalysis, baseline clinical factors that predicted treatment success, defined as HbA1c <7% (<53 mmol/mol) without experiencing hypoglycaemia after 26 weeks on BIAsp 30 therapy, were assessed. RESULTS: The composite endpoint was defined for 44,010 (77%) patients from the total cohort of 57,478, and 28,696 of these were included in the statistical examination. The results of the analysis suggest that those with lower baseline HbA1c of ≤8% (≤64 mmol/mol), shorter duration of diabetes at baseline (<5 years) and no incidence of major hypoglycaemia at 13 weeks, or minor hypoglycaemia at 4 weeks, before the beginning of the trial were more likely to achieve treatment success. CONCLUSION: Lower baseline HbA1c, shorter duration of diabetes and no incidence of hypoglycaemia up to 13 weeks prior to initiation are predictors of achieving HbA1c <7% without hypoglycaemia with a BIAsp 30 regimen. These results suggest that it is easier to reach target without hypoglycaemia with BIAsp 30 when prescribed earlier. As this was an observational study, lack of control groups or randomisation, as well as varying clinical practices in study countries, potentially introduced bias. TRIAL REGISTRATION: ClinicalTrials.gov NCT00659282.

Ten years of experience with biphasic insulin aspart 30: from drug development to the latest clinical findings.

Biphasic insulin aspart 30 (BIAsp 30) includes 30% soluble rapid-acting insulin aspart (IAsp) along with an intermediate-acting 70% protaminated IAsp that provides coverage of prandial and basal insulin in a single injection. As BIAsp 30 has been available internationally for 10 years, this review provides a comprehensive overview of the discovery of BIAsp 30, its pharmacokinetic and pharmacodynamic profile, safety and efficacy outcomes from the clinical trial programme, 'real-life' clinical insights provided by observational study data, and cost effectiveness and quality-of-life information. These studies have demonstrated that BIAsp 30 once or twice daily is an appropriate option for insulin initiation. BIAsp 30 also provides a switch option in patients on biphasic human insulin (BHI). Switching from BHI to BIAsp 30 is associated with improved postprandial glucose (PPG) and reduced nocturnal and major hypoglycaemia, although daytime hypoglycaemia is higher with BIAsp 30. Intensification of BIAsp 30 can be achieved by increasing the number of daily doses up to three times daily with meals. Therefore, BIAsp 30 provides an intensification option for individuals who are not achieving control with basal insulin and would prefer the simplicity of a single biphasic insulin instead of progressing to a basal-bolus approach. BIAsp 30 has a simple dose-titration algorithm, which enables patients to effectively self-titrate their insulin dose. Cost-effectiveness analyses have demonstrated that BIAsp 30 is cost effective or dominant compared with BHI 30 or insulin glargine in a number of healthcare settings. In conclusion, BIAsp 30 offers a simple and flexible option for insulin initiation and intensification that provides coverage of both fasting and prandial glucose.

Peri-operative management of glucose.

It is generally agreed that it is important to control blood glucose levels during the peri-operative period. However, there have been controversies surrounding the appropriateness of each regimen, as well as ideal glucose targets during surgery. This review focuses on a simple and practical strategy to control glucose during surgery, and sets out simple guidelines on instituting an insulin infusion protocol. From the available evidence, a fasting plasma glucose < 90 mg/dl, postprandial glucose < 180 mg/dl and an HbA1c < 7% is ideal before elective surgery. The blood glucose must be maintained between 140 and 180 mg/dl during the operative period as well as during the intensive care unit (ICU stay). Sliding scales are inappropriate for in-hospital glucose control. A basal-bolus insulin regimen is ideal for hospitalised peri-operative subjects outside the ICU. In the ICU, it is best to use an insulin infusion protocol for glucose control. The ideal regimen should be individualised for each patient. The success of peri-operative glucose control requires teamwork between the various medical personnel involved in patient care.

Quality of life as a key indicator of patient satisfaction and treatment compliance in people with type 2 diabetes mellitus in the IMPROVE study: a multicentre, open label, non-randomised, observational trial.

Diabetes is a debilitating chronic illness having multiple impacts on physical and mental well-being of patients. When treating chronic conditions like diabetes, psychosocial aspects and quality of life (QoL) have to be considered; however, these receive less attention due to various reasons. Patients with diabetic complications have increased levels of depression and decreased QoL This necessitates evaluating QoL of patient which now is used as a primary or secondary end point in clinical trials eg, Diab-MedSat QoL questionnaire used in diabetes. At some point all diabetic patients may require insulin to control hyperglycaemia and disease progression. The traditional insulin syringe and needle delivery system has been the principal barrier in the treatment of diabetes as it was not well accepted among the patients due to various reasons. A success over this approach has been pen like devices like FlexPen and Novopen3 which are becoming more popular than the conventional syringe-and-needles as they have several advantages like, easy to carry, use, maintain and also reduces administrative errors ensuring accurate doses are delivered. The objective of IMPROVE study is to evaluate the safety and effectiveness of biphasic insulin aspart (NovoMix 30) in normal clinical practice conditions, in India. This is an open label, non-randomised, non-interventional, observational, safety and effectiveness study in approximately 17,995 patients with type 2 diabetes mellitus. A cohort of Indian patients (n = 349) from all 4 geographical locations (North, West, East and South of India) were administered QoL instrument Diab-MedSat at baseline and 346 patients at final visit (n = 346) to assess their satisfaction with the treatment they received. The results were included in the final statistical analysis as additional outcome variables. The Diab-MedSat Novo Nordisk June 2004 English (UK) version is used. The Diab-MedSat has 21 items that need to be answered and it is scored as an overall score (all 21 items) as well as three subscale scores regarding burden (11 items), symptoms (5 items), efficacy (5 items). The complete analysis took into account all 21 items of Diab-MedSat questionnaire with their subscales. Analyses of the cohort showed higher patient satisfaction among the patients administered Diab-MedSat questionnaire from baseline (n = 349) to final visit (n = 346). The mean of overall score was 52.33 (baseline visit) versus 79.03 (final visit). The difference in the overall score and sub parameters like burden, symptoms and efficacy between the baseline and final visits were statistically significant (p-value < 0.001). The mean value of difference in overall score between the baseline visit and final visit was 26.73 +/- 20.83; while the difference for burden, symptoms and efficacy were respectively 27.86 +/- 20.81, 19.75 +/- 20.94 and 32.87 +/- 28.08. A fairly clear picture emerged that the use of biphasic insulin aspart resulted in improved QoL of the patients substantially. This is demonstrated in the results for all the parameters that were used like symptoms, efficacy and burden. The overall number of extremely satisfied patients had increased from 5.4% in the baseline visit to 91% in the final visit. This unambiguously proves that the satisfaction of patients on biphasic insulin aspart (NovoMix 30) is beyond question.