Development of a new health-related quality of life measure for people with diabetes who experience hypoglycaemia: the Hypo-RESOLVE QoL.

AIMS/HYPOTHESIS: Valid and reliable patient-reported outcome measures are vital for assessing disease impact, responsiveness to healthcare and the cost-effectiveness of interventions. A recent review has questioned the ability of existing measures to assess hypoglycaemia-related impacts on health-related quality of life for people with diabetes. This mixed-methods project was designed to produce a novel health-related quality of life patient-reported outcome measure in hypoglycaemia: the Hypo-RESOLVE QoL. METHODS: Three studies were conducted with people with diabetes who experience hypoglycaemia. In Stage 1, a comprehensive health-related quality of life framework for hypoglycaemia was elicited from semi-structured interviews (N=31). In Stage 2, the content validity and acceptability of draft measure content were tested via three waves of cognitive debriefing interviews (N=70 people with diabetes; N=14 clinicians). In Stage 3, revised measure content was administered alongside existing generic and diabetes-related measures in a large cross-sectional observational survey to assess psychometric performance (N=1246). The final measure was developed using multiple evidence sources, incorporating stakeholder engagement. RESULTS: A novel conceptual model of hypoglycaemia-related health-related quality of life was generated, featuring 19 themes, organised by physical, social and psychological aspects. From a draft version of 76 items, a final 14-item measure was produced with satisfactory structural (χ2=472.27, df=74, p<0.001; comparative fit index =0.943; root mean square error of approximation =0.069) and convergent validity with related constructs (r=0.46-0.59), internal consistency (α=0.91) and test-retest reliability (intraclass correlation coefficient =0.87). CONCLUSIONS/INTERPRETATION: The Hypo-RESOLVE QoL is a rigorously developed patient-reported outcome measure assessing the health-related quality of life impacts of hypoglycaemia. The Hypo-RESOLVE QoL has demonstrable validity and reliability and has value for use in clinical decision-making and as a clinical trial endpoint. DATA AVAILABILITY: All data generated or analysed during this study are included in the published article and its online supplementary files ( https://doi.org/10.15131/shef. DATA: 23295284.v2 ).

Risk factors and prediction of hypoglycaemia using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials.

AIMS/HYPOTHESIS: The objective of the Hypoglycaemia REdefining SOLutions for better liVES (Hypo-RESOLVE) project is to use a dataset of pooled clinical trials across pharmaceutical and device companies in people with type 1 or type 2 diabetes to examine factors associated with incident hypoglycaemia events and to quantify the prediction of these events. METHODS: Data from 90 trials with 46,254 participants were pooled. Analyses were done for type 1 and type 2 diabetes separately. Poisson mixed models, adjusted for age, sex, diabetes duration and trial identifier were fitted to assess the association of clinical variables with hypoglycaemia event counts. Tree-based gradient-boosting algorithms (XGBoost) were fitted using training data and their predictive performance in terms of area under the receiver operating characteristic curve (AUC) evaluated on test data. Baseline models including age, sex and diabetes duration were compared with models that further included a score of hypoglycaemia in the first 6 weeks from study entry, and full models that included further clinical variables. The relative predictive importance of each covariate was assessed using XGBoost's importance procedure. Prediction across the entire trial duration for each trial (mean of 34.8 weeks for type 1 diabetes and 25.3 weeks for type 2 diabetes) was assessed. RESULTS: For both type 1 and type 2 diabetes, variables associated with more frequent hypoglycaemia included female sex, white ethnicity, longer diabetes duration, treatment with human as opposed to analogue-only insulin, higher glucose variability, higher score for hypoglycaemia across the 6 week baseline period, lower BP, lower lipid levels and treatment with psychoactive drugs. Prediction of any hypoglycaemia event of any severity was greater than prediction of hypoglycaemia requiring assistance (level 3 hypoglycaemia), for which events were sparser. For prediction of level 1 or worse hypoglycaemia during the whole follow-up period, the AUC was 0.835 (95% CI 0.826, 0.844) in type 1 diabetes and 0.840 (95% CI 0.831, 0.848) in type 2 diabetes. For level 3 hypoglycaemia, the AUC was lower at 0.689 (95% CI 0.667, 0.712) for type 1 diabetes and 0.705 (95% CI 0.662, 0.748) for type 2 diabetes. Compared with the baseline models, almost all the improvement in prediction could be captured by the individual's hypoglycaemia history, glucose variability and blood glucose over a 6 week baseline period. CONCLUSIONS/INTERPRETATION: Although hypoglycaemia rates show large variation according to sociodemographic and clinical characteristics and treatment history, looking at a 6 week period of hypoglycaemia events and glucose measurements predicts future hypoglycaemia risk.

STYLCONNECT Study: An Assessment of Automatic Data Collection Devices by People Living with Diabetes and Using an Insulin Pen.

INTRODUCTION: The use of devices to connect insulin pens could facilitate management and improve glycaemic control in people with type 1 (PwT1D) and type 2 diabetes (PwT2D). However, their acceptance seems little studied. We conducted an online survey with the main objective of assessing the level of interest among insulin-treated people with diabetes (PwD) in a device connected to a disposable pen and secondary objectives of assessing the perceived benefits and important features expected of a connected device and identifying factors associated with interest scores. METHODS: An ad-hoc questionnaire, validated by PwD, was used. Responses from 1798 PwD (975 PwT1D and 823 PwT2D) were analysed. RESULTS: The mean interest rating was 7.4/10 (PwT1D: 7.2 vs PwT2D: 7.7; p < 0.001). PwD perceived that the device would make it easier to record their diabetes-related information (7.7/10) and keep all insulin and diabetes data in a single location (7.7/10). It was particularly important for PwD that this type of device could integrate data from glucose-measuring devices (7.8/10) and could set an alarm when all insulin in the body had been metabolised (7.7/10). CONCLUSION: Our study highlighted PwD's strong interest in automating the collection of their insulin therapy data, with significantly more interest among PwT2D than PwT1D, and the importance of interoperability between glucose measurement devices and interchangeability between the different brands of insulin. More generally, for the first time and on a large scale, our study provided a greater understanding of the expectations of PwD regarding these devices.

Producing a preference-based quality of LIFE measure to quantify the impact of HYPOGLYCAEMIA on people living with diabetes: A mixed-methods research protocol.

BACKGROUND: Assessment of patient-reported outcome measures (PROMs), including quality of life (QoL), is essential in diabetes research and care. However, a recent review concluded that current hypoglycaemia-specific PROMs have limited evidence of validity, reliability and responsiveness for assessing the impact of hypoglycaemia on QoL in people living with diabetes. None of the PROMs identified could be used directly to inform the cost-effectiveness of treatments and interventions. There is a need for a new hypoglycaemia-specific QoL PROM, which can be used directly to inform economic evaluations. AIMS: This project has three aims: (a) To develop draft PROM content for measuring the impact of hypoglycaemia on QoL in adults with diabetes. (b) To refine the draft content using cognitive debriefing interviews and psychometrics. This will result in a condition-specific PROM that can be used to quantify the impact of hypoglycaemia upon QoL. (c) To generate a preference-based measure (PBM) that will enable utility values to be calculated for economic evaluation. METHODS: A mixed-methods, three-stage design is used: (a) Qualitative interviews will inform the draft PROM content. (b) Cognitive debriefing interview data will be used to refine the draft PROM content. The PROM will be administered in a large-scale survey to enable psychometric validation. Final item selection for the PROM will be informed by psychometric performance, translatability assessment and input from stakeholder groups. (c) A classification system will be generated, comprising a reduced number of items from the PROM. A valuation survey will be conducted to derive a value set for the PBM.

The Real-World Observational Prospective Study of Health Outcomes with Dulaglutide and Liraglutide in Type 2 Diabetes Patients (TROPHIES): Design and Baseline Characteristics.

INTRODUCTION: The TROPHIES observational study enrolled patients with type 2 diabetes mellitus (T2DM) initiating their first injectable treatment with the glucagon-like peptide 1 receptor agonists (GLP-1 RAs) dulaglutide or liraglutide. This manuscript focuses on the study design, baseline characteristics of the enrolled population, and factors associated with GLP-1 RA choice. METHODS: TROPHIES is a prospective, observational, 24-month study conducted in France, Germany, and Italy. Inclusion criteria include adult patients with T2DM, naïve to injectable antihyperglycemic treatments, initiating dulaglutide or liraglutide per routine clinical practice. The primary outcome is the duration of treatment on dulaglutide or liraglutide without a significant treatment change. RESULTS: The analysis included 2181 patients (dulaglutide, 1130; liraglutide, 1051) (cutoff date May 15, 2019). The population was 56% male with mean [standard deviation (SD)] patient characteristics at baseline as follows: age, 59.2 (11.0) years; body mass index (BMI), 33.9 (6.6) kg/m2; T2DM duration, 8.5 (6.9) years; and glycated hemoglobin (HbA1c), 8.2 (1.3)%. Between-cohort demographic and clinical characteristics were balanced. The mean (SD) HbA1c and BMI values for French, German, and Italian patients were, respectively, 8.6 (1.4)%, 8.2 (1.4)%, 8.0 (0.8)%; 33.3 (6.1) kg/m2, 36.0 (7.2) kg/m2, and 32.6 (5.9) kg/m2. CONCLUSION: This study analysis at baseline provides an opportunity to evaluate between-country differences in baseline HbA1c, weight, macrovascular complications, and factors driving GLP-1 RA selection for patients with T2DM in daily practice.

Dulaglutide and liraglutide are medications that can help people with type 2 diabetes mellitus (T2DM) to control their blood sugar levels. These medications may also reduce body weight and reduce the risk of major cardiovascular disease. Given these treatment effects, it is essential to know how they are used in everyday clinical practice. Therefore, a study is being performed in three countries (France, Germany, and Italy) in people with T2DM who had a first-ever injectable therapy for T2DM with dulaglutide or liraglutide. Here, we present the study design, the patient characteristics at the start of treatment, and the factors driving the choice of one or the other medication. We analyzed data from 2181 people with T2DM. On average, it was shown that they were middle-aged and obese. On average, these people were diagnosed with T2DM 8.5 years before the start of dulaglutide or liraglutide and had high blood sugar levels when these medications were started. The patient characteristics were slightly different between the three countries. Country-specific factors driving the choice of either medication were also identified.

Treatment Patterns and Persistence With GLP-1 RA Treatments Among Patients With Type 2 Diabetes in France: A Retrospective Cohort Analysis.

INTRODUCTION: In type 2 diabetes (T2D), persistence with injectable glucose-lowering therapy is associated with better outcomes. This study used real-world pharmacy data to report on persistence with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with T2D in France. METHODS: This retrospective cohort analysis presents longitudinal data from approximately 7500 French retail pharmacies that filled GLP-1-RA prescriptions for GLP-1 RA-naïve patients with T2D ('index therapy': dulaglutide; once-weekly exenatide [exenatide QW]; twice-daily exenatide [exenatide BID]; liraglutide) between January 2015 and December 2016 (follow-up ≥ 12 months). The main outcome was treatment persistence (absence of discontinuation [gap following index therapy prescription ≥ 2-fold the expected duration of that prescription] or switch [new non-index glucose-lowering prescription issued ≤ 30 days before/after index therapy discontinuation]). Persistence was calculated as the median duration through Kaplan-Meier survival analysis over the variable follow-up period and as the proportion of patients persistent at 12 months. In addition to persistence outcomes (discontinuation/switch), three other treatment modifications were assessed: augmentation/intensification with a new non-index glucose-lowering therapy; off-label dose increase (daily dose > 20 µg for exenatide BID; two consecutive prescriptions with daily dose > 1.8 mg for liraglutide); and off-label dose decrease (two consecutive prescriptions with average daily dose lower than the index dose). Off-label dose changes were not assessed for dulaglutide or exenatide QW (as single-dose, prefilled pens). RESULTS: Median persistence was longest for dulaglutide (373 days) versus liraglutide (205 days), exenatide QW (184 days) and exenatide BID (93 days). Twelve months after treatment initiation, the percentage of persistent patients ranged from 51% (dulaglutide) to 21% (exenatide BID). Overall, treatment modification occurred less commonly for dulaglutide than for the other index GLP-1 RAs. CONCLUSION: This analysis revealed marked differences in persistence among GLP-1 RAs, which was highest for dulaglutide and lowest for exenatide BID. The prospective TROPHIES study will provide additional information about persistence with dulaglutide and liraglutide, including reasons for treatment modifications.

Patients with type 2 diabetes (T2D) who continue to take injectable glucose-lowering therapy for the duration of time recommended by their physician (i.e. those who are 'persistent') usually have better outcomes than those who do not. Persistence may be quantified as the "the duration of time from initiation to discontinuation of therapy". Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are glucose-lowering agents that are often used as the first injectable drug if oral treatments are no longer effective. The aim of the current study was to use data from approximately 7500 retail pharmacies to report persistence with each of four GLP-1 RAs (dulaglutide, once-weekly exenatide [exenatide QW], twice-daily exenatide [exenatide BID] or liraglutide) in GLP-1 RA-naïve patients with T2D in France. Patients (N = 15,074) initiated treatment between January 2015 and December 2016 and were followed for ≥ 12 months. The total duration of follow-up varied among patients. Among patients, persistence over the variable follow-up period was highest for dulaglutide and lowest for exenatide BID: median persistence was longer for dulaglutide (373 days) than for liraglutide (205 days), exenatide QW (184 days) or exenatide BID (93 days). Twelve months after treatment initiation, the percentage of persistent patients ranged from 51% (dulaglutide) to 21% (exenatide BID), with intermediate values for exenatide QW (35%) and liraglutide (36%). This analysis has revealed marked differences in the persistence of patients for various GLP-1 RAs, with patients on dulaglutide showing the highest persistence and those on exenatide BID the lowest.

The Real-World Observational Prospective Study of Health Outcomes with Dulaglutide and Liraglutide in Type 2 Diabetes Patients (TROPHIES): Baseline Patient-Reported Outcomes.

INTRODUCTION: Although patient-reported outcome (PRO) measures provide important information beyond clinical data, studies that assess the PROs of type 2 diabetes mellitus (T2DM) patients initiating injectable glucose-lowering medications in routine clinical practice are limited. We describe the perspectives of patients based on a diversified panel of generic and disease-specific PRO measures at the time of enrollment (baseline) in the TROPHIES study. METHODS: TROPHIES is a 24-month prospective observational study performed in France, Germany, and Italy in patients with T2DM who initiated their first injectable glucose-lowering medication with once-weekly dulaglutide or once-daily liraglutide. To better understand the perspectives of these patients regarding their overall health, treatment satisfaction, and quality of life and work, the patients' responses to the following questionnaires were collected at baseline before they initiated treatment with dulaglutide or liraglutide: EQ-5D-5L (scale: 0-1), EQ-VAS (visual analog scale: 0-100), Impact of Weight on Self-Perceptions Questionnaire (IW-SP; scale: 0-100), Diabetes Treatment Satisfaction Questionnaire Status (DTSQs; scale: 0-36), and Diabetes Productivity Measure (DPM; scale: 0-100). Analyses were descriptive in nature, with higher scores reflecting better outcomes. RESULTS: Data from patients at the time of enrollment were analyzed. At baseline, patients initiating dulaglutide (N = 1130) or liraglutide (N = 1051) rated their quality of life in terms of mean EQ-5D-5L index as 0.84 and 0.83, and in terms of mean EQ-VAS as 67.5 and 67.5, respectively. The mean baseline scores in patients initiating dulaglutide or liraglutide were 59.8 and 61.3 for IW-SP, 24.6 and 25.8 for DTSQs, 78.6 and 79.5 for DPM Life Productivity, and 87.5 and 86.8 for DPM Work Productivity, respectively. CONCLUSION: The information from this varied panel of PRO instruments collected at baseline complements clinical outcomes data.

Growth hormone in combination with leuprorelin in pubertal children with idiopathic short stature.

OBJECTIVE: There is a scarcity of data from randomised controlled trials on the association of growth hormone (GH) with gonadotrophin-releasing hormone agonists in idiopathic short stature (ISS), although this off-label use is common. We aimed to test whether delaying pubertal progression could increase near-adult height (NAH) in GH-treated patients with ISS. METHODS: Patients with ISS at puberty onset were randomised to GH with leuprorelin (combination, n = 46) or GH alone (n = 45). NAH standard deviation score (SDS) was the primary outcome measure. The French regulatory authority requested premature discontinuation of study treatments after approximately 2.4 years; patients from France were followed for safety. RESULTS: Mean (s.d.) baseline height SDS was -2.5 (0.5) in both groups, increasing at 2 years to -2.3 (0.6) with combination and -1.8 (0.7) with GH alone. NAH SDS was -1.8 (0.5) with combination (n = 19) and -1.9 (0.8) with GH alone (n = 16). Treatment-emergent adverse events and bone fractures occurred more frequently with combination than GH alone. CONCLUSION: Due to premature discontinuation of treatments, statistical comparison of NAH SDS between the two cohorts was not possible. During the first 2-3 years of treatment, patients treated with the combination grew more slowly than those receiving GH alone. However, mean NAH SDS was similar in the two groups. No new GH-related safety concerns were revealed. A potentially deleterious effect of combined treatment on bone fracture incidence was identified.

20 Years of insulin lispro in pediatric type 1 diabetes: a review of available evidence.

BACKGROUND: Insulin lispro, the first rapid-acting insulin analog, was developed 20 years ago and has been studied in multiple situations and various populations. OBJECTIVE: To review the literature on the use of insulin lispro in children, adolescents, and young adults. PATIENTS: Children, adolescents, and young adults with type-1-diabetes. METHODS: One hundred and twenty-two relevant publications, identified by a systematic (MEDLINE) and manual literature search, were reviewed. RESULTS: Multiple daily injection (MDI) treatment with insulin lispro or other rapid-acting insulins, mainly using neutral protamine Hagedorn (NPH) insulin as the basal component, was associated with reduced postprandial glucose excursions, similar or improved HbA1c levels, and similar or reduced risks of severe hypoglycemia when compared with regular human insulin across all age-groups. Continuous subcutaneous insulin infusion (CSII)-treatment with insulin lispro also showed similar or improved glycemic control vs. MDI- or other CSII-regimens across all age-groups, without increasing the rate of severe hypoglycemia. The other two more recently developed rapid-acting insulins (aspart, glulisine) demonstrated non-inferiority to lispro on HbA1c. Long-term observational studies and real-life experience indicate that the increasing use of optimized MDI- and CSII-regimens with insulin lispro was associated with improvements in overall glycemic control. CONCLUSIONS: For almost 20 years, rapid-acting insulins, in particular insulin lispro as the first-in-class, have contributed to broadening the treatment options for the unique needs of pediatric patients with type-1-diabetes across all age-groups, and have enabled more physiological insulin administration. Now widely used, they have allowed pediatric patients to safely reach better glycemic control, with more flexibility in their daily lives.

Safety Outcomes and Near-Adult Height Gain of Growth Hormone-Treated Children with SHOX Deficiency: Data from an Observational Study and a Clinical Trial.

BACKGROUND/AIMS: To assess auxological and safety data for growth hormone (GH)-treated children with SHOX deficiency. METHODS: Data were examined for GH-treated SHOX-deficient children (n = 521) from the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). For patients with near-adult height information, GeNeSIS results (n = 90) were compared with a clinical trial (n = 28) of SHOX-deficient patients. Near-adult height was expressed as standard deviation score (SDS) for chronological age, potentially increasing the observed effect of treatment. RESULTS: Most SHOX-deficient patients in GeNeSIS had diagnoses of Leri-Weill syndrome (n = 292) or non-syndromic short stature (n = 228). For GeNeSIS patients with near-adult height data, mean age at GH treatment start was 11.0 years, treatment duration 4.4 years, and height SDS gain 0.83 (95% confidence interval 0.49-1.17). Respective ages, GH treatment durations and height SDS gains for GeNeSIS patients prepubertal at baseline (n = 42) were 9.2 years, 6.0 years and 1.19 (0.76-1.62), and for the clinical trial cohort they were 9.2 years, 6.0 years and 1.25 (0.92-1.58). No new GH-related safety concerns were identified. CONCLUSION: Patients with SHOX deficiency who had started GH treatment before puberty in routine clinical practice had a similar height gain to that of patients in the clinical trial on which approval for the indication was based, with no new safety concerns.

Genotype-Phenotype Relationship in Patients and Relatives with SHOX Region Anomalies in the French Population.

BACKGROUND: The aim of our study was to describe a large population with anomalies involving the SHOX region, responsible for idiopathic short stature and Léri-Weill dyschondrosteosis (LWD), and to identify a possible genotype/phenotype correlation. METHODS: We performed a retrospective multicenter study on French subjects with a SHOX region anomaly diagnosed by multiplex ligation-dependent probe amplification or Sanger sequencing. Phenotypes were collected in each of the 7 genetic laboratories practicing this technique for SHOX analysis. RESULTS: Among 205 index cases and 100 related cases, 91.3% had LWD. For index cases, median age at evaluation was 11.7 (9.0; 15.9) years and mean height standard deviation score was -2.3 ± 1.1. A deletion of either SHOX or PAR1 or both was found in 74% of patients. Duplications and point mutations/indels affected 8 and 18% of the population, respectively. Genotype-phenotype correlation showed that deletions were more frequently associated with Madelung deformity and mesomelic shortening in girls, as well as with presence of radiologic anomalies, than duplications. CONCLUSIONS: Our results highlight genotype-phenotype relationships in the French population with a SHOX defect and provide new information showing that clinical expression is milder in cases of duplication compared to deletions.

Ten-year change in quality of life in adults on growth hormone replacement for growth hormone deficiency: an analysis of the hypopituitary control and complications study.

CONTEXT: Previous studies showed improvement in impaired quality of life (QoL) in adult patients with growth hormone (GH) deficiency (GHD) who were treated with GH; improvement was sustained over a few years after GH therapy. OBJECTIVE: To evaluate the QoL over 10 years. DESIGN: This was a prospective observational study. SETTING: The study was conducted in clinical practice. PATIENTS: 1436 adult patients with adult-onset (AO) GHD (mean age [standard deviation (SD)]: 49.0 [12.2] years; 49% female) and 96 with childhood-onset (CO) GHD (31.3 [10.0] years; 60% female) (total N = 1532). INTERVENTION: GH therapy. MAIN OUTCOME MEASURES: QoL was measured by Questions on Life Satisfaction-Hypopituitarism (QLS-H) in countries where validated questionnaires and normative data for calculation of Z-scores were available. Change in QoL was tested by Student's t test and predicted by mixed-model repeated measures (MMRM) analysis. RESULTS: At study entry, patients had diminished QoL Z-scores (mean [SD] AO, -1.55 [1.69]; CO -0.98 [1.32]). The largest QoL improvements were in the first year: mean (SD) increase 0.77 (1.37) for AO (P < .001) and 0.50 (1.37) for CO (P < .001). The initial improvement from study entry remained statistically significant throughout 10 years for AO and in years 1 to 4, 6, and 7 for CO (P < .05). MMRM analysis predicted a greater QoL improvement in those who were not depressed, lived in Europe, had poorer Z-scores at entry, had lower body mass index at entry, and had no impaired vision. CONCLUSION: These data suggest that GH replacement provides sustained improvement in QLS-H scores toward normality for up to 10 years.

How can the quality of medical data in pharmacovigilance, pharmacoepidemiology and clinical studies be guaranteed?

The development of medicinal products is subject to quality standards aimed at guaranteeing that database contents accurately reflect the source documents. Paradoxically, these standards hardly address the quality of the source data itself. The objective of this work was to propose recommendations to improve data quality in three fields (pharmacovigilance, pharmacoepidemiology and clinical studies). The analysis was focused on the data and on the critical stages presenting critical quality problems, for which the current guidelines are insufficiently detailed, unsuitable and/or poorly applied. Finally, recommendations have been proposed, mainly focused on the origin of the data and its transcription.

Genotypes and phenotypes of children with SHOX deficiency in France.

CONTEXT: The prevalence of SHOX deficiency in children with short stature (SS) is variable in the literature and various genotypes have been identified. OBJECTIVES: The aim of our study was to determine the frequency and distribution of SHOX genotypes in a large sample of children with SS in France. DESIGN, SETTING, AND PATIENTS: Children were enrolled in 38 French pediatric endocrinology centers and were either diagnosed with Leri-Weill syndrome (LWS), idiopathic short stature (ISS), or disproportionate short stature (DSS). INTERVENTION AND MAIN OUTCOME MEASURE: SHOX analysis was performed centrally as part of the Genetics and Neuroendocrinology of Short Stature International Study observational study. We compared patients with (SHOX-D) and without SHOX deficiency (non-SHOX-D). RESULTS: Among the 537 patients tested [58.3% females, mean age 11.0 (4.2) yr], 27.7% had SHOX deficiency (LWS, 48.9%; ISS, 16.9%; DSS, 18.8%). Mean height [-2.3 (0.9) sd score] was similar in SHOX-D and non-SHOX-D patients. The majority of SHOX-D patients with LWS had either a deletion encompassing SHOX or a point mutation (69%), whereas 59% of those with ISS had a deletion downstream of SHOX in the enhancer region. The height of the parents carrying a deletion downstream of SHOX was higher than the height of the parents carrying the other gene anomalies. CONCLUSIONS: SHOX deletions and point mutations as well as downstream SHOX enhancer deletions were identified in almost one third of the patients tested. An anomaly in this latter region seemed to be linked to a milder phenotype. Although further confirmation is needed, we suggest that the enhancer region should be systematically analyzed in patients suspected of SHOX deficiency.

Clinical and radiological characteristics of 22 children with SHOX anomalies and familial short stature suggestive of Léri-Weill Dyschondrosteosis.

AIMS: To describe genetic, clinical, anthropometric and radiological characteristics of 22 children with SHOX gene anomalies and familial short stature suggestive of Léri-Weill dyschondrosteosis. METHODS: Monocentric retrospective observational study. RESULTS: Six children (27%) presented with deletions located downstream of SHOX (mean height -1.4 ± 0.9 SDS) and 16 (68%) with either deletions encompassing SHOX, intragenic deletions or point mutations of SHOX (mean patient height for the 3 latter types of anomalies: -2.6 ± 0.8 SDS). In our sample, the two most frequently observed dysmorphic signs were clinical and/or radiological Madelung deformity (86%) and high arched palate (77%). Half the girls were born small for gestational age. Sixteen children treated with recombinant growth hormone had an increase in height from -2.7 ± 0.7 to -1.4 ± 0.7 SDS. Four children achieved adult height (-2.0 ± 0.9 SDS) with a gain over baseline height of 1.0 ± 0.5 SDS after a mean treatment duration of 5.8 ± 2.1 years. CONCLUSION: Patients shared common clinical, anthropometric and radiological signs but their height deficit varied, depending on the type of the SHOX gene anomaly. Due to the small size of our sample, our findings need to be confirmed in a larger population of patients.

Effect of recombinant human growth hormone on intestinal absorption and body composition in children with short bowel syndrome.

This prospective study aimed to establish the effect of recombinant human growth hormone (rhGH) on intestinal function in children with short bowel syndrome (SBS). Eight children with neonatal SBS were included. All were dependent on parenteral nutrition (PN) for >3 years (range, 3.8-11.6 years), with PN providing >50% of recommended dietary allowance for age (range, 50%-65%). The subjects received rhGH (Humatrope) 0.13 mg/kg/d subcutaneously over a 12-week period. The follow-up was continued over a 12-month period after rhGH discontinuation. Clinical and biological assessments were performed at baseline, at the end of the treatment period, and 12 months after the end of treatment. No side effects related to rhGH were observed. PN requirements were decreased in all children during the course of rhGH treatment. Between baseline and the end of treatment, significant increases were observed in concentrations (mean ± standard deviation) of serum insulin-like growth factor 1 (103.1 ± 49.9 µg/L vs 153.5 ± 82.2 µg/L; P < .01), serum insulin-like growth factor-binding protein 3 (1.7 ± 0.6 mg/L vs 2.5 ± 0.9 mg/L; P < .001), and plasma citrulline (16.5 ± 14.8 µmol/L vs 25.2 ± 18.3 µmol/L; P < .05). A median 54% increase in enteral intake (range, 10%-244%) was observed (P < .001) and net energy balance improved significantly (P < .002). It was necessary for 6 children to be maintained on PN or restarted after discontinuation of rhGH treatment, and they remained on PN until the end of the follow-up period. A 12-week high-dose rhGH treatment allowed patients to decrease PN, but only 2 patients could be definitively weaned from PN. Indications and cost-effectiveness of rhGH treatment for SBS pediatric patients need further evaluation.

Growth hormone treatment for short stature in children born small for gestational age.

Children born small for gestational age (SGA) who do not show catch-up in the first 2 years generally remain short for life. Although the majority of children born SGA are not growth hormone (GH) deficient, GH treatment is known to improve average growth in these children.Early studies using GH in children born SGA demonstrated increased height velocity, but these effects tended to be short-term with effects decreasing when GH treatment stopped. With refined GH regimens, significant effects on height have been shown, with gains of approximately 1 standard deviation score after 2 years. Studies have also shown that long-term continuous GH therapy can significantly increase final height to within the normal range. GH treatment of children born SGA does not appear to unduly affect bone age or pubertal development. Growth prediction models have been used to identify various factors involved in the response to GH therapy with age at start, treatment duration, and GH dose showing strong effects. Genetic factors such as the exon 3 deletion of the GH receptor may contribute to short stature of children born SGA and may also be involved in the responsiveness to GH treatment, but there remain other unknown genetic and/or environmental factors. No unexpected safety concerns have arisen in GH therapy trials. In particular, no long-term adverse effects have been seen for glucose metabolism, and positive effects have been shown for lipid profiles and blood pressure.GH treatment in short children born SGA has shown a beneficial, growth-promoting effect in both the short-and long-term, and has become a recognized indication in both the US and Europe. Further studies on individualized treatment regimens and long-term safety are ongoing.

[State of unmet medical needs in France in 2006: necessity of reinforcing research effort]. / Besoins médicaux non couverts en France en 2006: l'effort de recherche doit être poursuivi.

Leem (French Pharmaceutical Companies) realized an inventory of unmet medical needs in 2006 in France for 12 pathologies. All of them are considered as national public health priorities by the law of August 9th, 2004. Allied to the epidemiological projections, analyses concerned various stages and/or pathology forms, impact of guidelines in clinical practice, therapeutic strategies, marketed therapeutics and pharmacological products in an advanced phase of clinical development. With more than 100 products listed in clinical phase III or pre-registration/marketed for those pathologies, French Pharmaceutical Companies contribute, quasi exclusively, to the development of innovative pharmaceutical products to answer unmet medical needs. This study illustrates the necessity of French Government to support therapeutic innovation led by Pharmaceutical Companies in France.

Adult height of prepubertal short children born small for gestational age treated with GH.

OBJECTIVE: Human GH (hGH) treatment leads to catch-up growth in children with short stature born small for gestational age (SGA). However, long-term efficacy and safety results in this patient group remain scarce. The present study assessed the efficacy and safety of late childhood treatment with biosynthetic hGH (Humatrope) in a group of short children born SGA (height <-2 standard deviation scores (SDS)). DESIGN: Patients in this open-label, Phase III, multicenter study received a daily hGH dose of 0.067 mg/kg for 2 years, and then received no treatment for the following 2 years. After the fourth year on study, patients whose height had decreased more than 0.5 SDS but who still showed growth potential based on bone age were allowed to resume treatment until they reached adult height. METHODS: Height gain SDS was assessed for 11 girls and 24 boys (mean age+/-s.d. 9.6+/-0.9 years) at the end of the 2 years of hGH treatment, during the subsequent 2-year off-treatment period, and upon reaching adult height. RESULTS: At the end of the initial 2-year treatment period, 83% of patients had reached a height within the normal range, with a mean increase in height SDS vs baseline of 1.3+/-0.3 (P <0.001). Adult heights (n = 20) were within the normal range for 50% of patients, and mean height gain from baseline was statistically significant (0.7+/-0.8 SDS, P <0.001). Fasting glucose and glycosylated hemoglobin levels were not significantly modified during treatment. CONCLUSIONS: High-dose hGH treatment for a minimum of 2 years in short children born SGA was well tolerated and resulted in a significant increase in adolescent and adult height.