Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.

BACKGROUND: Weight reduction is essential for improving health outcomes in people with obesity and type 2 diabetes. We assessed the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, versus placebo, for weight management in people living with obesity and type 2 diabetes. METHODS: This phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m2 or higher and glycated haemoglobin (HbA1c) of 7-10% (53-86 mmol/mol) were randomly assigned (1:1:1), using a computer-generated random sequence via a validated interactive web-response system, to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. All participants, investigators, and the sponsor were masked to treatment assignment. Coprimary endpoints were the percent change in bodyweight from baseline and bodyweight reduction of 5% or higher. The treatment-regimen estimand assessed effects regardless of treatment discontinuation or initiation of antihyperglycaemic rescue therapy. Efficacy and safety endpoints were analysed with data from all randomly assigned participants (intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT04657003. FINDINGS: Between March 29, 2021, and April 10, 2023, of 1514 adults assessed for eligibility, 938 (mean age 54·2 years [SD 10·6], 476 [51%] were female, 710 [76%] were White, and 561 [60%] were Hispanic or Latino) were randomly assigned and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315). Baseline mean bodyweight was 100·7 kg (SD 21·1), BMI 36·1 kg/m2 (SD 6·6), and HbA1c 8·02% (SD 0·89; 64·1 mmol/mol [SD 9·7]). Least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was -12·8% (SE 0·6) and -14·7% (0·5), respectively, and -3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of -9·6% percentage points (95% CI -11·1 to -8·1) with tirzepatide 10 mg and -11·6% percentage points (-13·0 to -10·1) with tirzepatide 15 mg (all p<0·0001). More participants treated with tirzepatide versus placebo met bodyweight reduction thresholds of 5% or higher (79-83% vs 32%). The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group, but deaths were not considered to be related to the study treatment by the investigator. INTERPRETATION: In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management. FUNDING: Eli Lilly and Company.

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.

Conversations and reactions around severe hypoglycemia (CRASH) global survey of people with type 1 diabetes or insulin-treated type 2 diabetes and caregivers: Findings from the French cohort.

AIM: The objective of the CRASH (Conversations and Reactions Around Severe Hypoglycemia) survey was to further our understanding of the characteristics, experience, behavior and conversations with healthcare professionals (HCPs) of people with diabetes (PWD) receiving insulin, and of caregivers (CGs) caring for such people, concerning hypoglycemia requiring external assistance (severe hypoglycemic events [SHEs]). METHODS: CRASH was an online cross-sectional survey conducted across eight countries. PWD with self-reported type 1 (T1D) or insulin-treated type 2 (T2D) diabetes were aged≥18 years and had experienced one or more SHEs in the past 3 years; CGs were non-medical professionals aged ≥18 years, caring for PWD meeting all the above criteria except for PWD age (≥4 rather than ≥18 years). The present report is a descriptive analysis of data from France. RESULTS: Among PWD who had ever discussed SHEs with an HCP, 38.9% of T1D PWD and 50.0% of T2D PWD reported that SHEs were discussed at every consultation; 26.3% and 8.8%, respectively, had not discussed the most recent SHE with an HCP. In total, 35.7% of T1D PWD and 53.8% of T2D PWD reported that glucagon was not available to them at the time of their most recent SHE. Only 16.9% of T1D PWD and 6.5% of T2D PWD who had discussed their most recent SHE with an HCP reported that the HCP recommended obtaining a glucagon kit or asked them to confirm that they already had one. High proportions of PWD and CGs reported that the most recent SHE had made them feel unprepared, scared and helpless and had affected mood, emotional state and activities. CONCLUSION: CRASH survey data from France identify a need for greater discussion about SHEs between HCPs and PWD and the CGs of such people, and reveal gaps in the diabetes education of PWDs and CGs.

Perceptions of insulin therapy in people with type 2 diabetes and physicians: a cross-sectional survey conducted in France.

OBJECTIVE: To evaluate perceptions of people with type 2 diabetes (T2D) and treating physicians living in France toward insulin therapy. METHODS: Adults with T2D receiving oral glucose-lowering treatment alone (INS-) or basal insulin for ≥2 months (INS+) completed an online cross-sectional survey comprising 39 questions, including some regarding perceptions and fears of insulin therapy. Physicians were interviewed by telephone using eleven similar questions. The survey was designed by French clinicians experienced in treating diabetes and conducted under the auspices of an independent market-research agency. RESULTS: The questionnaire was completed by 590 adults with T2D (two-thirds INS+) and 130 physicians (65 diabetologists/endocrinologists, 65 general practitioners). INS+ adults reported fewer negative feelings and more positive feelings than INS- adults. Two-thirds of INS+ adults reported that transitioning to insulin therapy was less difficult than expected. Overall, 44% of INS+ adults and 26% of physicians reported a fear of diabetic complications as being important, and 80% of physicians and 21% of INS+ adults considered injections to be a major patient fear. CONCLUSION: Most people with T2D reported that transitioning to insulin therapy was less difficult than they had feared. People with T2D and physicians exhibited differing perceptions regarding the transition. Reasons for the apprehension surrounding the transition to insulin therapy in people with T2D need to be better identified. Support from insulin-treated peers may enable this transition to occur with fewer anxieties in insulin-naïve people with T2D.

Growth Hormone Treatment for Short Stature in the USA, Germany and France: 15 Years of Surveillance in the Genetics and Neuroendocrinology of Short-Stature International Study (GeNeSIS).

BACKGROUND/AIMS: To describe characteristics, auxological outcomes and safety in paediatric patients with growth disorders treated with growth hormone (GH), for cohorts from the USA, Germany and France enrolled in GeNeSIS, a post-authorisation surveillance programme. METHODS: Diagnosis and biochemical measurement data were based on reporting from, and GH treatment was initiated at the discretion of, treating physicians. Auxological outcomes during the first 4 years of GH treatment and at near-adult height (NAH) were analysed. Serious and treatment-emergent adverse events were described. RESULTS: Children in the USA (n = 9,810), Germany (n = 2,682) and France (n = 1,667) received GH (dose varied between countries), most commonly for GH deficiency. Across diagnostic groups and countries, mean height velocity standard deviation score (SDS) was > 0 and height SDS increased from baseline during the first 4 years of treatment, with greatest improvements during year 1. Most children achieved NAH within the normal range (height SDS >-2). No new or unexpected safety concerns were noted. CONCLUSION: GH treatment improved growth indices to a similar extent for patients in all three countries despite variations in GH doses. Data from these three countries, which together contributed > 60% of patients to GeNeSIS, indicated no new safety signals and the benefit-risk profile of GH remains unchanged.

[LY2963016 insulin glargine: The first biosimilar insulin approved in the European Union]. / Développement des biosimilaires de l'insuline : exemple de l'insuline glargine LY2963016.

Biosimilars are not generics. They are similar, but not exactly identical to the biological reference product. The development plan of a biosimilar should assess the physical, chemical and biological properties (quality), as well as toxicological (safety), pharmacodynamic, pharmacokinetic, and clinical (efficacy and safety) characteristics of the biosimilar developed. The development of generics requires bioequivalence studies in healthy volunteers. Abasaglar®, a biosimilar of insulin glargine, is the first insulin biosimilar approved in the European Union. Phase III studies, ELEMENT 1 in patients with type 1 diabetes mellitus and ELEMENT 2 in patients with type 2 diabetes mellitus, showed LY2963016 insulin glargine to have similar efficacy and a comparable safety profile to the insulin glargine Lantus®. Policies for interchangeability/substitutability between a biosimilar and the reference product are decided at national level in Europe (LFSP, ANSM).

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.

Water and electrolyte disorders at long-term post-treatment follow-up in paediatric patients with suprasellar tumours include unexpected persistent cerebral salt-wasting syndrome.

BACKGROUND: Patients with brain tumours have a high risk of water and electrolyte disorders (WED). Postsurgery diabetes insipidus (DI) may be transient or permanent, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt-wasting syndrome (CSWS) are usually transient. METHODS: Retrospective study, including patients with suprasellar tumours, treated at Hôpital Necker, Institut Gustave-Roussy or Institut Curie, in Île-de-France, between 2007 and 2011. WED were noted if they persisted >1 month after surgery. RESULTS: 159 patients were included, 54.1% girls, 43.9% boys. Tumour types were: glioma (43.4%), craniopharyngioma (43.4%), germinoma (11.3%), others (1.9%). Age at diagnosis was 7.1 ± 4.6 years. The median time from end of treatment was 1.9 (0-7.8) years. DI was the most frequent disorder after tumour treatment (50.3%) and was significantly associated with surgery (p < 0.001). Persistent CSWS was present in 3.6%, persistent SIADH in 1.3%. Two cases of hypernatraemia were due to adipsia. Thyrotropin deficiency after treatment was noted in 68.9% of patients tested, adrenocorticotropin deficiency in 66.2%. CONCLUSIONS: Patients with suprasellar tumours have a high incidence of long-term WED, mainly DI. Assessment of thyrotroph and corticotroph function, and thirst sensation, is necessary to diagnose and manage these disorders correctly. CSWS may be persistent in few patients and requires special attention to prescribe the appropriate care.