Ped endo journal scan

Efficacy and safety of tirzepatide in children and adolescents with type 2 diabetes (SURPASS-PEDS): A randomized, double-blind, placebo-controlled, phase 3 trial

Hannon TS, Chao LC, Barrientos-Pérez M, Pamidipati KC, Landó LF, Lee CJ, et al. Lancet. 2025 Oct 4;406(10511):1484-1496.

Objective: The objective of this study was to investigate the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, compared with placebo in participants with youth-onset type 2 diabetes (T2D) inadequately controlled with metformin and/or basal insulin.

Study Methodology and Results: This was a phase 3, randomized, double-blind, parallel-group, placebo-controlled trial that investigated the efficacy and safety of once-weekly tirzepatide compared with placebo for 30 weeks, followed by an open-label extension to 52 weeks, during which all participants received tirzepatide. Participants were 10–<18 years of age with a bodyweight of at least 50 kg and body mass index (BMI) >85^th percentile of the age- and sex-matched population for that country or region and were diagnosed with T2D (glycated hemoglobin [HbA1c] >6.5% to ≤11% at screening) and treated with lifestyle measures and metformin (≥1000 mg/day) and/or basal insulin. Participants were randomly assigned (1:1:1) to receive once-weekly tirzepatide (5 mg or 10 mg) or volume-matched placebo administered by subcutaneous injection with a single-dose pen. The primary endpoint was the change in HbA1c from baseline to week 30 for pooled tirzepatide doses (5 and 10 mg) compared with placebo. Key secondary efficacy endpoints (controlled for type I error) were changes in HbA1c for tirzepatide compared with placebo (for individual doses); and for both individual and pooled doses: incidence of HbA1c 6.5% or lower, change from baseline in fasting serum glucose and BMI standard deviation score (BMI-SDS; age- and sex-matched), and percentage change from baseline in BMI at week 30. A total of 99 participants were randomly assigned to receive tirzepatide 5 mg (n = 32), tirzepatide 10 mg (n = 33), or placebo (n = 34). At week 30, mean HbA1c had decreased by 2.23% in the pooled tirzepatide group versus an increase of 0.05% in the placebo group (estimated treatment difference [ETD] −2.28%; 95% confidence interval −2.87–−1.69; P < 0.0001). Both doses of tirzepatide were superior to placebo, with an ETD of −2.21% (−2.89–−1.53; P < 0.0001) for 5 mg and −2.35% (−3.03–−1.66; P < 0.0001) for 10 mg. The percentage of participants with HbA1c below 7% at week 30 was 84% and 92% in the tirzepatide 5 mg and 10 mg groups versus 34% in the placebo group; the percentage of participants with HbA1c 6.5% or lower at week 30 was 71% and 86% in the tirzepatide 5 mg and 10 mg groups versus 28% in the placebo group. Glycemic efficacy on tirzepatide treatment was sustained over 52 weeks, with 2.1% and 2.3% reductions in HbA1c for tirzepatide 5 mg and 10 mg. Tirzepatide (pooled and individual doses) was superior to placebo for percentage change in BMI and BMI-SDS. At 30 weeks, the tirzepatide 5 mg and 10 mg groups showed mean percentage reductions in BMI of 7.4% and 11.2%, respectively, compared with 0.4% in the placebo group. Reductions in BMI and BMI-SDS continued up to 52 weeks for participants assigned to tirzepatide, with mean reductions in BMI of 8.9% and 15.1% and in BMI-SDS of 0.7 and 1.1 for tirzepatide 5 mg and 10 mg, respectively. At 30 weeks, tirzepatide groups had substantial reductions in triglycerides and total, low-density lipoprotein, and very low-density lipoprotein cholesterol compared with no change or small increases in the placebo group. Adverse events were reported by 44% of the placebo group, 66% of the tirzepatide 5 mg group, and 70% of the tirzepatide 10 mg group of which gastrointestinal side effects were most commonly reported. Two (6%) patients in the tirzepatide 5 mg group discontinued study drug due to an adverse event. The safety profile of tirzepatide was consistent with that reported in adults.

Critical Review: This is an important study that provides evidence for the use of additional pharmacotherapy options for youth with T2D, who have limited therapeutic options. Compared with typical HbA1c and weight effects seen with GLP-1 monotherapy in adolescents, tirzepatide’s dual GIP+GLP-1 mechanism appears to produce greater weight loss and larger HbA1c reductions in this trial. However, head-to-head pediatric comparisons with semaglutide or other agents are lacking. In addition, the small sample size and underrepresentation of other minority and ethnic youth limit the generalizability of the results. Long-term follow-up studies are warranted to confirm these findings and provide additional evidence of long-term safety and impact on weight, cardiometabolic risk factors and microvascular complications of pediatric T2D.

Insulin for early glycemic abnormality in children with cystic fibrosis without cystic fibrosis-related diabetes: A randomized controlled trial

Hameed S, Barnes EH, Briody J, Wainwright CE, Hilton J, Field PI, et al. Lancet Child Adolesc Health. 2025 Jun;9(6):371-382.

Objective: The objective of this study was to establish whether early insulin therapy has beneficial effects on weight gain, lung function, and other relevant outcomes in children and adolescents with cystic fibrosis (CF).

Study Methodology and Results: This was a multicenter, randomized controlled trial (RCT) conducted in five children’s hospitals in Australia and one in the USA. Eligible participants between the ages of 5–18 years with either CF, insulin deficiency stage 1 (defined as a peak glucose 8.2–11.0 mmol/L, on a five-point oral glucose tolerance test [OGTT]) or stage 2 (peak glucose ≥11.1 mmol/L) were randomly assigned (1:1) to insulin or observation. Participants in the insulin group received once-daily, long-acting insulin detemir by subcutaneous injection before breakfast, starting at 0.1 units/kg/day, and adjusted in 0.5-unit increments to achieve all fingerstick blood glucose concentrations between 4 mmol/L and 8 mmol/L. The primary outcome measures were absolute changes in weight Z-score, percentage predicted forced expiratory volume in 1 s (ppFEV1), and percentage predicted forced vital capacity (ppFVC). One hundred and nine participants were randomly assigned to either observation (n = 54) or insulin (n = 55) groups. Five participants withdrew after the baseline visit; therefore, 104 were included in the analysis. Only 8% of participants (five in the observation and three in the insulin group) received CF transmembrane conductance regulator (CFTR) modulator treatment during the trial. The median daily insulin dose in the insulin group at 6 months was 0.12 units per kg per day (range, 0.07–0.45) and at 12 months was 0.12 units/kg/day (range, 0.05–0.41). Participants in the insulin and observation groups showed no statistically or clinically significant differences in the changes in weight Z-score, ppFEV1, and ppFVC. Analyses of the CF insulin deficiency stage 1 and stage 2 glycemic subgroups did not reveal any statistically or clinically significant differences between study groups, with no evidence of interaction between the subgroup and treatment on outcome measures. Continuous glucose monitor (CGM) percentage time with glucose >7.8 mmol/L and other CGM measures at the 6-month visit were similar between the observation and insulin groups. There were no episodes of severe hypoglycemia and no reported adverse events relating to insulin use. There was no evidence of difference between the observation and insulin groups in the proportion of CGM time <3.9 mmol/L.

Critical Review: This study is the first RCT to assess the usefulness of early insulin initiation in CF patients with dysglycemia. Contrary to previous small, uncontrolled studies suggesting a benefit, this study found no evidence of statistically or clinically significant differences in weight Z-score or lung function between treatment and observation groups when once-daily insulin detemir was given to children and adolescents aged 5–18 years with CF who had peak glucose of more than or equal to 8.2 mmol/L during five-point OGTT but not CF-related diabetes. The lack of a placebo control group introduces potential bias. In addition, interpretation must consider the limited use of CFTR modulators during enrollment and potential under-dosing or adherence issues with once-daily detemir. Overall, CF-IDEA convincingly refutes early insulin therapy as routine practice in pre-diabetic CF, marking an important evidence-based shift in clinical management.

Growth hormone treatment adjusted for growth hormone sensitivity in idiopathic short stature

Kruijsen AR, Wit JM, de Groote K, Punt LD, van Trotsenburg AS, Pijnenburg-Kleizen KJ, et al. Eur J Endocrinol. 2025 Jun 30;193(1):156-166.

Objective: The objective of this study was to investigate the long-term growth responses to recombinant human growth hormone (rhGH) in children with idiopathic short stature (ISS), decreased insulin-like growth factor I (IGF-1) levels, and a normal stimulated growth hormone (GH) peak, after assessing their GH sensitivity using the IGF-1 generation test (IGFGT).

Study Methodology and Results: This was a retrospective descriptive case series, which included data from 129 patients. IGFGT was performed on children with a serum IGF-1 <−2.0 standard deviation score (SDS) on two separate occasions, and the stimulated GH peak >10 µg/L. Children were subsequently categorized as having normal (group 1), intermediate (group 2) or low (group 3) GH sensitivity. The suggested rhGH dosage for long-term treatment of group 1 was 0.7–1.0 mg/m² (≈0.025–0.035 mg/kg/day) and 1.0–1.4 mg/m² for groups 2–3 (≈0.035–0.050 mg/kg/day). One hundred and six patients were prepubertal during 1 year of follow-up and showed a similar increase in height SDS (combined average 0.8 ± 0.4 SDS), height velocity (4.0 ± 2.1 cm/year), and predicted adult height (PAH) (0.6 ± 0.7 SDS) in all groups, although with lower rhGH doses in group 1 (P = 0.001). Similar patterns were seen in the 23 pubertal patients with an increase in height of 0.6 ± 0.4 SDS, height velocity of 2.8 ± 1.4 cm/year, and PAH of 0.7 ± 0.1 SDS, with lower rhGH doses in group 1 (P = 0.034). In the multivariate analysis for Δ height SDS, the model showed an association with age at start (β = −0.06, P = 0.001) and being pubertal (β = 0.269, P = 0.043). Three-year responses in 81 patients also showed a similar increase in height (1.5 ± 0.6 SDS) in all groups. Height velocity was highest in the first year (9.8 ± 1.8 cm/year), decreased to 7.2 ± 1.1 cm/year in the 3^rd year of treatment, but was still significantly higher than pre- treatment (mean difference

3.6 ± 3.0 cm/year, P < 0.001). Of the 58 patients who reached near adult height, average height at discontinuation was −1.0 ± 1.0 SDS, which was 2.1 ± 0.8 SDS higher than at start and only 0.3 ± 0.9 SDS lower than target height.

Critical Review: This study demonstrated that the IGFGT can be used to assess GH sensitivity in children with ISS and then guide rhGH treatment with improved growth outcomes. However, the three-step IGFGT is a cumbersome and labor-intensive procedure limiting its use. With increasing accessibility of comprehensive genetic testing, a genetics-first approach may be a more efficient and informative strategy before considering IGFGT.

Gonadal function and its evolution in 46,XX testicular/ovotesticular disorders of sex development

Sepich M, Bertelloni S, Tyutyusheva N, Lucas-Herald A, Mazen I, Cools M, et al. J Clin Endocrinol Metab. 2025 Nov 3:dgaf603.

Objective: The objective of this study was to understand the natural history of gonadal function in cases of 46,XX testicular disorders of sex development (T-DSD) and ovotesticular DSD (OT-DSD) that had been recruited to international DSD Registry (I-DSD).

Study Methodology and Results: This was a retrospective review of 46,XX cases of T-DSD or OT-DSD registered in the I-DSD registry. The clinical, biochemical features, and gonadal outcomes of these cases were reported. The study included 61 cases, of which 29 had a diagnosis of T-DSD and 32 of OT-DSD. At birth, the male gender was assigned to 24 (83%) of the T-DSD individuals, and the female gender to 4 (14%). Of the 32 cases with OT-DSD, those registered as male and female were 18 (56%) and 13 (40%), respectively. Genetic results were available in 34 (56%). Of these, 13 (38%) were positive for SRY, all with T-DSD. In the remainder, three had a SF1 variant (missense, R92W) and there was one case each of an X chromosome duplication KANK1 deletion (chr 9), DMRT1 duplication, and SOX3 duplication. All SRY-positive cases were T-DSD while, of the 21 SRY negative cases, 10 were T-DSD and 11 OT-DSD. A total of 14 individuals underwent gonadal removal, 10 unilateral and 4 bilateral. Of the 10 out of 14 where a reason for gonadectomy was reported, six were for gender conforming, two for gender conforming and tumor risk mitigation, and two for tumor risk mitigation only. Of the 18 males over 14 years of age, 14 had information on pubertal development. Of these, 7 (50%) had spontaneous onset of puberty, while 7 (50%) required pubertal induction (two of them had gonadal removal). Of the four females who were over 14 years old at the time of the study, two had spontaneous puberty while two required pubertal induction. In 8/9 (89%) male and 1/2 (50%) female adolescents and adults, serum gonadotropins were above the reference range. However, in 8/9 (89%) males, serum testosterone was within the reference range. In 34 cases with available data, gonadal tumors had not been reported at a median age of 11.3 years.

Critical Review: This study examines a large international cohort of 46 individuals with 46,XX T-DSD and OT-DSD. The data demonstrate a gradual trend toward deterioration in gonadal function in both T-DSD and OT-DSD, as evidenced by rising gonadotropins and low anti-Müllerian hormone in boys, despite relative preservation of androgen production. While this study sheds important light on the gonadal phenotype in a rare cause of DSD, the heterogeneous cohort, the retrospective data collection, and the lack of standardized follow-up limit a thorough understanding of the natural history of this condition.

Adjunct-to-insulin therapy using sodium-glucose cotransporter 2 inhibitors in youth with type 1 diabetes: A randomized controlled trial

Mahmud FH, Bjornstad P, Clarson C, Clarke A, Anthony SJ, Curtis J, et al. Nat Med. 2025 Jul;31(7):2317-2324.

Objective: The objective of this study was to evaluate the effect of dapagliflozin, compared to placebo, as an adjunct to insulin on measured glomerular filtration rate (mGFR) and glycemic control, as well as safety outcomes in youth with type 1 diabetes (T1D).

Study Methodology and Results: This was a multicenter, double-blind, randomized, placebo-controlled trial conducted in Canada and the USA, which enrolled participants between the ages of 12 and 21 years who had T1D for more than 12 months. Participants were randomized in a 1:1 ratio to daily dapagliflozin 5 mg or its equivalent placebo for a 16-week treatment period alongside ketone monitoring and diabetic ketoacidosis (DKA) risk mitigation education. The intervention phase was preceded by a 4-week pre-treatment period and followed by a 2-week post-treatment period, for a 22-week evaluation. The primary outcome was the change in mGFR using iohexol clearance. A total of 98 participants were recruited and randomized to receive either dapagliflozin (n = 49) or placebo (n = 49) from January 2021 to September 2023, and 97 (99%) completed the trial by February 2024. Dapagliflozin significantly reduced mGFR by an average of −8.8 mL/min 1.73 m⁻² when compared to placebo (95% confidence interval [CI]: −12.7–−4.8; P < 0.0001) after adjusting for baseline mGFR and site. Dapagliflozin decreased glycated hemoglobin (HbA1c) by 0.47% (95% CI: −0.66–−0.28; P < 0.0001) compared to placebo. The effect was more pronounced in participants with higher baseline HbA1c. No differences in total daily insulin dose were observed with dapagliflozin versus placebo. Dapagliflozin treatment resulted in weight reduction of −2.8 kg (95% CI: −3.7–−2.0; P < 0.0001) and body mass index (BMI) reduction of −1.2 kg m⁻² (95% CI: −1.72–−0.65; P < 0.0001) when compared to placebo as well as a reduction in BMI Z-score of −0.18 among pediatric participants (95% CI: −0.27–−0.09; P < 0.001). Dapagliflozin was well tolerated, with no study-related serious adverse events reported. One confirmed case of ketoacidosis was reported in the dapagliflozin arm.

Critical Review: This is one of the first RCTs exploring the therapeutic potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors in youth with T1D and demonstrates a reduction in mGFR and improved glycemic outcomes when used with careful DKA mitigation. Strengths include a rigorous design, high adherence, and the use of measured GFR, which is rarely done in youth studies. However, the relatively short treatment period limits the interpretation of long-term renal or safety outcomes, and the relatively low baseline HbA1c and prevalence of hyperfiltration restrict generalizability. Overall, findings are promising but warrant longer, adequately powered studies to define durability and safety of SGLT2 inhibitors in youth with T1D.