Safety and Efficacy of Efruxifermin in Combination With a GLP-1 Receptor Agonist in Patients With NASH/MASH and Type 2 Diabetes in a Randomized Phase 2 Study.

BACKGROUND & AIMS: In phase 2 studies, efruxifermin, an Fc-FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with non-alcoholic steatohepatitis, now called metabolic dysfunction-associated steatohepatitis (MASH), for which there is no approved treatment. Type 2 diabetes (T2D) and obesity are prevalent among patients with MASH and increasingly treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This study evaluated the safety and efficacy of efruxifermin in patients with MASH, fibrosis, and T2D taking a GLP-1RA. METHODS: Cohort D was a double-blind, placebo-controlled, phase 2b study in adults with T2D and MASH with fibrosis (F1-F3) on stable GLP-1RA therapy randomized (2:1) to receive efruxifermin 50 mg or placebo, once weekly for 12 weeks. The primary endpoint was safety and tolerability of efruxifermin added to a stable dose of GLP-1RA. Secondary endpoints included changes in hepatic fat fraction (HFF), markers of liver injury and fibrosis, and metabolic parameters. RESULTS: Adults (N = 31) with T2D and MASH fibrosis (F1-F3) on a stable GLP-1RA (semaglutide, 48.4%; dulaglutide, 45.2%; liraglutide, 6.5%) received efruxifermin 50 mg (n = 21) or placebo (n = 10) for 12 weeks. The addition of efruxifermin to a GLP-1RA appeared safe and well-tolerated. The most frequent efruxifermin-related adverse events were mild to moderate gastrointestinal events. One patient receiving efruxifermin discontinued due to nausea, and another withdrew consent. There were no treatment-related serious adverse events. After 12 weeks, efruxifermin reduced HFF by 65% (P < .0001 vs placebo) compared with a 10% reduction for placebo (GLP-1RA alone). Efruxifermin also improved noninvasive markers of liver injury, fibrosis, glucose, and lipid metabolism while maintaining GLP-1RA-mediated weight loss. CONCLUSIONS: The tolerability profile of efruxifermin added to GLP-1RA appeared comparable to that of either drug alone, while also significantly reducing HFF and noninvasive markers of fibrosis in patients with MASH and T2D. Liver health in patients already on a GLP-1RA may be further improved by addition of efruxifermin. CLINICALTRIALS: gov, Number: NCT05039450.

An Examination of Sex Differences in a Disease-Specific Model of Disordered Eating Behaviors in Type 1 Diabetes.

OBJECTIVE: Preliminary evidence supports the integration of type 1 diabetes (T1D) disease-specific factors into eating disorder risk models. The current study explored whether cross-sectional associations among constructs included in the modified dual pathway model of eating disorder risk for individuals with T1D are similar across sex among adolescents and young adults with T1D. METHODS: Original study participants were recruited from the T1D Exchange Clinic Network, a U.S. registry of individuals with T1D. Online surveys included measures of general eating disorder risk factors, hypothesized T1D-specific risk factors, and a T1D-specific eating disorder questionnaire. The current study is a secondary analysis with the adolescents (13-17 years; n = 307; 46.9% female) and young adults (18-25 years; n = 313; 62.6% female) from the original sample. In the absence of strong measurement invariance for all measures of interest, sex-specific path models were estimated among the adolescent and young adult cohorts. RESULTS: Only two paths emerged as significant in the female, but not male, adolescent model. In the young adult cohort, all significant paths were the same across sex. CONCLUSIONS: Both general and T1D-specific risk factors are associated with disordered eating behaviors in the T1D population. Patterns of associations were similar across male and female youth with T1D, suggesting that sex-specific prevention approaches to disordered eating behaviors among T1D youth may not be warranted.

School-Based Management of Pediatric Type 1 Diabetes: Recommendations, Advances, and Gaps in Knowledge.

PURPOSE OF REVIEW: Children and adolescents with type 1 diabetes (T1D) spend much of their waking time in the school environment. However, there is limited empirical understanding of the challenges youth face in managing their T1D at school. There is even less literature focused on potential interventions to improve health or psychological outcomes in youth with T1D in this milieu. This review seeks to summarize the recent literature on diabetes T1D management in the school setting, including recommendations for care, barriers, and targets for intervention. RECENT FINDINGS: T1D organizations recommend strong collaboration amongst families, school personnel, and health care providers to enable successful T1D management in schools. While challenges remain according to parent, child, and teacher reports, perceptions of school-based management of T1D show signs of improvement. The few existing school-based intervention studies have generally focused on educational or structural interventions to improve diabetes care. The management of T1D within the school setting is critical for overall diabetes management. While barriers to effective T1D care have been examined, a greater understanding of the impact of new diabetes technologies and well-characterized interventions is lacking in this area.

Test of the modified dual pathway model of eating disorders in individuals with type 1 diabetes.

OBJECTIVE: Adolescents and young adults with type 1 diabetes (T1D) demonstrate high rates of disordered eating behaviors (DEBs) and may experience physiological and psychological vulnerabilities not currently included in established risk models of DEBs. This study examined associations among constructs included in the recently proposed T1D-specific modified dual pathway model and examined age as a moderator of these associations. METHOD: Participants included adolescents (n = 307; age M = 15.71, SD = 1.33), young adults (n = 313; age M = 21.20, SD = 2.10), and adults (n = 198; age M = 30.51, SD = 2.81) recruited via the T1D Exchange Clinic Registry. Data were collected from participants' medical records and from self-report questionnaires assessing dietary regimen, dietary restraint, body dissatisfaction, hunger/satiety, diabetes-specific negative affect, and DEBs. Multiple group path modeling was used to test hypotheses. RESULTS: Approximately 31% of participants were at risk for an eating disorder. The original modified dual pathway model had poor model fit. The addition of three empirically defensible paths improved model fit. Diabetes-specific dietary regimen, diabetes-specific negative affect, and hunger/satiety disruption all were associated with DEBs. A fully varying multiple group model by age fit best; however, only the dietary restraint to DEBs pathway demonstrated a distinct pattern across age cohort, which attenuated from the adolescent to the adult cohort. DISCUSSION: This study provides preliminary support for associations proposed in the modified dual pathway model and suggests potential for intervening on disease-specific risk factors of DEBs in a T1D population.

Oxandrolone for the treatment of bone marrow failure in Fanconi anemia.

BACKGROUND: A majority of Fanconi anemia (FA) patients will experience bone marrow failure (BMF) and androgen therapy (most often oxymetholone) may be utilized as a treatment to improve BMF-related cytopenias. However, oxymetholone is associated with toxicities making identification of other agents of interest. In this study we aimed to evaluate the toxicity profile and hematologic response in patients with FA who are treated with low-dose oxandrolone, a synthetic non-fluorinated anabolic steroid, similar to oxymetholone, with known dosing thresholds for virilization. PROCEDURE: A single arm, Phase I/II study was designed to treat patients on low-dose oxandrolone. If no toxicity or hematologic response was noted at 16 weeks, a single dose escalation was offered. Subjects were regularly assessed for toxicity, including determinations of virilization, behavioral changes, and liver and kidney function. At 32 weeks, those who demonstrated hematologic response were allowed to continue study treatment, and those without improvement were deemed non-responsive. RESULTS: Nine subjects completed the study and were followed for a median of 99 weeks (46-136 weeks). Three (33.3%) subjects developed mild sub-clinical virilization and continued treatment with a dose reduction. None (0%) had adverse behavioral changes. Two (22.2%) developed elevated liver function tests at 42 and 105 weeks. Seven (77.8%) subjects had a hematologic response. CONCLUSION: Oxandrolone appears to be well-tolerated, has limited toxicities at the administered doses in FA with patients, and may be an alternative androgen for the treatment of BMF in FA.

Hypopituitarism in pediatric survivors of inflicted traumatic brain injury.

Endocrine dysfunction is common after accidental traumatic brain injury (TBI). Prevalence of endocrine dysfunction after inflicted traumatic brain injury (iTBI) is not known. The aim of this study was to examine endocrinopathy in children after moderate-to-severe iTBI. Children with previous iTBI (n=14) were evaluated for growth/endocrine dysfunction, including anthropometric measurements and hormonal evaluation (nocturnal growth hormone [GH], thyrotropin surge, morning and low-dose adrenocorticotropin stimulated cortisol, insulin-like growth factor 1, IGF-binding protein 3, free thyroxine, prolactin [PRL], and serum/urine osmolality). Analysis used Fisher's exact test and Wilcoxon's rank-sum test, as appropriate. Eighty-six percent of subjects had endocrine dysfunction with at least one abnormality, whereas 50% had two or more abnormalities, significantly increased compared to an estimated 2.5% with endocrine abnormality in the general population (p<0.001). Elevated prolactin was common (64%), followed by abnormal thyroid function (33%), short stature (29%), and low GH peak (17%). High prolactin was common in subjects with other endocrine abnormalities. Two were treated with thyroid hormone and 2 may require GH therapy. In conclusion, children with a history of iTBI show high risk for endocrine dysfunction, including elevated PRL and growth abnormalities. This effect of iTBI has not been well described in the literature. Larger, multi-center, prospective studies would provide more data to determine the extent of endocrine dysfunction in iTBI. We recommend that any child with a history of iTBI be followed closely for growth velocity and pubertal changes. If growth velocity is slow, PRL level and a full endocrine evaluation should be performed.

Association of FTO gene variants with adiposity in African-American adolescents.

The prevalence of obesity continues to increase significantly, with the largest rise in the African-American adolescents. Genetic contributions to obesity are being identified with the advent of genome-wide association studies (GWAS). Specifically, variants of the fat mass and obesity associated (FTO) gene have been associated with obesity in populations of European descent. The studies in African Americans have been inconclusive. To further evaluate the association of the FTO gene and adiposity in African Americans, we genotyped 47 single-nucleotide polymorphisms (SNPs), including seven SNPs previously reported to be significant in the literature in a cohort consisting of 561 non-Hispanic white and 497 African-American individuals. Analysis of our data showed 17 SNPs to be associated with BMI Z-score (BMI-Z) in our study population. The strongest association was found in the African Americans. The most significant SNP was rs8057044, which was associated with BMI-Z in the African Americans (P = 0.00054). SNP rs9939609 was found to be significant in the non-Hispanic white population (P = 0.028). Our data confirm the association between FTO and adiposity suggesting that FTO is a childhood obesity susceptibility gene. Our data also identify a novel SNP of the FTO gene (rs8057044) that is associated with measures of adiposity in the African-American population.

Asymmetric large-for-gestational-age infants of type 1 diabetic women: morbidity and abdominal growth.

We sought to examine neonatal morbidity in four groups of offspring (asymmetric large for gestational age [LGA], symmetric LGA, asymmetric non-LGA, symmetric non-LGA) exposed in utero to maternal type 1 diabetes, and the association between rate of fetal abdominal circumference growth and asymmetric LGA. We performed a secondary analysis of 302 singleton pregnancies. Neonatal morbidity (respiratory distress syndrome, polycythemia, hypoglycemia, hyperbilirubinemia, acidosis, and composite morbidity [any of the five]) was assessed. Serial ultrasound examinations after 20 weeks' gestation were available for 35 fetuses. Logistic regression and general linear mixed modeling were used for analysis. Asymmetric LGA infants had 3.5-, 2.2-, and 3.2-fold greater odds of hypoglycemia, hyperbilirubinemia, and composite morbidity, respectively, compared with symmetric non-LGA infants. The rate of growth of the abdominal circumference in asymmetric LGA infants (1.11 cm/wk) was greater than for both the symmetric LGA infants (0.87 cm/wk, P = 0.09) and the symmetric non-LGA infants (0.87 cm/wk, P = 0.03). Asymmetric LGA infants are at higher risk for morbidity than symmetric LGA and non-LGA infants. Intrauterine growth rate of the abdominal circumference may potentially be used as a marker to identify the asymmetric LGA and thereby aid in the identification of newborns at greatest risk for perinatal complications.