Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials.

AIMS: To assess the effect of baseline body mass index (BMI) and the occurrence of nausea and/or vomiting on weight loss induced by semalgutide, a once-weekly glucagon-like peptide 1 analogue for the treatment of type 2 diabetes. Semaglutide demonstrated superior reductions in HbA1c and superior weight loss (by 2.3-6.3 kg) versus different comparators across the SUSTAIN 1 to 5 trials; the contributing factors to weight loss are not established. MATERIALS AND METHODS: Subjects with inadequately controlled type 2 diabetes (drug-naïve or on background treatment) were randomized to subcutaneous semaglutide 0.5 mg (excluding SUSTAIN 3), 1.0 mg (all trials), or comparator (placebo, sitagliptin, exenatide extended release or insulin glargine). Subjects were subdivided by baseline BMI and reporting (yes/no) of any nausea and/or vomiting. Change from baseline in body weight was assessed within each trial and subgroup. A mediation analysis separated weight loss into direct or indirect (mediated by nausea or vomiting) effects. RESULTS: Clinically relevant weight-loss differences were observed across all BMI subgroups, with a trend towards higher absolute weight loss with higher baseline BMI. Overall, 15.2% to 24.0% and 21.5% to 27.2% of subjects experienced nausea or vomiting with semaglutide 0.5 and 1.0 mg, respectively, versus 6.0% to 14.1% with comparators. Only 0.07 to 0.5 kg of the treatment difference between semaglutide and comparators was mediated by nausea or vomiting (indirect effects). CONCLUSIONS: In SUSTAIN 1 to 5, semaglutide-induced weight loss was consistently greater versus comparators, regardless of baseline BMI. The contribution of nausea or vomiting to this weight loss was minor.

Picornavirus-Induced Airway Mucosa Immune Profile in Asymptomatic Neonates.

BACKGROUND: Bacterial airway colonization is known to alter the airway mucosa immune response in neonates whereas the impact of viruses is unknown. The objective was therefore to examine the effect of respiratory viruses on the immune signature in the airways of asymptomatic neonates. METHODS: Nasal aspirates from 571 asymptomatic 1-month-old neonates from the Copenhagen Prospective Studies on Asthma in Childhood 2010 birth cohort were investigated for respiratory viruses. Simultaneously, unstimulated airway mucosal lining fluid was obtained and quantified for levels of 20 immune mediators related to type 1, type 2, type 17, and regulatory immune paths. The association between immune mediator levels and viruses was tested by conventional statistics and partial least square discriminant analysis. RESULTS: Picornaviruses were detected in 58 neonates (10.2%) and other viruses in 10 (1.8%). A general up-regulation of immune mediators was found in the neonates with picornavirus (P < .0001; partial least square discriminant analysis). The association was pronounced for type 1- and type 2-related markers and was unaffected by comprehensive confounder adjustment. Detection of picornavirus and bacteria was associated with an additive general up-regulating effect. CONCLUSIONS: Asymptomatic presence of picornavirus in the neonatal airway is a potent activator of the topical immune response. This is relevant to understanding the immune potentiating effect of early life exposure to viruses.

Maternal fatty acid desaturase genotype correlates with infant immune responses at 6 months.

Breast milk long-chain PUFA (LCPUFA) have been associated with changes in early life immune responses and may modulate T-cell function in infancy. We studied the effect of maternal fatty acid desaturase (FADS) genotype and breast milk LCPUFA levels on infants' blood T-cell profiles and ex vivo-produced cytokines after anti-CD3/CD28 stimulation of peripheral blood mononuclear cells in 6-month-old infants from the Copenhagen Prospective Study of Asthma in Childhood birth cohort. LCPUFA concentrations of breast milk were assessed at 4 weeks of age, and FADS SNP were determined in both mothers and infants (n 109). In general, breast milk arachidonic acid (AA) levels were inversely correlated with the production of IL-10 (r -0.25; P=0.004), IL-17 (r -0.24; P=0.005), IL-5 (r -0.21; P=0.014) and IL-13 (r -0.17; P=0.047), whereas EPA was positively correlated with the counts of blood regulatory T-cells and cytotoxic T-cells and decreased T-helper cell counts. The minor FADS alleles were associated with lower breast milk AA and EPA, and infants of mothers carrying the minor allele of FADS SNP rs174556 had higher production of IL-10 (r -0.23; P=0.018), IL-17 (r -0.25; P=0.009) and IL-5 (r -0.21; P=0.038) from ex vivo-activated immune cells. We observed no association between T-cell distribution and maternal or infant FADS gene variants. We conclude that increased maternal LCPUFA synthesis and breast milk AA are associated with decreased levels of IL-5, IL-13 (type-2 related), IL-17 (type-17 related) and IL-10 (regulatory immune responses), but not with interferon-γ and TNF-α, which could be due to an effect of the maternal FADS variants on the offspring immune response transferred via breast milk LCPUFA.

Children with asthma by school age display aberrant immune responses to pathogenic airway bacteria as infants.

BACKGROUND: Asthma is a highly prevalent chronic lung disease that commonly originates in early childhood. Colonization of neonatal airways with the pathogenic bacterial strains Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae is associated with increased risk of later childhood asthma. We hypothesized that children with asthma have an abnormal immune response to pathogenic bacteria in infancy. OBJECTIVE: We aimed to assess the bacterial immune response in asymptomatic infants and the association with later development of asthma by age 7 years. METHODS: The Copenhagen Prospective Studies on Asthma in Childhood birth cohort was followed prospectively, and asthma was diagnosed at age 7 years. The immune response to H influenzae, M catarrhalis, and S pneumoniae was analyzed in 292 infants using PBMCs isolated and stored since the age of 6 months. The immune response was assessed based on the pattern of cytokines produced and T-cell activation. RESULTS: The immune response to pathogenic bacteria was different in infants with asthma by 7 years of age (P = .0007). In particular, prospective asthmatic subjects had aberrant production of IL-5 (P = .008), IL-13 (P = .057), IL-17 (P = .001), and IL-10 (P = .028), whereas there were no differences in T-cell activation or peripheral T-cell composition. CONCLUSIONS: Children with asthma by school age exhibited an aberrant immune response to pathogenic bacteria in infancy. We propose that an abnormal immune response to pathogenic bacteria colonizing the airways in early life might lead to chronic airway inflammation and childhood asthma.

Dasiglucagon for the Treatment of Congenital Hyperinsulinism: A Randomized Phase 3 Trial in Infants and Children.

CONTEXT: Congenital hyperinsulinism (CHI) is characterized by dysregulated insulin secretion causing hypoglycemia and consequent brain damage. Dasiglucagon is a glucagon analogue under investigation to treat CHI. OBJECTIVE: To evaluate the efficacy and safety of dasiglucagon delivered via continuous subcutaneous infusion to children with CHI and persistent hypoglycemia as add-on to standard of care (SoC). METHODS: In this open-label trial, patients were randomized 1:1 to SoC or SoC + dasiglucagon (10-70 µg/h) for 4 weeks. In the following 4 weeks, all patients received dasiglucagon + SoC. Hypoglycemia was assessed by self-monitored plasma glucose (SMPG) and blinded continuous glucose monitoring (CGM). Primary endpoint was average number of SMPG-detected hypoglycemia episodes/week (SMPG <3.9 mmol/L) during Weeks 2 to 4. RESULTS: Thirty-two patients (0.6-10.9 years) were randomly assigned to dasiglucagon + SoC (n = 16) or SoC (n = 16). The rate of SMPG-detected hypoglycemia decreased from baseline in both groups, but with no statistically significant difference during Weeks 2 to 4 (event rate ratio: 0.85 [0.54; 1.36], P = .5028). However, dasiglucagon administration resulted in a 43% reduction in CGM-detected hypoglycemia (<3.9 mmol/L) vs SoC alone during Weeks 2 to 4 (post hoc analysis; event rate ratio: 0.57 [0.39; 0.83], P = .0029). Dasiglucagon enabled reductions (of 37% to 61%) in all other measures of hypoglycemia assessed by CGM vs SoC alone including extent and percent time in hypoglycemia (post hoc analyses). Dasiglucagon appeared safe and well tolerated. Skin and gastrointestinal events were more frequent with dasiglucagon + SoC than SoC only. CONCLUSION: Clinically meaningful reductions in all CGM-recorded measures of hypoglycemia support using dasiglucagon as a potential treatment for CHI.

Efficacy of Dose-Titrated Glucagon Infusions in the Management of Congenital Hyperinsulinism: A Case Series.

Background: Congenital hyperinsulinism (CHI), a rare disease of excessive and dysregulated insulin secretion, can lead to prolonged and severe hypoglycemia. Dextrose infusions are a mainstay of therapy to restore normal glycemia, but can be associated with volume overload, especially in infants. By releasing intrahepatic glucose stores, glucagon infusions can reduce dependency on dextrose infusions. Recent studies have reported positive outcomes with glucagon infusions in patients with CHI; however, to date, there are no reports describing the clinical utility of titrated doses of infused glucagon to achieve glycemic stability. Objective: To assess the potential clinical utility of dose-titrated glucagon infusions in stabilizing glycemic status in pediatric patients with CHI, who were managed by medical and/or surgical approaches. Methods: Patients with CHI (N = 33), with or without mutations in the ATP-sensitive K+ channel genes, ABCC8, and KCNJ11 requiring glucagon by dose titration in addition to intravenous dextrose and medical therapy with diazoxide/octreotide to achieve glycemic stability were recruited. Following glucagon titration and a 24-h glucose stable period, glucose infusion rate (GIR) was reduced over a 24-h period. Achievement of glycemic stability and decrease in GIR were considered end points of the study. Results: All patients achieved glycemic stability with glucagon infusion, demonstrating clinical benefit. GIR reduced from 15.6 (4.5) to 13.4 (4.6) mg/kg/min mean (SD) (p = 0.00019 for difference; n = 32; paired t-test) over 24 h. By univariate analysis, no individual baseline characteristic was associated with changes in the GIR. However, by baseline-adjusted modeling, mutational status of the patient (p = 0.011) was inversely associated with a reduction in GIR. Adverse events were infrequent with diarrhea possibly attributed to glucagon treatment in 1 patient. With long-term treatment following GIR reduction, necrolytic migratory erythema was observed in another patient. Conclusion: These data suggest that dose-titrated glucagon infusion therapy aids hypoglycemia prevention and reduction in GIR in the clinical management of patients with CHI.

Corrigendum: Efficacy of Dose-Titrated Glucagon Infusions in the Management of Congenital Hyperinsulinism: A Case Series.

[This corrects the article DOI: 10.3389/fendo.2020.00441.].

Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Subjects With Type 1 Diabetes: The ADJUNCT TWO Randomized Trial.

OBJECTIVE: To investigate the efficacy and safety of liraglutide added to capped insulin doses in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A 26-week, placebo-controlled, double-blind, parallel-group trial enrolling 835 subjects randomized 3:1 receiving once-daily subcutaneous liraglutide (1.8, 1.2, and 0.6 mg) or placebo added to an individually capped total daily dose of insulin. RESULTS: Mean baseline glycated hemoglobin (HbA1c) (8.1% [65.0 mmol/mol]) was significantly decreased with liraglutide versus placebo at week 26 (1.8 mg: -0.33% [3.6 mmol/mol]; 1.2 mg: -0.22% [2.4 mmol/mol]; 0.6 mg: -0.23% [2.5 mmol/mol]; placebo: 0.01% [0.1 mmol/mol]). Liraglutide significantly reduced mean body weight (-5.1, -4.0, and -2.5 kg for 1.8, 1.2, and 0.6 mg, respectively) versus placebo (-0.2 kg). Significant reductions in daily insulin dose and increases in quality of life were seen with liraglutide versus placebo. There were higher rates of symptomatic hypoglycemia (21.3 vs. 16.6 events/patient/year; P = 0.03) with liraglutide 1.2 mg vs. placebo and of hyperglycemia with ketosis >1.5 mmol/L with liraglutide 1.8 mg vs. placebo (0.5 vs. 0.1 events/patient/year; P = 0.01). CONCLUSIONS: In a broad population of subjects with long-standing type 1 diabetes, liraglutide added to capped insulin reduced HbA1c, body weight, and insulin requirements but with higher rates of hypoglycemia for liraglutide 1.2 mg and hyperglycemia with ketosis for liraglutide 1.8 mg.

Airway mucosal immune-suppression in neonates of mothers receiving A(H1N1)pnd09 vaccination during pregnancy.

BACKGROUND: It is recommended to vaccinate pregnant women against influenza. A possible impact on the immune expression of the fetus has never been studied. We aim to study the immune signature in the upper airways and the incidence of infections in neonates born to mothers receiving Influenza A(H1N1)pnd09 vaccination during pregnancy. METHODS: One hundred and fifty-six women from the unselected Copenhagen Prospective Study on Asthma in Childhood (COPSAC2010) received Influenza A(H1N1)pnd09-vaccination during the 2009 pandemic. Fifty-one mothers received the vaccine during pregnancy and 105 after pregnancy; 332 neonates of nonvaccinated mothers were included as secondary controls. Nasal mucosal lining fluid was sampled in 488 neonates and assessed for interleukin (IL)-12p70, IP-10, interferon-gamma (IFN)-γ, tumor necrosis factor-alpha (TNF)-α, MIP-1ß, MCP-1, MCP-4, IL-4, IL-5, IL-13, eotaxin-1, eotaxin-3, TARC, MDC, IL-17, IL-1ß, IL-8, transforming growth factor beta (TGF)-ß1, IL-10 and IL-2. Infections were monitored the first year of life by daily diary cards and clinical controls. RESULTS: Neonates of mothers vaccinated during pregnancy had significant up-regulation of TGF-ß1 [ratio = 1.52 (1.22-1.90), P = 0.0002], and corresponding down-regulation (P < 0.05) of IL-12p70, IFN-γ, IL-5, eotaxin-1, TARC, MDC, IL-8 in comparison to those vaccinated after pregnancy. The lag-time from vaccination during pregnancy to assessment of the immune signature showed significant and positive association to up-regulation of TGF-ß1 levels (P = 0.0003) and significant negative association to other mediators. The study was not powered to study differences in the incidence of infections in early infancy which did not differ between the study groups. CONCLUSION: Influenza A(H1N1)pnd09 vaccination during pregnancy up-regulates TGF-ß1 and down-regulates key mediators of the protective immunity.

Altered response to A(H1N1)pnd09 vaccination in pregnant women: a single blinded randomized controlled trial.

BACKGROUND: Pregnant women were suspected to be at particular risk when H1N1pnd09 influenza became pandemic in 2009. Our primary objective was to compare the immune responses conferred by MF59®-adjuvanted vaccine (Focetria®) in H1N1pnd09-naïve pregnant and non-pregnant women. The secondary aims were to compare influences of dose and adjuvant on the immune response. METHODS: The study was nested in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) pregnancy cohort in 2009-2010 and conducted as a single-blinded block-randomised [1∶1∶1] controlled clinical trial in pregnant women after gestational week 20: (1) 7.5 µg H1N1pnd09 antigen with MF59-adjuvant (Pa7.5 µg); (2) 3.75 µg antigen half MF59-adjuvanted (Pa3.75 µg); (3) 15 µg antigen unadjuvanted (P15 µg); and in non-pregnant women receiving (4) 7.5 µg antigen full adjuvanted (NPa7.5 µg). Blood samples were collected at baseline, 3 weeks, 3 and 10 months after vaccination, adverse events were recorded prospectively. RESULTS: 58 pregnant women were allocated to Pa7.5 µg and 149 non-pregnant women were recruited to NPa7.5 µg. The sero-conversion rate was significantly increased in non-pregnant (NPa7.5 µg) compared with pregnant (Pa7.5 µg) women (OR = 2.48 [1.03-5.95], p = 0.04) and geometric mean titers trended towards being higher, but this difference was not statistically significant (ratio 1.27 [0.85-1.93], p = 0.23). The significant titer increase rate showed no difference between pregnant (Pa7.5 µg) and non-pregnant (NPa7.5 µg) groups (OR = 0.49 [0.13-1.85], p = 0.29). CONCLUSION: Our study suggests the immune response to the 7.5 µg MF59-adjuvanted Focetria® H1N1pnd09 vaccine in pregnant women may be diminished compared with non-pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01012557.