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Introduction A post hoc analysis of the PIONEER 1–5 and 8 trials assessed the clinically relevant composite endpoints of HbA1c (glycated haemoglobin) reduction ≥ 1% and body weight loss of ≥ 5% or ≥ 10% with orally administered semaglutide versus comparators. Methods In the PIONEER trials, people with type 2 diabetes were randomised to orally administered semaglutide versus placebo (PIONEER 1, 4, 5 and 8), empagliflozin (PIONEER 2), sitagliptin (PIONEER 3) and liraglutide (PIONEER 4) for 26–78 weeks. This analysis assessed the proportion of people achieving an HbA1c reduction of ≥ 1% and body weight loss of ≥ 5% at week 26 and at end of treatment, and the proportion of people achieving an HbA1c reduction of ≥ 1% and body weight loss of ≥ 10% at end of treatment. Results Overall, 3506 people in PIONEER 1–5 and 8 were included. At week 26 and at end of treatment, odds of achieving the composite endpoint of an HbA1c reduction of ≥ 1% and body weight loss of ≥ 5% were significantly greater with orally administered semaglutide 14 mg than with placebo (PIONEER 1, 4, 5 and 8; all p

To evaluate the efficacy and safety of oral semaglutide versus comparators by patient characteristic subgroups in patients with type 2 diabetes.Change from baseline in glycated haemoglobin (HbA1c) and body weight, and achievement of HbA1c 7.0% with oral semaglutide 7 mg, oral semaglutide 14 mg, flexibly dosed oral semaglutide (flex) and comparators were assessed across baseline subgroups (age, race, ethnicity, diabetes duration, body mass index and HbA1c) from the PIONEER programme. Treatment differences were analysed using a mixed model for repeated measurements for continuous variables and a logistic regression model for the binary endpoint. Pooled safety data were analysed descriptively.Changes from baseline in HbA1c and body weight, and the odds of achieving HbA1c 7.0%, were greater with oral semaglutide 14 mg/flex (n = 1934) and higher or similar with oral semaglutide 7 mg (n = 823) versus comparators (n = 2077) across most subgroups. Changes in HbA1c with oral semaglutide 14 mg/flex were greater for patients with higher baseline HbA1c (HbA1c 9.0%: -1.7% to -2.6%; HbA1c 8.0%: -0.7% to -1.2%). In some trials, Asian patients experienced greater HbA1c reductions with oral semaglutide 14 mg/flex (-1.5% to -1.8%) than other racial groups (-0.6% to -1.6%). The overall incidence of adverse events (AEs) with oral semaglutide was similar to that with comparators and was consistent across subgroups. More gastrointestinal AEs were observed with oral semaglutide, versus comparators, across subgroups.Oral semaglutide demonstrated consistently greater HbA1c and body weight reductions across a range of patient characteristics, with greater HbA1c reductions seen at higher baseline HbA1c levels.

Background It remains unclear how SSRIs and other antidepressants are associated with the risk of repeated suicide attempts. We aimed to analyse the association between redeemed antidepressant prescriptions and the risk of repeated suicide attempts, hypothesising that antidepressant treatment is associated with increased risk of repeated suicide attempts. Methods The study was based on Danish register data and a validated cohort of 1842 suicide attempts. We used three Cox regression models (crude, adjusted and propensity score matched) to analyse the data; these models included both static and dynamic time-dependent factors. Results 1842 individuals attempted suicide in the study period, with a total of 210 repeated attempts. Individuals redeeming antidepressant prescriptions were more likely to repeat a suicide attempt. All crude models showed all antidepressants to be significant risk factors (HR around 1.39), whereas all adjusted models showed all antidepressants to be insignificant risk factors. Conclusion We found no significant increased risk of repeated suicide attempts in individuals redeeming a prescription for any antidepressant (or only SSRIs) when considering the individuals' baseline risk of repetition. This study is based on validated suicide attempts, register data, and strong epidemiology designs, but it still has some limitations, and the results should be replicated and confirmed in other studies.

Aim: The aim of this study is to analyse the potential impact from the financial crisis (onset in 2009) on suicide rates in Denmark. The hypothesis is that the global financial crisis raised unemployment which leads to raising the suicide rate in Denmark and that the impact is most prominent in men. Method: This study used an ecological study design, including register data from 2001 until 2016 on unemployment, suicide, gender and calendar time which was analysed using Poisson regression models and interrupted time series analysis. Results: The correlation between unemployment and suicide rates was positive in the period and statistically significant for all, but at a moderate level. A dichotomised version of time (calendar year) showed a significant reduction in the suicide rate for women (incidence rate ratio 0.87, P=0.002). Interrupted time series analysis showed a significant decreasing trend for the overall suicide rate and for men in the pre-recession period, which in both cases stagnated after the onset of recession in 2009. The difference between the genders’ suicide rate changed significantly at the onset of recession, as the rate for men increased and the rate for women decreased. Discussion: The Danish social welfare model might have prevented social disintegration and suicide among unemployed, and suicide prevention programmes might have prevented deaths among unemployed and mentally ill individuals. Conclusions: We found some indications for gender-specific differences from the impact of the financial crises on the suicide rate. We recommend that men should be specifically targeted for appropriate prevention programmes during periods of economic downturn.

Background The first oral glucagon-like peptide-1 receptor agonist (GLP-1RA) comprises semaglutide co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Oral semaglutide may alter the pharmacokinetics of co-administered drugs via effects of semaglutide or SNAC. Two separate one-sequence crossover trials investigated the effects of oral semaglutide and SNAC on the pharmacokinetics of ethinylestradiol, levonorgestrel, furosemide and rosuvastatin. Methods Healthy, postmenopausal women (n = 25) received once-daily combined ethinylestradiol and levonorgestrel (Trial 1) and healthy male and female subjects (n = 41) received single doses of furosemide and rosuvastatin (Trial 2), either alone, with SNAC alone or with oral semaglutide. Lack of drug–drug interaction was concluded if 90% confidence intervals (CIs) for the ratio of area under the plasma concentration–time curve (AUC) or maximum concentration (Cmax), with/without oral semaglutide, were within a pre-specified interval (0.80–1.25). Results The AUC values of ethinylestradiol and levonorgestrel were not affected by oral semaglutide co-administration (estimated ratios [90% CI] 1.06 [1.01–1.10] and 1.06 [0.97–1.17], respectively); Cmax was not affected. The no-effect criterion was not met for furosemide or rosuvastatin for the AUC (1.28 [1.16–1.42] and 1.41 [1.24–1.60], respectively) or Cmax. SNAC alone did not affect the AUC or Cmax of ethinylestradiol, levonorgestrel or rosuvastatin; the Cmax of furosemide was slightly decreased. Adverse events were similar to those previously observed for GLP-1RAs (both trials). Conclusion Co-administration with oral semaglutide did not affect the pharmacokinetics of ethinylestradiol or levonorgestrel. There was a small increase in exposure of furosemide and rosuvastatin; however, these increases are not expected to be of clinical relevance. Clinical Trial Registration Numbers NCT02845219 and NCT03010475. Supplementary Information The online version contains supplementary material available at (10.1007/s40262-020-00976-x).

Omtale af selvmord i medierne har mulighed for at forebygge, medføre eller ikke påvirke selvmord blandt sårbare mennesker. WHO’s medieguide præsenterer den seneste viden og giver anbefalinger for ansvarlig omtale af selvmordsproblematikken i trykte medier. Dette studie undersøgte, om 7 udvalgte trykte danske aviser i 2018 fulgte WHO’s medieguide, og om der var anbefalinger, som ikke blev fulgt. Data blev indsamlet systematisk gennem medieovervågningstjenesten Infomedia, som leverede artikler med specifikke søgeord. 7 af de målbare anbefalinger fulgtes i høj grad. Anbefalingerne om henvisninger til, hvor man kan få hjælp til selvmordstanker, og hvor man kan få hjælp til at mestre belastende livsomstændigheder, fulgteskun i mindre grad. Det samme gjorde sig gældende for artiklens placering på siden. Sprogbrug og illustrationer var overvejende hensigtsmæssige og anbefalingerne herfor fulgtes derfor i høj grad. Journalister og medieprofessionelle, som oftebeskæftiger sig med selvmordsproblematikken, formidlede generelt etisk og oplysende.

Aims Evaluate 26 weeks’ liraglutide treatment in type 1 diabetes (T1D) by subgroups in the ADJUNCT ONE and TWO trials. Materials and Methods ADJUNCT ONE and TWO were randomized controlled phase 3 trials in 1,398 and 835 participants with T1D treated with liraglutide (1.8, 1.2 or 0.6 mg) or placebo (adjuncts to insulin). This post hoc analysis evaluated treatment effects by subgroups: HbA1c (textless or ≥ 8.5; body mass index (BMI) (textless or ≥ 27 kg/m2) and insulin regimen (basal bolus or continuous subcutaneous insulin infusion). Results In both trials at week 26, reductions in HbA1c, body weight and daily insulin dose did not differ significantly (ptextgreater0.05) by baseline HbA1c or BMI. Risk of clinically significant hypoglycemia or hyperglycemia with ketosis did not differ significantly (ptextgreater0.05) by baseline HbA1c, BMI or insulin regimen. At week 26 in ADJUNCT ONE, these risks did not differ (ptextgreater0.05) between treatment groups. Placebo-adjusted reductions in HbA1c, body weight and insulin dose (-0.30 points, -5.0 kg, and -12 respectively, with liraglutide 1.8 mg) were significant (ptextless0.05), greater than at week 52 and similar to those in ADJUNCT TWO (-0.35 -4.8 kg and -10 respectively, with liraglutide 1.8 mg). Conclusions In ADJUNCT ONE and TWO, the efficacy and glycemic safety of liraglutide did not depend on subgroups, leaving residual beta-cell function the only identified parameter impacting the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in T1D. These findings support a role for GLP-1 RAs as adjuncts to insulin in T1D, warranting further study. Abstract Aim To evaluate 26 weeks of liraglutide treatment in type 1 diabetes (T1D) by subgroups in the ADJUNCT ONE and ADJUNCT TWO trials. Materials and Methods ADJUNCT ONE and ADJUNCT TWO were randomized controlled phase 3 trials in 1398 and 835 participants with T1D treated with liraglutide (1.8, 1.2, or 0.6 mg) or placebo (adjuncts to insulin). This post hoc analysis evaluated treatment effects by subgroups: HbA1c (< or ≥8.5%), body mass index (BMI; < or ≥27 kg/m2), and insulin regimen (basal bolus or continuous subcutaneous insulin infusion). Results In both trials at week 26, reductions in HbA1c, body weight, and daily insulin dose did not differ significantly (P > .05) by baseline HbA1c or BMI. Risk of clinically significant hypoglycaemia or hyperglycaemia with ketosis did not differ significantly (P > .05) by baseline HbA1c, BMI, or insulin regimen. At week 26 in ADJUNCT ONE, these risks did not differ (P > .05) between treatment groups. Placebo-adjusted reductions in HbA1c, body weight, and insulin dose (−0.30%-points, −5.0 kg, and −12%, respectively, with liraglutide 1.8 mg), were significant (P

AIMS To evaluate, through exploratory post hoc subgroup analyses, the efficacy and safety of oral semaglutide versus comparators in Japanese patients enrolled in the global PIONEER 1, 3, 4 and 8 clinical trials. MATERIALS AND METHODS Patients were randomized to once-daily oral semaglutide 3, 7 or 14 mg or comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg). Change from baseline in glycated haemoglobin (HbA1c) and body weight, and proportions of patients attaining HbA1c

A standard objective in the management of T2D is the achievement and maintenance of HbA1c targets, but the duration of time that patients spend within glycemic control targets has not been previously reported for oral semaglutide (sema). In this exploratory analysis, the duration of time that patients were in glycemic control (HbA1c In conclusion, despite an 8-week dose escalation schedule and a mean baseline HbA1c of 8.1%, nearly half of patients receiving oral sema achieved glycemic control (HbA1c Disclosure J. Rosenstock: Board Member; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Consultant; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Research Support; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Genentech, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics, Sanofi. B. Cariou: Board Member; Self; Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Sanofi, Research Support; Self; Amgen Inc., AstraZeneca, Regeneron Pharmaceuticals Inc., Speaker’s Bureau; Self; Abbott Diabetes, Akcea Therapeutics. E. Christiansen: None. C. L. Hertz: Advisory Panel; Spouse/Partner; SNIPR BIOME APS, Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. E. Montanya: Advisory Panel; Self; Sanofi, Consultant; Self; Merck Sharp & Dohme Corp., Employee; Spouse/Partner; Almirall, S. A., Research Support; Self; Menarini Group, Roche Diagnostics SL, Speaker’s Bureau; Self; Novo Nordisk A/S. M. Abildlund nielsen: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Lundbeck, Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding Novo Nordisk A/S

We re-evaluated the efficacy and safety of liraglutide, a GLP-1 analog, for use as adjunctive therapy in people with type 1 diabetes (T1D). Results from the two ADJUNCT trials suggested that residual beta-cell function is associated with more pronounced benefits and less risk of hypoglycemia. Here we analyze results of the two trials according to other baseline anthropometrics. ADJUNCT ONE (NCT01836523) and TWO (NCT02098395) were randomized controlled phase 3 trials in broad T1D populations (1398 and 835 participants, respectively) treated with liraglutide (1.8, 1.2 or 0.6 mg) or placebo. ADJUNCT ONE was a 52-week trial with a treat-to-target design and no limits on insulin titration; ADJUNCT TWO was a 26-week trial with an individual maximal insulin dose. In a post hoc analysis, we evaluated certain estimated placebo-adjusted treatment effects across clinically relevant participant subgroups. At week 26 in ADJUNCT ONE, placebo-adjusted reductions in HbA1c, body weight (BW) and daily insulin dose (up to -0.30 %-points, -5.0 kg and -12%, respectively, with liraglutide 1.8 mg) were significant (p0.05) on baseline HbA1c or BMI at neither week 26 nor 52. The risk of clinically significant hypoglycemia (symptomatic episodes with blood glucose 0.05 vs. placebo) by baseline HbA1c, BMI or insulin regimen. In ADJUNCT ONE and TWO, the efficacy and glycemic safety of liraglutide did not depend on key baseline anthropometrics. This leaves residual beta-cell function the only identified parameter impacting the treatment effect of the GLP-1 analog used as an adjunct to insulin in T1D. Together with recent progress in the understanding of T1D and of the benefits of GLP-1 receptor agonism, these findings suggest a role for GLP-1 receptor agonists in T1D, warranting further study. Disclosure T. F. Dejgaard: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Boehringer Ingelheim International GmbH, Research Support; Self; AstraZeneca, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. L. Bardtrum: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. E. Christiansen: None. F. Kreiner: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. S. Madsbad: Advisory Panel; Self; AstraZeneca; Boehringer Ingelheim; Eli Lilly; Merck Sharp & Dohme; Novo Nordisk; Sanofi, Research Support; Self; Novo Nordisk, Boehringer Ingelheim, Speaker’s Bureau; Self; AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi. M. G. Von herrath: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. B. Von scholten: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. C. Mathieu: Advisory Panel; Self; Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Insulet and Zealand Pharma, Research Support; Self; Medtronic, Novo Nordisk, Sanofi and ActoBio Therapeutics, Speaker’s Bureau; Self; Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca and Novartis. Funding Novo Nordisk A/S

OBJECTIVE This trial compared the efficacy and safety of the first oral glucagon-like peptide 1 (GLP-1) receptor agonist, oral semaglutide, as monotherapy with placebo in patients with type 2 diabetes managed by diet and exercise alone. Two estimands addressed two efficacy-related questions: a treatment policy estimand (regardless of trial product discontinuation or rescue medication use) and a trial product estimand (on trial product without rescue medication use) in all randomized patients. RESEARCH DESIGN AND METHODS This was a 26-week, phase 3a, randomized, double-blind, placebo-controlled, parallel-group trial conducted in 93 sites in nine countries. Adults with type 2 diabetes insufficiently controlled with diet and exercise were randomized (1:1:1:1) to once-daily oral semaglutide 3 mg, 7 mg, 14 mg, or placebo. The primary end point was change from baseline to week 26 in HbA1c. The confirmatory secondary end point was change from baseline to week 26 in body weight. RESULTS In the 703 patients randomized (mean age 55 years, 50.8% male, and mean baseline HbA1c 8.0% [64 mmol/mol]), oral semaglutide reduced HbA1c (placebo-adjusted treatment differences at week 26: treatment policy estimand, −0.6% [3 mg], −0.9% [7 mg], and −1.1% [14 mg]; trial product estimand, −0.7% [3 mg], −1.2% [7 mg], and −1.4% [14 mg]; P < 0.001 for all) and body weight (treatment policy, −0.1 kg [3 mg], −0.9 kg [7 mg], and −2.3 kg [14 mg, P < 0.001]; trial product, −0.2 kg [3 mg], −1.0 kg [7 mg, P = 0.01], and −2.6 kg [14 mg, P < 0.001]). Mild-to-moderate transient gastrointestinal events were the most common adverse events with oral semaglutide. Trial product discontinuations occurred in 2.3–7.4% with oral semaglutide and 2.2% with placebo. CONCLUSIONS In patients with type 2 diabetes, oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA1c (all doses) and body weight loss (14 mg dose) versus placebo, with a safety profile consistent with other GLP-1 receptor agonists.

Purpose: Severe mental illness (SMI) may interfere with parental caregiving practices and offspring development. Adhering to preventive well-child visits and maintaining good oral hygiene during early childhood requires parental involvement. Whether these activities are affected by parental SMI is unclear. The purpose of the present study was to determine whether children exposed to parental SMI are at increased risk of non-attendance to preventive well-child visits and vaccinations at age 0–5 years and of child dental caries experience at age 5 years. Furthermore, interactions between maternal psychiatric and sociodemographic variables in relation to an adverse child outcome were assessed. Methods: Data were obtained from national Danish health registers. All children born in Denmark between January 1997 and December 2010 were followed from birth until their 6th birthday. Results: 679,339 children were included in the study (51% male). Of these, 49,059 children (7.8%) had at least one parent with a lifetime SMI diagnosis. Children of parents with SMI had elevated odds of missing well-child visits and vaccinations (OR 1.41; 95% CI 1.39–1.44, p < 0.0001), and of child dental caries (OR 1.58; 95% CI 1.55–1.62, p < 0.0001). In the presence of maternal SMI, low socioeconomic classification and single-mother status added more to the elevated risk than specific maternal diagnosis or timing of last psychiatric contact. Conclusion: Parents with SMI are less compliant with preventive child healthcare activities than parents without SMI. This indicates a need for practical support to these families in order to prevent inequality in health among their offspring.

An exploratory subgroup analysis of the 52-week, double-blind PIONEER 8 trial (NCT03021187) evaluated the effect of background insulin regimen (basal, premixed, or basal-bolus) with or without metformin on the efficacy and safety of oral semaglutide (sema). Patients (pts) (N=731) with type 2 diabetes and treated with insulin were randomized to once-daily oral sema (3, 7, or 14 mg) or placebo (pbo). Endpoints included change from baseline in HbA1c, body weight (BW), and total daily insulin dose at week 52. Baseline age and HbA1c were similar across insulin regimen subgroups whereas BW was greater and diabetes duration was longer in pts on basal-bolus vs. basal and premix subgroups. There were greater dose-dependent HbA1c and BW reductions with oral sema vs. pbo; these were generally similar across all insulin subgroups (Table). Total daily insulin dose at week 52 was decreased for pts on basal (oral sema 7 and 14 mg), premix (oral sema 14 mg), and basal-bolus (oral sema 3, 7, and 14 mg), mainly driven by the bolus component for pts on basal-bolus (Table). Most hypoglycemic episodes were in pts on basal-bolus insulin. Fewer pts had hypoglycemia with oral sema vs. pbo except in the basal-bolus subgroup (Table). In conclusion, oral sema reduced HbA1c and BW in a dose-dependent manner, and reduced insulin dose regardless of background insulin regimen, with a safety profile similar to other glucagon-like peptide-1 receptor agonists. Disclosure O. Mosenzon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Teva Pharmaceutical Industries Ltd. V.R. Aroda: Consultant; Self; Duke, Novo Nordisk Inc., Sanofi. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Applied Therapeutics, Fractyl Laboratories, Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; IMNE, Medscape. E. Christiansen: None. S.B. Harris: Advisory Panel; Self; Abbott, AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Abbott, AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; AstraZeneca, Canadian Institutes of Health Research, Eli Lilly and Company, Health Canada/First Nations and Inuit Health Branch, Janssen Pharmaceuticals, Inc., JDRF, Lawson Foundation, Novo Nordisk Inc., Sanofi. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Sanofi. K. Pedersen: Employee; Self; Novo Nordisk A/S. M. Tarp-Johansen: Employee; Self; Novo Nordisk A/S. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. Funding Novo Nordisk A/S

Severe mental illness (SMI) may interfere with parental caregiving practices and offspring development. Adhering to preventive well-child visits and maintaining good oral hygiene during early childhood requires parental involvement. Whether these activities are affected by parental SMI is unclear. The purpose of the present study was to determine whether children exposed to parental SMI are at increased risk of non-attendance to preventive well-child visits and vaccinations at age 0-5 years and of child dental caries experience at age 5 years. Furthermore, interactions between maternal psychiatric and sociodemographic variables in relation to an adverse child outcome were assessed.Data were obtained from national Danish health registers. All children born in Denmark between January 1997 and December 2010 were followed from birth until their 6th birthday.679,339 children were included in the study (51% male). Of these, 49,059 children (7.8%) had at least one parent with a lifetime SMI diagnosis. Children of parents with SMI had elevated odds of missing well-child visits and vaccinations (OR 1.41; 95% CI 1.39-1.44, p 0.0001), and of child dental caries (OR 1.58; 95% CI 1.55-1.62, p 0.0001). In the presence of maternal SMI, low socioeconomic classification and single-mother status added more to the elevated risk than specific maternal diagnosis or timing of last psychiatric contact.Parents with SMI are less compliant with preventive child healthcare activities than parents without SMI. This indicates a need for practical support to these families in order to prevent inequality in health among their offspring.

Plants can form an immunological memory known as defense priming, whereby exposure to a priming stimulus enables quicker or stronger response to subsequent attack by pests and pathogens. Such priming of inducible defenses provides increased protection and reduces allocation costs of defense. Defense priming has been widely studied for short-lived model plants such as Arabidopsis, but little is known about this phenomenon in long-lived plants like spruce. We compared the effects of pretreatment with sublethal fungal inoculations or application of the phytohormone methyl jasmonate (MeJA) on the resistance of 48-year-old Norway spruce (Picea abies) trees to mass attack by a tree-killing bark beetle beginning 35 days later. Bark beetles heavily infested and killed untreated trees but largely avoided fungus-inoculated trees and MeJA-treated trees. Quantification of defensive terpenes at the time of bark beetle attack showed fungal inoculation induced 91-fold higher terpene concentrations compared with untreated trees, whereas application of MeJA did not significantly increase terpenes. These results indicate that resistance in fungus-inoculated trees is a result of direct induction of defenses, whereas resistance in MeJA-treated trees is due to defense priming. This work extends our knowledge of defense priming from model plants to an ecologically important tree species.

Oral semaglutide (sema) is the first oral GLP-1 receptor agonist (RA). Flexible dose adjustment of oral sema (3, 7, and 14 mg) once daily (N=253) was tested vs. sitagliptin (sita, 100 mg; N=251) in a 52-week (week), randomized, open-label phase 3a trial in patients (pts) with T2D uncontrolled on 1-2 oral glucose-lowering drugs (NCT02849080). Oral sema dose could be adjusted every 8 weeks based on HbA1c (escalated if ≥7.0%) and tolerability. Endpoints at week 52: HbA1c In conclusion, flexible dose adjustment with oral sema provided superior glycemic control and weight loss at week 52 vs. sita, and was well tolerated with safety consistent with the GLP-1RA class. Disclosure J.B. Buse: Consultant; Self; Neurimmune AG. Research Support; Self; AstraZeneca, National Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk A/S, Sanofi, vTv Therapeutics. Stock/Shareholder; Self; Mellitus Health, PhaseBio Pharmaceuticals, Inc., Stability Health. Other Relationship; Self; ADOCIA, AstraZeneca, Dance Biopharm Holdings Inc., Eli Lilly and Company, MannKind Corporation, NovaTarg, Novo Nordisk A/S, Senseonics, vTv Therapeutics, Zafgen, Inc. B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research & Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. Y. Cho: Consultant; Self; Hanmi Pharm. Co., Ltd. Research Support; Self; AstraZeneca, Sanofi-Aventis. E. Christiansen: None. C.L. Hertz: Employee; Self; Novo Nordisk A/S. A. Mertens: None. S.O. Wallenstein: None. T.R. Pieber: Advisory Panel; Self; ADOCIA, Arecor Limited, AstraZeneca, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; Novo Nordisk A/S. Funding Novo Nordisk A/S

BACKGROUND: Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg. METHODS: In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA1c of 7·5-9·5% (58-80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA1c and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA1c of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing. FINDINGS: Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 [57%] of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA1c of 8·3% (SD 0·6%; 67 mmol/mol [SD 6·4]), a greater proportion of participants achieved an HbA1c of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% [134 of 230] vs 25% [60 of 238]; and trial product estimand: 63% [123 of 196] vs 28% [52 of 184]). The odds of achieving an HbA1c of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio [OR] 4·40, 95% CI 2·89-6·70, p

Diabetes mellitus (DM) was previously considered a contraindication to recreational diving by means of self-contained underwater breathing apparatus (SCUBA), the main concern being the risk of the divers developing underwater hypoglycaemia. However, an increasing body of scientific evidence including epidemiologic surveys and controlled case studies have shown, that some patients with DM can dive safely under the right circumstances. In this review, we summarise the Danish national guidelines based on existing literature and guidelines as well as patient instructions on how to improve safety when diving with DM.

Aim: Few population-based, family studies have examined associations between exposure to one vs. two parent(s) with alcohol use disorder (AUD) and the risk of offspring developing substance use disorder (SUD). Moreover, these studies have focused solely on the development of AUD, and not SUD, in offspring. The purpose of this study was to investigate whether exposure to one vs. two parent(s) with AUD increases the risk of offspring developing SUD. Methods: A population-based, cohort study was conducted in which offspring born in Denmark between 1983 and 1989 were followed through national registries until 2011. Register-based data were obtained from the: Psychiatric Central Research Register, National Patient Registry, Civil Registration System, Fertility Database, and Cause of Death Register. Adjusted hazard ratios were calculated using multivariate Cox-regression models.Findings: A total of 398,881 offspring were included in this study. Of these, 3.9 % had at least one parent with AUD. Parental AUD was significantly associated with the development of SUD in offspring. Having one parent with AUD was linked to a 1.44-fold increased risk (95% CL, 1.29 - 1.61), while having two parents with AUD was linked to a 2.29-fold increased risk (95% CI, 1.64 – 3.20). No significant differences were found in relation to either parental or offspring gender.Conclusions: Exposure to parental AUD is linked to an increased risk of offspring developing SUD. This risk is additive for offspring exposed to double parental AUD. The findings have important implications for clinical assessment and intervention strategies, as well as the management of offspring exposed to parental AUD.

Background The pharmacokinetic properties of liraglutide, a glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus (T2D), have been established in healthy individuals and subjects with T2D. Liraglutide has been under investigation as adjunct treatment to insulin in type 1 diabetes mellitus (T1D). This single-center, double-blind, placebo-controlled, crossover, clinical pharmacology trial is the first to analyze the pharmacokinetic properties of liraglutide as add-on to insulin in T1D. Methods Subjects (18–64 years; body mass index 20.0–28.0 kg/m2; glycated hemoglobin ≤9.5 %) were randomized 1:1:1 to 0.6, 1.2, or 1.8 mg liraglutide/placebo. Each group underwent two 4-week treatment periods (liraglutide then placebo or placebo then liraglutide) separated by a 2- to 3-week washout. Both trial drugs were administered subcutaneously, once daily, as adjunct to insulin. A stepwise hypoglycemic clamp was performed at the end of each treatment period (data reported previously). Pharmacokinetic endpoints were derived from liraglutide concentration–time curves after the final dose and exposure was compared with data from previous trials in healthy volunteers and subjects with T2D. Results The pharmacokinetic properties of liraglutide in T1D were comparable with those observed in healthy volunteers and subjects with T2D. Area under the steady-state concentration–time curve (AUC) and maximum plasma concentration data were consistent with dose proportionality of liraglutide. Comparison of dose-normalized liraglutide AUC suggested that exposure in T1D, when administered with insulin, is comparable with that observed in T2D. Conclusions Liraglutide, administered as adjunct to insulin in subjects with T1D, shows comparable pharmacokinetics to those in subjects with T2D. ClinicalTrials.gov Identifier: NCT01536665.