Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes.

BACKGROUND: Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes. METHODS: We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group. CONCLUSIONS: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials.

BACKGROUND: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. METHODS: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. FINDINGS: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. INTERPRETATION: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. FUNDING: Novo Nordisk.

Why Do Bystanders Report Intimate Partner Violence? Insights into Real-Life Reasoning from Those Who Actually Intervened.

As intimate partner violence (IPV) often remains unknown to police, bystanders can play a crucial role in prevention and further escalation of IPV. However, little is known about what brings them into action by reporting incidents of IPV to authorities. As such, we use statements of bystanders who filed reports about IPV incidents to an official domestic violence agency in the Netherlands (N = 78), to investigate the reasoning and motivations for reporting their suspicions. Results show that the reasons for bystanders to report IPV differ depending on the relational dynamics between partners. In situations perceived as intimate terrorism, involving a hierarchical abusive relationship between a man offender and a woman victim, bystanders primarily reported when previous helping initiatives proved inefficient, and they did so to prevent further harm, often particularly in relation to the woman victim. In situations perceived as situational couple violence, involving a symmetrical abusive relationship, bystanders primarily reported when escalation appeared, and they did so to prevent further harm to involved children. We conclude that bystanders report IPV incidents when the need for help is clear, and their motivation for acting concerns the well-being of victims. Our findings add to the growing body of evidence about real-life bystander intervention in emergencies and highlight the need for understanding intervention as context-specific in order to design effective intervention initiatives.

Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity.

BACKGROUND: Heart failure with preserved ejection fraction is increasing in prevalence and is associated with a high symptom burden and functional impairment, especially in persons with obesity. No therapies have been approved to target obesity-related heart failure with preserved ejection fraction. METHODS: We randomly assigned 529 patients who had heart failure with preserved ejection fraction and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or higher to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The dual primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in the 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P<0.001), and the mean percentage change in body weight was -13.3% with semaglutide and -2.6% with placebo (estimated difference, -10.7 percentage points; 95% CI, -11.9 to -9.4; P<0.001). The mean change in the 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo (estimated difference, 20.3 m; 95% CI, 8.6 to 32.1; P<0.001). In the analysis of the hierarchical composite end point, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37 to 2.15; P<0.001). The mean percentage change in the CRP level was -43.5% with semaglutide and -7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). Serious adverse events were reported in 35 participants (13.3%) in the semaglutide group and 71 (26.7%) in the placebo group. CONCLUSIONS: In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo. (Funded by Novo Nordisk; STEP-HFpEF ClinicalTrials.gov number, NCT04788511.).

Design and Baseline Characteristics of STEP-HFpEF Program Evaluating Semaglutide in Patients With Obesity HFpEF Phenotype.

BACKGROUND: The majority of patients with heart failure with preserved ejection fraction (HFpEF) have the obesity phenotype, but no therapies specifically targeting obesity in HFpEF exist. OBJECTIVES: The aim of this study was to describe the design and baseline characteristics of 2 trials of semaglutide, a glucagon-like peptide-1 receptor agonist, in patients with the obesity HFpEF phenotype: STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF; NCT04788511) and STEP-HFpEF DM (Semaglutide Treatment Effect in People with obesity and HFpEF and type 2 diabetes; NCT04916470). METHODS: Both STEP-HFpEF and STEP-HFpEF DM are international multicenter, double-blind, placebo-controlled trials that randomized adults with HFpEF and a body mass index ≥30 kg/m2 to once-weekly semaglutide at a dose of 2.4 mg or placebo. Participants were eligible if they had a left ventricular ejection fraction (LVEF) ≥45%; NYHA functional class II to IV; a Kansas City Cardiomyopathy Questionnaire (KCCQ)-Clinical Summary Score (CSS) <90 points; and ≥1 of the following: elevated filling pressures, elevated natriuretic peptides plus structural echocardiographic abnormalities, recent heart failure hospitalization plus ongoing diuretic use, and/or structural abnormalities. The dual primary endpoints are the 52-week change in the KCCQ-CSS and body weight. RESULTS: In STEP-HFpEF and STEP-HFpEF DM (N = 529 and N = 617, respectively), nearly half were women, and most had severe obesity (median body mass index of 37 kg/m2) with typical features of HFpEF (median LVEF of 57%, frequent comorbidities, and elevated natriuretic peptides). Most participants received diuretic agents and renin-angiotensin blockers at baseline, and approximately one-third were on mineralocorticoid receptor antagonists. Sodium-glucose cotransporter-2 inhibitor use was rare in STEP-HFpEF but not in STEP HFpEF DM (32%). Patients in both trials had marked symptomatic and functional impairments (KCCQ-CSS ∼59 points, 6-minute walking distance ∼300 m). CONCLUSIONS: In total, STEP-HFpEF program randomized 1,146 participants with the obesity phenotype of HFpEF and will determine whether semaglutide improves symptoms, physical limitations, and exercise function in addition to weight loss in this vulnerable group.

How common are high-risk coronavirus contacts? A video-observational analysis of outdoor public place behavior during the COVID-19 pandemic.

Epidemiological evidence and recommendations from the World Health Organization suggest that close face-to-face interactions pose a particular coronavirus transmission risk. The real-life prevalence and nature of such high-risk contacts are understudied, however. Here, we video-observed high-risk contacts in outdoor public places in Amsterdam, the Netherlands, during the COVID-19 pandemic. We found that high-risk contacts were relatively uncommon: Of the 7,813 individuals observed, only 20 (0.26%) displayed high-risk contacts. Further, we qualitatively examined the 20 high-risk contacts identified and found that they occurred disproportionally between affiliated persons engaged in affiliative behaviors. We discuss the potential public health implications of the relatively low incident rate of high-risk contacts.

No evidence that mask-wearing in public places elicits risk compensation behavior during the COVID-19 pandemic.

Face masks have been widely employed as a personal protective measure during the COVID-19 pandemic. However, concerns remain that masks create a false sense of security that reduces adherence to other public health measures, including social distancing. This paper tested whether mask-wearing was negatively associated with social distancing compliance. In two studies, we combined video-observational records of public mask-wearing in two Dutch cities with a natural-experimental approach to evaluate the effect of an area-based mask mandate. We found no observational evidence of an association between mask-wearing and social distancing but found a positive link between crowding and social distancing violations. Our natural-experimental analysis showed that an area-based mask mandate did not significantly affect social distancing or crowding levels. Our results alleviate the concern that mask use reduces social distancing compliance or increases crowding levels. On the other hand, crowding reduction may be a viable strategy to mitigate social distancing violations.

Face-touching behaviour as a possible correlate of mask-wearing: A video observational study of public place incidents during the COVID-19 pandemic.

Most countries in the world have recommended or mandated face masks in some or all public places during the COVID-19 pandemic. However, mask use has been thought to increase people's face-touching frequency and thus risk of self-inoculation. Across two studies, we video-observed the face-touching behaviour of members of the public in Amsterdam and Rotterdam (the Netherlands) during the first wave of the pandemic. Study 1 (n = 383) yielded evidence in favour of the absence of an association between mask-wearing and face-touching (defined as touches of face or mask), and Study 2 (n = 421) replicated this result. Secondary outcome analysis of the two studies-analysed separately and with pooled data sets-evidenced a negative association between mask-wearing and hand contact with the face and its t-zone (i.e. eyes, nose and mouth). In sum, the current findings alleviate the concern that mask-wearing has an adverse face-touching effect.

Third Parties Mirror the Aggression of the Antagonists: A Video-Based Analysis of Third-Party Aggression in Interpersonal Conflicts.

Third parties tend to take an active role and intervene in interpersonal conflicts in public. Previous research has shown that the level of aggression of these interventions determines how they influence the conflict. No previous study has, however, systematically investigated whether the aggression of third-party interventions is influenced by the development of the conflict situation. The objective of this study is twofold. First, the study determines the extent to which the aggression level of intervening third parties changes during the course of interpersonal conflicts. Second, the study identifies and investigates the factors that affect the aggression levels displayed by intervening third parties. We systematically observed and coded CCTV footage of 46 interpersonal conflicts in public space, recorded by surveillance cameras in Amsterdam, the Netherlands. The data included 565 intervention behaviors by 125 third parties. We recorded the levels of aggression of the individuals involved in the conflict and conducted a multinomial logistic regression analysis to investigate what influenced the aggression level of the third-party interventions. We found that the aggression levels of the preceding intervention behaviors by the third parties predict aggression levels of their subsequent interventions. This shows a consistency in third-party interventions over the course of a conflict. We also found that the aggression levels of the conflict parties that are the targets of the interventions influence the aggression levels of third-party intervention. This finding demonstrates that the development of the conflict situation influences how aggressive the third parties are. Our study emphasizes the importance of taking the interactional dynamics of interpersonal conflicts into consideration when explaining third-party behavior.

Social distancing compliance: A video observational analysis.

PURPOSE: Virus epidemics may be mitigated if people comply with directives to stay at home and keep their distance from strangers in public. As such, there is a public health interest in social distancing compliance. The available evidence on distancing practices in public space is limited, however, by the lack of observational data. Here, we apply video observation as a method to examine to what extent members of the public comply with social distancing directives. DATA: Closed Circuit Television (CCTV) footage of interactions in public was collected in inner-city Amsterdam, the Netherlands. From the footage, we observed instances of people violating the 1.5-meter distance directives in the weeks before, during, and after these directives were introduced to mitigate the COVID-19 pandemic. RESULTS: We find that people complied with the 1.5-meter distance directives when these directives were first introduced, but that the level of compliance started to decline soon after. We also find that violation of the 1.5-meter distance directives is strongly associated with the number of people observed on the street and with non-compliance to stay-at-home directives, operationalized with large-scale aggregated location data from cell phones. All three measures correlate to a varying extent with temporal patterns in the transmission of the COVID-19 virus, temperature, COVID-19 related Google search queries, and media attention to the topic. CONCLUSION: Compliance with 1.5 meter distance directives is short-lived and coincides with the number of people on the street and with compliance to stay-at-home directives. Potential implications of these findings are that keep- distance directives may work best in combination with stay-at-home directives and place-specific crowd-control strategies, and that the number of people on the street and community-wide mobility as captured with cell phone data offer easily measurable proxies for the extent to which people keep sufficient physical distance from others at specific times and locations.

Dissecting the Role of Dominance in Robberies: An Analysis and Implications for Microsociology of Violence.

The influential microsociological theory of violence advanced by Randall Collins suggests that emotional dominance preconditions physical violence. Here, we examine robbery incidents as counterevidence of this proposition. Using 50 video clips of real-life commercial robberies recorded by surveillance cameras, we observed, coded, and analyzed the interpersonal behaviors of offenders and victims in microdetail. We found no support for Collins's hypothesized link between dominance and violence, but evidence against it instead. It is the absence, not the presence, of emotional offender dominance that promotes offender violence. We consider these results in the light of criminological research on robbery violence and suggest that Collins's strong situational stance would benefit from a greater appreciation of instrumental motivation and cold-headed premeditation.

Would I be helped? Cross-national CCTV footage shows that intervention is the norm in public conflicts.

Half a century of research on bystander behavior concludes that individuals are less likely to intervene during an emergency when in the presence of others than when alone. By contrast, little is known regarding the aggregated likelihood that at least someone present at an emergency will do something to help. The importance of establishing this aggregated intervention baseline is not only of scholarly interest but is also the most pressing question for actual public victims-will I receive help if needed? The current article describes the largest systematic study of real-life bystander intervention in actual public conflicts captured by surveillance cameras. Using a unique cross-national video dataset from the United Kingdom, the Netherlands, and South Africa (N = 219), we show that in 9 of 10 public conflicts, at least 1 bystander, but typically several, will do something to help. We record similar likelihoods of intervention across the 3 national contexts, which differ greatly in levels of perceived public safety. Finally, we find that increased bystander presence is related to a greater likelihood that someone will intervene. Taken together these findings allay the widespread fear that bystanders rarely intervene to help. We argue that it is time for psychology to change the narrative away from an absence of help and toward a new understanding of what makes intervention successful or unsuccessful. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Social relations and presence of others predict bystander intervention: Evidence from violent incidents captured on CCTV.

Are individuals willing to intervene in public violence? Half a century of research on the "bystander effect" suggests that the more bystanders present at an emergency, the less likely each of them is to provide help. However, recent meta-analytical evidence questions whether this effect generalizes to violent emergencies. Besides the number of bystanders present, an alternative line of research suggests that pre-existing social relations between bystanders and conflict participants are important for explaining whether bystanders provide help. The current paper offers a rare comparison of both factors-social relations and the number of bystanders present-as predictors of bystander intervention in real-life violent emergencies. We systematically observed the behavior of 764 bystanders across 81 violent incidents recorded by surveillance cameras in Copenhagen, Denmark. Bystanders were sampled with a case-control design, their behavior was observed and coded, and the probability of intervention was estimated with multilevel regression analyses. The results confirm our predicted association between social relations and intervention. However, rather than the expected reversed bystander effect, we found a classical bystander effect, as bystanders were less likely to intervene with increasing bystander presence. The effect of social relations on intervention was larger in magnitude than the effect of the number of bystanders. We assess these findings in light of recent discussions about the influence of group size and social relations in human helping. Further, we discuss the utility of video data for the assessment of real-life bystander behavior.

Lessons Learned from Crime Caught on Camera.

OBJECTIVES: The widespread use of camera surveillance in public places offers criminologists the opportunity to systematically and unobtrusively observe crime, their main subject matter. The purpose of this essay is to inform the reader of current developments in research on crimes caught on camera. METHODS: We address the importance of direct observation of behavior and review criminological studies that used observational methods, with and without cameras, including the ones published in this issue. We also discuss the uses of camera recordings in other social sciences and in biology. RESULTS: We formulate six key insights that emerge from the literature and make recommendations for future research. CONCLUSIONS: Camera recordings of real-life crime are likely to become part of the criminological tool kit that will help us better understand the situational and interactional elements of crime. Like any source, it has limitations that are best addressed by triangulation with other sources.

Weapons, Body Postures, and the Quest for Dominance in Robberies: A Qualitative Analysis of Video Footage.

OBJECTIVE: A small-scale exploration of the use of video analysis to study robberies. We analyze the use of weapons as part of the body posturing of robbers as they attempt to attain dominance. METHODS: Qualitative analyses of video footage of 23 shop robberies. We used Observer XT software (version 12) for fine-grained multimodal coding, capturing diverse bodily behavior by various actors simultaneously. We also constructed story lines to understand the robberies as hermeneutic whole cases. RESULTS: Robbers attain dominance by using weapons that afford aggrandizing posturing and forward movements. Guns rather than knives seemed to fit more easily with such posturing. Also, victims were more likely to show minimizing postures when confronted with guns. Thus, guns, as part of aggrandizing posturing, offer more support to robbers' claims to dominance in addition to their more lethal power. In the cases where resistance occurred, robbers either expressed insecure body movements or minimizing postures and related weapon usage or they failed to impose a robbery frame as the victims did not seem to comprehend the situation initially. CONCLUSIONS: Video analysis opens up a new perspective of how violent crime unfolds as sequences of bodily movements. We provide methodological recommendations and suggest a larger scale comparative project.

Consolation in the aftermath of robberies resembles post-aggression consolation in chimpanzees.

Post-aggression consolation is assumed to occur in humans as well as in chimpanzees. While consolation following peer aggression has been observed in children, systematic evidence of consolation in human adults is rare. We used surveillance camera footage of the immediate aftermath of nonfatal robberies to observe the behaviors and characteristics of victims and bystanders. Consistent with empathy explanations, we found that consolation was linked to social closeness rather than physical closeness. While females were more likely to console than males, males and females were equally likely to be consoled. Furthermore, we show that high levels of threat during the robbery increased the likelihood of receiving consolation afterwards. These patterns resemble post-aggression consolation in chimpanzees and suggest that emotions of empathic concern are involved in consolation across humans and chimpanzees.

A Phase 2, Randomized, Dose-Finding Study of the Novel Once-Weekly Human GLP-1 Analog, Semaglutide, Compared With Placebo and Open-Label Liraglutide in Patients With Type 2 Diabetes.

OBJECTIVE: To investigate the dose-response relationship of semaglutide versus placebo and open-label liraglutide in terms of glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a 12-week, randomized, double-blind phase 2 trial. Patients (n = 415) were randomized to receive a subcutaneous injection of semaglutide once weekly without dose escalation (0.1-0.8 mg) or with dose escalation (E) (0.4 mg steps to 0.8 or 1.6 mg E over 1-2 weeks), open-label liraglutide once daily (1.2 or 1.8 mg), or placebo. The primary end point was change in HbA1c level from baseline. Secondary end points included change in body weight, safety, and tolerability. RESULTS: Semaglutide dose-dependently reduced the level of HbA1c from baseline (8.1 ± 0.8%) to week 12 by up to -1.7%, and body weight by up to -4.8 kg (1.6 mg E, P < 0.001 vs. placebo). Up to 81% of patients achieved an HbA1c level of <7%. HbA1c level and weight reductions with semaglutide 1.6 mg E were greater than those with liraglutide 1.2 and 1.8 mg (based on unadjusted CIs), but adverse events (AEs) and withdrawals occurred more frequently. The incidence of nausea, vomiting, and withdrawal due to gastrointestinal AEs increased with the semaglutide dose; most events were mild to moderate, transient, and ameliorated by dose escalation. There were no major episodes of hypoglycemia and few cases of injection site reactions. CONCLUSIONS: After 12 weeks, semaglutide dose-dependently reduced HbA1c level and weight in patients with type 2 diabetes. No unexpected safety or tolerability concerns were identified; gastrointestinal AEs typical of glucagon-like peptide 1 receptor agonists were mitigated by dose escalation. On this basis, weekly semaglutide doses of 0.5 and 1.0 mg with a 4-week dose escalation were selected for phase 3.

Copeptin and MR-proADM in umbilical cord plasma reflect perinatal stress in neonates born to mothers with diabetes and MR-proANP reflects maternal diabetes.

AIM: To examine concentrations of three cardiovascular propeptides in umbilical cord plasma of neonates born to mothers with Type 1, Type 2 and gestational diabetes. Measurement of cardiovascular markers in umbilical cord plasma may potentially help identify neonates at risk of postnatal complications. Neonates born to mothers with diabetes have an increased risk of neonatal morbidity and mortality, and measurement of these new biomarkers may potentially help identify neonates at risk of these complications. SUBJECTS & METHODS: Copeptin, midregional proadrenomedullin (MR-proADM) and mid-regional pro-A-type natriuretic peptide (MR-proANP) were measured in cord plasma of neonates (n = 63) born to mothers with the three types of diabetes. Associations with maternal glycemic control, mode of delivery and neonatal metabolic acidosis were examined. RESULTS: Umbilical cord plasma copeptin concentrations were lowest in neonates after elective cesarean sections (6.1 pmol/l; interquartile range [IQR]: 4.5-9.1) compared with emergency cesarean sections (156 pmol/l; IQR: 9.6-311; p = 0.019) and vaginal delivery (831 pmol/l; IQR: 107-2407; p < 0.0001). MR-proADM was also affected by mode of delivery; however, this seemed more likely to be caused by an inverse association with the acid-base balance. In this population, only MR-proANP plasma concentrations were related to type of diabetes. Neonates born to mothers with Type 1 diabetes had higher concentrations (median 260 pmol/l; IQR: 222-318) compared with Type 2 diabetes (175 pmol/l; IQR: 169-200; p = 0.003) and gestational diabetes (200 pmol/l; IQR: 149-276; p = 0.009). CONCLUSION: Umbilical cord plasma copeptin and MR-proADM concentrations primarily reflect perinatal stress associated with mode of delivery and the degree of fetal acidosis, whereas MR-proANP concentrations are higher in neonates born to mothers with Type 1 diabetes.

Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome.

Patients with Smith-Lemli-Opitz syndrome (SLOS) are born with multiple congenital abnormalities. Postnatal cholesterol supplementation is provided; however, it cannot correct developmental malformations due to in utero cholesterol deficit. Increased transport of cholesterol from maternal to fetal circulation might attenuate congenital malformations. The cholesterol transporters Abca1, Abcg1, and Sr-b1 are present in placenta; however, their potential role in placental transport remains undetermined. In mice, expression analyses showed that Abca1 and Abcg1 transcripts increased 2-3-fold between embryonic days 13.5 and 18.5 in placental tissue; whereas, Sr-b1 expression decreased. To examine the functional role of Abca1, Abcg1 and Sr-b1 we measured the maternal-fetal transfer of (14)C-cholesterol in corresponding mutant embryos. Disruption of either Abca1 or Sr-b1 decreased cholesterol transfer by approximately 30%. In contrast, disruption of the Abcg1 had no effect. Treatment of pregnant C57Bl/6 female mice with TO901317, an LXR-agonist, increased both Abca1 expression and maternal-fetal cholesterol transfer to the fetus. In an SLOS mouse model (Dhcr7(-/-)), which is incapable of de novo synthesis of cholesterol, in utero treatment with TO901317 resulted in increased cholesterol content in Dhcr7(-/-) embryos. Our data support the hypothesis that Abca1, and possibly Sr-b1, contributes to transport maternal cholesterol to the developing fetus. Furthermore, we show, as a proof of principle, that modulating maternal-fetal cholesterol transport has potential for in utero therapy of SLOS.

Increased LDL cholesterol and CRP in infants of mothers with type 1 diabetes.

BACKGROUND: Proatherogenic stimuli during foetal life may predispose to development of atherosclerosis in adulthood. Elevated plasma low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP) expression is associated with increased risk of atherosclerosis. METHODS AND RESULTS: In this study, we examined how maternal type 1 diabetes affects foetal plasma LDL cholesterol and CRP. In comparison with healthy mothers, the plasma LDL cholesterol was not increased in the mothers with diabetes, however, the umbilical-cord plasma LDL cholesterol was increased in their infants. CRP was increased in infants of mothers with diabetes and high haemoglobin A1c (HbA1c, > or = 6.2%). Human placenta expresses microsomal triglyceride transfer protein (MTP), which facilitates secretion of apolipoprotein B-containing lipoproteins. Microsomal triglyceride transfer activity was slightly higher (11%) in placentas from mothers with diabetes and HbA1c > or = 6.2% compared with the controls. CONCLUSION: The results suggest that maternal type 1 diabetes increases the foetal plasma LDL cholesterol and CRP concentration and thus might predispose the offspring to development of atherosclerosis.