Association between weight reduction achieved with tirzepatide and quality of life in adults with obesity: Results from the SURMOUNT-1 study.

AIMS: The SURMOUNT-1 trial investigated effects of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, on body weight in participants with obesity or overweight. This analysis evaluated changes in patient-reported outcomes (PROs) assessing physical function, psychosocial well-being, and overall health aspects of participants' health-related quality of life (HRQoL) in SURMOUNT-1. METHODS: PRO instruments included the Impact of Weight on Quality of Life-Lite Clinical Trials version (IWQOL-Lite-CT), Short Form Survey-36 version 2 (SF-36v2) and EQ-5D-5L. Scores were analysed by treatment group and by categorical degree of weight reduction group: >0 to <5%, ≥5 to <10%, ≥10 to <20% and ≥20%. Relevant PROs were evaluated for participants with or without physical or psychosocial limitations at baseline, as measured by Patient Global Impression of Status for physical activity (PGIS) and Patient Health Questionnaire-2 (PHQ-2), respectively. RESULTS: All tirzepatide groups demonstrated significant improvements in PRO scores versus placebo. There was a consistent trend of incremental PRO improvement with greater degrees of weight reduction, starting from ≥5% weight reduction. Participants achieving ≥20% weight reduction demonstrated the greatest changes from baseline to week 72 (SF-36v2 Physical Component Summary, 4.60; SF-36v2 Mental Component Summary, 0.80; IWQOL-Lite CT Total score, 24.7). Those with baseline physical and psychosocial limitations experienced greater improvements than those without. CONCLUSIONS: Tirzepatide treatment was associated with improved HRQoL compared to placebo in people with overweight or obesity. Higher percentages of weight reduction were associated with greater improvements. Clinical trial registration number for SURMOUNT-1: NCT04184622.

The multinational Conversations and Reactions Around Severe Hypoglycemia (CRASH) study: Impact of health care provider communications and recommendations on people with diabetes.

The multinational CRASH study found that substantive recommendations from health care providers were predictive of actions taken by people with diabetes during and after a severe hypoglycemic event, which highlights the importance of equipping people with actionable strategies to prevent and treat severe hypoglycemia should a severe hypoglycemic event arise.

Evaluation of the cost and medical resource use outcomes associated with nasal glucagon versus injectable glucagon for treatment of severe hypoglycemia in people with diabetes in Canada: a modeling analysis.

OBJECTIVES: Treatments for severe hypoglycemia aim to restore blood glucose through successful administration of rescue therapy, and choosing the most effective and cost-effective option will improve outcomes for patients and may reduce costs for healthcare payers. The present analysis aimed to compare costs and use of medical services with nasal glucagon and injectable glucagon in people with type 1 and 2 diabetes in Canada when used to treat severe hypoglycemic events when impaired consciousness precludes treatment with oral carbohydrates using an economic model, based on differences in the frequency of successful administration of the two interventions. METHODS: A decision tree model was prepared in Microsoft Excel to project outcomes with nasal glucagon and injectable glucagon. The model structure reflected real-world decision-making and treatment outcomes, based on Canada-specific sources. The model captured the use of glucagon, emergency medical services (EMS), emergency room, inpatient stay, and follow-up care. Costs were accounted for in 2019 Canadian dollars (CAD). RESULTS: Nasal glucagon was associated with reduced use of all medical services compared with injectable glucagon. EMS call outs were projected to be reduced by 45%, emergency room treatments by 52%, and inpatient stays by 13%. Use of nasal glucagon was associated with reduced direct, indirect, and combined costs of CAD 1,249, CAD 460, and CAD 1,709 per severe hypoglycemic event, respectively, due to avoided EMS call outs and hospital costs, resulting from a higher proportion of successful administrations. CONCLUSIONS: When a patient with type 1 or type 2 diabetes is being treated for a severe hypoglycemic event when impaired consciousness precludes treatment with oral carbohydrate, use of nasal glucagon was projected to be dominant versus injectable glucagon in Canada reducing costs and use of medical services.

Conversations and Reactions Around Severe Hypoglycemia Study: Results of Hypoglycemia Experiences in Canadian Adults With Insulin-Treated Diabetes and Their Caregivers.

OBJECTIVES: The Conversations and Reactions Around Severe Hypoglycemia cross-sectional study was conducted to better understand the severe hypoglycemia experiences in persons with diabetes (PWD) and their caregivers (CGs). METHODS: Adults with type 1 or type 2 diabetes and CGs were recruited in 8 countries; Canadian cohort data are reported in this study. Insulin-treated PWD who reported a severe hypoglycemic event within the past 3 years and CGs who care for PWD ≥4 years old and who met the criteria were eligible for the study. Participants completed an online survey about their experience with severe hypoglycemia, its treatment and actions during and after severe hypoglycemia. RESULTS: Of the 324 respondents, 139 (43%) reported discussions about severe hypoglycemia with a health-care provider (HCP) at every visit. During the most recent severe hypoglycemic event, the most common actions taken included ingestion of oral carbohydrates and calling emergency medical services; glucagon was rarely used. Despite many respondents (67%) feeling scared because of the most recent severe hypoglycemic event, only 55% (51% with type 1 and 61% with type 2) discussed this event with an HCP. The event affected the mood/emotional status, physical activities and sleep of PWD and CGs. CONCLUSIONS: Severe hypoglycemia impacts the emotional and physical status of PWD and CGs. Despite this, many respondents did not report discussions about the most recent severe hypoglycemic event with HCPs. Furthermore, <50% of the respondents reported discussions about severe hypoglycemia with HCPs at every visit. Purposeful communication about severe hypoglycemia can help fulfil Diabetes Canada guideline recommendations to review experiences with hypoglycemia among PWD at every visit.

Fc gamma R-mediated phagocytosis stimulates localized pinocytosis in human neutrophils.

Engulfment of IgG-coated particles by neutrophils and macrophages is an essential component of the innate immune response. This process, known as phagocytosis, is triggered by clustering of FcgammaR at sites where leukocytes make contact with the opsonized particles. We found that phagocytosis is accompanied by a burst of fluid phase pinocytosis, which is largely restricted to the immediate vicinity of the phagosomal cup. FcgammaR-induced pinocytosis preceded and appeared to be independent of phagosomal sealing. Accordingly, fluid phase uptake was accentuated by actin depolymerization, which precludes phagocytosis. Stimulation of pinocytosis required phosphatidylinositol 3-kinase activity and was eliminated when changes in the cytosolic free Ca(2+) concentration were prevented. Because stimulation of FcgammaR also induces secretion, which is similarly calcium and phosphatidylinositol 3-kinase dependent, we studied the possible relationship between these events. Neutrophil fragments devoid of secretory granules (cytoplasts) were prepared by sedimentation through Ficoll gradients. Cytoplasts could perform FcgammaR-mediated phagocytosis, which was not accompanied by activation of pinocytosis. This observation suggests that granule exocytosis is required for stimulation of pinocytosis. Analysis of the cytosolic Ca(2+) dependence of secretion and pinocytosis suggests that primary (lysosomal) granule exocytosis is the main determinant of pinocytosis during FcgammaR stimulation. Importantly, primary granules are secreted in a polarized fashion near forming phagosomes. Focal pinocytosis during particle engulfment may contribute to Ag processing and presentation and/or to retrieval of components of the secretory machinery. Alternatively, it may represent an early event in the remodeling of the phagosomal membrane, leading to phagosomal maturation.