Reducing the burden of hypoglycaemia in people with diabetes through increased understanding:design of the Hypoglycaemia Redefining Solutions for Better Lives (Hypo-RESOLVE) project

Background Hypoglycaemia is the most frequent complication of treatment with insulin or insulin secretagogues in people with diabetes. Severe hypoglycaemia, i.e. an event requiring external help because of cognitive dysfunction, is associated with a higher risk of adverse cardiovascular outcomes and all‐cause mortality, but underlying mechanism(s) are poorly understood. There is also a gap in the understanding of the clinical, psychological and health economic impact of ‘non‐severe’ hypoglycaemia and the glucose level below which hypoglycaemia causes harm. Aim To increase understanding of hypoglycaemia by addressing the above issues over a 4‐year period. Methods Hypo‐RESOLVE is structured across eight work packages, each with a distinct focus. We will construct a large, sustainable database including hypoglycaemia data from >100 clinical trials to examine predictors of hypoglycaemia and establish glucose threshold(s) below which hypoglycaemia constitutes a risk for adverse biomedical and psychological outcomes, and increases healthcare costs. We will also investigate the mechanism(s) underlying the antecedents and consequences of hypoglycaemia, the significance of glucose sensor‐detected hypoglycaemia, the impact of hypoglycaemia in families, and the costs of hypoglycaemia for healthcare systems. Results The outcomes of Hypo‐RESOLVE will inform evidence‐based definitions regarding the classification of hypoglycaemia in diabetes for use in daily clinical practice, future clinical trials and as a benchmark for comparing glucose‐lowering interventions and strategies across trials. Stakeholders will be engaged to achieve broadly adopted agreement. Conclusion Hypo‐RESOLVE will advance our understanding and refine the classification of hypoglycaemia, with the ultimate aim being to alleviate the burden and consequences of hypoglycaemia in people with diabetes

AGENDA: Seeds of Change: Responding to Global Change in a Bottom-up World

Sponsors: Posner Center for International Development, RESOLVE, Inc., Newmont Mining Corporation, and Getches-Wilkinson Center for Natural Resources, Energy, and the Environment. Conference moderators, panelists and speakers included University of Colorado Law School professors Phil Weiser, Sarah Krakoff, Britt Banks, and Lakshman Guruswamy. This conference is made possible through the generous support of donors who sponsored this year’s Martz Sustainability Symposium (including Newmont Mining Corporation) and those who have invested in our Clyde O. Martz Endowed Fund for Natural Resources Management (including Brian Dolan and Davis Graham and Stubbs LLP). The Martz Natural Resources Management Fund was established in the memory of natural resources law pioneer Clyde Martz and supports innovative programming at Colorado Law in best practices in natural resources management. Many believe that global institutions and frameworks are failing to generate necessary progress on issues such as climate change, water scarcity, biodiversity, food security, and poverty eradication; and that state, tribal and local governments and communities, innovative companies, social and technology entrepreneurs, NGOs, impact investors, consumers and philanthropists increasingly are taking the lead in creating bottom-up solutions to these challenges. The conference will explore this dynamic in detail, with an emphasis on the drivers behind these ground level innovations, and on how they can better “filter up” to inform the global conversations occurring on how best to address the various dimensions of “global change”

AGENDA: Seeds of Change: Responding to Global Change in a Bottom-up World

Sponsors: Posner Center for International Development, RESOLVE, Inc., Newmont Mining Corporation, and Getches-Wilkinson Center for Natural Resources, Energy, and the Environment. Conference moderators, panelists and speakers included University of Colorado Law School professors Phil Weiser, Sarah Krakoff, Britt Banks, and Lakshman Guruswamy. This conference is made possible through the generous support of donors who sponsored this year’s Martz Sustainability Symposium (including Newmont Mining Corporation) and those who have invested in our Clyde O. Martz Endowed Fund for Natural Resources Management (including Brian Dolan and Davis Graham and Stubbs LLP). The Martz Natural Resources Management Fund was established in the memory of natural resources law pioneer Clyde Martz and supports innovative programming at Colorado Law in best practices in natural resources management. Many believe that global institutions and frameworks are failing to generate necessary progress on issues such as climate change, water scarcity, biodiversity, food security, and poverty eradication; and that state, tribal and local governments and communities, innovative companies, social and technology entrepreneurs, NGOs, impact investors, consumers and philanthropists increasingly are taking the lead in creating bottom-up solutions to these challenges. The conference will explore this dynamic in detail, with an emphasis on the drivers behind these ground level innovations, and on how they can better “filter up” to inform the global conversations occurring on how best to address the various dimensions of “global change”

Changes in quality of life following hypoglycaemia in adults with type 2 diabetes: A systematic review of longitudinal studies

Aim To conduct a systematic review of published studies reporting on the longitudinal impacts of hypoglycaemia on quality of life (QoL) in adults with type 2 diabetes. Method Database searches with no restrictions by language or date were conducted in MEDLINE, Cochrane Library, CINAHL and PsycINFO. Studies were included for review if they used a longitudinal design (e.g. cohort studies, randomised controlled trials) and reported on the association between hypoglycaemia and changes over time in patient-reported outcomes related to QoL. Results In all, 20 longitudinal studies published between 1998 and 2020, representing 50,429 adults with type 2 diabetes, were selected for review. A descriptive synthesis following Synthesis Without Meta-analysis guidelines indicated that self-treated symptomatic hypoglycaemia was followed by impairments in daily functioning along with elevated symptoms of generalised anxiety, diabetes distress and fear of hypoglycaemia. Severe hypoglycaemic events were associated with reduced confidence in diabetes self-management and lower ratings of perceived health over time. Frequent hypoglycaemia was followed by reduced energy levels and diminished emotional well-being. There was insufficient evidence, however, to conclude that hypoglycaemia impacted sleep quality, depressive symptoms, general mood, social support or overall diabetes-specific QoL. Conclusions Longitudinal evidence in this review suggests hypoglycaemia is a common occurrence among adults with type 2 diabetes that impacts key facets in the physical and psychological domains of QoL. Nonetheless, additional longitudinal research is needed—in particular, studies targeting diverse forms of hypoglycaemia, more varied facets of QoL and outcomes assessed using hypoglycaemia-specific measures

Efficacy and Safety of Lenabasum, a Cannabinoid Type 2 Receptor Agonist, in a Phase 3 Randomized Trial in Diffuse Cutaneous Systemic Sclerosis

INTRODUCTION: Efficacy and safety of lenabasum, a cannabinoid type 2-receptor agonist, was tested in a Phase 3 study in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: A multi-national double-blind study was conducted in 365 dcSSc patients who were randomized and dosed 1:1:1 with lenabasum 20 mg, lenabasum 5 mg, or placebo, each twice daily and added to background treatments including immunosuppressive therapies (IST). RESULTS: The primary endpoint, ACR Combined Response Index in dcSSc (ACR-CRISS) score at Week 52, lenabasum 20 mg BID versus placebo, was not met, with ACR-CRISS scores of 0.888 versus 0.887, P = 0.4972, mixed models repeated measures (MMRM). Change in modified Rodnan Skin Score (mRSS) at Week 52 was -6.7 versus -8.1 points for lenabasum 20 mg BID versus placebo, P = 0.1183, MMRM. Pre-specified analyses showed higher ACR-CRISS scores, greater improvement in mRSS, and less decline in forced vital capacity in subjects on background mycophenolate and those receiving IST for ≤ 1 year duration. No deaths or excess in serious or severe adverse events related to lenabasum were observed. CONCLUSIONS: A benefit of lenabasum in dcSSc was not demonstrated. The majority of patients were treated with background IST, and treatment with MMF in particular was associated with better outcomes. This supports the use of IST in the treatment of dcSSc, and highlights the challenge of demonstrating a treatment effect when investigational treatment is added to standard of care IST. These findings have relevance to trial design in SSc, as well as clinical care

Hyperinsulinaemic–hypoglycaemic glucose clamps in human research: a systematic review of the literature

Abstract: Aims/hypothesis: The hyperinsulinaemic–hypoglycaemic glucose clamp technique has been developed and applied to assess effects of and responses to hypoglycaemia under standardised conditions. However, the degree to which the methodology of clamp studies is standardised is unclear. This systematic review examines how hyperinsulinaemic–hypoglycaemic clamps have been performed and elucidates potential important differences. Methods: A literature search in PubMed and EMBASE was conducted. Articles in English published between 1980 and 2018, involving adults with or without diabetes, were included. Results: A total of 383 articles were included. There was considerable variation in essential methodology of the hypoglycaemic clamp procedures, including the insulin dose used (49-fold difference between the lowest and the highest rate), the number of hypoglycaemic steps (range 1−6), the hypoglycaemic nadirs (range 2.0–4.3 mmol/l) and the duration (ranging from 5 to 660 min). Twenty-seven per cent of the articles reported whole blood glucose levels, most venous levels. In 70.8% of the studies, a dorsal hand vein was used for blood sampling, with some form of hand warming to arterialise venous blood in 78.8% of these. Key information was missing in 61.9% of the articles. Conclusions/interpretation: Although the hyperinsulinaemic–hypoglycaemic clamp procedure is considered the gold standard to study experimental hypoglycaemia, a uniform standard with key elements on how to perform these experiments is lacking. Methodological differences should be considered when comparing results between hypoglycaemic clamp studies. PROSPERO registration: This systematic review is registered in PROSPERO (CRD42019120083). Graphical abstract

Investigating the day-to-day impact of hypoglycaemia in adults with type 1 or type 2 diabetes: design and validation protocol of the Hypo-METRICS application

Introduction: Hypoglycaemia is a frequent adverse event and major barrier for achieving optimal blood glucose levels in people with type 1 or type 2 diabetes using insulin. The Hypo-RESOLVE (Hypoglycaemia—Redefining SOLutions for better liVEs) consortium aims to further our understanding of the day-to-day impact of hypoglycaemia. The Hypo-METRICS (Hypoglycaemia—MEasurement, ThResholds and ImpaCtS) application (app) is a novel app for smartphones. This app is developed as part of the Hypo-RESOLVE project, using ecological momentary assessment methods that will minimise recall bias and allow for robust investigation of the day-to-day impact of hypoglycaemia. In this paper, the development and planned psychometric analyses of the app are described. Methods and analysis: The three phases of development of the Hypo-METRICS app are: (1) establish a working group—comprising diabetologists, psychologists and people with diabetes—to define the problem and identify relevant areas of daily functioning; (2) develop app items, with user-testing, and implement into the app platform; and (3) plan a large-scale, multicountry study including interviews with users and psychometric validation. The app includes 7 modules (29 unique items) assessing: self-report of hypoglycaemic episodes (during the day and night, respectively), sleep quality, well-being/cognitive function, social interactions, fear of hypoglycaemia/hyperglycaemia and work/productivity. The app is designed for use within three fixed time intervals per day (morning, afternoon and evening). The first version was released mid-2020 for use (in conjunction with continuous glucose monitoring and activity tracking) in the Hypo-METRICS study; an international observational longitudinal study. As part of this study, semistructured user-experience interviews and psychometric analyses will be conducted. Ethics and dissemination: Use of the novel Hypo-METRICS app in a multicountry clinical study has received ethical approval in each of the five countries involved (Oxford B Research Ethics Committee, CMO Region Arnhem-Nijmegen, Ethikkommission der Medizinischen Universität Graz, Videnskabsetisk Komite for Region Hovedstaden and the Comite Die Protection Des Personnes SUD Mediterranne IV). The results from the study will be published in peer review journals and presented at national and international conferences. Trial registration number: NCT04304963

Quality of life, coping strategies and support needs of women seeking Traditional Chinese Medicine for infertility and viable pregnancy in Australia: a mixed methods approach

Extent: 11p.Background: Infertility affects about 15% of couples in Western-societies with most progressing to fertility clinics for treatment. Despite being common, infertility is often experienced as a lonely road for affected couples. In this paper we expand on our previously published findings of women’s experiences with infertility or difficulty of viable pregnancy who had sought Traditional Chinese Medicine (TCM) therapy in Australia, and focus on women’s quality of life, coping strategies, and support needs. Methods: We applied mixed methods using the Tuebingen Quality of Life and the COPE questionnaires and in-depth interviews with 25 women with primary or secondary infertility, recurrent miscarriages or unexplained stillbirth, and who had consulted a TCM practitioner. We used a thematic approach to analyse the interviews, and descriptive statistics to evaluate questionnaire responses. Results: Women reported through both questionnaires and interviews compromised quality of life due to the high level of distress, guilt, grief, and frustration caused by infertility. However, our women represented a highly motivated sample, actively seeking alternative support. While the TCM approach to infertility management increased women’s sense of personal agency and control through education and continuity of care, the need for greater understanding and support on a societal level remains. Conclusions: In infertility, ongoing emotional and instrumental support is pivotal to the wellbeing and quality of life of the affected. Traditional Chinese Medicine addresses some support needs in infertility not routinely available in the Western model of care. More peer-led and professional-led support groups are greatly needed for women experiencing infertility to help break isolation and raise awareness of integrative approaches to fertility management.Karin Ried and Ann Alfre