Development of a new health-related quality of life measure for people with diabetes who experience hypoglycaemia: the Hypo-RESOLVE QoL.

AIMS/HYPOTHESIS: Valid and reliable patient-reported outcome measures are vital for assessing disease impact, responsiveness to healthcare and the cost-effectiveness of interventions. A recent review has questioned the ability of existing measures to assess hypoglycaemia-related impacts on health-related quality of life for people with diabetes. This mixed-methods project was designed to produce a novel health-related quality of life patient-reported outcome measure in hypoglycaemia: the Hypo-RESOLVE QoL. METHODS: Three studies were conducted with people with diabetes who experience hypoglycaemia. In Stage 1, a comprehensive health-related quality of life framework for hypoglycaemia was elicited from semi-structured interviews (N=31). In Stage 2, the content validity and acceptability of draft measure content were tested via three waves of cognitive debriefing interviews (N=70 people with diabetes; N=14 clinicians). In Stage 3, revised measure content was administered alongside existing generic and diabetes-related measures in a large cross-sectional observational survey to assess psychometric performance (N=1246). The final measure was developed using multiple evidence sources, incorporating stakeholder engagement. RESULTS: A novel conceptual model of hypoglycaemia-related health-related quality of life was generated, featuring 19 themes, organised by physical, social and psychological aspects. From a draft version of 76 items, a final 14-item measure was produced with satisfactory structural (χ2=472.27, df=74, p<0.001; comparative fit index =0.943; root mean square error of approximation =0.069) and convergent validity with related constructs (r=0.46-0.59), internal consistency (α=0.91) and test-retest reliability (intraclass correlation coefficient =0.87). CONCLUSIONS/INTERPRETATION: The Hypo-RESOLVE QoL is a rigorously developed patient-reported outcome measure assessing the health-related quality of life impacts of hypoglycaemia. The Hypo-RESOLVE QoL has demonstrable validity and reliability and has value for use in clinical decision-making and as a clinical trial endpoint. DATA AVAILABILITY: All data generated or analysed during this study are included in the published article and its online supplementary files ( https://doi.org/10.15131/shef. DATA: 23295284.v2 ).

Estimating risk of consequences following hypoglycaemia exposure using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials.

AIMS/HYPOTHESIS: Whether hypoglycaemia increases the risk of other adverse outcomes in diabetes remains controversial, especially for hypoglycaemia episodes not requiring assistance from another person. An objective of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project was to create and use a dataset of pooled clinical trials in people with type 1 or type 2 diabetes to examine the association of exposure to all hypoglycaemia episodes across the range of severity with incident event outcomes: death, CVD, neuropathy, kidney disease, retinal disorders and depression. We also examined the change in continuous outcomes that occurred following a hypoglycaemia episode: change in eGFR, HbA1c, blood glucose, blood glucose variability and weight. METHODS: Data from 84 trials with 39,373 participants were pooled. For event outcomes, time-updated Cox regression models adjusted for age, sex, diabetes duration and HbA1c were fitted to assess association between: (1) outcome and cumulative exposure to hypoglycaemia episodes; and (2) outcomes where an acute effect might be expected (i.e. death, acute CVD, retinal disorders) and any hypoglycaemia exposure within the last 10 days. Exposures to any hypoglycaemia episode and to episodes of given severity (levels 1, 2 and 3) were examined. Further adjustment was then made for a wider set of potential confounders. The within-person change in continuous outcomes was also summarised (median of 40.4 weeks for type 1 diabetes and 26 weeks for type 2 diabetes). Analyses were conducted separately by type of diabetes. RESULTS: The maximally adjusted association analysis for type 1 diabetes found that cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of neuropathy, kidney disease, retinal disorders and depression, with risk ratios ranging from 1.55 (p=0.002) to 2.81 (p=0.002). Associations of a similar direction were found when level 1 episodes were examined separately but were significant for depression only. For type 2 diabetes cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of death, acute CVD, kidney disease, retinal disorders and depression, with risk ratios ranging from 2.35 (p<0.0001) to 3.00 (p<0.0001). These associations remained significant when level 1 episodes were examined separately. There was evidence of an association between hypoglycaemia episodes of any kind in the previous 10 days and death, acute CVD and retinal disorders in both type 1 and type 2 diabetes, with rate ratios ranging from 1.32 (p=0.017) to 2.68 (p<0.0001). These associations varied in magnitude and significance when examined separately by hypoglycaemia level. Within the range of hypoglycaemia defined by levels 1, 2 and 3, we could not find any evidence of a threshold at which risk of these consequences suddenly became pronounced. CONCLUSIONS/INTERPRETATION: These data are consistent with hypoglycaemia being associated with an increased risk of adverse events across several body systems in diabetes. These associations are not confined to severe hypoglycaemia requiring assistance.

Risk factors and prediction of hypoglycaemia using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials.

AIMS/HYPOTHESIS: The objective of the Hypoglycaemia REdefining SOLutions for better liVES (Hypo-RESOLVE) project is to use a dataset of pooled clinical trials across pharmaceutical and device companies in people with type 1 or type 2 diabetes to examine factors associated with incident hypoglycaemia events and to quantify the prediction of these events. METHODS: Data from 90 trials with 46,254 participants were pooled. Analyses were done for type 1 and type 2 diabetes separately. Poisson mixed models, adjusted for age, sex, diabetes duration and trial identifier were fitted to assess the association of clinical variables with hypoglycaemia event counts. Tree-based gradient-boosting algorithms (XGBoost) were fitted using training data and their predictive performance in terms of area under the receiver operating characteristic curve (AUC) evaluated on test data. Baseline models including age, sex and diabetes duration were compared with models that further included a score of hypoglycaemia in the first 6 weeks from study entry, and full models that included further clinical variables. The relative predictive importance of each covariate was assessed using XGBoost's importance procedure. Prediction across the entire trial duration for each trial (mean of 34.8 weeks for type 1 diabetes and 25.3 weeks for type 2 diabetes) was assessed. RESULTS: For both type 1 and type 2 diabetes, variables associated with more frequent hypoglycaemia included female sex, white ethnicity, longer diabetes duration, treatment with human as opposed to analogue-only insulin, higher glucose variability, higher score for hypoglycaemia across the 6 week baseline period, lower BP, lower lipid levels and treatment with psychoactive drugs. Prediction of any hypoglycaemia event of any severity was greater than prediction of hypoglycaemia requiring assistance (level 3 hypoglycaemia), for which events were sparser. For prediction of level 1 or worse hypoglycaemia during the whole follow-up period, the AUC was 0.835 (95% CI 0.826, 0.844) in type 1 diabetes and 0.840 (95% CI 0.831, 0.848) in type 2 diabetes. For level 3 hypoglycaemia, the AUC was lower at 0.689 (95% CI 0.667, 0.712) for type 1 diabetes and 0.705 (95% CI 0.662, 0.748) for type 2 diabetes. Compared with the baseline models, almost all the improvement in prediction could be captured by the individual's hypoglycaemia history, glucose variability and blood glucose over a 6 week baseline period. CONCLUSIONS/INTERPRETATION: Although hypoglycaemia rates show large variation according to sociodemographic and clinical characteristics and treatment history, looking at a 6 week period of hypoglycaemia events and glucose measurements predicts future hypoglycaemia risk.

From educator to facilitator: Healthcare professionals' experiences of, and views about, delivering a type 1 diabetes structured education programme (DAFNEplus ) informed by behavioural science.

AIMS: The DAFNEplus programme incorporates behaviour change techniques into a modified educational intervention and was developed to help address the glycaemic drift observed amongst graduates of standard DAFNE programmes. As the programme's success will be contingent on staff buy-in, we explored healthcare professionals' experiences of, and views about, delivering DAFNEplus during a clinical trial to help inform decision making about rollout post-trial. METHODS: We interviewed n = 18 nurses and dieticians who delivered DAFNEplus during the trial. Data were analysed thematically. RESULTS: While many shared initial reservations, all described how their experiences of DAFNEplus programme delivery had had a positive, transformative impact upon their perceptions and working practices. This transformation was enabled by initial training and supervision sessions, the confidence gained from using scripts to support novel programme content delivery, and experiences of delivering the programme and observing DAFNEplus principles being well received by, and having a positive impact on, attendees. Due to these positive experiences, interviewees described a strongly felt ethical mandate to use some DAFNEplus techniques and curriculum content in routine clinical care. While being supportive of a national rollout, they anticipated a variety of attitudinal and logistical (e.g. workload) challenges. CONCLUSIONS: This study provides a vital dimension to the evaluation of the DAFNEplus programme. Interviewees found the intervention to be acceptable and expressed high levels of buy-in. As well as offering potential endorsement for a national rollout, our findings offer insights which could help inform development and rollout of future behaviour change interventions to support diabetes self-management.

Participants' experiences of attending a structured education course (DAFNEplus) informed by behavioural science.

AIMS: As part of a broader process evaluation, we explored participants' experiences of, and engagement with, the DAFNEplus programme's group-based structured education course. This course, which was informed by behavioural science, provided participants with education and instruction to use flexible intensive insulin therapy (FIIT) together with techniques to identify and address unhelpful cognitive and emotional influences on their type 1 diabetes self-management. METHODS: We interviewed n = 28 DAFNEplus participants. Data were analysed thematically and took account of previous work exploring individuals' experiences of standard DAFNE courses. RESULTS: As well as benefitting from the DAFNEplus course's skills-based training and educational curriculum, participants' accounts suggested they had experienced cognitive and emotional changes that had positively influenced their confidence and motivation to adopt and sustain the use of FIIT. These benefits were most keenly felt by those who reported negative emotional states and mind-sets pre-course which had made their diabetes self-management challenging. Participants' cognitive and emotional changes were enabled through techniques used during the course to normalise setbacks and imperfect diabetes self-management, capitalise upon group synergies and encourage the use of social support, including from healthcare professionals. Participants also highlighted motivational gains arising from being reassured that diabetes complications are not common or inevitable if a FIIT regimen is followed. CONCLUSIONS: Our findings suggest that offering training in FIIT, in conjunction with behaviour change techniques that target unhelpful mindsets and emotional resilience, may be more effective in promoting diabetes self-management than offering education and skills training alone.

Sustaining the benefits of structured education: Participants' experiences of receiving structured individual support during a programme (DAFNEplus) informed by behavioural science.

AIMS: The DAFNEplus programme seeks to promote sustained improvements in glycaemic management by incorporating techniques from behavioural science. It includes five sessions of structured individual support delivered over 12 months following group education. As part of a broader evaluation, and to inform decision-making about roll-out in routine care, we explored participants' experiences of, and engagement with, that individual support. METHODS: We interviewed DAFNEplus participants (n = 28) about their experiences of receiving individual support and the impact they perceived it as having on their self management practices. We analysed data thematically. RESULTS: Participants described several important ways individual support had helped strengthen their self management, including: consolidating and expanding their understandings of flexible intensive insulin therapy; promoting ongoing review and refinement of behaviour; encouraging continued and effective use of data; and facilitating access to help from healthcare professionals to pre-empt or resolve emergent difficulties. Participants characterised themselves as moving towards independence in self management over the time they received individual support, with their accounts suggesting three key stages in that journey: 'Working with healthcare professionals'; 'Growing sense of responsibility'; and, 'Taking control'. Whilst all portrayed themselves as changed, participants' progress through those stages varied; a few continued to depend heavily on DAFNEplus facilitators for advice and/or direction at 12 months. CONCLUSIONS: While all participants benefited from individual support, our findings suggest that some may need, or gain further benefit from, longer-term, tailored support. This has important implications for decision-making about roll-out of DAFNEplus post-trial and for the development of future programmes seeking to bring about sustainable changes in self management practices.

Cost-effectiveness of a Novel Hypoglycaemia Programme: The 'HARPdoc vs BGAT' RCT.

AIMS: To assess the cost-effectiveness of HARPdoc (Hypoglycaemia Awareness Restoration Programme for adults with type 1 diabetes and problematic hypoglycaemia despite optimised care), focussed upon cognitions and motivation, versus BGAT (Blood Glucose Awareness Training), focussed on behaviours and education, as adjunctive treatments for treatment-resistant problematic hypoglycaemia in type 1 diabetes, in a randomised controlled trial. METHODS: Eligible adults were randomised to either intervention. Quality of life (QoL, measured using EQ-5D-5L); cost of utilisation of health services (using the adult services utilization schedule, AD-SUS) and of programme implementation and curriculum delivery were measured. A cost-utility analysis was undertaken using quality-adjusted life years (QALYs) as a measure of trial participant outcome and cost-effectiveness was evaluated with reference to the incremental net benefit (INB) of HARPdoc compared to BGAT. RESULTS: Over 24 months mean total cost per participant was £194 lower for HARPdoc compared to BGAT (95% CI: -£2498 to £1942). HARPdoc was associated with a mean incremental gain of 0.067 QALYs/participant over 24 months post-randomisation: an equivalent gain of 24 days in full health. The mean INB of HARPdoc compared to BGAT over 24 months was positive: £1521/participant, indicating comparative cost-effectiveness, with an 85% probability of correctly inferring an INB > 0. CONCLUSIONS: Addressing health cognitions in people with treatment-resistant hypoglycaemia achieved cost-effectiveness compared to an alternative approach through improved QoL and reduced need for medical services, including hospital admissions. Compared to BGAT, HARPdoc offers a cost-effective adjunct to educational and technological solutions for problematic hypoglycaemia.

Diabetic autonomic neuropathy does not impede improvement in hypoglycaemia awareness in adults: Sub-study results from the HypoCOMPaSS trial.

AIMS: Impaired awareness of hypoglycaemia (IAH) increases the risk of severe hypoglycaemia in people with type 1 diabetes mellitus (T1DM). IAH can be reversed through meticulous avoidance of hypoglycaemia. Diabetic autonomic neuropathy (DAN) has been proposed as an underlying mechanism contributing to IAH; however, data are inconsistent. The aim of this study was to examine the effects of cardiac autonomic neuropathy (CAN) on IAH reversibility inT1DM. METHODS: Participants with T1DM and IAH (Gold score ≥4) recruited to the HypoCOMPaSS (24-week 2 × 2 factorial randomised controlled) trial were included. All underwent screening for cardiac autonomic function testing at baseline and received comparable education and support aimed at avoiding hypoglycaemia and improving hypoglycaemia awareness. Definite CAN was defined as the presence of ≥2 abnormal cardiac reflex tests. Participants were grouped according to their CAN status, and changes in Gold score were compared. RESULTS: Eighty-three participants (52 women [62.7%]) were included with mean age (SD) of 48 (12) years and mean HbA1c of 66 (13) mmol/mol (8.2 [3.3] %). The mean duration of T1DM was 29 (13) years. The prevalence of CAN was low with 5/83 (6%) participants having definite autonomic neuropathy with 11 (13%) classified with possible/early neuropathy. All participants, regardless of the autonomic function status, showed a mean improvement in Gold score of ≥1 (mean improvement -1.2 [95% CI -0.8, -1.6]; p < 0.001). CONCLUSIONS: IAH can be improved in people with T1DM, and a long duration of disease, with and without cardiac autonomic dysfunction. These data suggest that CAN is not a prime driver for modulating IAH reversibility.

Associations of clinical, psychological, and sociodemographic characteristics and ecological momentary assessment completion in the 10-week Hypo-METRICS study: Hypoglycaemia MEasurements ThResholds and ImpaCtS.

INTRODUCTION: Reporting of hypoglycaemia and its impact in clinical studies is often retrospective and subject to recall bias. We developed the Hypo-METRICS app to measure the daily physical, psychological, and social impact of hypoglycaemia in adults with type 1 and insulin-treated type 2 diabetes in real-time using ecological momentary assessment (EMA). To help assess its utility, we aimed to determine Hypo-METRICS app completion rates and factors associated with completion. METHODS: Adults with diabetes recruited into the Hypo-METRICS study were given validated patient-reported outcome measures (PROMs) at baseline. Over 10 weeks, they wore a blinded continuous glucose monitor (CGM), and were asked to complete three daily EMAs about hypoglycaemia and aspects of daily functioning, and two weekly sleep and productivity PROMs on the bespoke Hypo-METRICS app. We conducted linear regression to determine factors associated with app engagement, assessed by EMA and PROM completion rates and CGM metrics. RESULTS: In 602 participants (55% men; 54% type 2 diabetes; median(IQR) age 56 (45-66) years; diabetes duration 19 (11-27) years; HbA1c 57 (51-65) mmol/mol), median(IQR) overall app completion rate was 91 (84-96)%, ranging from 90 (81-96)%, 89 (80-94)% and 94(87-97)% for morning, afternoon and evening check-ins, respectively. Older age, routine CGM use, greater time below 3.0 mmol/L, and active sensor time were positively associated with app completion. DISCUSSION: High app completion across all app domains and participant characteristics indicates the Hypo-METRICS app is an acceptable research tool for collecting detailed data on hypoglycaemia frequency and impact in real-time.

Association between recent exposure to continuous glucose monitoring-recorded hypoglycaemia and counterregulatory and symptom responses to subsequent controlled hypoglycaemia in people with type 1 diabetes.

AIM: Experimental hypoglycaemia blunts the counterregulatory hormone and symptom responses to a subsequent episode of hypoglycaemia. In this study, we aimed to assess the associations between antecedent exposure and continuous glucose monitoring (CGM)-recorded hypoglycaemia during a 1-week period and the counterregulatory responses to subsequent experimental hypoglycaemia in people with type 1 diabetes. MATERIALS AND METHODS: Forty-two people with type 1 diabetes (20 females, mean ± SD glycated haemoglobin 7.8% ± 1.0%, diabetes duration median (interquartile range) 22.0 (10.5-34.9) years, 29 CGM users, and 19 with impaired awareness of hypoglycaemia) wore an open intermittently scanned CGM for 1 week to detect hypoglycaemic exposure before a standardized hyperinsulinaemic-hypoglycaemic [2.8 ± 0.1 mmol/L (50.2 ± 2.3 mg/dl)] glucose clamp. Symptom responses and counterregulatory hormones were measured during the clamp. The study is part of the HypoRESOLVE project. RESULTS: CGM-recorded hypoglycaemia in the week before the clamp was negatively associated with adrenaline response [ß -0.09, 95% CI (-0.16, -0.02) nmol/L, p = .014], after adjusting for CGM use, awareness of hypoglycaemia, glycated haemoglobin and total daily insulin dose. This was driven by level 2 hypoglycaemia [<3.0 mmol/L (54 mg/dl)] [ß -0.21, 95% CI (-0.41, -0.01) nmol/L, p = .034]. CGM-recorded hypoglycaemia was negatively associated with total, autonomic, and neuroglycopenic symptom responses, but these associations were lost after adjusting for potential confounders. CONCLUSIONS: Recent exposure to CGM-detected hypoglycaemia was independently associated with an attenuated adrenaline response to experimental hypoglycaemia in people with type 1 diabetes.

Referral to the NHS Diabetes Prevention Programme and conversion from nondiabetic hyperglycaemia to type 2 diabetes mellitus in England: A matched cohort analysis.

BACKGROUND: The NHS Diabetes Prevention Programme (NDPP) is a behaviour change programme for adults who are at risk of developing type 2 diabetes mellitus (T2DM): people with raised blood glucose levels, but not in the diabetic range, diagnosed with nondiabetic hyperglycaemia (NDH). We examined the association between referral to the programme and reducing conversion of NDH to T2DM. METHODS AND FINDINGS: Cohort study of patients attending primary care in England using clinical Practice Research Datalink data from 1 April 2016 (NDPP introduction) to 31 March 2020 was used. To minimise confounding, we matched patients referred to the programme in referring practices to patients in nonreferring practices. Patients were matched based on age (≥3 years), sex, and ≥365 days of NDH diagnosis. Random-effects parametric survival models evaluated the intervention, controlling for numerous covariates. Our primary analysis was selected a priori: complete case analysis, 1-to-1 practice matching, up to 5 controls sampled with replacement. Various sensitivity analyses were conducted, including multiple imputation approaches. Analysis was adjusted for age (at index date), sex, time from NDH diagnosis to index date, BMI, HbA1c, total serum cholesterol, systolic blood pressure, diastolic blood pressure, prescription of metformin, smoking status, socioeconomic status, a diagnosis of depression, and comorbidities. A total of 18,470 patients referred to NDPP were matched to 51,331 patients not referred to NDPP in the main analysis. Mean follow-up from referral was 482.0 (SD = 317.3) and 472.4 (SD = 309.1) days, for referred to NDPP and not referred to NDPP, respectively. Baseline characteristics in the 2 groups were similar, except referred to NDPP were more likely to have higher BMI and be ever-smokers. The adjusted HR for referred to NDPP, compared to not referred to NDPP, was 0.80 (95% CI: 0.73 to 0.87) (p < 0.001). The probability of not converting to T2DM at 36 months since referral was 87.3% (95% CI: 86.5% to 88.2%) for referred to NDPP and 84.6% (95% CI: 83.9% to 85.4%) for not referred to NDPP. Associations were broadly consistent in the sensitivity analyses, but often smaller in magnitude. As this is an observational study, we cannot conclusively address causality. Other limitations include the inclusion of controls from the other 3 UK countries, data not allowing the evaluation of the association between attendance (rather than referral) and conversion. CONCLUSIONS: The NDPP was associated with reduced conversion rates from NDH to T2DM. Although we observed smaller associations with risk reduction, compared to what has been observed in RCTs, this is unsurprising since we examined the impact of referral, rather than attendance or completion of the intervention.

Diabetes prevention at scale: Narrative review of findings and lessons from the DIPLOMA evaluation of the NHS Diabetes Prevention Programme in England.

AIMS: The NHS Diabetes Prevention Programme (NHS DPP) is a large-scale, England-wide behaviour change programme for people at high risk of progressing to type 2 diabetes. We summarise the findings of our six-year DIPLOMA evaluation of its implementation and impact and highlight insights for future programmes. METHODS: Using qualitative interviews, document analysis, observation, surveys and large dataset analysis, eight interlinked work packages considered: equity of access; implementation; service delivery and fidelity; programme outcomes; comparative effectiveness and cost-effectiveness in reducing diabetes incidence; and patient decision making and experience. RESULTS: Delivery of the NHS DPP encountered barriers across many aspects of the programme, and we identified inequalities in terms of the areas, organisations and patient populations most likely to engage with the programme. There was some loss of fidelity at all stages from commissioning to participant understanding. Despite these challenges, there was evidence of significant reductions in diabetes incidence at individual and population levels. The programme was cost-effective even within a short time period. CONCLUSIONS: Despite the challenge of translating research evidence into routine NHS delivery at scale, our findings suggest that an individual-level approach to the prevention of type 2 diabetes in a 'high-risk' population was more effective than usual care. By embedding evaluation with programme delivery and working closely with the NHS DPP team, we provided actionable insights for improving communications with potential participants, supporting primary care referral, honing the delivery model with better provider relationships and more patient choice, increasing understanding of behaviour change techniques, and enriching the educational and health coaching content.

Producing a preference-based quality of LIFE measure to quantify the impact of HYPOGLYCAEMIA on people living with diabetes: A mixed-methods research protocol.

BACKGROUND: Assessment of patient-reported outcome measures (PROMs), including quality of life (QoL), is essential in diabetes research and care. However, a recent review concluded that current hypoglycaemia-specific PROMs have limited evidence of validity, reliability and responsiveness for assessing the impact of hypoglycaemia on QoL in people living with diabetes. None of the PROMs identified could be used directly to inform the cost-effectiveness of treatments and interventions. There is a need for a new hypoglycaemia-specific QoL PROM, which can be used directly to inform economic evaluations. AIMS: This project has three aims: (a) To develop draft PROM content for measuring the impact of hypoglycaemia on QoL in adults with diabetes. (b) To refine the draft content using cognitive debriefing interviews and psychometrics. This will result in a condition-specific PROM that can be used to quantify the impact of hypoglycaemia upon QoL. (c) To generate a preference-based measure (PBM) that will enable utility values to be calculated for economic evaluation. METHODS: A mixed-methods, three-stage design is used: (a) Qualitative interviews will inform the draft PROM content. (b) Cognitive debriefing interview data will be used to refine the draft PROM content. The PROM will be administered in a large-scale survey to enable psychometric validation. Final item selection for the PROM will be informed by psychometric performance, translatability assessment and input from stakeholder groups. (c) A classification system will be generated, comprising a reduced number of items from the PROM. A valuation survey will be conducted to derive a value set for the PBM.

Integrated safety and efficacy analysis of dasiglucagon for the treatment of severe hypoglycaemia in individuals with type 1 diabetes.

AIMS: To perform an integrated analysis of the safety and efficacy of dasiglucagon, a glucagon analogue available in a ready-to-use aqueous formulation, to treat severe hypoglycaemia (SH) in type 1 diabetes (T1D). MATERIALS AND METHODS: An integrated analysis of dasiglucagon safety was conducted on data from two placebo-controlled trials (placebo-controlled pool) and two placebo-controlled and four non-placebo-controlled trials (broad pool) in adults with T1D. An integrated analysis of dasiglucagon efficacy was conducted of pooled data and within demographic subgroups from the two placebo-controlled and two non-placebo-controlled trials in adults with T1D. RESULTS: Dasiglucagon had a similar safety and tolerability profile to that of reconstituted glucagon. In the placebo-controlled datasets, no serious adverse events (AEs), AEs leading to withdrawal from the trial, or deaths were reported. The most common causally related AEs were nausea (56.5%) and vomiting (24.6%). The broad pool safety analysis showed similar results. Dasiglucagon efficacy in time to plasma glucose recovery from insulin-induced SH was similar to that of reconstituted glucagon (median 10.0 and 12.0 minutes, respectively) and superior to placebo (median 40.0 minutes; P < 0.0001). The median recovery time was consistent across all placebo-controlled trial subgroups. CONCLUSIONS: Dasiglucagon was well tolerated and effective as a rapid rescue agent for insulin-induced SH in people with T1D.

The Effect of a Liberal Approach to Glucose Control in Critically Ill Patients with Type 2 Diabetes: A Multicenter, Parallel-Group, Open-Label Randomized Clinical Trial.

Rationale: Blood glucose concentrations affect outcomes in critically ill patients, but the optimal target blood glucose range in those with type 2 diabetes is unknown. Objectives: To evaluate the effects of a "liberal" approach to targeted blood glucose range during ICU admission. Methods: This mutlicenter, parallel-group, open-label randomized clinical trial included 419 adult patients with type 2 diabetes expected to be in the ICU on at least three consecutive days. In the intervention group intravenous insulin was commenced at a blood glucose >252 mg/dl and titrated to a target range of 180-252 mg/dl. In the comparator group insulin was commenced at a blood glucose >180 mg/dl and titrated to a target range of 108-180 mg/dl. The primary outcome was incident hypoglycemia (<72 mg/dl). Secondary outcomes included glucose metrics and clinical outcomes. Measurements and Main Results: By Day 28, at least one episode of hypoglycemia occurred in 10 of 210 (5%) patients assigned the intervention and 38 of 209 (18%) patients assigned the comparator (incident rate ratio, 0.21 [95% confidence interval (CI), 0.09 to 0.49]; P < 0.001). Those assigned the intervention had greater blood glucose concentrations (daily mean, minimum, maximum), less glucose variability, and less relative hypoglycemia (P < 0.001 for all comparisons). By Day 90, 62 of 210 (29.5%) in the intervention and 52 of 209 (24.9%) in the comparator group had died (absolute difference, 4.6 percentage points [95% CI, -3.9% to 13.2%]; P = 0.29). Conclusions: A liberal approach to blood glucose targets reduced incident hypoglycemia but did not improve patient-centered outcomes. Clinical trial registered with Australian New Zealand Clinical Trials Registry (ACTRN 12616001135404).

Breaking Barriers With Basal Insulin Biosimilars in Type 2 Diabetes.

Despite increases in the availability and effectiveness of other therapies, insulin remains an essential treatment for approximately 30 million people with type 2 diabetes worldwide. The development of biosimilars has created the potential for significant health care cost savings and may lead to greater access to basal insulin for vast populations. In this review, we discuss evidence demonstrating equipoise between basal insulin biosimilars and the patented analogs they may replace.

A higher non-severe hypoglycaemia rate is associated with an increased risk of subsequent severe hypoglycaemia and major adverse cardiovascular events in individuals with type 2 diabetes in the LEADER study.

AIMS/HYPOTHESIS: Hypoglycaemia is a common side effect of insulin and some other antihyperglycaemic agents used to treat diabetes. Severe hypoglycaemia has been associated with adverse cardiovascular events in trials of intensive glycaemic control in type 2 diabetes. The relationship between non-severe hypoglycaemic episodes (NSHEs) and severe hypoglycaemia in type 2 diabetes has been documented. However, an association between more frequent NSHEs and cardiovascular events has not been verified. This post hoc analysis of the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial aimed to confirm whether there is an association between NSHEs and severe hypoglycaemic episodes in individuals with type 2 diabetes. In addition, the possible association between NSHEs and major adverse cardiac events (MACE), cardiovascular death and all-cause mortality was investigated. METHODS: LEADER was a double-blind, multicentre, placebo-controlled trial that found that liraglutide significantly reduced the risk of MACE compared with the placebo. In this post hoc analysis, we explored, in all LEADER participants, whether the annual rate of NSHEs (defined as self-measured plasma glucose <3.1 mmol/l [56 mg/dl]) was associated with time to first severe hypoglycaemic episode (defined as an episode requiring the assistance of another person), time to first MACE, time to cardiovascular death and time to all-cause mortality. Participants with <2 NSHEs per year were used as reference for HR estimates. Cox regression with a time-varying covariate was used. RESULTS: We demonstrate that there is an association between NSHEs (2-11 NSHEs per year and ≥12 NSHEs per year) and severe hypoglycaemic episodes (unadjusted HRs 1.98 [95% CI 1.43, 2.75] and 5.01 [95% CI 2.84, 8.84], respectively), which was consistent when baseline characteristics were accounted for. Additionally, while no association was found between participants with 2-11 NSHEs per year and adverse cardiovascular outcomes, higher rates of NSHEs (≥12 episodes per year) were associated with higher risk of MACE (HR 1.50 [95% CI 1.01, 2.23]), cardiovascular death (HR 2.08 [95% CI 1.17, 3.70]) and overall death (HR 1.80 [95% CI 1.11, 2.92]). CONCLUSIONS/INTERPRETATION: The analysis of data from the LEADER trial demonstrated that higher rates of NSHEs were associated with both a higher risk of severe hypoglycaemia and adverse cardiovascular outcomes in individuals with type 2 diabetes. Therefore, irrespective of the cause of this association, it is important that individuals with high rates of hypoglycaemia are identified so that the potentially increased risk of cardiovascular events can be managed and steps can be taken to reduce NSHEs. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01179048).

Glycaemic thresholds for counterregulatory hormone and symptom responses to hypoglycaemia in people with and without type 1 diabetes: a systematic review.

AIM/HYPOTHESIS: The physiological counterregulatory response to hypoglycaemia is reported to be organised hierarchically, with hormone responses usually preceding symptomatic awareness and autonomic responses preceding neuroglycopenic responses. To compare thresholds for activation of these responses more accurately between people with or without type 1 diabetes, we performed a systematic review on stepped hyperinsulinaemic-hypoglycaemic glucose clamps. METHODS: A literature search in PubMed and EMBASE was conducted. We included articles published between 1980 and 2018 involving hyperinsulinaemic stepped hypoglycaemic glucose clamps among people with or without type 1 diabetes. Key exclusion criteria were as follows: data were previously published; other patient population; a clamp not the primary intervention; and an inadequate clamp description. Glycaemic thresholds for counterregulatory hormone and/or symptom responses to hypoglycaemia were estimated and compared using generalised logrank test for interval-censored data, where the intervals were either extracted directly or calculated from the data provided by the study. A glycaemic threshold was defined as the glucose level at which the response exceeded the 95% CI of the mean baseline measurement or euglycaemic control clamp. Because of the use of interval-censored data, we described thresholds using median and IQR. RESULTS: A total of 63 articles were included, whereof 37 papers included participants with type 1 diabetes (n=559; 67.4% male sex, aged 32.7±10.2 years, BMI 23.8±1.4 kg/m2) and 51 papers included participants without diabetes (n=733; 72.4% male sex, aged 31.1±9.2 years, BMI 23.6±1.1 kg/m2). Compared with non-diabetic control individuals, in people with type 1 diabetes, the median (IQR) glycaemic thresholds for adrenaline (3.8 [3.2-4.2] vs 3.4 [2.8-3.9 mmol/l]), noradrenaline (3.2 [3.2-3.7] vs 3.0 [2.8-3.1] mmol/l), cortisol (3.5 [3.2-4.2]) vs 2.8 [2.8-3.4] mmol/l) and growth hormone (3.8 [3.3-3.8] vs. 3.2 [3.0-3.3] mmol/l) all occurred at lower glucose levels in people with diabetes than in those without diabetes (all p≤0.01). Similarly, although both autonomic (median [IQR] 3.4 [3.4-3.4] vs 3.0 [2.8-3.4] mmol/l) and neuroglycopenic (median [IQR] 3.4 [2.8-N/A] vs 3.0 [3.0-3.1] mmol/l) symptom responses were elicited at lower glucose levels in people with type 1 diabetes, the thresholds for autonomic and neuroglycopenic symptoms did not differ for each individual subgroup. CONCLUSIONS/INTERPRETATION: People with type 1 diabetes have glycaemic thresholds for counterregulatory hormone and symptom responses at lower glucose levels than people without diabetes. Autonomic and neuroglycopenic symptoms responses are generated at about similar levels of hypoglycaemia. There was a considerable variation in the methodology of the articles and the high insulin doses in most of the clamps may affect the counterregulatory responses. FUNDING: This article has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 777460. REGISTRATION: This systematic review is registered in PROSPERO (CRD42019120083).

Characteristics of adults with type 1 diabetes and treatment-resistant problematic hypoglycaemia: a baseline analysis from the HARPdoc RCT.

AIMS/HYPOTHESIS: Problematic hypoglycaemia still complicates insulin therapy for some with type 1 diabetes. This study describes baseline emotional, cognitive and behavioural characteristics in participants in the HARPdoc trial, which evaluates a novel intervention for treatment-resistant problematic hypoglycaemia. METHODS: We documented a cross-sectional baseline description of 99 adults with type 1 diabetes and problematic hypoglycaemia despite structured education in flexible insulin therapy. The following measures were included: Hypoglycaemia Fear Survey II (HFS-II); Attitudes to Awareness of Hypoglycaemia questionnaire (A2A); Hospital Anxiety and Depression Index; and Problem Areas In Diabetes. k-mean cluster analysis was applied to HFS-II and A2A factors. Data were compared with a peer group without problematic hypoglycaemia, propensity-matched for age, sex and diabetes duration (n = 81). RESULTS: The HARPdoc cohort had long-duration diabetes (mean ± SD 35.8 ± 15.4 years), mean ± SD Gold score 5.3 ± 1.2 and a median (IQR) of 5.0 (2.0-12.0) severe hypoglycaemia episodes in the previous year. Most individuals had been offered technology and 49.5% screened positive for anxiety (35.0% for depression and 31.3% for high diabetes distress). The cohort segregated into two clusters: in one (n = 68), people endorsed A2A cognitive barriers to hypoglycaemia avoidance, with low fear on HFS-II factors; in the other (n = 29), A2A factor scores were low and HFS-II high. Anxiety and depression scores were significantly lower in the comparator group. CONCLUSIONS/INTERPRETATION: The HARPdoc protocol successfully recruited people with treatment-resistant problematic hypoglycaemia. The participants had high anxiety and depression. Most of the cohort endorsed unhelpful health beliefs around hypoglycaemia, with low fear of hypoglycaemia, a combination that may contribute to persistence of problematic hypoglycaemia and may be a target for adjunctive psychological therapies.

Joint patient and clinician priority setting to identify 10 key research questions regarding the long-term sequelae of COVID-19.

Given the large numbers of people infected and high rates of ongoing morbidity, research is clearly required to address the needs of adult survivors of COVID-19 living with ongoing symptoms (long COVID). To help direct resource and research efforts, we completed a research prioritisation process incorporating views from adults with ongoing symptoms of COVID-19, carers, clinicians and clinical researchers. The final top 10 research questions were agreed at an independently mediated workshop and included: identifying underlying mechanisms of long COVID, establishing diagnostic tools, understanding trajectory of recovery and evaluating the role of interventions both during the acute and persistent phases of the illness.