Mitigating Severe Hypoglycemia in Users of Advanced Diabetes Technologies: Impaired Awareness of Hypoglycemia and Unhelpful Hypoglycemia Beliefs as Targets for Interventions.

Objective: A subgroup analysis of the Hypoglycemia Awareness Restoration Programme for people with type 1 diabetes and problematic hypoglycemia persisting despite optimized care (HARPdoc) trial was conducted to explore the impact of Blood Glucose Awareness Training (BGAT, a hypoglycemia awareness training program) and the HARPdoc (a psychoeducation addressing unhelpful hypoglycemia beliefs) in reducing severe hypoglycemia (SH) in individuals using advanced diabetes technologies (ADTs). Methods: Data from trial participants who utilized ADTs, including continuous glucose monitors or automated insulin delivery systems, were extracted. Generalized linear mixed-effects models with Poisson distribution or linear mixed-effects models were used to evaluate SH incidence, and Gold questionnaire, Attitudes to Awareness of Hypoglycemia (A2A), Problem Areas in Diabetes (PAID), Hospital Anxiety and Depress Scale (HADS)-anxiety, and HADS-depression scores as measures of hypoglycemia awareness, unhelpful hypoglycemia beliefs, diabetes distress, and anxiety and depression symptoms, respectively. Results: In the 45 participants using ADTs, the BGAT and HARPdoc interventions both reduced SH incidence by more than 50% (P < 0.0001) and yielded improvements in hypoglycemia awareness (P < 0.05). HARPdoc outperformed BGAT in reducing SH at month 24 (P = 0.01). HARPdoc also mitigated unhelpful hypoglycemia beliefs (P < 0.0001), diabetes distress (P < 0.05), and anxiety symptoms (P < 0.05); BGAT demonstrated no significant impacts in these respects. Neither HARPdoc nor BGAT had significant effects on depression symptoms. Conclusion: Psychoeducation (BGAT and HARPdoc) was effective in reducing SH in people using ADTs. HARPdoc may also provide greater long-term SH reduction and improves psychological well-being in this patient group.

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.

A parallel randomised controlled trial of the Hypoglycaemia Awareness Restoration Programme for adults with type 1 diabetes and problematic hypoglycaemia despite optimised self-care (HARPdoc).

Impaired awareness of hypoglycaemia (IAH) is a major risk for severe hypoglycaemia in insulin treatment of type 1 diabetes (T1D). To explore the hypothesis that unhelpful health beliefs create barriers to regaining awareness, we conducted a multi-centre, randomised, parallel, two-arm trial (ClinicalTrials.gov NCT02940873) in adults with T1D and treatment-resistant IAH and severe hypoglycaemia, with blinded analysis of 12-month recall of severe hypoglycaemia at 12 and/or 24 months the primary outcome. Secondary outcomes included cognitive and emotional measures. Adults with T1D, IAH and severe hypoglycaemia despite structured education in insulin adjustment, +/- diabetes technologies, were randomised to the "Hypoglycaemia Awareness Restoration Programme despite optimised self-care" (HARPdoc, n = 49), a psychoeducation programme uniquely focussing on changing cognitive barriers to avoiding hypoglycaemia, or the evidence-based "Blood Glucose Awareness Training" (BGAT, n = 50), both delivered over six weeks. Median [IQR] severe hypoglycaemia at baseline was 5[2-12] per patient/year, 1[0-5] at 12 months and 0[0-2] at 24 months, with no superiority for HARPdoc (HARPdoc vs BGAT incident rate ratios [95% CI] 1.25[0.51, 3.09], p = 0.62 and 1.26[0.48, 3.35], p = 0.64 respectively), nor for changes in hypoglycaemia awareness scores or fear. Compared to BGAT, HARPdoc significantly reduced endorsement of unhelpful cognitions (Estimated Mean Difference for Attitudes to Awareness scores at 24 months, -2.07 [-3.37,-0.560], p = 0.01) and reduced scores for diabetes distress (-6.70[-12.50,-0.89], p = 0.02); depression (-1.86[-3.30, -0.43], p = 0.01) and anxiety (-1.89[-3.32, -0.47], p = 0.01). Despite positive impact on cognitive barriers around hypoglycaemia avoidance and on diabetes-related and general emotional distress scores, HARPdoc was not more effective than BGAT at reducing severe hypoglycaemia.

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.

Hypoglycemia Subtypes in Type 1 Diabetes: An Exploration of the Hypoglycemia Fear Survey-II.

OBJECTIVE: The Hypoglycemia Fear Survey-II (HFS-II) is a well-validated measure of fear of hypoglycemia in people with type 1 diabetes. The aim of this study was to explore the relationships between hypoglycemia worries, behaviors, and cognitive barriers to hypoglycemia avoidance and hypoglycemia awareness status, severe hypoglycemia, and HbA1c. RESEARCH DESIGN AND METHODS: Participants with type 1 diabetes (n = 178), with the study population enriched for people at risk for severe hypoglycemia (49%), completed questionnaires for assessing hypoglycemia fear (HFS-II), hyperglycemia avoidance (Hyperglycemia Avoidance Scale [HAS]), diabetes distress (Problem Areas In Diabetes [PAID]), and cognitive barriers to hypoglycemia avoidance (Attitudes to Awareness of Hypoglycemia [A2A]). Exploratory factor analysis was applied to the HFS-II. We sought to establish clusters based on HFS-II, A2A, Gold, HAS, and PAID using k-means clustering. RESULTS: Four HFS-II factors were identified: Sought Safety, Restricted Activity, Ran High, and Worry. While Sought Safety, Restricted Activity, and Worry increased with progressively impaired awareness and recurrent severe hypoglycemia, Ran High did not. With cluster analysis we outlined four clusters: two clusters with preserved hypoglycemia awareness were differentiated by low fear/low cognitive barriers to hypoglycemia avoidance (cluster 1) versus high fear and distress and increased Ran High behaviors (cluster 2). Two clusters with impaired hypoglycemia awareness were differentiated by low fear/high cognitive barriers (cluster 3) as well as high fear/low cognitive barriers (cluster 4). CONCLUSIONS: This is the first study to define clusters of hypoglycemia experience by worry, behaviors, and cognitive barriers to hypoglycemia avoidance. The resulting subtypes may be important in understanding and treating problematic hypoglycemia.

Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function.

Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1-6 m posttransplant: 38%; 7-12 m: 44%; 13-24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN-γ-dominated response in the pretransplant group replaced by IL-10-dominated response in the 1-6 m posttransplant group, reverting to predominantly IFN-γ-oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10-oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10+ cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.

Predictors of Recurrent Severe Hypoglycemia in Adults With Type 1 Diabetes and Impaired Awareness of Hypoglycemia During the HypoCOMPaSS Study.

OBJECTIVE: The HypoCOMPaSS study was designed to test the hypothesis that successful avoidance of biochemical hypoglycemia without compromising overall glycemic control would restore sufficient hypoglycemia awareness to prevent recurrent severe hypoglycemia in the majority of participants with established type 1 diabetes. Before starting the study, we planned to investigate associations between baseline characteristics and recurrent severe hypoglycemia over 2 years' follow-up. RESEARCH DESIGN AND METHODS: A total of 96 adults with type 1 diabetes and impaired awareness of hypoglycemia participated in a 24-week 2 × 2 factorial randomized controlled trial comparing insulin delivery and glucose monitoring modalities, with the goal of rigorous biochemical hypoglycemia avoidance. The analysis included 71 participants who had experienced severe hypoglycemia in the 12-month prestudy with confirmed absence (complete responder) or presence (incomplete responder) of severe hypoglycemia over 24 months' follow-up. RESULTS: There were 43 (61%) complete responders and 28 (39%) incomplete responders experiencing mean ± SD 1.5 ± 1.0 severe hypoglycemia events/person-year. At 24 months, incomplete responders spent no more time with glucose ≤3 mmol/L (1.4 ± 2.1% vs. 3.0 ± 4.8% for complete responders; P = 0.26), with lower total daily insulin dose (0.45 vs. 0.58 units/24 h; P = 0.01) and greater impairment of hypoglycemia awareness (Clarke score: 3.8 ± 2.2 vs. 2.0 ± 1.9; P = 0.01). Baseline severe hypoglycemia rate (16.9 ± 16.3 vs. 6.4 ± 10.8 events/person-year; P = 0.002) and fear of hypoglycemia were higher in incomplete responders. Peripheral neuropathy was more prevalent in incomplete responders (11 [39%] vs. 2 [4.7%]; P < 0.001) with a trend toward increased autonomic neuropathy. CONCLUSIONS: Recurrent severe hypoglycemia was associated with higher preintervention severe hypoglycemia rate, fear of hypoglycemia, and concomitant neuropathy.

Hypoglycaemia Awareness Restoration Programme for People with Type 1 Diabetes and Problematic Hypoglycaemia Persisting Despite Optimised Self-care (HARPdoc): protocol for a group randomised controlled trial of a novel intervention addressing cognitions.

INTRODUCTION: Severe hypoglycaemia (SH), when blood glucose falls too low to support brain function, is the most feared acute complication of insulin therapy for type 1 diabetes mellitus (T1DM). 10% of people with T1DM contribute nearly 70% of all episodes, with impaired awareness of hypoglycaemia (IAH) a major risk factor. People with IAH may be refractory to conventional approaches to reduce SH, with evidence for cognitive barriers to hypoglycaemia avoidance. This paper describes the protocol for the Hypoglycaemia Awareness Restoration Programme for People with Type 1 Diabetes and Problematic Hypoglycaemia Persisting Despite Optimised Self-care (HARPdoc) study, a trial to assess the impact on hypoglycaemia experience of a novel intervention that addresses cognitive barriers to hypoglycaemia avoidance, compared with an existing control intervention, recommended by the National Institute of Health and Care Excellence. METHODS AND ANALYSIS: A randomised parallel two-arm trial of two group therapies: HARPdoc versus Blood Glucose Awareness Training, among 96 adults with T1DM and problematic hypoglycaemia, despite attendance at education with or without technology use, in four centres providing specialist T1DM services. The primary outcome will be the SH rate at 12 and/or 24 months after randomisation to either course. Secondary outcomes include rates of SH requiring parenteral therapy, involving unconsciousness or needing emergency services; hypoglycaemia awareness status, overall diabetes control and quality of life measures. An implementation study to evaluate how the interventions are delivered and how implementation impacts on clinical effectiveness is planned as a parallel study, with its own protocol. ETHICS AND DISSEMINATION: The protocol was approved by the London Dulwich Research Ethics Committee, the Health Research Authority, National Health Service R&D and the Institutional Review Board of the Joslin Diabetes Center in the USA. Study findings will be disseminated to study participants and through peer-reviewed publications and conference presentations, including user groups. TRIAL REGISTRATION NUMBER: NCY02940873; Pre-results.

Intensive structured education for type 1 diabetes management using BERTIE: Long-term follow-up to assess impact on glycaemic control and quality of life indices.

AIMS: Bournemouth Type 1 Intensive Education (BERTIE) is a structured education course delivered 1 day a week for 4 weeks for self-management of type 1 diabetes. BERTIE outcomes were analysed to assess long-term effectiveness: primary outcome assessed impact of BERTIE on glycaemic control, secondary outcomes assessed impact on Problem Area in Diabetes (PAID) scale, severe hypoglycaemia and diabetic ketoacidosis incidence (DKA). METHODS: Prospectively collected outcome data from attendees included glycated haemoglobin (HbA1c), PAID, severe hypoglycaemia and DKA incidence recorded pre-course, 6 months and 1 year post-attendance, with HbA1c assessed annually at subsequent clinic visits. RESULTS: Between 1999 and 2015, 524 people attended BERTIE with 5 year follow-up in 316 (60.3%) attendees. HbA1c was reduced from 74 ±â€¯17 mmol/mol (8.9 ±â€¯1.6%) at baseline to 71 ±â€¯15 mmol/mol (8.6 ±â€¯1.4%) at 1 year and 70 ±â€¯15 mmol/mol (8.6 ±â€¯1.3%) at 5 years (p < 0.0001); severe hypoglycaemia incidence reduced from 0.8 ±â€¯2.1 to 0.4 ±â€¯2.2 episodes/person/year at 1 year (p < 0.0001); PAID scale reduced from 23 ±â€¯16 to 15 ±â€¯12 (p < 0.0001) at 1 year; DKA incidence was 0.06 ±â€¯0.34 episodes/person/year pre-course and 0.03 ±â€¯0.21 at 1 year (p = 0.5271). CONCLUSIONS: BERTIE outcome data demonstrate favorable biochemical and psychological outcomes supporting recommendations that structured education be provided to adults with type 1 diabetes.

Fever of unknown origin in a patient initially presenting with traveller's diarrhoea.

A 17-year-old male presented with diarrhoea and malaise following his return from Kenya and Tunisia. He was managed as a case of traveller's diarrhoea. Stool cultures were negative for pathogenic bacterial growth. Two weeks later he presented with worsening lower back pain. MRI of lumbosacral spine suggested L1 osteomyelitis. CT-guided spinal aspirate grew no organisms and repeat viral serology and blood cultures (including tuberculosis screening) were negative. He was treated with a 6-week course of ceftriaxone. Back pain did not improve and a repeat MRI scan 8 weeks after his antibiotic course indicated progressive changes in L1 extending to L2 with an intradiscal abscess. Repeat CT-guided spinal aspirate grew Salmonella arizonae sensitive to cotrimoxazole and ceftriaxone. He was treated with intravenous ceftriaxone and cotrimoxazole for 12 weeks. A 4-month follow-up MRI scan showed progressive improvement of the L1/L2 discitis with resolution of intradiscal fluid.

Demonstration of an intrinsic relationship between endogenous C-peptide concentration and determinants of glycemic control in type 1 diabetes following islet transplantation.

OBJECTIVE: Maintenance of endogenous pancreatic ß-cell function could be an important goal in the management of type 1 diabetes. However, the impact of stimulated C-peptide level on overall glycemic control is unknown. The relationship between C-peptide and parameters of glucose control was therefore characterized in a cohort with rapidly changing ß-cell function following islet transplantation. RESEARCH DESIGN AND METHODS: Standardized mixed-meal tolerance test was undertaken in 12 consecutive islet recipients at 1-6-month intervals, with graft function determined by 90-min stimulated C-peptide. Continuous glucose monitoring was undertaken in the week preceding each assessment and the relationship between C-peptide and glucose control evaluated by mixed Poisson regression. RESULTS: Recipients completed 5 (1-14) [median (range)] clinical assessments over 18 (1-51) months posttransplant encompassing a wide range of stimulated C-peptide levels (7-2,622 pmol/L). Increasing ß-cell function across predefined C-peptide groups was associated with reduced insulin dose, HbA1c, mean glucose (low [<200 pmol/L] 10.7 vs. excellent [>1,000 pmol/L] 7.5 mmol/L), and glucose SD (low, 4.4 vs. excellent, 1.4 mmol/L). Highly statistically significant continuous associations between stimulated C-peptide and mean interstitial glucose (lower by 2.5% [95% CI 1.5-3.5%] per 100 pmol/L higher C-peptide), glucose SD, time outside glucose target range, and measures of hyper-/hypoglycemia risk were confirmed. CONCLUSIONS: Repeated assessment of islet transplant recipients has enabled modeling of the relationship between endogenous ß-cell function and measures of glycemic control providing quantitative estimates of likely impact of an acute change in ß-cell function in individuals with type 1 diabetes.

Home urine C-peptide creatinine ratio can be used to monitor islet transplant function.

OBJECTIVE: Islet graft function is defined by serum C-peptide in a standardized challenge test. We assessed whether urine C-peptide creatinine ratio (UCPCR) sent from home could provide a viable alternative. RESEARCH DESIGN AND METHODS: Seventeen islet recipients provided 90-min serum C-peptide (sCP90) and 120-min UCPCR (UCPCR120) samples during 68 interval posttransplant mixed-meal tolerance tests, also posting from home a 120-min postbreakfast UCPCR sample every 2 weeks. UCPCR was compared with a clinical score of islet function, derived from HbA1c and insulin dose. RESULTS: UCPCR120 and mean home postmeal UCPCR were strongly correlated with sCP90 (r(s) = 0.73, P < 0.001; and rs = 0.73, P < 0.01, respectively). Mean home UCPCR increased with clinical score (r(s) = 0.75; P < 0.001) and with graft function defined both by sCP90 >200 pmol/L and insulin independence. UCPCR cutoffs to detect insulin independence and poor graft function were sensitive and specific. CONCLUSIONS: Home UCPCR provides a valid measure of C-peptide production in islet transplant recipients.