Impaired Awareness Of Hypoglycemia Research Articles

Hypoglycemia-associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes.

Hypoglycemia remains a major barrier to the achievement of target levels of glycemic control for most individuals with insulin-dependent type 1 diabetes (T1D). Both the loss of β cells and an accompanying defect in the α cell response to hypoglycemia predispose patients with T1D to the development of low blood glucose. Increased glucose variability, exposure to hypoglycemia, and impaired awareness of hypoglycemia all contribute to increased risk of experiencing severe hypoglycemia, which is explained by progressive impairment in epinephrine secretion and autonomic symptom generation in response to hypoglycemia leading to defective glucose counterregulation and hypoglycemia unawareness that characterize hypoglycemia-associated autonomic failure (HAAF). Interruption of HAAF requires interfering with the mechanisms of brain adaptation to low blood glucose that affect central glucose sensing and the autonomic response to hypoglycemia, or avoidance of hypoglycemia that may allow for eventual recovery of counterregulatory and autonomic symptom responses. Strategies for hypoglycemia avoidance that include continuous glucose monitoring may reduce, but do not eliminate, clinically significant hypoglycemia, with ongoing counterregulatory defects and impaired awareness of hypoglycemia. Complete avoidance of hypoglycemia can be achieved following pancreatic islet transplantation and allows for the restoration of counterregulatory and autonomic symptom responses that evidences the potential for reversing HAAF in T1D.

A multiparameter model for non-invasive detection of hypoglycemia

Objective: Severe hypoglycemia is the most serious acute complication for people with type 1 diabetes (T1D). Approximately 25% of people with T1D have impaired ability to recognize impending hypoglycemia, and nocturnal episodes are feared. Approach: We have investigated the use of non-invasive sensors for detection of hypoglycemia based on a mathematical model which combines several sensor measurements to identify physiological responses to hypoglycemia. Data from randomized single-blinded euglycemic and hypoglycemic glucose clamps in 20 participants with T1D and impaired awareness of hypoglycemia was used in the analyses. Main results: Using a sensor combination of sudomotor activity at three skin sites, ECG-derived heart rate and heart rate corrected QT interval, near-infrared and bioimpedance spectroscopy; physiological responses associated with hypoglycemia could be identified with an F1 score accuracy up to 88%. Significance: We present a novel model for identification of non-invasively measurable physiological responses related to hypoglycemia, showing potential for detection of moderate hypoglycemia using a wearable sensor system.

Prepregnancy care in women with type 1 diabetes improves HbA1c and glucose variability without worsening hypoglycaemia time and awareness: Glycaemic variability during prepregnancy care

AimsTo evaluate the impact of a prepregnancy care (PPC) programme, beyond HbA1c, on hypoglycaemia awareness and glycaemic variability (GV). MethodsProspective pilot study. We selected women with Type 1 diabetes who initiated a PPC programme with normal hypoglycaemia awareness (n = 24). Hypoglycaemia awareness, hypoglycaemic events and GV derived from masked-continuous glucose monitoring were evaluated in the first visit and within 2 weeks after pregnancy confirmation. ResultsThe duration was 16.5 ± 13.0 months. HbA1c significantly decreased (−0.8 ± 0.7; p < 0.001). The Clarke score increased (0[0–1] vs. 1[0–2] points, p = 0.164), 2 out of 24 were reclassified as having impaired awareness of hypoglycaemia and 2 presented severe hypoglycaemia. GV decreased: standard deviation (p = 0.008), coefficient of variation (p = 0.021), mean amplitude of glycaemic excursions (p = 0.007), average daily risk range (p < 0.001), J-index (p = 0.010), high blood glucose index (HBGI) (p = 0.004), continuous overall net glycaemic action (CONGA) (p = 0.018), mean of daily differences (p = 0.045) and glycaemic risk assessment diabetes equation (p = 0.012). Final HbA1c was associated with baseline J-index, CONGA and HBGI (β = 0.535, β = 0.466, β = 0.534, respectively; p < 0.05). ConclusionsA PPC programme improved HbA1c as well as GV with no significant impact on hypoglycaemia awareness. Moreover, GV could help to identify women less likely to achieve glycaemic targets. Larger studies are needed to confirm these results.

381-P: Real-World Evidence that Impaired Awareness of Hypoglycemia Increases Severe Hypoglycemia Rates in T2DM (InHypo-DM Study)

Impaired awareness of hypoglycemia (IAH) has been linked to an increased rate of severe hypoglycemia (SH) in T1DM. Yet, few investigations have focused on quantifying this relationship in the context of T2DM, particularly from a pragmatic epidemiological lens. This study leverages the value of self-reported SH data to explore the real-world, population-based effect of IAH severity on SH rates in T2DM. A validated questionnaire (InHypo-DMPQ) was administered online to a nationally representative panel comprising Canadians (≥18 years) with T2DM using insulin and/or secretagogues. Data were collected on respondents’ socio-demographic/clinical traits; self-reported incidence of SH (in the past year); and IAH severity, trisected by no, moderate, and severe impairment. Multivariable negative binomial regression (NBR) analysis was used to isolate the effect of IAH on SH. A directed acyclic graph was devised to identify the minimally sufficient adjustment set. Of the 452 complete respondents (mean age: 53.2 (SD: 14.7) years; male: 56%), 6% were classified with severe IAH, 67% with moderate IAH, and 27% with no IAH. Those with severe IAH had the highest crude annual SH rate (5.89 events/person-year, 95% CI: 5.01-6.88), which over doubled and tripled the SH rate in people with moderate IAH (p&amp;lt;0.001) and no IAH (p&amp;lt;0.001), respectively. The adjusted NBR analysis revealed a statistically significant association between IAH and SH (p=0.039). Individuals with severe IAH reported an adjusted annual SH rate that was 3.23 (95% CI: 1.13-9.27, p=0.029) times greater than those with no IAH. A similar trend was observed for moderate IAH versus no IAH (p=0.038). This real-world, population-based study provides timely insight into the high prevalence of moderate and severe IAH in people with T2DM using insulin and/or secretagogues. The marked impact of IAH on increased SH rates underscores a pressing need for the clinical prioritization of IAH assessment and management in T2DM. Disclosure A. Ratzki-Leewing: None. S.B. Harris: Advisory Panel; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Lilly/Boehringer Ingelheim, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Lilly/Boehringer Ingelheim, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. Other Relationship; Self; Canadian Diabetes Association, Canadian Institutes of Health Research, The Lawson Foundation. N.H. Au: None. S. Webster-Bogaert: None. J.B. Brown: None. S.M. Reichert: Advisory Panel; Self; Abbott, AstraZeneca, Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Canadian Institutes of Health Research. Speaker's Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi. B.L. Ryan: None. Funding Sanofi Canada

2198-PUB: Real-World Risk Indicators of Impaired Awareness of Hypoglycemia in T2DM (InHypo-DM Study)

Further investigation into the real-world etiology of impaired awareness of hypoglycemia (IAH) in T2DM is needed. The present study aims to address this research gap by providing pragmatic, population-based insight into IAH and its risk indicators. A validated questionnaire (InHypo-DMPQ) was administered online to a nationally representative panel comprising Canadians (≥18 years) with T2DM taking insulin and/or secretagogues. Data were collected on respondents’ socio-demographic/clinical traits, self-reported hypoglycemia, and severity of IAH (no, moderate, and severe). Multivariable partial proportional odds (PPO) regression was used to identify the relevant risk indicators of moderate and severe IAH. Covariates were selected in consultation with the literature and clinical experts. A complete case analysis of 432 respondents (mean age: 53.0 (SD: 14.7) years; male: 56%) was undertaken. Of these individuals, 28% were classified with severe IAH, 66% with moderate IAH, and 6% with no IAH. Age, diabetes duration, A1C, total annual history of hypoglycemia (any type), therapeutic regimen, comorbidity status, gender, income, education, and drug coverage status were assessed for their influence on IAH severity. Based on the multivariable PPO model, a 5-year increase in diabetes duration decreased the adjusted odds of moderate or severe IAH, relative to no IAH, by 24% (95% CI: 12-35%, p&amp;lt;0.001). Moreover, the adjusted odds of severe IAH classification, versus no or moderate IAH, increased by a factor of 1.09 (95% CI: 1.02-1.15, p=0.008) for every 15 hypoglycemic events reported (in the past year). These results will help inform the improved management of IAH in real-world clinical settings. To reduce the risk of severe IAH in T2DM, clinical interventions should prioritize the reduction of hypoglycemic events. In particular, supporting patients with more recent T2DM diagnoses toward accurately recognizing their hypoglycemia symptoms may forestall the onset of IAH and related sequelae. Disclosure A. Ratzki-Leewing: None. S.B. Harris: Advisory Panel; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Lilly/Boehringer Ingelheim, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Lilly/Boehringer Ingelheim, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. Other Relationship; Self; Canadian Diabetes Association, Canadian Institutes of Health Research, The Lawson Foundation. N.H. Au: None. S. Webster-Bogaert: None. J.B. Brown: None. S.M. Reichert: Advisory Panel; Self; Abbott, AstraZeneca, Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Canadian Institutes of Health Research. Speaker's Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi. B.L. Ryan: None. Funding Sanofi Canada

370-P: Changes in Glutamate Dynamics in the Anterior Cingulate Cortex with Recurrent Hypoglycemia in Type 1 Diabetes

The mechanisms of how recurrent hypoglycemia (HG) leads to impaired awareness of HG (IAH) remain elusive. Cortical glutamate (Glu) dynamics may be involved, as Glu levels were shown to decrease during HG in healthy controls and in patients with type 1 diabetes (T1D) and normal awareness of HG (T1D-NAH), but not in patients with IAH. While these data supported an association between blunted Glu response to HG and IAH, whether recurrent HG causes a blunting of the Glu response to HG remains unclear. We measured the neurochemical response to HG before and after induction of IAH in T1D-NAH patients undergoing four 2-hour HG clamps over 2 days. 1H-magnetic resonance spectroscopy at 7 tesla was used to measure Glu levels in the anterior cingulate cortex (ACC, 24x12x30 mm3) during the first (C1) and fourth clamps (C4), before and after induction of IAH, respectively. We focused on the ACC as differences in PET-measured glucose kinetics in ACC were associated with IAH. Epinephrine and symptom responses to HG during C1 and C4 confirmed induction of IAH. Glu levels significantly decreased in response to HG during C1, but not during C4. Glucose+Taurine (reported as sum due to cross-correlation) dropped by 40% with HG in C1, whereas it dropped by 32% in C4. We show that recurrent HG blunts the cortical Glu response to HG, which may be due to higher glucose or alternative fuel availability, eliminating the need to oxidize Glu. Disclosure Y. Park: None. D. Deelchand: None. A. Kumar: None. A. Moheet: None. Y. Zhang: None. L.E. Eberly: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company, Zucara Therapeutics Inc. Consultant; Self; 360 Consulting, MannKind Corporation. Research Support; Self; Eli Lilly and Company, JDRF, National Institutes of Health. Other Relationship; Self; American Diabetes Association, Sanofi, WebMD. G. Oz: None. Funding National Institutes of Health (R01NS035192, P41EB015894, P30NS076408)

114-OR: Evidence for Alterations in Salience Processing in People with Type 1 Diabetes and Impaired Awareness of Hypoglycemia

Resting state networks are functionally connected neurons that show similar low-frequency blood oxygen-level dependent (BOLD) signal oscillations. The salience network (SN) is crucial for switching between two other networks: the default mode network (DMN) and the central executive network (CEN). The DMN is active when the brain is not cognitively engaged; the CEN is active when the brain is engaged in a specific task. We hypothesized that impaired awareness of hypoglycemia (IAH) in people with type 1 diabetes (T1D) would be associated with disruption of the integrity of the salience network at hypoglycemia. Methods: Fourteen nondiabetic (ND), 15 T1D with normal awareness of hypoglycemia (NAH) and 22 T1D with IAH participants, matched for age and T1D duration, underwent a two-step hypoglycemic clamp. Resting state BOLD functional magnetic resonance image (fMRI) time series were obtained, one at 90 mg/dL, one at 47 mg/dL. Images were analyzed using the CONN toolbox in SPM12. We used the right anterior insula (AI) as a seed region for the SN in a seed to voxel analysis. Results: The SN was identified in all three groups at euglycemia. At hypoglycemia ND and NAH had brisk symptom response and altered coupling between SN and regions associated with the DMN: precuneus (ND p &amp;lt;0.01) and pregenual anterior cingulate cortex (ACC, NAH p &amp;lt;0.01), IAH had lower symptoms and no change in SN coupling. Mean symptom increase at hypoglycemia was 15.3 (ND and NAH) and 1.5 (IAH, p&amp;lt;0.00001). A 2x2 mixed ANOVA interaction between aware groups (HC and NAH n=29) and IAH (n=22) showed differences in connectivity reduction between the ACC and AI at hypoglycemia (pFEW-Corr=0.04). Conclusions: During hypoglycemia, reduced connectivity between SN and DMN, seen in ND and NAH, may be an important switch for hypoglycemia recognition, facilitating protective behavioral responses. Lack of SN connectivity change may underpin impaired awareness and failure of appropriate responses to hypoglycemia seen in IAH. Disclosure P. Jacob: None. C.E. Osborne: None. F. Zelaya: None. S.A. Amiel: None. P. Choudhary: Advisory Panel; Self; AstraZeneca, Insulet Corporation, Medtronic, Roche Diabetes Care, Sanofi. Speaker's Bureau; Self; Eli Lilly and Company, Novartis AG, Novo Nordisk Inc., WebMD.

113-OR: ADA Presidents' Select Abstract: Dishabituation with High Intensity Exercise Improves Epinephrine Response and Symptomatic Awareness to Hypoglycemia in People with Type 1 Diabetes and Impaired Awareness of Hypoglycemia

Impaired awareness of hypoglycemia (IAH) affects approx. 20-25% of all people with type 1 diabetes (T1D) and is a major risk factor for severe hypoglycemia. We recently proposed that IAH may develop as a form of adaptive memory to repeated hypoglycemia; referred to as Habituation. Consistent with this hypothesis, we demonstrated restoration of defective counterregulatory (CRR) responses to hypoglycemia in a rodent model of IAH following introduction of a novel stress stimulus [high intensity exercise (HIT)]; referred to as Dishabituation. In this study we sought to further test our hypothesis by examining whether a single episode of HIT would amplify counterregulatory response to subsequent hypoglycemia in people with T1D who had IAH (assessed by Gold score ≥4, Modified Clark score≥4 or DAFNE hypoglycaemia awareness rating 2 or 3). We recruited 12 participants to a single-centre, randomized, cross-over study. Individuals were randomized to one episode of HIT (4 x 30 s cycle sprints [2 min recovery] at 150% of max Watts achieved during VO2peak assessment) or rest. The following day they underwent a 90-minute hyperinsulinaemic hypoglycemic clamp study at 2.5 mmol/l with measurement of hormonal CRR and symptom scores. Each clamp study was separated by at least 2-weeks. We found that a single episode of HIT led to a 30% increase in the epinephrine response [mean (SEM) 418.8 +/- 62.84 vs. 541.1 +/- 70.5 pg/ml; p&amp;lt;0.05] accompanied by a significant increase in total symptom scores (Edinburgh Hypoglycemia scale: 24.25 +/- 2.96 vs. 27.5 +/- 3.9, p&amp;lt;0.05) during equivalent hypoglycemia induced the following day. These findings are consistent with the hypothesis that IAH develops in people with T1D as a habituated response and that introduction of a novel stressor can restore, at least partially, the CRR response to hypoglycemia. HIT may represent a novel therapeutic intervention for people with IAH. Disclosure C.M. Farrell: None. D.J. West: Research Support; Self; Arla Foods Ingredients, Dexcom, Inc. S.M. Hapca: None. T. Jones: Research Support; Self; Dexcom, Inc., Medtronic MiniMed, Inc. Speaker's Bureau; Self; Eli Lilly and Company, Roche Diabetes Care. A.D. McNeilly: None. R.J. McCrimmon: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust. Funding JDRF; Diabetes UK

Impaired Awareness of Hypoglycemia Continues to be a Risk Factor for Severe Hypoglycemia Despite the Use of Continuous Glucose Monitoring System in Type 1 Diabetes

Objective: Impaired awareness of hypoglycemia (IAH) is a risk factor for severe hypoglycemia in patients with type 1 diabetes (T1D) not using a continuous glucose monitoring (CGM) system. The current study investigated the prevalence of IAH and its relationship with severe hypoglycemia in T1D patients using CGM systems. Methods: This cross-sectional observational study enrolled 135 patients with T1D and ongoing real-time CGM use. A survey was conducted to assess hypoglycemia awareness with the Gold, Clarke, and Pedersen-Bjergaard questionnaires and the 6-month history of severe hypoglycemia. Other diabetes histories and the CGM glucose data were collected. Results: The Gold, Clarke, and Pedersen-Bjergaard questionnaires demonstrated the overall prevalence of IAH/abnormal awareness to be 33.3%, 43.7%, and 77.0%, respectively. Participant age and duration of T1D were consistently related to IAH or hypoglycemia unawareness with all three questionnaires (P<.05). Amongst the patients using CGM for >6 months, 24.5% were found to have at least one episode of severe hypoglycemia in the preceding 6 months. IAH identified by the Gold and Clarke questionnaires and hypoglycemia unawareness identified by the Pedersen-Bjergaard questionnaire were related to 6-, 4.63-, and 5.83-fold increased risk of severe hypoglycemia (P = .001, .004, and .013), respectively. IAH identified by the Gold/Clarke questionnaires was associated with a longer duration of CGM glucose <54 mg/dL and higher glucose coefficients of variation (P<.05). Conclusion: IAH is highly prevalent and related to a higher risk for severe hypoglycemia in T1D patients using CGM. Abbreviations: CGM = continuous glucose monitoring; CI = confidence interval; HAAF = hypoglycemia-associated autonomic failure; HbA1c = hemoglobin A1C; IAH = impaired awareness of hypoglycemia; T1D = type 1 diabetes.

Effect of Education on Impaired Hypoglycemia Awareness and Glycemic Variability in Children and Adolescents with Type 1 Diabetes Mellitus

Objective:The aim of this study was to determine the prevalence of impaired hypoglycemia awareness (IHA) in children and adolescents with type 1 diabetes mellitus using a professional continuous glucose monitoring (CGM) system and to show the effect of structured education on glycemic variability (GV) in children and adolescents with IHA.Methods:Forty type 1 diabetic children and adolescents with a diabetes duration of at least five years were eligible for inclusion in this prospective, quantitative study. All subjects were asked about their history of being aware of the symptoms of hypoglycemia using a questionnaire. Professional CGM was conducted in all of the patients for six days. The frequency of IHA detected by comparison of CGM and logbook reports were analyzed. Patients with identified IHA underwent a structured training program. After three months, CGM was re-applied to patients with IHA.Results:The study was completed by 37 diabetic children and adolescents. After the initial CGM, nine patients (24.3%) were found to have had episodes of IHA. Area under the curve (AUC) for hypoglycemia and number of low excursions were; 1.81±0.95 and 8.33±3.60 for the IHA group at the beginning of the study. AUC for hypoglycemia was 0.43±0.47 after three months of structured education the IHA patients (p=0.01). Coefficient of variation which shows primary GV decreased significantly although unstable at the end of education in IHA patients (p=0.03).Conclusion:CGM is a valuable tool to diagnose IHA. IHA, GV and time in range can be improved by education-based intervention.

387-P: N-acetyl Cysteine Does Not Prevent Impaired Awareness of Hypoglycemia

Impaired awareness of hypoglycemia (IAH) is common in diabetes. Administration of N-acetyl cysteine (NAC) during episodes of hypoglycemia (HG) prevents the development of IAH in rodents (Fioramonti 2013). Here we tested the hypothesis that NAC will be effective in preventing IAH in healthy humans using a double blind cross over study design where subjects received either NAC or saline (S) in random order on day 1 of a 2 day protocol that involved 3 HG clamps. On day 1, 350 mg NAC or S was given IV over 5 hours starting 30 min before start of IV insulin (2 mg/kg/min). Blood glucose (BG) was targeted at 50 mg/dl for 2 hours, then at 95 mg/dl for 2 hours, then 50 mg/dl for 2 hours. After BG recovery subjects were sent home to return on day 2 for a final 2-hour HG clamp. During the 1st and 3rd HG periods, serum epinephrine (EPI) and hypoglycemic symptoms (HSx) were collected. Subjects received 25 mg diphenhydramine IV at 0 and 4 hours due to a high occurrence of drug reactions. Additional doses or odansetron were given as needed. EPI during clamp 1 was higher during NAC compared to S but the HSx were the same. No difference was seen between subjects who did or did not have a reaction to NAC. EPI and HSx on day 2 following NAC were lower than on day 1 but no different from response measured following S on day 1. NAC elicited many adverse events, enhanced EPI during HG, and did not alter EPI or HSx during HG on day 2 compared to S. Further development of IV NAC as a therapy for IAH is unwarranted. Disclosure A. Moheet: None. A. Kumar: None. L. Coles: None. N. Rubin: None. L.E. Eberly: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company, Zucara Therapeutics Inc. Consultant; Self; 360 Consulting, MannKind Corporation. Research Support; Self; Eli Lilly and Company, JDRF, National Institutes of Health. Other Relationship; Self; American Diabetes Association, Sanofi, WebMD. Funding JDRF

936-P: Annual Cost to Achieve Cost Effectiveness of Continuous Glucose Monitoring in Hypoglycemia-Unaware Type 1 Diabetes Patients Using Intensive Insulin in the United Kingdom

Background: Type 1 diabetes (T1D) patients with impaired awareness of hypoglycemia (IAH) face higher risk of severe hypoglycemic events. Continuous glucose monitoring (CGM) has been found to prevent severe hypoglycemic events in this population (van Beers 2016) compared to self-monitoring of blood glucose (SMBG). This study aimed to evaluate the annual cost of a hypothetical CGM intervention that would be cost-effective vs. SMBG in the United Kingdom (UK) according to a willingness-to-pay threshold of £30,000/QALY. Methods: The IQVIA Core Diabetes Model was used to run analyses over multiple time horizons (50-, 5-, and 1-year to test impact of assuming continued intervention effects over time) with an IAH population reflecting the IN CONTROL study (van Beers 2016). This study evaluated impact of CGM on hypoglycemia in an IAH population. CGM intervention effects included: odds ratio 0.45 for severe hypoglycemic events (requiring third party intervention); 0.03 utility benefit associated with reduced finger prick requirements of CGM (Matza 2016). HbA1c was assumed equivalent between CGM and SMBG. All other inputs reflected published literature and/or public tariffs, with costs in 2018 GBP. Threshold analyses were performed to identify the annual cost of intervention associated with incremental cost-effectiveness ratio (ICER) threshold £30,000/QALY over each time horizon. Sensitivity analyses were also performed on key input variables. Results: Over 50 years, up to £1,354 could be spent annually on CGM to achieve a £30,000/QALY ICER threshold. With shorter time horizons, the annual intervention cost to achieve cost-effectiveness was slightly lower, ranging from £1,344 over 5 years to £1,301 for a 1-year horizon. Conclusions: Based on recent evidence that CGM reduces severe hypoglycemia in IAH T1D patients, CGM can be considered cost-effective in the UK at costs per year of up to approximately £1,350. Disclosure S. Bilir: Employee; Self; IQVIA. C. Campbell: Consultant; Self; Abbott. R. Hellmund: Employee; Self; Abbott Laboratories. Stock/Shareholder; Self; Abbott Laboratories. J. Munakata: Employee; Self; IQVIA.

282-OR: Impact of a Hybrid Closed-Loop Insulin Delivery System on Hypoglycemia Awareness in Individuals with Type 1 Diabetes

Background: Individuals with impaired awareness of hypoglycemia (IAH) are at risk of severe hypoglycemia. Although it is known that elimination of hypoglycemia can restore hypoglycemia awareness in this high-risk group, this has been challenging in real life. Technological advancements like closed loop system provide an opportunity to minimize hypoglycemia. Hence, the aim of this study was to evaluate whether a hybrid closed loop insulin delivery system can improve hypoglycemia awareness in individuals with IAH. Methods: Participants with type 1 diabetes and IAH (Gold Score ≥4) were randomized to either a hybrid closed loop system (Medtronic 670G) (intervention) or standard insulin pump therapy (control) for 8 weeks. Gold scores and hyperinsulinemic hypoglycemic clamp studies were undertaken at baseline and at the end of the study with evaluation of the hormonal and symptomatic responses to hypoglycemia. Results: A total of 17 participants completed the study (mean (SD) age 35.8 years (11.2), diabetes duration 24.2 years (11.3), HbA1c 7.8% (1.2)). 8 participants were randomized to control and 9 participants to intervention. The baseline (Median, IQR) Gold score was 6.0 (5.0; 6.0) in the overall cohort and did not differ between groups. At the study end, Gold score improved in the intervention group: control vs. intervention 6.0 (4.5; 6.0) vs. 3.5 (3.0; 4.5); p = 0.027. Symptom scores (adrenergic and neuroglycopenic) during the clamp were not different between the control and intervention groups. Conclusions: The use of a hybrid closed loop system over 8 weeks improved self-reported hypoglycemia awareness, however there was no evidence for improvement in the symptomatic responses to experimentally induced hypoglycemia. Disclosure M. Burckhardt: None. J. Dart: None. G.J. Smith: None. M.B. Abraham: None. N. Paramalingam: None. J.M. O'Dea: None. M. de Bock: None. E.A. Davis: None. T. Jones: Research Support; Self; Dexcom, Inc., Medtronic MiniMed, Inc. Speaker's Bureau; Self; Eli Lilly and Company, Roche Diabetes Care.

403-P: Cerebral Blood Flow Responses to Hypoglycemia in Healthy Humans Treated with Induction Protocol to Produce Impaired Awareness of Hypoglycemia

In this study, we sought to determine by 3T MRI the cerebral blood flow (CBF) responses to hypoglycemia (HG) in nondiabetic controls exposed to either two euglycemic or two hypoglycemic clamps on the day before the MRI (EU- or HYPO-preconditioning, respectively). Under the belief that HYPO-preconditioning induces hypoglycemia-associated autonomic failure (HAAF) with blunting of the counter-regulatory hormone and symptom responses to HG (Arbelaez et al, 2008), we hypothesized that CBF responses after HYPO-preconditioning would resemble those reported in T1D subjects with impaired awareness of hypoglycemia (IAH) (Weigers et al, 2017). CBF was measured by arterial spin labeling during a 2-step hyperinsulinemic clamp [step 1 = 95 mg/dL normoglycemia (NG), step 2 = 50 mg/dL (HG)]. Symptom and counter-regulatory hormone were also measured. Full CBF datasets were obtained from 10 participants who underwent EU-preconditioning (7F/3M, age 37 ± 14 years, BMI 27.2 ± 3.7 kg/m2) and 9 who underwent HYPO-preconditioning (5F/4M, age 40 ± 14 years, BMI 26.2 ± 2.6 kg/m2). In contrast with our assumption, the HYPO-preconditioning did not induce blunting of symptom or counter-regulatory hormone responses to HG other than for glucagon (33 ± 19 and 14 ± 21 pg/mL for EU- and HYPO-preconditioning, respectively, p=0.04 uncorr). CBF responses did not differ between the two pre-conditionings, and resembled those reported in the literature in naïve nondiabetic controls (Weigers et al, 2017). In particular, the cortical grey matter CBF did not change during HG vs. NG for either the EU- or HYPO-preconditioning settings (1 ± 10% and 2 ± 10%, respectively), while thalamic CBF increased in both settings (21 ± 20%, p=0.012 corr, and 27 ± 30%, p=0.06 corr, respectively). We conclude that the preconditioning protocols should be used with caution in nondiabetic controls for investigating IAH, as the mechanisms of HAAF in T1D patients may be specific to their disease condition. Disclosure A. Canna: None. H. Grohn: None. D. Mascali: None. P. Filip: None. A. Moheet: None. A. Kumar: None. X. Li: None. E.A. Olawsky: None. L.E. Eberly: None. F. Esposito: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company, Zucara Therapeutics Inc. Consultant; Self; 360 Consulting, MannKind Corporation. Research Support; Self; Eli Lilly and Company, JDRF, National Institutes of Health. Other Relationship; Self; American Diabetes Association, Sanofi, WebMD. S. Mangia: None. Funding National Institutes of Health

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

IntroductionSevere 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...

907-P: Striking Improvements in HbA1c following Commencement of Flash Glucose Monitoring in Type 1 Diabetes

Little evidence currently supports the efficacy of Flash Monitoring (FM) in type 1 diabetes. We present the largest prospective study of clinical outcomes following FM. National Health Service (NHS) funding for FM was introduced in Feb 2018 in our center. We evaluated outcomes in 900 people with T1DM. Baseline HbA1c was the most recent value prior to commencing FM. Control HbA1c data were obtained from 518 people with no prior or current FM use. Pre- and post-FM hypoglycemia and Hospital Anxiety and Depression Scale (HADS) data were available in 57%. Hospital admission and test-strip prescription data were obtained for the 6 months following NHS-funding and the corresponding period the previous year. Median age was 42 years (IQR 30 - 55). Mean baseline HbA1c was 65±15 mmol/mol. Pre-FM, 34.2% had HbA1c &amp;lt;58 mmol/mol (7.5%) which rose to 50.9% at next follow-up (median 343 days from baseline HbA1c), P &amp;lt; 0.001. Those with HbA1c &amp;gt; 75 mmol/mol (9.0%) fell from 17.8% to 8.5%, P &amp;lt; 0.001. Mean reduction in HbA1c was 5.6±10.9 mmol/mol (P &amp;lt; 0.001) but was greater in those with baseline HbA1c above 75mmol/mol (-15.4±16.8 mmol/mol, P &amp;lt; 0.001). In the control group, HbA1c did not change across the corresponding period (+0.2 mmol/mol, P = 0.66). In multivariate analysis, less frequent SMBG pre-FM (P = 0.03), higher HbA1c (P &amp;lt;0.001) and higher socioeconomic status (P = 0.02) were all associated with greater likelihood of a ≥5 mmol/mol fall in HbA1c. Impaired awareness of hypoglycemia (IAH) improved, in those with a prior history of IAH, after FM use (P &amp;lt; 0.001). HADS depression (2 [1 - 5] vs. 1 [0 - 3], P &amp;lt; 0.0001) and anxiety scores (2 [1 - 5] vs. 1 [0 - 3], P = 0.03) were higher following FM use. DKA admissions fell significantly (2 vs. 8, P = 0.02) but no effect was observed on total admissions or emergency department attendance. Blood glucose test strip prescribing fell to 14.3% of pre-FM levels (P &amp;lt; 0.01). FM is associated with reduced DKA admissions and marked improvement in glycemic control across a wide range of people with T1DM. Disclosure F.W. Gibb: None. R.H. Stimson: None. J.A. McKnight: Other Relationship; Self; Boehringer Ingelheim International GmbH, Lilly Diabetes, MedImmune, Novo Nordisk Inc. V. Tyndall: None. S.A. Ritchie: Other Relationship; Self; MedImmune, Novo Nordisk Inc. N.N. Zammitt: None. A.R. Dover: Other Relationship; Self; Abbott.

959-P: The Association of British Clinical Diabetologists' Audit of Freestyle Libre in Diabetes in United Kingdom—Effect on Hypoglycaemia Awareness

The FSL flash glucose monitoring device can reduce hypoglycaemia in people with diabetes. This national audit explores UK real world experience of FSL with respect to hypoglycaemia awareness in people with diabetes. Clinicians using FSL were invited to submit data to a secure web-based tool held within the NHS N3 network. Data were analysed from available initial submissions from the 60 out of 120 NHS trusts registered for the audit. R3.5 was used for statistical analysis and T-test and Mann Whitney-U tests was used to compare the baseline and follow-up GOLD score and brief Diabetes Distress Screening Score (DDSS) respectively. Data were available for 2,438 (2,348 people with type 1 diabetes) FSL users; age 34(IQR =19-51) years, 54% female, diabetes duration 14 (IQR=19-51) years, and BMI of 24(IQR=21-28) kg/m2. In those with follow-up and baseline GOLD score (n=566), the median Gold score decreased significantly from 3.29(±1.85) at baseline to 2.79(±1.91), P&amp;lt;0.0001. Of those with GOLD score ≥4 (impaired awareness of hypoglycaemia) (n=228) at baseline, 23 (10%) improved their hypoglycaemia awareness (GOLD score of &amp;lt;4) following FSL initiation. From the user feedback questionnaire 78% reported that with use of FSL they were able to reduce the proportion of time in hypoglycaemia, 33% had been able to reduce rate of hypoglycaemia and 32% had reduced nocturnal hypoglycaemia. The initiation of FSL was associated with significant improvement in diabetes-related emotional distress with significant improvement [3 (2-4) at baseline to 2 (1-3) at follow-up P&amp;lt;0.0001] in both components of brief DDSS. These initial FSL audit data demonstrated a significant improvement in GOLD score and hypoglycaemic awareness following introduction of the FSL. Ongoing data collection and analysis will help explain if this transforms into reduced rate of hospital admissions and third party assistance due to hypoglycaemia and will inform future clinical practice and policy. Disclosure E.G. Wilmot: Advisory Panel; Self; Dexcom, Inc. Research Support; Self; Diabetes UK. Speaker's Bureau; Self; Abbott, Eli Lilly and Company, Novo Nordisk Inc., Sanofi. H. Deshmukh: None. D. Bishop: None. D.W. Lipscomb: Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Stock/Shareholder; Self; ABCAM, EKF Diagnostics, GlaxoSmithKline plc., Renalytix AI PLC. R. Banatwalla: None. R. Zaidi: None. Z.V. Smith: None. L. Overend: Other Relationship; Self; Lilly Diabetes, Novo Nordisk Inc. S. Kamaruddin: None. C.M. Hall: None. A. Kilvert: Advisory Panel; Self; Sanofi. J. Macfadyen: None. T. Sathyapalan: Speaker's Bureau; Self; Novo Nordisk Foundation. Other Relationship; Self; Bristol-Myers Squibb Company, Eli Lilly and Company, Sanofi-Aventis. C. Walton: Advisory Panel; Spouse/Partner; Celgene Corporation. Speaker's Bureau; Spouse/Partner; Leo Pharma, Novartis Pharmaceuticals Corporation. R.E. Ryder: Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Bioquest.

369-P: Effects of Nocturnal Hypoglycemia on Quality of Life and Mood During Daily Life in Type 1 Diabetes—A CGM-Based Analysis

Objective: To assess the effect of spontaneous nocturnal hypoglycemia on quality of life and mood the subsequent days in type 1 diabetes. Research Design and Methods: A total of 153 persons with type 1 diabetes participated in 6 days of blinded continuous glucose monitoring (CGM) while daily documenting hypoglycemic symptoms, quality of life and mood. Hypoglycemia was defined by interstitial glucose ≤ 70 mg/dl (IG70) and ≤ 54 mg/dl (IG54) for &amp;gt; 15 minutes and was classified as asymptomatic if no hypoglycemic symptoms were reported in the diary. Results: Self-estimated quality of life assessed by the EQ-5D VAS (but not by the WHO Well-Being Index) was higher the day after an asymptomatic (but not after a symptomatic) hypoglycemic night as compared with non-hypoglycemic nights (IG70: p = 0.021 and IG54: p = 0.048). The effect increased with longer duration and lower glucose nadir of nocturnal hypoglycemia (IG70: p = 0.04). The finding was confined to participants with reduced hypoglycemia awareness. There was no effect on mood of nocturnal hypoglycemia. Conclusions: Individuals with type 1 diabetes and impaired awareness report higher quality of life following nights with asymptomatic - but not symptomatic - hypoglycemia. The effect was amplified by lower glucose nadir and longer duration of the episodes and may contribute to explain resistance to implementation of interventions against hypoglycemia in many people with impaired hypoglycemia awareness. Disclosure M.M. Henriksen: None. H.U. Andersen: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Nordic Infucare. Stock/Shareholder; Self; Novo Nordisk Inc. B. Thorsteinsson: None. U. Pedersen-Bjergaard: Advisory Panel; Self; AstraZeneca, Sanofi-Aventis, Zealand Pharma A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Funding Nordsjællands Hospital; Jascha Foundation; Danish Medical Research Grant; The Toyota Foundation, Denmark

377-P: Prospective Risk Assessment of Hypoglycemia in Type 1 Diabetes Mellitus Outpatient Pediatric Population

Objectives: The goal was to implement a risk profile that would prospectively identify youth with T1D at risk of severe hypoglycemia (SH) over the course of 1 year. We hypothesized that subjects with specific risk factors such as prior SH, a high frequency of nocturnal hypoglycemia (NH), and impaired hypoglycemia awareness would have a high rate of SH within the following year. If confirmed, an accurate assessment can lead to efficient application of interventions to reduce future risk of SH. Methods: 404 subjects were followed for 14 months for SH, defined as a seizure, coma or loss of consciousness in the setting of presumed hypoglycemia (ISPAD guidelines). Subjects completed a survey that queried about SH, NH, and hypoglycemia unawareness. Comparisons were made using Chi-squared or Fisher’s exact tests for categorical variables and Wilcoxon Rank-Sum tests for continuous variables. Results: Of the 404 enrolled, 18 subjects had SH in 14 months (4.46%). In the univariate analysis, those who had SH had indicated SH on the enrollment questionnaire (p-value 0.0015) and hypoglycemia unawareness as always or often (p-value 0.0259). Subjects with SH were more likely to wear CGMs (p-value 0.0369). Subject characteristics, T1D management, insurance, and NH were not statistically significant. In addition, we evaluated the 13 subjects who indicated on their initial questionnaire SH in the prior three months. In the univariate analysis, those subjects had more NH defined as ≥2 nights in a 3 month period (P=0.006) and less hypoglycemia awareness (P=0.030). With regards to insulin management, they had a lower insulin sensitivity factor (P=0.012) and higher proportion of basal insulin (P=0.003). Conclusions: In a diverse cohort of T1D, this study shows the ability to identify pediatric subjects at risk for SH with hypoglycemia unawareness and prior SH. As SH is a rare event, as this study is expanded, there is the opportunity for a scored risk questionnaire to capture T1D youth at risk for SH. Disclosure K. Cossen: None. J. Figueroa: None. A.B. Muir: None.

Impaired awareness of hypoglycaemia: A new risk factor for adverse pregnancy outcomes in type 1 diabetes.

The aim of this study is to evaluate the impact of impaired awareness of hypoglycaemia (IAH) on metabolic control and pregnancy outcomes in women with type 1 diabetes. This was a single-centre prospective cohort study of singleton pregnant women with type 1 diabetes. IAH was assessed at the first antenatal visit using Clarke's test (score≥3). Data on metabolic control, hypoglycaemic events, and the lipid profile were collected from prior to pregnancy and in each trimester of gestation. Pregnancy outcomes were also recorded. A total of 77 patients with type 1 diabetes were included; 24 (31.2%) were classified as having IAH. Compared with the normal awareness of hypoglycaemia (NAH) group, the IAH group did not show differences in HbA1c , weight gain, insulin doses, or severe and nonsevere hypoglycaemia events throughout pregnancy. IAH was associated with higher triglyceride concentrations in the second trimester (IAH: 154.8±61.1mg/dL, NAH: 128.6±31.2mg/dL, P=.034) and an increased risk of neonatal respiratory distress (odds ratio [OR] 11.24; 95% CI, 1.01-124.9, P=.041) in adjusted models. Increased risk of pre-eclampsia was related to higher second trimester triglyceride concentrations (OR 1.028; 95% CI, 1.004-1.053, P=.023) adjusted for confounders. The IAH was associated with increased risk of neonatal respiratory distress and pre-eclampsia, despite showing no differences in metabolic control. Hypoglycaemia awareness in the first antenatal visit should be assessed to identify the subgroup of pregnant women with increased risk of complications.