Gold Score Research Articles

354-P: Interstitial Fluid Glucose as a Measure of Hypoglycemia Burden in Elderly Subjects with Type 2 Diabetes Mellitus

Background: Elderly patients with type 2 diabetes mellitus (T2DM) are at high risk of severe hypoglycemia, but evidence addressing this problem is lacking. Aims: To assess and compare the burden of exposure to low interstitial fluid glucose (IFG) in elderly subjects with tightly controlled T2DM on sulphonylurea (SU) or insulin therapy. Methods: Outpatient T2DM subjects ≥65 years of age with HbA1c ≤7.5% were recruited to wear a Freestyle Libre-Pro sensor for 2 weeks. Collected data was analyzed for low IFG burden. Results: A total of 65 subjects (35 male, 30 female), 72.0 ± 5.0 years old with diabetes duration of 21.4 ± 11.1 years and HbA1c of 6.8 ± 0.5% were recruited; 27 were insulin treated and 38 were SU treated. Patients on insulin had longer diabetes duration (25.4 ± 10.9 vs. 18.0 ± 10.4 years, p<0.05) and poorer kidney function (eGFR 58.6 ± 24.7 vs. 87.3 ± 48.0, p<0.05). Greater proportion of the insulin group performed regular capillary blood glucose (CBG) monitoring (74.1% vs. 29.7%). This group also had more monthly self reported hypoglycemic events (0.85 ± 1.70 vs. 0.14 ± 0.35, p<0.05) and a lower GOLD score (2.42 ± 1.72 vs. 3.73 ± 1.75, p<0.05). While there was no difference in mean number of low IFG events with glucose <72.0mg/dL between the 2 groups (0.92 ± 0.79 vs. 0.59 ± 0.48 events, p value >0.05), very low IFG events with glucose <50.0mg/dL occurred in higher proportions (52% vs. 23%, p<0.05), higher frequency (0.48 ± 0.70 vs. 0.16 ± 0.19 events/person, p <0.05) and for longer durations (1.56 ± 2.94 vs. 0.27 ± 0.43 hours/day, p<0.05) in the insulin group. 62.2% of the SU group and 63.0% of insulin group had at least 1 episode of very low IFG, but none of the SU group and only 2 in the insulin group reported hypoglycemic symptoms. Conclusion: Low IFG was common among the studied population, with a greater burden in insulin treated patients. Majority were unable to detect events despite regular CBG monitoring suggesting the potential use of IFG in evaluating hypoglycemia burden. Disclosure K. Tian: None. L. C. Ang: None. Y. Bee: None. S. Goh: None. M. M. Teh: None.

HbA1c and hypoglycaemia outcomes for people with type 1 diabetes due to the introduction of a single-day structured education programme and flash glucose monitoring

People with type 1 diabetes who met NHS England funding criteria attended an accredited, intensive one-day structured education programme and completed the online FreeStyle Libre Academy training module followed by a 30-minute healthcare professional face-to-face practical training session. HbA1c, Gold hypoglycaemia score and Diabetes Distress Screening score were documented before commencement of the intervention and at 6 months. 213 people with type 1 diabetes (52% men; average age 48 years (range 18–87)) completed the 6-month intervention. Overall mean HbA1c reduced by 6 mmol/mol (0.5%) from 62±14 mmol/mol (7.8%) to 56±12 mmol/mol (7.3%) (p<0.0001). Subgroup analysis of participants with a baseline HbA1c ≥54 mmol/mol (7.1%) revealed a more dramatic reduction of 10 mmol/mol (0.9%) from 69±12 mmol/mol (8.5%) to 59±11 mmol/mol (7.6%). No deterioration was demonstrated for people with HbA1c <54 mmol/mol (7.1%). 143 people (75%) reported a reduction in hypoglycaemia episodes and 162 (85%) reported a reduction in time spent in the hypoglycaemic range. There was significant improvement in the Gold score (p<0.0001) and Diabetes Distress Screening score (p=0.0001). Rates of hospital admissions, paramedic call-outs and third-party assistance were reduced. The combination of a one-day intensive structured education programme alongside flash glucose monitoring initiation provides a pragmatic, cost-effective and easily implemented intervention with positive clinical outcomes at 6 months.

EVALUATION OF THE RELATIONSHIP BETWEEN VITAMIN D LEVELS IN COPD PATIENTS WITH ACUTE RESPIRATORY FAILURE

COPD with the development of inflammation in the alveoli as a result of exposure of harmful gases to the bronchi and bronchioles in the lungs, irreversible airflow restriction and respiratory symptoms occur. In our study;It is aimed to evaluate the serum D vitamin level in COPD patients with acute respiratory failure and to investigate the effect of vitamin D in COPD stages. This study is a prospective cross-sectional study. The study was conducted with a total of 75 COPD patient groups and 65 control groups. GOLD score, CAT score and Mmrc score were used in the study. Kruskal-Wallis H test and Mann-Whitney U test were used for statistical analysis.The results were evaluated in terms of p <0.05 significance level. According to the results of our study, vitamin D level in acute exacerbation was lower in patients with acute obstructive pulmonary disease than in the control group. According to the results obtained in our study, when CAT scores, Mmrc scores, vitamin D levels and gold scores,which are the measured assessment for chronic obstructive pulmonary disease patients, are evaluated; With increasing vitamin D deficiency, patient clinics become more severe. We believe that patients diagnosed with COPD add vitamin D to their treatment protocols according to their vitamin D levels and their vital activities will increase while reducing the severity of COPD.

POLYGENIC RISK SCORES PREDICT HYPERTENSION ONSET AND CARDIOVASCULAR RISK

Abstract Objective: We aimed to quantify the predictive ability of polygenic risk scores in hypertension and demonstrate that they improve a gold standard clinical risk score of hypertension in the general population. Design and method: Our study sample comprised N = 218,792 FinnGen Study participants with lifetime follow-up (mean age 58 years, 56% women). We used recently developed Bayesian methodology and publicly available genome-wide association data to compute polygenic risk scores (PRS) for systolic (SBP) and diastolic blood pressure (DBP). Next, in a well-phenotyped subset of 22,624 FINRISK study participants, we calculated the 4-year clinical risk of hypertension and 10-year clinical risk of cardiovascular disease (CVD) using gold standard risk scores. Using time-to-event analysis, we then assessed (1) the association of blood pressure PRSs with hypertension, age of hypertension onset, and CVD in all FinnGen participants, and (2) the incremental improvement in model discrimination when combining blood pressure PRSs with the 4-year and 10-year clinical risk predictions of hypertension and CVD in the FINRISK cohorts. Results: Compared to having an average PRS, elevated PRS was associated with up to 2.3-fold risk of hypertension and an 11-year earlier disease onset (Figure). In subgroup analyses, the risk was only 1.6-fold for late-onset hypertension (age > = 55 years), whereas it was 2.8-fold for early-onset hypertension (age < 55 years). Elevated SBP PRS was also associated with up to 1.3-fold risk of CVD and a 4-year earlier disease onset. SBP and DBP PRSs improved clinical risk prediction for hypertension, increasing the C-statistic by 0.7% (0.3–1.1; P = 0.0017) and generating a category-free Net Reclassification Improvement of 9.3% (1.9–16.8; P = 0.014). Inclusion of blood pressure PRSs did not improve the clinical CVD risk score. Conclusions: We demonstrated that genetic information improves clinical risk prediction of hypertension. Blood pressure PRSs could be used together with traditional risk factors to improve prediction of hypertension and particularly early-onset hypertension, which confers substantially increased CVD risk. When used independently, PRSs offer a simple and increasingly affordable way to measure genetic predisposition to hypertension at any point in life. Individuals with elevated blood pressure PRSs could benefit from genetic counseling and intensive early intervention.

Impact of Hybrid Closed Loop Therapy on Hypoglycemia Awareness in Individuals with Type 1 Diabetes and Impaired Hypoglycemia Awareness.

Objective: This study evaluated the efficacy of using a hybrid closed loop (HCL) system in restoring hypoglycemia awareness in individuals with impaired awareness of hypoglycemia (IAH). Research Design and Methods: Participants with IAH (Gold score ≥4) were recruited into a randomized crossover pilot study. They participated in two 8-week periods using a HCL system (Medtronic 670G™) (intervention) and standard insulin pump therapy (control). Hyperinsulinemic hypoglycemic clamp studies were undertaken at baseline and at the end of each study period for the evaluation of the counter-regulatory hormonal and symptomatic responses to hypoglycemia. Results: Seventeen participants (mean age [standard deviation] 35.8 years [11.2 years]) were included in the study. Peak epinephrine levels (median, interquartile range [IQR]) in response to hypoglycemia were similar postintervention and control periods; 234.7 pmol/L (109.2; 938.9) versus 188.3 pmol/L (133.7; 402.9), P = 0.233. However, both peak adrenergic and neuroglycopenic symptom scores were higher after intervention; 5.0 (4.5; 9.0) versus 4.0 (4.0; 5.5), P = 0.009, and 8.5 (6.0; 15.0) versus 6.5 (6.0; 7.0) P = 0.014, respectively. Self-reported hypoglycemia awareness improved: median (IQR) Gold score was 4.0 (3.0; 5.5) versus 5.5 (4.5; 6.0); intervention versus control, P = 0.033. Time spent <3.9 and <3.0 mmol/L was lower in the intervention group than in control, P = 0.002. Other patient-reported outcomes (hypoglycemia fear and diabetes treatment satisfaction) did not change. Conclusions: A short-term use of a HCL system failed to demonstrate an improvement in counter-regulatory hormonal responses. However, higher hypoglycemia symptom scores during controlled hypoglycemia, better self-reported hypoglycemia awareness, and less time spent in hypoglycemia suggest the potential benefits of a HCL system in people with IAH. Trial Registration: anzctr.org.au Identifier: ACTRN12616000909426.

Design, synthesis, spectral characterization and molecular docking studies of novel pyranoquinolinyl dihydropyridine carboxylates as potential antibacterial agents including Vibrio cholerae with minimal cytotoxity towards fibroblast cell line (L-929)

Novel pyranoquinolinyl dihydropyridine carboxylate (PDC) derivatives were designed by incorporating the multi-drug resistance modulating effects of 1,4 dihydropyridines along with potential antibacterial activity of quinolines in the molecular design. The designed PDC derivatives were synthesized by multi-step synthesis involving Michael addition, reduction followed by inverse electro demand Diels-Alder reaction to produce pyranoquinolinyl dihydropyridine carboxylates in good yields. All the PDC derivatives were characterized by 1H NMR, 13C NMR, FT-IR, Mass spectral and CHN analysis. The Quinolinyl dihydropyridine carboxylate derivatives were evaluated for in vitro antibacterial activity by agar well diffusion method. Molecular docking studies revealed that the exo diethyl 4-(4aR,5S,10bR)-5-(4-chlorophenyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-8-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate diastereomer (5c) forms four hydrogen bonds with the cell wall protein of vibrio cholerae in comparison to the endo diethyl 4-((4aR,5R,10bR)-5-(4-chlorophenyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-8-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate diastereomer (4c) which forms two hydrogen bonds with the cell wall protein of vibrio cholerae and hence leading to better anchorage, enhanced gold score and relatively good antibacterial activity for the exo PDC derivatives. Minimum inhibitory concentration (MIC) of the active compounds was evaluated by macro dilution method. The mechanism of antibacterial action of the PDC derivatives was investigated by SEM studies. The cytotoxicity of PDC derivatives were evaluated against fibroblast cells (L-929).

Potential natural inhibitors of xanthine oxidase and HMG-CoA reductase in cholesterol regulation: in silico analysis

BackgroundHypercholesterolemia has posed a serious threat of heart diseases and stroke worldwide. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid biosynthesis, is regarded as the root of reactive oxygen species (ROS) that generate atherosclerosis and cholesterol crystals. β-Hydroxy β-methylglutaryl-coenzyme A reductase (HMGR) is a rate-limiting enzyme in cholesterol biosynthesis. Although some commercially available enzyme inhibiting drugs have effectively reduced cholesterol levels, most of them have failed to meet potential drug candidates’ requirements. Here, we have carried out an in-silico analysis of secondary metabolites that have already shown good inhibitory activity against XO and HMGR in a wet lab setup.MethodsOut of 118 secondary metabolites reviewed, sixteen molecules inhibiting XO and HMGR were selected based on the IC50 values reported in in vitro assays. Further, receptor-based virtual screening was carried out against secondary metabolites using GOLD Protein-Ligand Docking Software, combined with subsequent post-docking, to study the binding affinities of ligands to the enzymes. In-silico ADMET analysis was carried out to explore their pharmacokinetic properties, followed by toxicity prediction through ProTox-II.ResultsThe molecular docking of amentoflavone (GOLD score 70.54, ∆G calc. = − 10.4 Kcal/mol) and ganomycin I (GOLD score 59.61, ∆G calc. = − 6.8 Kcal/mol) displayed that the drug has effectively bound at the competitive site of XO and HMGR, respectively. Besides, 6-paradol and selgin could be potential drug candidates inhibiting XO. Likewise, n-octadecanyl-O-α-D-glucopyranosyl (6′ → 1″)-O-α-D-glucopyranoside could be potential drug candidates to maintain serum cholesterol. In-silico ADMET analysis has shown that these sixteen metabolites were optimal within the categorical range compared to commercially available XO and HMGR inhibitors, respectively. Toxicity analysis through ProTox-II revealed that 6-gingerol, ganoleucoin K, and ganoleucoin Z are toxic for human use.ConclusionThis computational analysis supports earlier experimental evidence towards the inhibition of XO and HMGR by natural products. Further study is necessary to explore the clinical efficacy of these secondary molecules, which might be alternatives for the treatment of hypercholesterolemia.

Restoration of Hypoglycemia Awareness Alters Brain Activity in Type 1 Diabetes.

Impaired awareness of hypoglycemia (IAH) in type 1 diabetes (T1D) is a major risk factor for severe hypoglycemia (SH) and is associated with atypical responses to hypoglycemia in brain regions involved in arousal, decision making, and memory. Whether restoration of hypoglycemia awareness alters these responses is unknown. We sought to investigate the impact of awareness restoration on brain responses to hypoglycemia. Twelve adults with T1D and IAH underwent pseudocontinuous arterial spin labeling functional MRI during a hypoglycemic clamp (5-2.6 mmol/L) before and after a hypoglycemia avoidance program of structured education (Dose Adjustment for Normal Eating), specialist support, and sensor-augmented pump therapy (Medtronic MiniMed 640G). Hypoglycemic cerebral blood flow (CBF) responses were compared pre- and postintervention using predefined region-of-interest analysis of the thalamus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and hippocampus. Postintervention, Gold and Clarke scores fell (6.0 ± 1.0 to 4.0 ± 1.6, P = 0.0002, and 5.7 ± 1.7 to 3.4 ± 1.8, P = 0.0008, respectively), SH rates reduced (1.5 ± 2 to 0.3 ± 0.5 episodes per year, P = 0.03), hypoglycemic symptom scores increased (18.8 ± 6.3 to 27.3 ± 12.7, P = 0.02), and epinephrine responses did not change (P = 0.2). Postintervention, hypoglycemia induced greater increases in ACC CBF (P = 0.01, peak voxel coordinates [6, 40, -2]), while thalamic and OFC activity did not change. Increased blood flow is seen within brain pathways involved in internal self-awareness and decision making (ACC) after restoration of hypoglycemia awareness, suggesting partial recovery of brain responses lost in IAH. Resistance of frontothalamic networks, involved in arousal and emotion processing, may explain why not all individuals with IAH achieve awareness restoration with education and technology alone.

LEADS-FRAG: A Benchmark Data Set for Assessment of Fragment Docking Performance.

Fragment-based drug design is a popular approach in drug discovery, which makes use of computational methods such as molecular docking. To assess fragment placement performance of molecular docking programs, we constructed LEADS-FRAG, a benchmark data set containing 93 high-quality protein-fragment complexes that were selected from the Protein Data Bank using a rational and unbiased process. The data set contains fully prepared protein and fragment structures and is publicly available. Moreover, we used LEADS-FRAG for evaluating the small-molecule docking programs AutoDock, AutoDock Vina, FlexX, and GOLD for their fragment docking performance. GOLD in combination with the scoring function ChemPLP and AutoDock Vina performed best and generated near-native conformations (root mean square deviation <1.5 Å) for more than 50% of the data set considering the top-ranked docking pose. Taking into account all docking poses, the tested programs generated near-native conformations for up to 86% of the fragments in LEADS-FRAG. By rescoring all docking poses with the GOLD scoring functions and the Protein-Ligand Informatics force field, the number of near-native conformations increased up to 40% with respect to the top-rescored poses. Our results show that conventional small-molecule docking programs achieve a satisfactory fragment docking performance when utilizing rescoring.

A Comparison of Validated Methods Used to Assess Impaired Awareness of Hypoglycaemia in Type1 Diabetes: An Observational Study.

IntroductionClarke, Gold and Pedersen are validated methods to assess awareness of hypoglycaemia. Identifying impaired awareness of hypoglycaemia (IAH) is critical for supporting people with structured education and diabetes technologies, to reduce harm of hypoglycaemia. This study compares the Clarke score, Gold score and Pedersen methods and their correlations with features of hypoglycaemia unawareness and patient characteristics, to evaluate the accuracy of the methods in identifying IAH.MethodsThis retrospective, observational questionnaire-based study collected routine clinical data from 100 people with type 1 diabetes. The questionnaire included the three validated scoring methods, frequency of severe and nocturnal hypoglycaemia, knowledge and worry of hypoglycaemia and hypoglycaemia symptom scores using the Edinburgh Hypoglycaemia Scale. Data were analysed for IAH prevalence and the associations with features of IAH. The concordance of Clarke, Gold and Pedersen methods was evaluated using Spearman’s correlation coefficient.ResultsThe prevalence of IAH in this cohort identified by Clarke, Gold and Pedersen methods was 18%, 19% and 61% respectively. The mean autonomic symptom score in people with IAH was significantly reduced using the Clarke method (P = 0.0002) but not on Gold (P = 0.12) and Pedersen methods (P = 0.79). For people with IAH assessed using the Clarke method, scores for night-time worry regarding hypoglycaemia (P = 0.04) and self-reported frequency of nocturnal hypoglycaemia (P = 0.001) were increased. Spearman’s correlation coefficients between Pedersen and Clarke and Pedersen and Gold were Rs = 0.555 (P < 0.001) and Rs = 0.645 (P < 0.001) respectively. A moderate association was observed between Clarke and Gold Rs = 0.5669 (P < 0.001).ConclusionWhilst Clarke and Gold methods determined a similar prevalence of IAH, people identified with IAH assessed by the Clarke method had a significant association with the features and characteristics of IAH, including reduced autonomic symptoms. This study suggests that performing more than one score is important for a reliable risk assessment of IAH.Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-020-00965-0) contains supplementary material, which is available to authorized users.

Real-time CGM Is Superior to Flash Glucose Monitoring for Glucose Control in Type 1 Diabetes: The CORRIDA Randomized Controlled Trial.

OBJECTIVEThe aim of this trial was to compare the efficacy of real-time and intermittently scanned continuous glucose monitoring (rtCGM and isCGM, respectively) in maintaining optimal glycemic control.RESEARCH DESIGN AND METHODSIn this randomized study, adults with type 1 diabetes (T1D) and normal hypoglycemia awareness (Gold score <4) used rtCGM (Guardian Connect Mobile) or isCGM (FreeStyle Libre) during 4 days of physical activity (exercise phase) and in the subsequent 4 weeks at home (home phase). Primary end points were time in hypoglycemia (<3.9 mmol/L [<70 mg/dL]) and time in range (3.9–10.0 mmol/L [70–180 mg/dL]). The isCGM group wore an additional masked Enlite sensor (iPro2) for 6 days to check for bias between the different sensors used by the rtCGM and isCGM systems.RESULTSSixty adults with T1D (mean age 38 ± 13 years; A1C 62 ± 12 mmol/mol [7.8 ± 1.1%]) were randomized to rtCGM (n = 30) or isCGM (n = 30). All participants completed the study. Percentage of time in hypoglycemia (<3.9 mmol/L [<70 mg/dL]) was lower among rtCGM versus isCGM participants in the exercise phase (6.8 ± 5.5% vs. 11.4 ± 8.6%, respectively; P = 0.018) and during the home phase (5.3 ± 2.5% vs. 7.3 ± 4.4%, respectively; P = 0.035). Hypoglycemia differences were significant and most notable during the night. rtCGM participants spent more time in range (3.9–10 mmol/L [70–180 mg/dL]) than isCGM participants throughout both the exercise (78.5 ± 10.2% vs. 69.7 ± 16%, respectively; P = 0.0149) and home (75.6 ± 9.7% vs. 67.4 ± 17.8%, respectively; P = 0.0339) phases. The results were robust to the insignificant bias between rtCGM and isCGM sensors that masked CGM found in the isCGM arm.CONCLUSIONSrtCGM was superior to isCGM in reducing hypoglycemia and improving time in range in adults with T1D with normal hypoglycemia awareness, demonstrating the value of rtCGM alarms during exercise and in daily diabetes self-management.

Effect of Flash Glucose Monitoring on Glycemic Control, Hypoglycemia, Diabetes-Related Distress, and Resource Utilization in the Association of British Clinical Diabetologists (ABCD) Nationwide Audit.

OBJECTIVEThe FreeStyle Libre (FSL) flash glucose-monitoring device was made available on the U.K. National Health Service (NHS) drug tariff in 2017. This study aims to explore the U.K. real-world experience of FSL and the impact on glycemic control, hypoglycemia, diabetes-related distress, and hospital admissions.RESEARCH DESIGN AND METHODSClinicians from 102 NHS hospitals in the U.K. submitted FSL user data, collected during routine clinical care, to a secure web-based tool held within the NHS N3 network. The t and Mann-Whitney U tests were used to compare the baseline and follow-up HbA1c and other baseline demographic characteristics. Linear regression analysis was used to identify predictors of change in HbA1c following the use of FSL. Within-person variations of HbA1c were calculated using .RESULTSData were available for 10,370 FSL users (97% with type 1 diabetes), age 38.0 (±18.8) years, 51% female, diabetes duration 16.0 (±49.9) years, and BMI of 25.2 (±16.5) kg/m2 (mean [±SD]). FSL users demonstrated a −5.2 mmol/mol change in HbA1c, reducing from 67.5 (±20.9) mmol/mol (8.3%) at baseline to 62.3 (±18.5) mmol/mol (7.8%) after 7.5 (interquartile range 3.4–7.8) months of follow-up (n = 3,182) (P < 0.0001). HbA1c reduction was greater in those with initial HbA1c ≥69.5 mmol/mol (>8.5%), reducing from 85.5 (±16.1) mmol/mol (10%) to 73.1 (±15.8) mmol/mol (8.8%) (P < 0.0001). The baseline Gold score (score for hypoglycemic unawareness) was 2.7 (±1.8) and reduced to 2.4 (±1.7) (P < 0.0001) at follow-up. A total of 53% of those with a Gold score of ≥4 at baseline had a score <4 at follow-up. FSL use was also associated with a reduction in diabetes distress (P < 0.0001). FSL use was associated with a significant reduction in paramedic callouts and hospital admissions due to hypoglycemia and hyperglycemia/diabetic ketoacidosis.CONCLUSIONSWe show that the use of FSL was associated with significantly improved glycemic control and hypoglycemia awareness and a reduction in hospital admissions.

Differentiating Hypoglycemia Awareness Status from Hypoglycemia Experience in Tools for Measuring Impaired Awareness of Hypoglycemia.

Background: Developing technologies in real-time continuous glucose monitoring (CGM) are successfully reducing severe hypoglycemia (SH) in trials and clinical practice. Their impact on impaired awareness of hypoglycemia, a major risk factor for SH, is uncertain.Methods: The present study examined two scales for assessing hypoglycemia awareness status, the Gold score and the eight-item Minimally Modified Clarke Hypoglycemia Survey (MMCHS), commonly used in trials of CGM, in Portuguese-speaking adults with type 1 diabetes and conducted an exploratory factor analysis on MMCHS.Results: A bifactorial structure in MMCHS was revealed, with a clear distinction between items that measure SH experience and those that measure hypoglycemia awareness status. The latter is associated with the same risk for SH as the Gold score.Conclusions: We conclude that improvement in awareness scores by the MMCHS may reflect only a reduction in SH with no restoration of endogenous awareness, making the current literature consistent in evidence that CGM does not improve endogenous awareness and nonsensor supported protection from SH. This has implications for risk of SH when CGM is not being worn.

157-OR: People with Type 1 Diabetes and Impaired Awareness of Hypoglycemia Have a Delayed Reaction to Perform a Glucose Scan during Hypoglycemia: A Prospective Observational Study

Background: Considering that people with type 1 diabetes (T1D) and impaired awareness of hypoglycemia (IAH) have a delayed perception of hypoglycemia, the question arises if they perform scans later in case of hypoglycemia compared to those with normal hypoglycemia awareness (non-IAH). We assessed if the time until performing a scan after reaching hypoglycemia while using a flash glucose monitoring (Flash GM) system is different in people with T1D and IAH compared to people with T1D and non-IAH. Material and Methods: 92 people with T1D (age of 42±14 years, BMI 25.1±4.0 kg/m2, HbA1c 57±9 mmol/mol (7.3±0.8%), 73 MDI/19 CSII) using a Flash GM system for 3 months were included. Flash GM data were downloaded and assessed for time until scan after reaching hypoglycemia level 1 (&amp;lt;70 mg/dL) and level 2 (&amp;lt;54 mg/dL) and compared for T1D with IAH versus non-IAH via unpaired t-test or Mann-Whitney-U test (p&amp;lt;0.05). IAH was routinely assessed by means of Gold, Clarke and Pedersen-Bjergaard Score. Results: Significant differences were only found for the delay between reaching hypoglycemia and scan between IAH and non-IAH for both Gold Score (hypoglycemia level 1: IAH 78 min [51-105] vs. non-IAH 63 min [42-89], p=0.03; nighttime hypoglycemia level 2: IAH 140 min [107-227] vs. non-IAH 96 min [41-155], p=0.004) and Pedersen-Bjergaard Score (hypoglycemia level 1: IAH 76 min [52-97] vs. non-IAH 54 min [38-71], p=0.01; nighttime hypoglycemia level 1: IAH 132 min [79-209] vs. non-IAH 89 min [59-143], p=0.01; nighttime hypoglycemia level 2: IAH 134 min [66-212] vs. non-IAH 80 min [37-131], p=0.002). Conclusion: These preliminary data suggest that the time until scan after reaching hypoglycemia may serve as an objective assessment tool for IAH in people with T1D. Disclosure O. Moser: Other Relationship; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi. H. Ziko: None. H. Elsayed: None. D.A. Hochfellner: None. T. Poettler: None. A. Mueller: None. M.L. Eckstein: Research Support; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi-Aventis. L. Knoll: None. H. Sourij: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. J.K. Mader: Advisory Panel; Self; Becton, Dickinson and Company, Eli Lilly and Company, Medtronic, Prediktor Medical, Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis.

11-LB: A Phase 2 Study of Liquid Stable Glucagon to Treat Hypoglycemia-Associated Autonomic Failure

Objective: To evaluate a novel, ready-to-use, liquid stable, continuous subcutaneous (SC) glucagon infusion (CSGI; Xeris Pharmaceuticals) for the treatment of Hypoglycemia Associated Autonomic Failure (HAAF) in adults with type 1 diabetes (T1D). Method: This was a Phase 2 double-blind, randomized, placebo-controlled parallel trial in T1D adults with HAAF (Gold Score ≥4). Subjects were randomized to receive 1 month of high-rate CSGI (HCSGI, 80 μg/hour), low-rate CSGI (LCSGI, 20 μg/hour), or placebo. Epinephrine hormone response to hypoglycemia (assessed during stepwise hypoglycemia clamp procedure) and Gold Scores were measured at baseline, end of treatment, and both 3- and 6-months post-treatment. Results: Forty-nine subjects were randomized to receive treatment (HCSGI n=15; LCSGI n=18; placebo n=16). No statistically significant differences in mean epinephrine hormone response or Gold Scores were observed across treatment arms at end of treatment. Long-term follow-up of the subjects was stopped early. For completed follow-up clamps (31 subjects, 3 months; 22 subjects, 6 months), LCSGI did not exhibit differences to placebo. However, HCSGI 3 and 6 month mean epinephrine hormone responses were greater (p=NS) and Gold Scores improved [(-1.1±1.5 vs. 0.5±1.5; 3 months, p=NS) and (-1.2±1.5 vs. -0.6±0.9; 6 months, p=NS)]. The administration of CSGI was associated with mild to moderate nausea (5.9% for LCSGI and, 20% for HCSGI,) and vomiting (11.8% for LCSGI and 13.3% for HCSGI,). CSGI was not associated with pain, injection site reactions, or necrolytic migratory erythema. No related SAEs were reported. Conclusion: Compared to placebo in a small group of T1D adults with HAAF, HCSGI may exhibit improvements in Gold Score at both 3 and 6 months. Mean serum epinephrine may be a suboptimal biomarker of HAAF. CSGI was safely used with concomitant insulin, and there were no related SAEs. Disclosure J. Pettus: Consultant; Self; Diasome Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., MannKind Corporation, Novo Nordisk Inc., Sanofi. S. Nakhle: None. F. Ovalle: Research Support; Self; Gan &amp; Lee Pharmaceuticals, Gilead Sciences, Inc., Lilly Diabetes, Novo Nordisk A/S, Sanofi, Xeris Pharmaceuticals, Inc. M.K. Junaidi: Employee; Self; Xeris Pharmaceuticals, Inc. N.C. Close: Employee; Self; EmpiriStat, Inc. V. Conoscenti: None. A. Nguyen: None.

873-P: Flash Glucose Monitoring: Effect on Glycaemic Control, Hypoglycaemia, Diabetes-Related Distress, and Resource Utilization: A Nationwide Study

Aim: The FreeStyle Libre (FSL) flash glucose monitoring device was made available on the UK National Health Services (NHS) drug tariff in 2017. This study aims to explore the UK real-world experience of FSL and the impact on glycaemic control, hypoglycaemia, diabetes-related distress and hospital admissions. Methods: Clinicians from 102 National Health Service hospitals in the United Kingdom submitted FSL user data, collected during routine clinical care, to a secure web-based tool. T-tests and Mann-Whitney-U tests were used to compare the baseline and follow-up HbA1c and other baseline demographic characteristics. Linear regression analysis was used to identify predictors of change in HbA1c following the use of FSL. Within-person variations of HbA1c calculated adj-HbA1c-SD=SD/sq. Root [n/(n−1)]. Results: Data were available for 10,370 (97% with type 1 diabetes) FSL users; age 38 (±18.7) years, 54% female, diabetes duration 16 (±49) years, and BMI of 25.2 (±16.5) kg/m2. The baseline HbA1c was 69.8 (±18.2) (8.5%), and after a mean follow-up of 7.6 (±23)months (n=3182) HbA1c reduced to 62.3 (±18.5) (7.9%) mmol/l (P&amp;lt;0.0001)). HbA1c reduction was greater in those with initial HbA1c ≥69.5 (&amp;gt;8.5%) mmol/mol, HbA1c reduced from 85.5mmol/mol (±16.07) (10%) to 73.1 mmol/mol (±15.8) (8.8%)) (P&amp;lt;0.0001). The baseline Gold score (score for hypoglycaemic unawareness) was 2.7 (±1.8) and reduced to 2.4 (±1.7) (P&amp;lt;0.0001) at follow-up. 53% of those with a Gold score of ≥4 at baseline, regained hypoglycaemic awareness at follow-up. FSL use was also associated with a reduction in diabetes distress (P&amp;lt;0.0001). Use of FSL was associated with significantly reduced paramedic callouts and hospital admissions due to hypoglycaemia and to hyperglycaemia/Diabetic Ketoacidosis (DKA). Conclusion: We show that the use of FSL was associated with significantly improved glycaemic control and hypoglycaemia awareness, and a reduction in hospital admissions. Disclosure H. Deshmukh: None. E.G. Wilmot: Advisory Panel; Self; Abbott, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic. Speaker’s Bureau; Self; Abbott, Eli Lilly and Company, Insulet Corporation, Novo Nordisk Inc., Sanofi. J. Patmore: None. C. Walton: Speaker’s Bureau; Spouse/Partner; Celgene, LEO Pharma, Novartis Pharmaceuticals Corporation. R. Herring: None. R.E. Ryder: Consultant; Self; GI Dynamics Inc. Other Relationship; Self; Novo Nordisk A/S. T. Sathyapalan: Research Support; Self; Amgen, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S. Other Relationship; Self; Ipsen Biopharmaceuticals.

66-OR: Effect of Time-in-Range over 14 Days on Glycaemic Controls and Hypoglycaemia Unawareness in Patients Using Freestyle Libre

Objective: Time in range (TIR) is a novel measure of glucose control endorsed by an international consensus group. Given the increased use of FreeStyle Libre (FSL) in the UK, we wanted to investigate the effects of TIR over 14 days of FSL (TIR-14) use on glycaemic control, hypoglycaemia unawareness. Methods: Clinicians from 101 National Health Service hospitals in the United Kingdom submitted FSL user data, collected during routine clinical care. TIR-14 was defined as the percentage of time the patients with type 1 diabetes spent in the individualised target range of blood sugar which ranged from 3.9 to 10 mmol/L(70-180mg/dl) over 14 days of FSL use. TIR-14 was divided into two categories &amp;lt;= 50%, (Group 1) and TIR-14&amp;gt;50% (Group 2). T-tests were used to compare the baseline and follow-up HbA1c, and GOLD score in the two groups. Results: Data were available for 10,370 FSL users; age 38 (±18.7) years, 54% female, diabetes duration 16 (±49) years, and BMI of 25.2 (±16.5) kg/m2. TIR-14 data was available for 2191 patients who had at least one follow-up (1422 in Group 1 and 769 in Group 2). There were large variations in the individualised target TIR-14; however, more than 99% of patients had ranges in-between 3.9-10 mmol/mol with a median TIR-14 of 43%(27%-56%). The mean follow-up period was 7.6(±23) months. In Group 1 HbA1c dropped from 8.6% to 7.6% (P&amp;lt;0.0001) while in Group 2 the HbA1c dropped from 7.6% to 7%. (P&amp;lt;0.0001). In an analysis restricted to those with baseline HbA1c of &amp;gt;8.5%, HbA1c dropped from 9.8% to 8.8% (P&amp;lt;0.0001) in Group 1 while in Group 2 it fell from 9.6% to 7.7% (P&amp;lt;0.0001). In the Group I the GOLD score fell by 0.25 (P=0.0005) units while in Group II the GOLD score fell by 0.45 units (P&amp;lt;0.0001). Conclusion: This population-based study of FSL users demonstrates that TIR-14 of more than 50% is associated with a significantly improved glycaemic control in especially in those with higher baseline HbA1c and is associated with a larger improvement in hypoglycaemia unawareness. Disclosure H. Deshmukh: None. E.G. Wilmot: Advisory Panel; Self; Abbott, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic. Speaker’s Bureau; Self; Abbott, Eli Lilly and Company, Insulet Corporation, Novo Nordisk Inc., Sanofi. R. Herring: None. J. Patmore: None. T. Sathyapalan: Research Support; Self; Amgen, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S. Other Relationship; Self; Ipsen Biopharmaceuticals. R.E. Ryder: Consultant; Self; GI Dynamics Inc. Other Relationship; Self; Novo Nordisk A/S. C. Walton: Speaker’s Bureau; Spouse/Partner; Celgene, LEO Pharma, Novartis Pharmaceuticals Corporation.

852-P: Is Real-Time CGM Superior to Flash Glucose Monitoring? Results of the Type 1 Diabetes CORRIDA Randomized Control Trial

Background: The trial aim was to compare the efficacy of real-time and intermittently-scanned continuous glucose monitoring (rtCGM and isCGM, respectively) in maintaining optimal glycemic control. Methods: In this randomized study, adults with T1D and normal hypoglycemia awareness (GOLD score Results: Sixty adults with T1D (age 38±13 years, HbA1c 7.8±1.1% [62±12 mmol/mol]) were randomized to rtCGM (n=30) or isCGM (n=30). All participants completed the study. Time in hypoglycemia ( Conclusion: rtCGM was superior to isCGM in preventing hypoglycemia and improving time in range in T1D adults with normal hypoglycemia awareness, demonstrating the value of rtCGM alarms during exercise and in daily diabetes self-management. Disclosure J. Soupal: Advisory Panel; Self; Abbott. Consultant; Self; Medtronic, Roche Diabetes Care. Speaker’s Bureau; Self; Dexcom, Inc. A. Haskova: None. G. Grunberger: Research Support; Self; Medtronic. L. Petruzelkova: None. C. Parkin: Consultant; Self; Abbott, CeQur Corporation, Dexcom, Inc., DreaMed Diabetes, Novo Nordisk Inc., Onduo, Roche Diabetes Care, Valeritas, Inc. J. Skrha: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. L. Radovnicka: None. E. Horova: None. M. Prazny: Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Roche Diabetes Care. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk A/S, Sanofi, Teva Pharmaceutical Industries Ltd. Funding 15-26705A (Program RVO-VFN00064165)

MON-LB110 A Phase 2 Evaluation of a Ready-To-Use Liquid Stable Continuous Subcutaneous Glucagon Infusion for the Treatment of Hypoglycemia Associated Autonomic Failure

OBJECTIVE:A novel, ready-to-use, liquid stable, continuous subcutaneous glucagon infusion (CSGI; Xeris Pharmaceuticals) was evaluated for the treatment of adults with type 1 diabetes (T1D) with documented Hypoglycemia Associated Autonomic Failure (HAAF). METHOD:This was a Phase 2 prospective, multi-center, randomized, placebo-controlled, double-blind, parallel trial in T1D adults with documented HAAF, defined as Gold Scale Score ≥4. Subjects were randomized in a 1:1:1 ratio to receive 4 weeks of continuous treatment (via Omnipod pump) with high rate CSGI (80mcg/hour), low rate CSGI, (20mcg/hour) or placebo (matched infusion rates for low and high rate CSGI). The primary endpoint evaluated at 4 weeks was the percent change of the epinephrine hormone response after 30 minutes of induced hypoglycemia. Epinephrine levels and hypoglycemia symptoms were recorded following a stepwise hypoglycemia clamp, and results compared between study treatment arms. Following the first four weeks, subjects continued for an additional 24 weeks to assess their epinephrine hormone response to hypoglycemia measured at 3 months post-treatment (16 weeks), and 6 months post-treatment (28 weeks). RESULTS:Forty-nine subjects were randomized to receive treatment with high rate CSGI (n=15), low rate CSGI (n=18), or matching placebo (n=16). At the end of study treatment, there were no statistically significant differences between the treatment arms for percent change of epinephrine hormone response during a stepwise hypoglycemia clamp (CSGI vs. placebo; p=0.160). As a result, long-term follow-up of the subjects was stopped early. The long-term follow-up data collected to date will be reported separately. The administration of low and high rate CSGI was associated with mild to moderate nausea (5.9%, 20%, respectively) and vomiting (11.8%, 13.3%, respectively) that was self-limited and required no additional intervention. In this 4-week assessment, CSGI was not associated with pain nor significant injection site reactions, and no SAEs related to CSGI were reported. CONCLUSION:In this proof-of-concept study, CSGI did not demonstrate statistically significant improvements in plasma epinephrine concentration when compared to placebo at 4 weeks. While there were positive epinephrine and improved hypoglycemia awareness responses observed in some subjects, the equivocal efficacy results observed may be explained by the unanticipated and incomplete elimination of hypoglycemia on CSGI therapy, and those on placebo therapy experienced hypoglycemia improvement. CSGI can be safely used with concomitant diabetes medications, and there were no SAEs related to CSGI. The 4-week administration of both low and high rate CSGI was safe and well tolerated.

A randomised controlled study of high intensity exercise as a dishabituating stimulus to improve hypoglycaemia awareness in people with type 1 diabetes: a proof-of-concept study

Aims/hypothesisApproximately 25% of people with type 1 diabetes have suppressed counterregulatory hormonal and symptomatic responses to insulin-induced hypoglycaemia, which renders them at increased risk of severe, disabling hypoglycaemia. This is called impaired awareness of hypoglycaemia (IAH), the cause of which is unknown. We recently proposed that IAH develops through habituation, a form of adaptive memory to preceding hypoglycaemia. Consistent with this hypothesis, we demonstrated restoration of defective counterregulatory hormonal responses to hypoglycaemia (referred to as dishabituation) in a rodent model of IAH following introduction of a novel stress stimulus (high intensity training [HIT]). In this proof-of-concept study we sought to further test this hypothesis by examining whether a single episode of HIT would amplify counterregulatory responses to subsequent hypoglycaemia in people with type 1 diabetes who had IAH (assessed by Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating (DAFNE) hypoglycaemia awareness rating 2 or 3). The primary outcome was the difference in adrenaline response to hypoglycaemia following both a single episode of HIT and rest.MethodsIn this randomised, crossover study 12 participants aged between 18 and 55 years with type 1 diabetes for ≥5 years and an HbA1c <75 mmol/mol (9%) were recruited. Individuals were randomised using computer generated block randomisation to start with one episode of HIT (4 × 30 s cycle sprints [2 min recovery] at 150% of maximum wattage achieved during dot{V}{mathrm{O}}_{2mathrm{peak}} assessment) or rest (control). The following day they underwent a 90 min hyperinsulinaemic–hypoglycaemic clamp study at 2.5 mmol/l with measurement of hormonal counterregulatory response, symptom scores and cognitive testing (four-choice reaction time and digit symbol substitution test). Each intervention and subsequent clamp study was separated by at least 2 weeks. The participants and investigators were not blinded to the intervention or measurements during the study. The investigators were blinded to the primary outcome and blood analysis results.ResultsAll participants (six male and six female, age 19–54 years, median [IQR] duration of type 1 diabetes 24.5 [17.3–29.0] years, mean [SEM] HbA1c 56 [3.67] mmol/mol; 7.3% [0.34%]) completed the study (both interventions and two clamps). In comparison with the rest study, a single episode of HIT led to a 29% increase in the adrenaline (epinephrine) response (mean [SEM]) (2286.5 [343.1] vs 2953.8 [384.9] pmol/l); a significant increase in total symptom scores (Edinburgh Hypoglycaemia Symptom Scale: 24.25 [2.960 vs 27.5 [3.9]; p<0.05), and a significant prolongation of four-choice reaction time (591.8 [22.5] vs 659.9 [39.86] ms; p<0.01] during equivalent hypoglycaemia induced the following day.Conclusions/interpretationThese findings are consistent with the hypothesis that IAH develops in people with type 1 diabetes as a habituated response and that introduction of a novel stressor can restore, at least partially, the adapted counterregulatory hormonal, symptomatic and cognitive responses to hypoglycaemia.Trial registrationISRCTN15236211.