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A questionnaire survey on severe hypoglycemia (SH) in pediatric patients with diabetes was distributed to pediatric diabetes specialists and members of the Committee of Pediatric Diabetes in the Japan Diabetes Society. Thirty-three hospitals answered the questionnaire survey, and 17 had treated the eligible patients under 15 years of age, including 506 with type 1 diabetes and 302 with type 2 diabetes. Of these patients, 25 experienced SH from January 2017 to December 2021. SH occurred in 3 patients at 0–5 years, 5 at 5–10 years, and 15 at 10–15 years, and it most frequently occurred between the times of 0:00 and 08:00 a.m. The majority of the patients had SH at home during the nighttime. Only 4 patients experienced SH during school time. Eleven patients took glucose orally, while 5 used glucagon nasal powder. Fifteen patients were transferred to hospital emergency units for the management of SH. From these results, the frequency of SH was estimated to be 0.01/patient/year, and the treatment for SH seemed insufficient. [ABSTRACT FROM AUTHOR]

Background: Severe hypoglycemia (SH) poses a significant challenge in the management of type 1 diabetes (T1D); however, the factors that offer protection other than diabetes technologies are under-studied. The primary objective of this study was to examine the association between hypoglycemia problem-solving (HPS) abilities and severe hypoglycemic events in adults with T1D using Poisson regression analysis. Methods: In this cross-sectional study, 287 adults with T1D (mean age: 50.3 ± 14.5 years, male: 36.2%, diabetes duration: 17.5 ± 11.2 years, mean HbA1c: 7.7 ± 0.9%) were included and categorized into two groups: non-SH (n = 262) and SH (n = 25). Data on diabetic complications, the hypoglycemia problem-solving scale (HPSS), and treatment details were collected. Impaired awareness of hypoglycemia (IAH) was evaluated using Gold's method. Univariate and multivariable Poisson regression models were used for the analysis, and the findings were presented as incidence rate ratios (IRRs) at 95% confidence interval (CI). Results: The incidence of SH was 16.7 (95% CI 7.5–26.0) per 100 person-years. In the univariate Poisson regression analysis, findings revealed associations between IAH, diabetic peripheral neuropathy (DPN), and HPSS1. On the other hand, the multivariate Poisson regression analysis, utilizing stepwise variable selection, identified DPN (IRR: 4.65, 95% CI 1.96–11.04; P < 0.001) and HPSS1 score (IRR: 0.51, 95% CI 0.34, 0.76; P = 0.001) as factors significantly associated with SH. Conclusion: We identified HPS abilities, in addition to DPN, were associated with SH in adults with T1D. Trial registration: University Hospital Medical Information Network (UMIN) Center: UMIN000039475), approval date: February 13, 2020. [ABSTRACT FROM AUTHOR]

Aims: To assess the effectiveness of the intermittent-scanned continuous glucose monitoring (isCGM) system in preventing severe hypoglycemic episodes and in improving glucose parameters and quality of life. Methods: Four hundred T1D individuals were enrolled in a prospective real-word study with an intermittently scanned continuous glucose monitoring device during the 12-months follow-up. The primary endpoint was the incidence of severe hypoglycemic events. Results: 82% of subjects were naïve to the use of the device (group A) and 18% were already wearing the system (group B). The cumulative incidence of severe hypoglycemia (SH) at 12 months was 12.06 per 100 person-year (95% CI: 8.35–16.85) in group A and 10.14 (95% CI: 4.08–20.90) in group B without inter-group differences. In group A there was a significant decrease in SH at 12 months compared to 3 months period (p = 0.005). Time in glucose range significantly increased in both groups accompanied with a significant decrease in glucose variability. HbA1c showed a progressive significant time-dependent decrease in group A. The use of the device significantly improved the perceived quality of life. Conclusion: This study confirmed the effectiveness of the isCGM in reducing hypoglycemic risk without glucose deterioration, with potential benefits on adverse outcomes in T1D individuals. Trial registration: ClinicalTrials.gov registration no. NCT04060732. [ABSTRACT FROM AUTHOR]

Hypoglycemia is common in people with type 1 diabetes. Sometimes, severe hypoglycemia can be fatal. The underlying mechanisms by which severe hypoglycemia can lead to death are unclear. The sympathetic nervous system is thought to be proarrhythmic. We hypothesized that norepinephrine is the main mediator of severe hypoglycemia‐induced fatal cardiac arrhythmias. To test this hypothesis, adult, non‐diabetic Sprague–Dawley rats were subjected to hyperinsulinemic‐severe hypoglycemic clamps (3 h, 10–15 mg/dL) during two different experiments: (1) intracerebroventricular (ICV) norepinephrine (n = 26) or artificial cerebrospinal fluid (aCSF) (n = 20) infusion or (2) blockade of norepinephrine release by intraperitoneal reserpine (n = 20) or control (n = 29). In experiment 1, brain norepinephrine infusion during severe hypoglycemia led to a 2.5‐fold increase in third‐degree heart block and a 24% incidence of ST elevation compared to no ST elevation in aCSF controls. In experiment 2, reserpine successfully reduced plasma and cardiac norepinephrine levels. During severe hypoglycemia, reserpine completely prevented second and third‐degree heart block and T wave increases, a marker of myocardial infarction, compared to controls. In conclusion, norepinephrine increases while reserpine, used to reduce norepinephrine nerve terminal release, reduces heart block and markers of myocardial infarction during severe hypoglycemia. [ABSTRACT FROM AUTHOR]

Objective: To assess the clinical impact of flash glucose monitoring (FGM) systems on fear of hypoglycemia (FoH) and quality of life in adults with type 1 diabetes mellitus (T1DM). Methods: Prospective quasi-experimental study with a 12-month follow-up. People with T1DM (18–80 years old) and self-monitoring by blood capillary glycemia controls were included. The FH15 questionnaire, a survey validated in Spanish in a comparable study population, was used to diagnose FoH with a cutoff point of 28 points. Results: A total of 181 participants were included, with a FoH prevalence of 69% (n = 123). A mean reduction in FH15 score of −4 points (95% confidence interval [−5.5 to −3]; P < 0.001) was observed, along with an improvement in quality of life (EsDQOL-test (Diabetes Quality of Life, Spanish version), −7 points [−10; −4], P < 0.001) and satisfaction with treatment (Diabetes Treatment Satisfaction questionnaire, self-reported version [DTSQ-s] test, +4.5 points [4; 5.5], P < 0.001). At the end of the follow-up, 64.2% of the participants saw an improved FoH intensity, compared to 35.8% who scored the same or higher. This improvement in FoH status was associated with a higher time-in-range at the end of the follow-up (P = 0.003), as well as a lower time spent in hyperglycemia (P = 0.005). In addition, it was linked to participants with a high baseline FoH levels (P < 0.001) and those who were university degree holders (P = 0.07). Conclusions: FGM is associated with an overall reduction of FoH in adults with T1DM and with an increase in their quality of life. Nevertheless, a significant percentage of patients may experience an increase of this phenomenon leading to clinical repercussions and a profound impact on quality of life. [ABSTRACT FROM AUTHOR]

Introduction: Tigecycline has a broad spectrum of activity, including activity against drug-resistant Gram-positive and -negative microorganisms. Its side effects are significant, but hypoglycemia is a rare finding during treatment. We aim to present an event of severe hypoglycemia in a patient with type 2 diabetes mellitus with replacement renal therapy, and hemodialysis after initiating tigecycline. Case presentation: A 54-year-old female diagnosed with type 2 diabetes mellitus was under treatment with basal-bolus insulin therapy and oral antihypertensive drugs. She started hemodialysis 24 months ago. She complained of recurrent fever for the last seven months and was treated with several antibiotics. In two separate blood cultures, she tested positive for methicillin-resistant Staphylococcus epidermidis (MRSE). Based on the antibiogram, we started treatment with tigecycline 100 mg/day. After 6-8 hours from the first dose, the patient is complicated with events of hypoglycemia and then continues with severe hypoglycemia (40-47 mg/dL). The patient continued to have hypoglycemia for about 16-18 hours after the last dose. We didn't find any reasons to explain the cause of episodes of hypoglycemia. She did not have high blood insulin levels (insulin 4.11 mIU/L [range 2.6-24.9]). We followed her for six months and the patient did not experience episodes of hypoglycemia. Conclusions: The association of severe hypoglycemia with tigecycline treatment is a very rare event and published papers on this topic are limited. Clinicians should be aware of this rare event when administering tigecycline and should routinely check blood glucose level during the treatment. [ABSTRACT FROM AUTHOR]

Aims: To explore the relationship between severe hypoglycemia (SH) and hypoglycemia awareness with preclinical atherosclerosis in type 1 diabetes (T1D). Materials and Methods: Cross‐sectional study in patients with T1D without cardiovascular disease (CVD), and with ≥1 of the following: ≥40 years, diabetic kidney disease, or ≥10 years of T1D duration with another risk factor. CVD risk was estimated with the Steno T1 Risk Engine (Steno‐Risk). Carotid plaque was evaluated using standardised ultrasonography protocol. Logistic regression models adjusted for CVD risk factors were constructed to test the independent associations with SH or hypoglycemia awareness assessed by the Clarke questionnaire (Clarke). The inclusion of SH and Clarke in Steno‐Risk was further evaluated. Results: We included 634 patients (52.4% men, age 48.3 ± 10.8 years, T1D duration 27.4 ± 11.1 years, 39.9% harbouring plaque). A stepped increase in the presence of plaque according to Steno‐Risk was observed (13.5%, 37.7%, and 68.7%, for low, moderate, and high risk, respectively; p < 0.001). SH history (OR 4.4 [1.3–14.6]) and Clarke score (OR 1.7 [1.2–2.2]) were associated with plaque in low‐risk patients (n = 192). Clarke score was also associated with plaque burden in low‐moderate‐risk participants (n = 436; ≥2 plaques: OR 1.2 [1.0–1.5], p = 0.031; ≥3 plaques: OR 1.4 [1.1–2.0], p = 0.025). The inclusion of SH and Clarke scores in Steno‐Risk significantly improved the identification of low‐risk individuals with atherosclerosis (area under the curve: 0.658 vs. 0.576; p = 0.036). Conclusions: In patients with T1D without an estimated high CVD risk, SH and hypoglycemia awareness assessment score were independently associated with preclinical atherosclerosis and improved identification of patients who would benefit from an intensive approach. [ABSTRACT FROM AUTHOR]

Aims: To explore the relationship between preconception severe hypoglycemia (PSH) and pregnancy outcomes in pregnancies complicated with type 1 diabetes mellitus (T1DM). Materials and Methods: In this multicenter prospective cohort study, women with pregestational T1DM were stratified by episodes of severe hypoglycemia within 1 year before conception: No PSH, sporadic PSH (1–6 times/year), and recurrent PSH (>6 times/year). We analysed the predictive ability of PSH for maternal and neonatal outcomes using log‐binomial regression models and receiver operating characteristic (ROC) curve. Results: Of the 124 women studied, 37.1% experienced at least one episode of severe hypoglycemia preconception. In the multiple adjusted regression models, recurrent PSH was significantly associated with increased incidence of preeclampsia (RR 17.59, 95% CI: 2.89–150.62, p for trend = 0.007), preterm birth (RR 6.34, 95% CI: 1.22–40.63, p for trend = 0.027), neonatal hypoglycemia (RR 4.52, 95% CI: 1.14–17.16, p for trend = 0.017), neonatal hyperbilirubinemia (RR 4.12, 95% CI: 1.11–15.56, p for trend = 0.004), and composite neonatal outcome (RR 3.85, 95% CI: 1.01–19.61, p for trend = 0.003). In the ROC analysis, PSH predicted preeclampsia, preterm birth, neonatal hypoglycemia, neonatal hyperbilirubinemia, and composite neonatal outcome with areas under the ROC curve all ≥0.6. Conclusions: Recurrent preconception severe hypoglycemia is associated with increased risks of adverse outcomes in pregnant women with T1DM. [ABSTRACT FROM AUTHOR]

Abstract Hypoglycemia is common in people with type 1 diabetes. Sometimes, severe hypoglycemia can be fatal. The underlying mechanisms by which severe hypoglycemia can lead to death are unclear. The sympathetic nervous system is thought to be proarrhythmic. We hypothesized that norepinephrine is the main mediator of severe hypoglycemia‐induced fatal cardiac arrhythmias. To test this hypothesis, adult, non‐diabetic Sprague–Dawley rats were subjected to hyperinsulinemic‐severe hypoglycemic clamps (3 h, 10–15 mg/dL) during two different experiments: (1) intracerebroventricular (ICV) norepinephrine (n = 26) or artificial cerebrospinal fluid (aCSF) (n = 20) infusion or (2) blockade of norepinephrine release by intraperitoneal reserpine (n = 20) or control (n = 29). In experiment 1, brain norepinephrine infusion during severe hypoglycemia led to a 2.5‐fold increase in third‐degree heart block and a 24% incidence of ST elevation compared to no ST elevation in aCSF controls. In experiment 2, reserpine successfully reduced plasma and cardiac norepinephrine levels. During severe hypoglycemia, reserpine completely prevented second and third‐degree heart block and T wave increases, a marker of myocardial infarction, compared to controls. In conclusion, norepinephrine increases while reserpine, used to reduce norepinephrine nerve terminal release, reduces heart block and markers of myocardial infarction during severe hypoglycemia.

Introduction: Second-generation basal insulin analogues have been shown to reduce hypoglycemia in several trials and observational studies of select populations; however, it remains unclear whether these results persist in real-world settings. Using self-reported hypoglycemia events, we assessed whether second-generation basal insulin analogues reduce rates of hypoglycemia events (non-severe/severe; overall/daytime/nocturnal) compared to earlier intermediate/basal insulin analogues among people with insulin-treated type 1 or 2 diabetes. Methods: We used prospectively collected data from the Investigating Novel Predictions of Hypoglycemia Occurrence Using Real-World Models (iNPHORM) panel survey. This US-wide, 1-year internet-based survey assessed hypoglycemia experiences and related sociodemographic and clinical characteristics of people with diabetes (February 2020−March 2021). We estimated population-average rate ratios for hypoglycemia comparing second-generation to earlier intermediate/basal insulin analogues using negative binomial regression, adjusting for confounders. Within-person variability of repeated observations was addressed with generalized estimating equations. Results: Among iNPHORM participants with complete data, N = 413 used an intermediate/basal insulin analogue for ≥ 1 month during follow-up. After adjusting for baseline and time-updated confounders, average second-generation basal insulin analogue users experienced a 19% (95% CI 3–32%, p = 0.02) lower rate of overall non-severe hypoglycemia and 43% (95% CI 26–56%, p < 0.001) a lower rate of nocturnal non-severe hypoglycemia compared to earlier intermediate/basal insulin users. Overall severe hypoglycemia rates were similar among second-generation and earlier intermediate/basal insulin users (p = 0.35); however, the rate of severe nocturnal hypoglycemia was reduced by 44% (95% CI 10–65%, p = 0.02) among second-generation insulin users compared to earlier intermediate/basal insulin users. Conclusion: Our real-world results suggest second-generation basal insulin analogues reduce rates of hypoglycemia, especially nocturnal non-severe and severe events. Whenever possible and feasible, clinicians should prioritize prescribing these agents over first-generation basal or intermediate insulin in people with type 1 and 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Parents of pediatric patients with type I diabetes require competence in hypoglycemia management and skills in glucagon administration to deal with potentially life-threatening severe hypoglycemia. We aimed to compare parents' subjective self-ratings to an objective expert assessment of competences and skills in dealing with severe hypoglycemia. Methods: We interviewed 140 participants to assess their subjective self-ratings. The objective expert assessments used a standardized clinical case scenario of severe hypoglycemia and a practical demonstration of glucagon administration. Results: The participants self-rated their competence in hypoglycemia management as good (5) or very good (6), and their skills in administering glucagon as acceptable (3) [Scale: very poor (1) to very good (6)]. In the standardized clinical case scenario, 1.4% (2/140) of participants named all relevant steps of severe hypoglycemia management. In the practical demonstration of glucagon administration, 92.9% (130/140) of participants committed at least one drug handling error; 52.1% (73/140) committed at least one drug handling error rated with high clinical risk. Conclusions: We found discrepancies regarding participants' subjective self-ratings compared to their performance in the respective objective expert assessments. These discrepancies indicate a lack of error awareness and the need for intervention studies to improve competence in hypoglycemia management and glucagon administration. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to understand the actual status of multimorbidity and polypharmacy among patients with type 2 diabetes using glucose-lowering drugs, and to assess the effects of patient characteristics on severe hypoglycemia and glycemic control. Methods: We designed a retrospective cohort study using health insurance claims and medical checkup data in Japan from April 2016 to February 2021 and identified patients with type 2 diabetes who were prescribed glucose-lowering drugs. We analyzed data on patient characteristics, including multimorbidity and polypharmacy, calculated the incidence rate for severe hypoglycemic events, applied a negative binomial regression model to explore factors that affected severe hypoglycemia, and analyzed the status of glycemic control in the subcohort for which HbA1c data were available. Results: Within the analysis population (n = 93,801), multimorbidity was present in 85.5% and mean ± standard deviation for oral drug prescriptions was 5.6 ± 3.5 per patient, while for those aged 75 years or older these numbers increased to 96.3% and 7.1 ± 3.5, respectively. The crude incidence rate for severe hypoglycemia was 5.85 (95% confidence interval 5.37, 6.37) per 1000 person-years. Risk factors for severe hypoglycemia included younger and older age, prior severe hypoglycemia, use of insulin, sulfonylurea, two-drug therapy including sulfonylurea or glinides, three-or-more-drug therapy, excessive polypharmacy, and comorbidities including end-stage renal disease (ESRD) requiring dialysis. Subcohort analysis (n = 26,746) showed that glycemic control is not always maintained according to guidelines. Conclusion: Patients with type 2 diabetes, particularly older patients, experienced high multimorbidity and polypharmacy. Several risk factors for severe hypoglycemia were identified, most notably younger age, ESRD, history of severe hypoglycemia, and insulin therapy. Trial Registration: The University Hospital Medical Information Network Clinical Trials Registry (UMIN000046736). [ABSTRACT FROM AUTHOR]

This study aims to evaluate the determinants and clinical markers of patients at risk for severe hypoglycemia (SH) in children and adolescents with type 1 diabetes. In the EPI-GLUREDIA study, clinical parameters and continuous glucose monitoring metrics from children and adolescents with type 1 diabetes were retrospectively analyzed between July 2017 and June 2022. Their clinical parameters were collected during traditional and quarterly medical consultations according to whether they experienced severe hypoglycemia or not. Then, continuous glucose monitoring metrics were analyzed on days surrounding SH during specific periods. According to the glycemic parameters, glycemic hemoglobin and glycemic mean were significantly lower in the three months preceding a SH compared with during three normal months (p < 0.05). Moreover, the time spent in hypoglycemia(time below the range, TBR<3.3) and its strong correlation (R = 0.9, p < 0.001) with the frequency of SH represent a sensitive and specific clinical parameter to predict SH (cut-off: 9%, sensitivity: 71%, specificity: 63%). The second finding of the GLUREDIA study is that SH is not an isolated event in the glycemic follow-up of our T1DM patients. Indeed, most of the glycemic parameters (i.e., glycemic mean, glycemic variability, frequency of hypoglycemia, and glycemic targets) vary considerably in the month preceding an SH (all p < 0.05), whereas most of these studied glycemic parameters remain stable in the absence of a severe acute complication (all p > 0.05). Furthermore, the use of ROC curves allowed us to determine for each glycemic parameter a sensitive or specific threshold capable of more accurately predicting SH. For example, a 10% increase in the frequency of hypoglycemia predicts a risk of near SH with good combination of sensitivity and specificity (sensitivity: 80%, specificity: 60%). The GLUREDIA study aimed to target clinical and glycemic parameters to predict patients at risk for SH. First, we identified TBR<3.3 < 9% as a sensitive and specific tool to reduce the frequency of SH. In addition, SH was not an isolated event but rather it was accompanied by glycemic disturbances in the 30 days before SH. [ABSTRACT FROM AUTHOR]

Background and Aims: Older people with type 2 diabetes (T2DM) on insulin are at increased risk of hypoglycemia and associated morbidity. Management of T2DM in older people must optimize glycemic control, while minimizing risks for hypoglycemia and diabetic ketoacidosis (DKA). In France, the FreeStyle Libre® (FSL) system has been reimbursed since June 2017 for T2DM on intensive insulin therapy. We assessed the impact of starting FSL on hospitalizations for acute diabetes events (ADEs) in people ≥65 years old, with T2DM on intensive insulin therapy. Materials and Methods: A retrospective study on the French Système National des Données de Santé (SNDS) claims database was conducted on people ≥65 years old with T2DM, treated with multiple daily injections (MDI) or insulin pump and starting FSL between August 1, 2017, to December 31, 2018. The analysis covered claims data for 12 months before, and up to 24 months after FSL initiation. Hospitalizations for severe hypoglycemia (SH), DKA, comas, and hyperglycemia were identified using ICD-10 codes. Results: We identified 38,312 people with T2DM ≥65 years old on intensive insulin therapy initiating FSL during the selection period. Hospitalizations for ADEs were observed in 1.6% of subjects in the 12 months before FSL initiation, compared to 1.05% after 12 months and 0.96% after 24 months, a −34% and −40% reduction, driven by fewer DKA admissions after 12 months and by fewer SH admissions at 24 months. Conclusions: These results indicate that FSL can reduce hospitalization for ADEs in this vulnerable older population of adults 65 years of age and older with T2DM on intensive insulin therapy, in whom optimal glycemic control must be achieved, while minimizing risk of hypoglycemia and other ADEs. [ABSTRACT FROM AUTHOR]

Abstract Glucagon (traditional kits for intramuscular administration, Glucagon and Glucagen), although recommended as a remedy for severe hypoglycemia (SH), has been reported to be under-utilized, likely because of technical problems. The aims of this study were to evaluate the use of glucagon in persons with type 1 diabetes in several countries, and to investigate if the availability of new ready-to-use glucagons (Baqsimi, Gvoke, Zegalogue, years 2019 to 2021) has expanded the overall use of glucagon. The source of data was IQVIA-MIDAS (units of glucagon sold), while data on persons with type 1 diabetes in countries were derived from IDF Diabetes Atlas. The use of glucagon has been steady from 2014 to 2019, with a small but significant increase from 2019 to 2021, paradoxically only in countries where new ready-to-use glucagons were not available. The use of glucagon has always been ten fold greater in countries where new ready-to-use glucagons became available than in the other countries (population 108,000,000 vs 28,100,000, 480,291 vs 182,018 persons with type 1 diabetes). A significant correlation was observed in all years between units of glucagon and persons with type 1 diabetes. Availability of new ready-to-use glucagons was associated with a small increase of sales, due only to new ready-to-use glucagons themselves. The use of glucagon (any type) remains low, approximately 1/10 of persons with type 1 diabetes. We conclude that use of glucagon is scarce in most countries, and so far has not been expanded by new ready-to-use glucagons such as the ones considered in this study.

Abstract Aims/Introduction Several factors are associated with hypoglycemia unawareness and severe hypoglycemia, but few large studies have analyzed Japanese patients with type 1 diabetes. The aim of this study was to analyze the risk factors for hypoglycemia unawareness and severe hypoglycemia in Japanese type 1 diabetes patients. Materials and Methods A self‐administered questionnaire investigated events, complications and treatments associated with hypoglycemia in patients with type 1 diabetes. Multiple logistic regression analysis of factors associated with hypoglycemia unawareness and severe hypoglycemia requiring medical treatment was carried out. The coefficient of variation (CV) of blood glucose levels was determined using blood samples collected at six outpatient visits. Results Of the 1,619 participants, 44.2% and 10.4% experienced hypoglycemia unawareness and severe hypoglycemia, respectively. Mean HbA1c levels in patients with hypoglycemia unawareness were lower than those in patients without hypoglycemia unawareness. The type 1 diabetes subtype, glycated hemoglobin (HbA1c) level, CV of blood glucose levels and history of severe hypoglycemia requiring medical treatment were significant independent variables predicting the presence of hypoglycemia unawareness. The glucose CV and a history of hypoglycemia unawareness were significant independent variables predicting severe hypoglycemia requiring medical treatment. In stratified analyses of patients divided into four groups according to glucose CV and HbA1c levels, the high‐glucose‐CV/low‐HbA1c group had the highest odds ratios for hypoglycemia unawareness (2.60) and severe hypoglycemia requiring medical treatment (2.55). Conclusions The ambulant glucose CV correlated with both hypoglycemia unawareness and severe hypoglycemia. Patients with high glucose CV and low HbA1c are at high risk of such adverse events, and their treatment strategies should be reviewed.

Abstract Aims/Introduction We investigated the associations between a combination of lifestyle factors and changes to these factors and the subsequent risk of severe hypoglycemia (SH) in type 2 diabetes patients. Materials and Methods Individuals with adult type 2 diabetes who underwent consecutive 2‐year interval health screening programs from 2009 to 2012 from the Korean National Health Insurance Service database were included and followed up until 2018. Information on history of smoking status, alcohol consumption and physical activity, as well as changes to these factors, was obtained. The primary outcome was incident SH. Results Of the 1,490,233 type 2 diabetes patients, 30,539 (2.1%) patients developed SH. Current smokers and heavy drinkers had increased risk of SH, compared with non‐smokers and non‐drinkers, respectively (hazard ratio 1.28, 95% confidence interval 1.23–1.34; hazard ratio 1.22, 95% confidence interval 1.15–1.30). However, regular physical activity was associated with reduced SH risk (hazard ratio 0.79, 95% confidence interval 0.77–0.82). A combination of unhealthy lifestyle habits was associated with increased SH risk in a dose‐dependent fashion (P for trend

Background: We aimed to investigate associations between exposure to various trajectories of severe hypoglycemic events and risk of dementia in patients with type 2 diabetes. Methods: In 2002–2003, 677,618 patients in Taiwan were newly diagnosed as having type 2 diabetes. Among them, 35,720 (5.3%) experienced severe hypoglycemic events during the 3-year baseline period following diagnosis. All patients were followed from the first day after baseline period to the date of dementia diagnosis, death, or the end of 2011. A group-based trajectory model was used to classify individuals with severe hypoglycemic events during the baseline period. Cox proportional hazard models with the competing risk method were used to relate dementia risk to various severe hypoglycemia trajectories. Results: After a median follow-up 6.70 and 6.10 years for patients with and without severe hypoglycemia at baseline, respectively, 1,952 (5.5%) individuals with severe hypoglycemia and 23,492 (3.7%) without developed dementia during follow-up, for incidence rates of 109.80 and 61.88 per 10,000 person-years, respectively. Four groups of severe hypoglycemia trajectory were identified with a proportion of 18.06%, 33.19%, 43.25%, and 5.50%, respectively, for Groups 1 to 4. Groups 3 (early manifestation but with later decrease) and 4 (early and sustained manifestation) were associated with a significantly increased risk of dementia diagnosis, with a covariate-adjusted subdistribution hazard ratio of 1.22 (95% confidence interval, 1.14–1.31) and 1.25 (95% confidence interval, 1.02–1.54), respectively. Conclusion: Our analysis highlighted that early manifestation of severe hypoglycemic events may contribute more than does late manifestation to the risk of dementia among individuals newly diagnosed as having type 2 diabetes.

Objective: Nationwide reimbursement of intermittently scanned continuous glucose monitoring (isCGM) was introduced in Belgium (2016). This real-world observational study investigates the impact of isCGM over 24 months on adults with type 1 diabetes with impaired or normal awareness of hypoglycemia (IAH or NAH). Methods: We included 1905 people who started first-generation 14-day FreeStyle Libre (without alerts). Sixteen percent had IAH. Primary endpoint was evolution of quality of life (QOL); secondary endpoints were evolution of severe hypoglycemia, work absenteeism, glycated hemoglobin (HbA1c), and sensor-measured outcomes. Results: At baseline, people with IAH (n = 308) had significantly worse QOL than people with NAH (n = 1594). Only people with IAH improved on the hypoglycemia fear survey-worry subscale after 24 months (22.8 [95% confidence interval: 21.4–24.2] at baseline; 20.6 [19.0–22.1] at 24 months, P = 0.002). For both groups, Diabetes Treatment Satisfaction Scale improved over 24 months (IAH: +3.1 [2.1–4.1], P < 0.001; NAH: +2.3 [1.9–2.7], P < 0.001), whereas general QOL, diabetes distress, and HbA1c remained stable. People with IAH showed the strongest decline in work absenteeism and severe hypoglycemia (36.4% having an event 6 months before isCGM initiation; 16.0% having an event during last 6 months of follow-up, P < 0.001), with similar observations for hypoglycemia hospitalization and hypoglycemia coma. Over 24 months, people with IAH spent more time in hypoglycemia, but less time in hyperglycemia than people with NAH. Conclusion: These data show sustained improvement of severe hypoglycemia, work absenteeism, and hypoglycemia fear after isCGM reimbursement, mostly driven by people with IAH. Together with improved treatment satisfaction, irrespective of hypoglycemia awareness level, isCGM without alerts is a valuable tool under long-term real-world conditions. Clinical Trial Registration number: NCT02898714. [ABSTRACT FROM AUTHOR]

Insulin and its secretagogues are essential for some patients with type 2 diabetes (T2D) to maintain good glycemic control (GC), but severe hypoglycemia (SH) is a concern. This network meta-analysis aimed to find optimal glucose-lowering drug treatment regimens in terms of GC and SH in T2D patients. MEDLINE and EMBASE were used to identify trials that compared two or more treatments including insulins and/or sulfonylurea or glinides and that examined both GC and SH. Treatment hierarchy was expressed as the surface under the cumulative ranking curve (SUCRA) probabilities. We identified 137 eligible trials comprising 42 treatments. The use of insulins and non-insulin glucose-lowering agents except for sulfonylurea or glinide had a higher SUCRA than insulins only for hemoglobin A1c (A1C) (p = 0.01) changes and achievement of A1C < 7.0% (p = 0.02) or A1C ≤ 6.5% (p = 0.002). The use of sulfonylurea or glinide and other non-insulin glucose-lowering agents resulted in a lower SUCRA for SH than insulins only when trials were analyzed for A1C change (p = 0.06) and achievement of A1C < 7.0% (p = 0.004) or A1C ≤ 6.5% (p = 0.004). Cluster analysis indicated that premixed insulin plus glucagon-like peptide-1 receptor agonist (Mix-ins + GLP1) belonged to the high-efficacy category for GC and glinide plus thiazolidinedione (glinide + TZD) belonged to the relatively high-efficacy category for GC among several high-safety categories regarding SH. In T2D patients, clinicians should consider appropriate combinations of non-insulin glucose-lowering agents (especially glinide + TZD) for reducing SH risk before switching to insulin therapies. If switching, they should be willing to add non-insulin glucose-lowering agents (especially, Mix-ins + GLP1) to insulins to further improve GC. [ABSTRACT FROM AUTHOR]

Abstract To estimate the trends in the prevalence of severe hypoglycemia (SH) in patients with type 2 diabetes in Korea, we investigated the total number of SH episodes among type 2 diabetes patients aged ≥30 years who visited the emergency department between 2002 and 2019, using the Korean National Health Insurance Service database. The prevalence of SH events increased from 2002 to 2012; however, it has decreased gradually since 2012. In 2019, the prevalence of SH was 0.6%, with an incidence rate of 4.43 per 1,000 person‐years. Approximately 23,000 SH events occur every year in Korea. Although the incidence is steadily decreasing, there are a considerable number of SH events in type 2 diabetes patients. The decline in the incidence of SH seems to most likely be due to the increased prescription rate of hypoglycemic agents without hypoglycemia risk, less‐strict treatment goals and the individualization of therapy.

Hypoglycemia is an often-observed acute complication in the management of children and adolescents with type 1 diabetes. It causes inappropriate glycemic outcomes and may impair the quality of life in the patients. Severe hypoglycemia with cognitive impairment, such as a convulsion and coma, is a lethal condition and is associated with later-onset cognitive impairment and brain-structural abnormalities, especially in young children. Therefore, reducing the frequency of hypoglycemia and minimizing the occurrence of severe hypoglycemia are critical issues in the management of children and adolescents with type 1 diabetes. Advanced diabetes technologies, including continuous glucose monitoring and sensor-augmented insulin pumps with low-glucose suspension systems, can reduce the frequency of hypoglycemia and the occurrence of severe hypoglycemia without aggravating glycemic control. The hybrid closed-loop system, an automated insulin delivery system, must be the most promising means to achieve appropriate glycemic control with preventing severe hypoglycemia. The use of these advanced diabetes technologies could improve glycemic outcomes and the quality of life in children and adolescents with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Aims/Hypothesis: Initiation of insulin therapy in people with type 2 diabetes (T2DM) may be necessary to achieve glycemic targets but is associated with acute diabetes events (ADEs), including severe hypoglycemia (SH) or diabetic ketoacidosis (DKA). We assessed the impact of initiating FreeStyle Libre® system (FSL) on hospitalizations for ADEs in people with T2DM on basal insulin only regimen±noninsulin antidiabetic drugs. Materials and Methods: A retrospective study of the French national Système National des Données de Santé reimbursement claims database (≈66 million French people) identified people with T2DM on basal insulin therapy receiving a first reimbursement of FSL between August 1, 2017 and December 31, 2018. Claims data for the 12 months before, and up to 24 months after FSL initiation, were analyzed. Hospitalizations for ADEs were identified, using ICD-10 codes as main or related diagnosis, for: SH events; DKA events; comas; and hyperglycemia-related admissions. Results: A total of 5933 people with T2DM on basal insulin therapy initiated FSL during the selection period. Of the patients, 78.9% were on basal insulin and other hypoglycemic agents. Among the 5933 patients identified, 2.01% had at least one hospitalization for any ADE in the year before FSL initiation, compared to 0.75% (1 year) and 0.60% (2 years). Reductions in ADEs were driven by 75% fewer DKA admissions, with a 44% reduction in SH admissions. These patterns of reduced ADEs persisted after 2 years, with a further 43% reduction in DKA rates. Conclusions/Interpretation: This study emphasizes the value of the FSL system in reducing ADEs in people with T2DM in France not on intensive insulin therapy and initially treated with basal-only insulin therapy. [ABSTRACT FROM AUTHOR]

Glucagon (traditional kits for intramuscular administration, Glucagon and Glucagen), although recommended as a remedy for severe hypoglycemia (SH), has been reported to be under-utilized, likely because of technical problems. The aims of this study were to evaluate the use of glucagon in persons with type 1 diabetes in several countries, and to investigate if the availability of new ready-to-use glucagons (Baqsimi, Gvoke, Zegalogue, years 2019 to 2021) has expanded the overall use of glucagon. The source of data was IQVIA-MIDAS (units of glucagon sold), while data on persons with type 1 diabetes in countries were derived from IDF Diabetes Atlas. The use of glucagon has been steady from 2014 to 2019, with a small but significant increase from 2019 to 2021, paradoxically only in countries where new ready-to-use glucagons were not available. The use of glucagon has always been ten fold greater in countries where new ready-to-use glucagons became available than in the other countries (population 108,000,000 vs 28,100,000, 480,291 vs 182,018 persons with type 1 diabetes). A significant correlation was observed in all years between units of glucagon and persons with type 1 diabetes. Availability of new ready-to-use glucagons was associated with a small increase of sales, due only to new ready-to-use glucagons themselves. The use of glucagon (any type) remains low, approximately 1/10 of persons with type 1 diabetes. We conclude that use of glucagon is scarce in most countries, and so far has not been expanded by new ready-to-use glucagons such as the ones considered in this study. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Several factors are associated with hypoglycemia unawareness and severe hypoglycemia, but few large studies have analyzed Japanese patients with type 1 diabetes. The aim of this study was to analyze the risk factors for hypoglycemia unawareness and severe hypoglycemia in Japanese type 1 diabetes patients. Materials and Methods: A self‐administered questionnaire investigated events, complications and treatments associated with hypoglycemia in patients with type 1 diabetes. Multiple logistic regression analysis of factors associated with hypoglycemia unawareness and severe hypoglycemia requiring medical treatment was carried out. The coefficient of variation (CV) of blood glucose levels was determined using blood samples collected at six outpatient visits. Results: Of the 1,619 participants, 44.2% and 10.4% experienced hypoglycemia unawareness and severe hypoglycemia, respectively. Mean HbA1c levels in patients with hypoglycemia unawareness were lower than those in patients without hypoglycemia unawareness. The type 1 diabetes subtype, glycated hemoglobin (HbA1c) level, CV of blood glucose levels and history of severe hypoglycemia requiring medical treatment were significant independent variables predicting the presence of hypoglycemia unawareness. The glucose CV and a history of hypoglycemia unawareness were significant independent variables predicting severe hypoglycemia requiring medical treatment. In stratified analyses of patients divided into four groups according to glucose CV and HbA1c levels, the high‐glucose‐CV/low‐HbA1c group had the highest odds ratios for hypoglycemia unawareness (2.60) and severe hypoglycemia requiring medical treatment (2.55). Conclusions: The ambulant glucose CV correlated with both hypoglycemia unawareness and severe hypoglycemia. Patients with high glucose CV and low HbA1c are at high risk of such adverse events, and their treatment strategies should be reviewed. [ABSTRACT FROM AUTHOR]

Artificial intelligence (AI) is increasingly being used to improve patient care and management. In this paper, we propose explainable AI (XAI) models for predicting severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) episodes in adults with type 1 diabetes (T1D) and relapses in adults with relapsing-remitting multiple sclerosis (RRMS). We follow a three-step process in this study: (1) develop baseline machine learning (ML) models, (2) improve the models using ReliefF feature selection technique, and develop sex-stratified models, (3) explain the models and their results using SHapley Additive exPlanations (SHAP). We built six ML models (XGBoost, LightGBM, CatBoost, AdaBoost, random forest, and linear regression) for all scenarios. Applying the ReliefF feature selection led to improved model performance in predicting all outcomes compared to the baseline models. Additionally, sex-stratified models further improved the prediction of SH episodes and relapses. The F1 scores for predicting SH episodes in male and female patients were 84.07% and 84.95%, respectively, and the DKA prediction model achieved an F1 score of 78.67%. The proposed relapse prediction models outperformed existing models with F1 scores of 84.55% (males) and 76.11% (females), and ROCs of 70.26% (males) and 69.05% (females). Our results highlight the importance of considering sex differences, socioeconomic factors, and physical and mental health in medical outcome prediction. Boosting ML algorithms were found to be effective in detecting SH and DKA in T1D patients and relapses in RRMS patients compared to conventional tree-based ML and statistical models.

School nurses must identify and advocate for change when student safety is at risk. Using a population-focused approach (one that addresses the needs of a whole group rather than an individual), one Illinois nurse successfully sought legislation to address the need for undesignated glucagon in all Illinois schools. This article will tell her story and describe the steps all school nurses can take to make a population-level change through legislative advocacy. [ABSTRACT FROM AUTHOR]

Objective: We combined data from two landmark trials (DIAMOND and HypoDE) to examine the diagnostic performance of low glucose measurements derived from open and masked continuous glucose monitoring (CGM) to predict the occurrence of future severe hypoglycemia (SH). Methods: We analyzed hypoglycemia parameters (low blood glucose index [LBGI], % <70 mg/dL, 54-69 mg/dL [level 1 hypoglycemia] and <54 mg/dL [level 2 hypoglycemia]) from masked CGM over 14 days during baseline and from open CGM over 14 days after randomization. We used receiver operating characteristics (ROC) curves to evaluate the screening performance of these measures to predict future SH. Positive likelihood ratios were calculated to indicate the overall diagnostic performance of these parameters. Results: Data from 288 individuals with type 1 diabetes (mean age 45.6 ± 12.8 years, diabetes duration 20.7 ± 13.7 years, HbA1c 8.2% ± 1.0%, Hypoglycemia Unawareness Score 3.4 ± 2.1) were analyzed. Area under ROC-curve (AUC) for LBGI and % <70 mg/dL ranged between 0.68 and 0.75, indicating that LBGI and % <70 mg/dL could significantly predict future SH. Significance of AUC regarding % <54 mg/dL were mixed (0.63-0.72). Positive and negative likelihood ratios ranged between 1.82 to 3.40 and 0.56 to 0.32, respectively. Suggested optimal cutoff values were remarkedly lower in open CGM than in masked CGM. Conclusion: These results indicate that CGM-derived hypoglycemic parameters have a good screening performance to significantly predict future clinical hypoglycemia. In addition, this analysis suggests that cutoff values to indicate elevated hypoglycemia risk in the future are substantially lower in open CGM than in masked CGM. ClinicalTrials.gov registration numbers: HypoDE: NCT02671968. DIAMOND: NCT02282397. [ABSTRACT FROM AUTHOR]

Aims/Introduction: We investigated the associations between a combination of lifestyle factors and changes to these factors and the subsequent risk of severe hypoglycemia (SH) in type 2 diabetes patients. Materials and Methods: Individuals with adult type 2 diabetes who underwent consecutive 2‐year interval health screening programs from 2009 to 2012 from the Korean National Health Insurance Service database were included and followed up until 2018. Information on history of smoking status, alcohol consumption and physical activity, as well as changes to these factors, was obtained. The primary outcome was incident SH. Results: Of the 1,490,233 type 2 diabetes patients, 30,539 (2.1%) patients developed SH. Current smokers and heavy drinkers had increased risk of SH, compared with non‐smokers and non‐drinkers, respectively (hazard ratio 1.28, 95% confidence interval 1.23–1.34; hazard ratio 1.22, 95% confidence interval 1.15–1.30). However, regular physical activity was associated with reduced SH risk (hazard ratio 0.79, 95% confidence interval 0.77–0.82). A combination of unhealthy lifestyle habits was associated with increased SH risk in a dose‐dependent fashion (P for trend <0.001). Compared with participants without changes in their unhealthy lifestyles, participants who improved lifestyles had decreased risk of SH. Conclusions: Greater adherence to healthy lifestyle factors and any improvement in unhealthy lifestyle habits were associated with a substantially lower risk of SH in individuals with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Parents of pediatric patients with type I diabetes require competence in hypoglycemia management and skills in glucagon administration to deal with potentially life-threatening severe hypoglycemia. We aimed to compare parents’ subjective self-ratings to an objective expert assessment of competences and skills in dealing with severe hypoglycemia. Methods: We interviewed 140 participants to assess their subjective self-ratings. The objective expert assessments used a standardized clinical case scenario of severe hypoglycemia and a practical demonstration of glucagon administration. Results: The participants self-rated their competence in hypoglycemia management as good (5) or very good (6), and their skills in administering glucagon as acceptable (3) [Scale: very poor (1) to very good (6)]. In the standardized clinical case scenario, 1.4% (2/140) of participants named all relevant steps of severe hypoglycemia management. In the practical demonstration of glucagon administration, 92.9% (130/140) of participants committed at least one drug handling error; 52.1% (73/140) committed at least one drug handling error rated with high clinical risk. Conclusions: We found discrepancies regarding participants’ subjective self-ratings compared to their performance in the respective objective expert assessments. These discrepancies indicate a lack of error awareness and the need for intervention studies to improve competence in hypoglycemia management and glucagon administration.

Background: Self-management of blood glucose levels to avoid hypoglycemia is vital for patients with type 2 diabetes mellitus (T2DM). The association between specific metrics of glycemic variability (glycosylated hemoglobin A1c [HbA1c] and fasting plasma glucose [FPG]) and severe hypoglycemia has not been fully studied in patients with T2DM. Methods: In this post hoc analysis, patients with established T2DM with a high risk of cardiovascular disease were included in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. The Cox proportional hazards model was used to investigate the relationship between glycemic variability and hypoglycemia requiring medical assistance (HMA) and hypoglycemia requiring any third-party assistance (HAA). The prognostic value of HbA1c/FPG variability for our predefined outcomes was compared using Harrell's C method. Results: After adjusting for confounders, each increase in HbA1c variability of 1 standard deviation (SD) indicated a higher risk of HAA (hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.03-1.16; P < 0.01) and HMA events (HR: 1.11; 95% CI: 1.03-1.20; P < 0.01). Meanwhile, each increase in FPG variability of 1 SD increased the risk of HAA (HR: 1.40; 95% CI: 1.31-1.49; P < 0.01) and HMA events (HR: 1.46; 95% CI: 1.35-1.57; P < 0.01). Meanwhile, models, including FPG variability, had better prognostic value for our predefined outcomes than HbA1c variability (P < 0.01). Conclusions: Increased visit-to-visit variability in HbA1c and fasting glycemia is associated with a greater risk of severe hypoglycemic events in T2DM patients. FPG variability is a more sensitive indicator than HbA1c variability. [ABSTRACT FROM AUTHOR]

To estimate the trends in the prevalence of severe hypoglycemia (SH) in patients with type 2 diabetes in Korea, we investigated the total number of SH episodes among type 2 diabetes patients aged ≥30 years who visited the emergency department between 2002 and 2019, using the Korean National Health Insurance Service database. The prevalence of SH events increased from 2002 to 2012; however, it has decreased gradually since 2012. In 2019, the prevalence of SH was 0.6%, with an incidence rate of 4.43 per 1,000 person‐years. Approximately 23,000 SH events occur every year in Korea. Although the incidence is steadily decreasing, there are a considerable number of SH events in type 2 diabetes patients. The decline in the incidence of SH seems to most likely be due to the increased prescription rate of hypoglycemic agents without hypoglycemia risk, less‐strict treatment goals and the individualization of therapy. [ABSTRACT FROM AUTHOR]

Aims: To estimate the number of people with diabetes (PWD) requiring emergency services for severe hypoglycemia (SH) in France and the associated costs. Methods: PWD were identified using the National Health Insurance database (SNDS). Type of diabetes was determined by the medications used. Matching of the emergency department (ED) visits database (RPU) and the SNDS was used to identify ED visits for SH in 2016 and 2017. SH was identified in the RPU using specific ICD-10 codes. The main SH-related costs analyzed were costs of ED visits, hospitalization, and transport. Results: Of 3,236,600 PWD in 2017, 781,084 had at least one ED visit (11.5% type 1 diabetes [T1D]) and 9,160 patients had at least one ED visit for SH (40.2% T1D; 55.9% male; mean age 63.0 years; mean diabetes duration 17.2 years). Nearly 50% of ED visits for SH led to immediate hospitalization. The total cost of emergency services for SH was €12.39 million. The mean (SD) cost per patient was €1,352 (€2,540). Conclusions: SH accounts for nearly 1% of ED visits in PWD, and nearly half of these patients are hospitalized during the visit. Beyond the patient impact, SH is associated with a substantial economic burden.

Abstract Background The objective of this study was to describe the epidemiology of severe hypoglycaemia in Kuwait, aiming to provide a preliminary background to update the current guidelines and improve patient management. Method This was a prospective analysis of severe hypoglycaemia cases retrieved from emergency medical services (EMS) archived data between 1 January and 30 June 2020. The severe hypoglycaemia cases were then sub-grouped based on EMS personal initial management and compared in terms of scene time, transportation rate, complications and outcomes. The primary outcomes were GCS within 10–30 min and normal random blood glucose (RBS) within 10–30 min. Results A total of 167 cases met the inclusion criteria. The incidence of severe hypoglycaemia in the national EMS was 11 per 100,000. Intramuscular glucagon was used on scene in 89% of the hypoglycaemic events. Most of the severe hypoglycaemia patients regained normal GCS on scene (76.5%). When we compared the two scene management strategies for severe hypoglycaemia cases, parenteral glucose administration prolonged the on-scene time (P = .002) but was associated with more favourable scene outcomes than intramuscular glucagon, with normal GCS within 10–30 min (P = .05) and normal RBS within 10–30 min (P = .006). Conclusion: Severe hypoglycaemia is not uncommon during EMS calls. Appropriate management by EMS personals is fruitful, resulting in favourable scene outcomes and reducing the hospital transportation rate. More research should be invested in improving and structuring the prehospital management of severe hypoglycaemia. One goal is to clarify the superiority of parenteral glucose over intramuscular glucagon in the prehospital setting.

Glucose-lowering medication and lifestyle modification are essential for optimal glycemic control in patients with type 2 diabetes mellitus (T2DM). However, glucose-lowering agents, particularly insulin and insulin secretagogues, may cause hypoglycemia, which has multiple negative effects on the cardiovascular (CV) system and may cause death. Previous studies using institutional data from the Korean Nationwide Health Insurance database have consistently found a causal relationship between severe hypoglycemia and CV outcomes and mortality. Screening for high-risk patients, appropriate management, and intensive individualized education are the most effective measures and essential for the prevention of harmful hypoglycemic events. Based on identified risk factors that predict severe hypoglycemia, we developed an 1-year risk prediction model for severe hypoglycemia that can be used in clinical settings. In this review, we describe the current understanding of severe hypoglycemia and the clinical implications in patients with T2DM. Furthermore, we highlight the importance of intensive individualized education for high-risk patients and the risk prediction model to reduce severe hypoglycemia.

Introduction: Severe hypoglycemic events (SHE) represent a clinical and economic burden in patients with diabetes. Nasal glucagon (NG) is a novel treatment for SHEs with similar efficacy, but with a usability advantage over injectable glucagon (IG) that may translate to improved economic outcomes. The economic implications of this usability advantage on SHE-related spending in Spain were explored in this analysis. Methods: A cost-offset and budget impact analysis (BIA) was conducted using a decision tree model, adapted for the Spanish setting. The model calculated average costs per SHE over the SHE treatment pathway following a treatment attempt with IG or NG. Analyses were performed separately in three populations with insulin-treated diabetes: children and adolescents (4–17 years) with type 1 diabetes (T1D), adults with T1D and adults with type 2 diabetes (T2D), with respective population estimates applied in BIA. Treatment probabilities were assumed to be equal for IG and NG, except for treatment success following glucagon administration. Epidemiologic and cost data were obtained from Spanish-specific sources. BIA results were presented at a 3-year time horizon. Results: On a per SHE level, NG was associated with lower costs compared to IG (children and adolescents with T1D, EUR 820; adults with T1D, EUR 804; adults with T2D, EUR 725). Lower costs were attributed to reduced costs of professional medical assistance in patients treated with NG. After 3 years, BIA showed that relative to IG, the introduction of NG was projected to reduce SHE-related spending by EUR 1,158,969, EUR 142,162,371, and EUR 6,542,585 in children and adolescents with T1D, adults with T1D, and adults with insulin-treated T2D, respectively. Conclusions: In Spain, the usability advantage of NG over IG translates to potential cost savings per SHE in three populations with insulin-treated diabetes, and the introduction of NG was associated with a lower budget impact versus IG in each group. [ABSTRACT FROM AUTHOR]

Purpose of Review: The purpose of this paper is to describe rescue glucagon types, safety, efficacy, and preferences, as well as to review articles regarding emergency glucagon usage, severe hypoglycemia, and the emotions of both phenomena. We conducted a review of current literature on glucagon usage and the emotional impact of severe hypoglycemia on people with diabetes (PwD) and the caregivers of people with type 1 diabetes (T1D). Recent Findings: Minimal research exists pertaining to glucagon and severe hypoglycemic experiences in PwD, which is troubling considering the severity of risks and possible side effects. Recent articles described negative emotions such as fear, anxiety, stress, helplessness, shame, embarrassment, loneliness, frustration, hopefulness, and uncertainty surrounding glucagon usage. Summary: There is scarce research regarding PwD's emotions surrounding severe hypoglycemia and rescue glucagon use. Additional research is needed to investigate the emotions and feelings people with T1D and their caregivers' experience pertaining to severe hypoglycemia and emergency glucagon use. [ABSTRACT FROM AUTHOR]

Aims: The CRASH study examined severe hypoglycemia (SH) experiences among people with diabetes (PWD) and caregivers across eight countries. Here we report findings from the Japan cohort, with references to data from the United Kingdom (UK) cohort. Materials and Methods: Adults with type 1 (T1DM) or insulin-treated type 2 diabetes mellitus (T2DM) and caregivers (not necessarily related) were recruited from online patient panels. Participants who had experienced at least one SH event in the past 3 years were eligible for study inclusion. Participants completed an online survey regarding their experience with SH, its treatment, and actions during and after an event. Results: Of the 9367 PWD and caregivers from the online patient panels, 8475 participants were ineligible and a total of 53 Japanese participants (35 T1DM, 9 T2DM, 9 caregivers) completed the survey. Most SH incidents occurred at home and were unattended by a healthcare provider. For T1DM, 29% of Japan PWD and 13% of the UK PWD called an ambulance during an SH event; of these, 90% (Japan) and 50% (UK) were transported to hospital. Glucagon use was low (3% Japan and 10% UK for T1DM). Japanese respondents reported emotional impacts of SH, including feeling scared (86% T1DM, 56% T2DM), unprepared (63% T1DM, 78% T2DM), and helpless (60% T1DM, 33% T2DM). Despite the emotional burden, most PWD did not immediately discuss their SH event with a healthcare provider, with the majority (75% T1DM, 71% T2DM) waiting until their next doctor's appointment. Conclusion: Conversations around SH between healthcare providers and PWD appear to be insufficient in Japan. An emotional burden of SH was reported by PWD and caregivers. Education regarding the prevention of SH and available treatment options may reduce SH events and improve treatment preparation, while alleviating PWD concerns. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is one of the most common chronic diseases in children and adolescents, with an increasing incidence globally. Major variations in serum glucose cause severe ketoacidosis and hypoglycemia, acute metabolic complications of the disease. We performed a retrospective study on a group of 119 children and adolescents with type 1 diabetes in whom only the cases with ketoacidosis and severe hypoglycemia that required emergency hospitalization were quantified. At the same time, we identified the causes and determinants of these acute complications. According to the case study, 28.6% of patients (34 cases) presented severe hypoglycemia, the most common causes of hypoglycemia being intense physical activity without additional carbohydrate intake, delayed carbohydrate intake, and excess insulin. 15.3% of patients (18 cases) had ketoacidosis, of which 55.55% were recurrent ketoacidosis. Ketoacidosis has been detected in patients with poor glycemic balance and poor treatment compliance by not following a diet and skipping insulin doses. Among the additional risk fac-tors, we identified age over 13 years and the age of diabetes greater than 5 years, for both acute complications.

The multinational CRASH study found that substantive recommendations from health care providers were predictive of actions taken by people with diabetes during and after a severe hypoglycemic event, which highlights the importance of equipping people with actionable strategies to prevent and treat severe hypoglycemia should a severe hypoglycemic event arise.

Purpose: Hospital pharmacists contribute to patient safety and quality initiatives by overseeing the prescribing of antidiabetic medications. A pharmacist-driven glycemic control protocol was developed to reduce the rate of severe hypoglycemia events (SHE) in high-risk hospitalized patients. Methods: We retrospectively analyzed the rates of SHE (defined as blood glucose ≤40 mg/dL), before and after instituting a pharmacist-driven glycemic control protocol over a 4-year period. A hospital glucose management team that included a lead Certified Diabetes Educator Pharmacist (CDEP), 5 pharmacists trained in diabetes, a lead hospitalist, critical care and hospital providers established a process to first identify patients at risk for severe hypoglycemia and then implement our protocol. Criteria from the American Diabetes Association and the American Association of Clinical Endocrinologists was utilized to identify and treat patients at risk for SHE. We analyzed and compared the rate of SHE and physician acceptance rates before and after protocol initiation. Results: From January 2015 to March 2019, 18 297 patients met criteria for this study; 139 patients experienced a SHE and approximately 80% were considered high risk diabetes patients. Physician acceptance rates for the new protocol ranged from 77% to 81% from the year of initiation (2016) through 2018. The absolute risk reduction of SHE was 9 events per 1000 hospitalized diabetic patients and the relative risk reduction was 74% SHE from the start to the end of the protocol implementation. Linear regression analysis demonstrated that SHE decreased by 1.5 events per 1000 hospitalized diabetic patients (95% confidence interval, −1.54 to −1.48, P <.001) during the 2 years following the introduction of the protocol. This represents a 15% relative reduction of SHE per year. Conclusion: The pharmacist-driven glycemic control protocol was well accepted by our hospitalists and led to a significant reduction in SHE in high-risk diabetes patient groups at our hospital. It was cost effective and strengthened our physician-pharmacist relationship while improving diabetes care. [ABSTRACT FROM AUTHOR]

Background: Hypoglycemia prognostic models contingent on prospective, self-reported survey data offer a powerful avenue for determining real-world event susceptibility and interventional targets. Objective: This protocol describes the design and implementation of the 1-year iNPHORM (Investigating Novel Predictions of Hypoglycemia Occurrence Using Real-world Models) study, which aims to measure real-world self-reported severe and nonsevere hypoglycemia incidence (daytime and nocturnal) in American adults with type 1 or 2 diabetes mellitus prescribed insulin and/or secretagogues, and develop and internally validate prognostic models for severe, nonsevere daytime, and nonsevere nocturnal hypoglycemia. As a secondary objective, iNPHORM aims to quantify the effects of different antihyperglycemics on hypoglycemia rates. Methods: iNPHORM is a prospective, 12-wave internet-based panel survey that was conducted across the United States. Americans (aged 18-90 years) with self-reported type 1 or 2 diabetes mellitus prescribed insulin and/or secretagogues were conveniently sampled via the web from a pre-existing, closed, probability-based internet panel (sample frame). A sample size of 521 baseline responders was calculated for this study. Prospective data on hypoglycemia and potential prognostic factors were self-assessed across 14 closed, fully automated questionnaires (screening, baseline, and 12 monthly follow-ups) that were piloted using semistructured interviews (n=3) before fielding; no face-to-face contact was required as part of the data collection. Participant responses will be analyzed using multivariable count regression and machine learning techniques to develop and internally validate prognostic models for 1-year severe and 30-day nonsevere daytime and nocturnal hypoglycemia. The causal effects of different antihyperglycemics on hypoglycemia rates will also be investigated. Results: Recruitment and data collection occurred between February 2020 and March 2021 (ethics approval was obtained on December 17, 2019). A total of 1694 participants completed the baseline questionnaire, of whom 1206 (71.19%) were followed up for 12 months. Most follow-up waves (10,470/14,472, 72.35%) were completed, translating to a participation rate of 179% relative to our target sample size. Over 70.98% (856/1206) completed wave 12. Analyses of sample characteristics, quality metrics, and hypoglycemia incidence and prognostication are currently underway with published results anticipated by fall 2022. Conclusions: iNPHORM is the first hypoglycemia prognostic study in the United States to leverage prospective, longitudinal self-reports. The results will contribute to improved real-world hypoglycemia risk estimation and potentially safer, more effective clinical diabetes management. [ABSTRACT FROM AUTHOR]

Background: Elderly adults with diabetes are at increased risk of severe hypoglycemia and hypoglycemic coma due to various conditions including decline in cognitive function, reduced activity of daily living (ADL) and reduced renal function; special cautions are, therefore, recommended to avoid these life-threatening events. Case presentation: A 92-year-old female was admitted to our institution because of severe coma. Upon arrival, her serum C-peptide was 1.64 ng/mL despite low plasma glucose (24 mg/dL) and serum glimepiride (40.85 ng/mL). She had past history of compression fracture of her lumbar spine, which substantially affected her ADL. Her score on the dementia assessment sheet for community-based integrated care system-8 items (DASC-8) was 26 points. She had been receiving 12 oral medications for diabetes, essential hypertension, chronic gastritis and constipation from her nearby clinic. Her physician-in-charge had found that she was not taking her medications properly and simplified her prescription regimen to 3 oral medications with vildagliptin 50 mg twice daily replaced by glimepiride 3 mg once daily and asked her son to assist in taking the drugs 6 days before her admission to our hospital. While her consciousness level was improved to some extent, she was transferred to a long-term care bed hospital because it had become too difficult to care for her at home. Conclusions: It is important to note that anti-diabetes drugs should be carefully selected based on each patient's cognitive function and ADL, and that the reasoning should be shared with the general practitioners involved to avoid severe hypoglycemic events. [ABSTRACT FROM AUTHOR]

Objective: We analyzed the effect of implementing a flash glucose monitoring (FGM) technology in a public health care system with universal coverage on the rate of severe hypoglycemia requiring urgent care in adults with type 1 diabetes mellitus (T1DM). Methods: Using a comprehensive regional dataset, we extracted emergency care codes with hypoglycemia in individuals with T1DM who initiated the use of FGM in Andalucia, Spain, from January 1, 2020, to December 31, 2021. Severe hypoglycemia was defined as a confirmed blood glucose <70 mg/dL, which required the urgent dispatch of an emergency medical service (EMS) for onsite management. We compared hypoglycemic events reported in the 12 months before and after the initiation of FGM to determine the population incidence rates. Results: A total of 13,616 participants with a mean age of 43.7 ± 13.5 years were included. The follow-up periods were 23.4 and 24.8 months before and after FGM. There were 969 and 737 cases of hypoglycemia before and after the initiation of FGM. The baseline incidence rate was 358.58 episodes per 10,000 person-years, which decreased to 260.9 at the end of the follow-up (rate-ratio 0.72 [0.66; 0.80]). The reduction in hypoglycemia was significant in individuals aged ≥60 years (rate-ratio 0.40 [0.28; 0.55]) and males (0.64 [0.56; 0.72]). In addition, there was a reduction in the overall median HbA1c of -0.35% (95% CI [-0.38; -0.33], P < 0.001). Conclusion: The implementation of FGM systems in a public health care system as a provision for adults with T1DM was associated with significant reductions in the rate of severe hypoglycemic events that required urgent EMS care.

Background: Severe hypoglycemia can cause cognitive impairment in diabetic patients, but the underlying molecular mechanism remains unclear. Objective: To assess the effect of severe hypoglycemia on cognitive function in diabetic mice to clarify the relationship between the mechanism and dysfunction of pericytes and the blood–brain barrier (BBB). Method: We established type 1 diabetes mellitus in 80 male C57BL/6J mice by intraperitoneal injection of streptozotocin (150 mg/kg). Further intraperitoneal injection of short-acting insulin induced severe hypoglycemia. The mice were divided into normal, diabetes, and diabetic + severe hypoglycemia groups, and their blood glucose and general weight index were examined. Pericyte and BBB morphology and function were detected by histological and western blot analyses, BBB permeability was detected by Evans blue staining, and cognitive function was detected with the Morris water maze. Results: Severe hypoglycemia aggravated the histological damage, BBB damage, brain edema, and pericyte loss in the diabetic mice. It also reduced the expression of the BBB tight junction proteins occludin and claudin-5, the expression of the pericyte-specific markers PDGFR-β (platelet-derived growth factor receptor-β) and α-SMA, and increased the expression of the inflammatory factor MMP9. At the same time, diabetic mice with severe hypoglycemia had significantly reduced cognitive function. Conclusion: Severe hypoglycemia leads to cognitive dysfunction in diabetic mice, and its possible mechanism is related to pericyte dysfunction and BBB destruction. [ABSTRACT FROM AUTHOR]

Numerous studies have demonstrated that use of continuous glucose monitoring (CGM) improves glycemic control and reduces diabetes-related hospitalizations and emergency room service utilization in individuals with diabetes who are treated with intensive insulin regimens. Recent studies have revealed disparities in use of CGM within racially and ethnically diverse and lower socioeconomic populations, leading to underutilization of CGM in these populations. This article reviews the scope and impact of these disparities on utilization of CGM and explores the factors that may be contributing to this issue. [ABSTRACT FROM AUTHOR]

Background: Severe hypoglycemia can cause cognitive impairment in diabetic patients, but the underlying molecular mechanism remains unclear.Objective: To assess the effect of severe hypoglycemia on cognitive function in diabetic mice to clarify the relationship between the mechanism and dysfunction of pericytes and the blood–brain barrier (BBB).Method: We established type 1 diabetes mellitus in 80 male C57BL/6J mice by intraperitoneal injection of streptozotocin (150 mg/kg). Further intraperitoneal injection of short-acting insulin induced severe hypoglycemia. The mice were divided into normal, diabetes, and diabetic + severe hypoglycemia groups, and their blood glucose and general weight index were examined. Pericyte and BBB morphology and function were detected by histological and western blot analyses, BBB permeability was detected by Evans blue staining, and cognitive function was detected with the Morris water maze.Results: Severe hypoglycemia aggravated the histological damage, BBB damage, brain edema, and pericyte loss in the diabetic mice. It also reduced the expression of the BBB tight junction proteins occludin and claudin-5, the expression of the pericyte-specific markers PDGFR-β (platelet-derived growth factor receptor-β) and α-SMA, and increased the expression of the inflammatory factor MMP9. At the same time, diabetic mice with severe hypoglycemia had significantly reduced cognitive function.Conclusion: Severe hypoglycemia leads to cognitive dysfunction in diabetic mice, and its possible mechanism is related to pericyte dysfunction and BBB destruction.

ABSTRACT This is a retrospective report of the frequency of severe hypoglycemia and the association between common mental disorders and type 1 diabetes mellitus treated with insulin analogues. Patients with severe hypoglycemia compared with those without this complication had a higher prevalence of positive screening for common mental disorders (88% vs.77%, respectively, p = 0.03).

Aim: Different guidelines provide similar, but not identical, therapeutic targets for HbA1c in type 2 diabetes. These targets can also depend from the different pharmacological strategies adopted for intensifying glycemic control.Data Synthesis: This meta-analysis includes randomized trials adopting any pharmacological regimen for intensifying glycemic control in T2DM (versus standard of care/placebo), with a trial duration ≥2 years and a between-group HbA1c difference≥0.5%. The primary outcome was to assess the effects of the improvement of glycemic control on major cardiovascular events (MACE), ocular and renal complications, and severe hypoglycemia. Mantel-Haenszel odds ratios (MH-OR) with 95% Confidence Intervals were calculated for all the outcomes considered. We included 13 trials fulfilling the inclusion criteria. The improvement of glycemic control was associated with a lower risk of MACE (MH-OR:0.89 [95%CI 0.85-0.94]) and renal adverse events (MH-OR 0.73 [0.65-0.82]), but not all-cause mortality (MH-OR 0.95 [0.88-1.01]) and ocular adverse complications (MH-OR 0.94 [0.72-1.22]). For glucose-lowering drugs inducing hypoglycemia, a protective effect on the risk of microvascular complications, but not of MACE and all-cause mortality, was observed only for HbA1c ≤ 48 mmol/mol, but with higher risk of severe hypoglycaemia (MH-OR 2.72 [1.79-4.13]). Drugs not inducing hypoglycaemia were associated with a reduction of MACE, renal adverse events, and all-cause mortality, for HbA1c< 7% (no data for lower targets).Conclusions: The present meta-analysis show that the improvement of glycemic control with drugs not inducing hypoglycemia is associated with a reduction in the risk of long-term chronic vascular and renal complications, and all-cause mortality. [ABSTRACT FROM AUTHOR]