Severe Hypoglycemic Events Research Articles

Therapeutic Inertia and Delays in Insulin Intensification in Type 2 Diabetes: A Literature Review.

Therapeutic inertia leading to delays in insulin initiation or intensification is a major contributor to lack of optimal diabetes care. This report reviews the literature summarizing data on therapeutic inertia and delays in insulin intensification in the management of type 2 diabetes. A literature search was conducted of the Allied & Complementary Medicine, BIOSIS Previews, Embase, EMCare, International Pharmaceutical Abstracts, MEDLINE, and ToxFile databases for clinical studies, observational research, and meta-analyses from 2012 to 2022 using search terms for type 2 diabetes and delay in initiating/intensifying insulin. Twenty-two studies met inclusion criteria. Time until insulin initiation among patients on two to three antihyperglycemic agents was at least 5 years, and mean A1C ranged from 8.7 to 9.8%. Early insulin intensification was linked with reduced A1C by 1.4%, reduction of severe hypoglycemic events from 4 to <1 per 100 person-years, and diminution in risk of heart failure (HF) by 18%, myocardial infarction (MI) by 23%, and stroke by 28%. In contrast, delayed insulin intensification was associated with increased risk of HF (64%), MI (67%), and stroke (51%) and a higher incidence of diabetic retinopathy. In the views of both patients and providers, hypoglycemia was identified as a primary driver of therapeutic inertia; 75.5% of physicians reported that they would treat more aggressively if not for concerns about hypoglycemia. Long delays before insulin initiation and intensification in clinically eligible patients are largely driven by concerns over hypoglycemia. New diabetes technology that provides continuous glucose monitoring may reduce occurrences of hypoglycemia and help overcome therapeutic inertia associated with insulin initiation and intensification.

396-P: The Humanistic Burden of Type 1 Diabetes in U.S. Adults With or Without Recurrent Severe Hypoglycemic Events—A Qualitative Interview Study

Introduction: Despite advances in technology, many people with type 1 diabetes (T1D) still experience severe hypoglycemic events (SHEs). This study explored the perceived humanistic burden of T1D in adults using continuous glucose monitor (CGM) in the US with or without recurrent SHEs. Methods: In 60-minute semi-structured interviews, adult CGM users with self-reported T1D diagnosis (≥5 yrs.) described the burden of TID on quality of life (QoL). Participants ranked the ‘top 3’ negative impacts of T1D on QoL. Subgroup analyses were conducted in participants with recurrent SHE (rSHE; ≥2 SHEs last yr.) and without recurrent SHE (nSHE; ≤1 SHEs last yr.). Results: Participants (N=31; 42% rSHEs, 58% nSHEs) were 74% female and 81% were married. Mean age of T1D diagnosis was 28 yrs. Median SHEs in the past year in the rSHE group were 3 and in the nSHE group were 0. Both groups had mean HbA1c of 7.1%. rSHE and nSHE participants used hybrid closed loop systems (hCLS) (53.8% vs. 44.4%), multiple daily injections (23.1% vs. 33.3%) and continuous subcutaneous insulin infusion pump without hCLS (23.1% vs. 22.2%), respectively. All participants reported negative impacts on physical health, mental health, sleep, relationships, leisure activities, work/studies, and sex life. The ‘top 3’ ranked impacts for the rSHE cohort were physical health and sleep (tied at first) followed by leisure activities. Impacts to physical health, mental health, and relationships were ‘top 3’ for the nSHE cohort. Conclusions: Recurrent severe hypoglycemia is observed to persist despite use of advanced diabetes technology. Negative impacts on physical health ranked as the primary concern in both rSHE and nSHE cohorts. However, moderate variability in ranked negative impact order was observed between the cohorts. Disclosure A.Boateng-kuffour: None. P.Callahan: Consultant; Rhythm Pharmaceuticals, Inc., Abbott Diabetes, HealthCore Inc., BMS, Employee; Vertex Pharmaceuticals Incorporated, Genesis Research. K.Chandarana: Employee; Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. J.L.Gaglia: Advisory Panel; Dompé, Consultant; Vertex Pharmaceuticals Incorporated, Abata Therapeutics, Avotres Inc., Current Health, Research Support; Avotres Inc., Dompé, Imcyse, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. M.Phinney: None. E.Guzman ortega: Research Support; Vertex Pharmaceuticals Incorporated. R.N.Krupnick: Consultant; Vertex Pharmaceuticals Incorporated. M.Reaney: None. W.H.Polonsky: Consultant; Abbott Diabetes, Boehringer Ingelheim and Eli Lilly Alliance, Eli Lilly and Company, Insulet Corporation, Intuity Medical, Inc., MannKind Corporation, Provention Bio, Inc., Sanofi-Aventis U.S., Vertex Pharmaceuticals Incorporated.

142-LB: Cost-Effectiveness of Real-Time Continuous Glucose Monitoring (rt-CGM) vs. Intermittent-Scanning Continuous Glucose Monitoring (is-CGM) in Patients with Type 2 Diabetes on Multiple Daily Injections of Insulin (T2D MDI) in Canada

Rt-CGM systems provide real-time glucose values, hypo- and hyperglycemia alerts, and predictive “urgent low soon” alerts that have been shown to improve glycemic outcomes and reduce severe hypoglycemic events (SHEs) in patients with T2D, without the need for periodic scanning. The economic value of rt-CGM vs is-CGM is unknown for patients with T2D MDI in Canada. We conducted a cost-effectiveness analysis comparing the two systems for this patient population using the INESSS Canadian payer perspective. ­ A 30-year analysis was performed using the validated ECHO-T2DM. Patient characteristics were sourced from Karter (2021). Efficacy and safety were derived from the DIAMOND T2D and REPLACE RCTs. The HbA1c difference of -0.33 (favoring rt-CGM) was derived using Bucher's adjusted indirect comparison, SHE rates were 0.014 and 0 Per Person-Year (PPY) for is-CGM and rt-CGM, respectively, and severe hyperglycemia/DKA rates were proxied by the difference in time above range (0.0313 and 0 PPY, respectively). Costs and disutility weights were sourced from published Canadian literature and discounted at 1.5% annually. A reduction in fear of hypoglycemia (FOH) utility was sourced from the ALERTT1 RCT. Sensitivity analyses were performed. Rt-CGM was associated with quality-adjusted life year gains of 0.346 and incremental costs of CAD 5,737, with an incremental cost-effectiveness ratio (ICER) of CAD 16,598. No DKA events for is-CGM and a 50% reduction in FOH utility increased the ICERs to CAD 30,987 and CAD 29,116, respectively. ICER was CAD 2,278 when both CGM costs were reduced by 50% and rt-CGM became cost-saving (dominant) at a 65% reduction. These results suggest rt-CGM is cost-effective vs is-CGM in patients with T2D MDI in Canada. These findings can inform government and commercial healthcare decision-makers when considering reimbursement of CGM systems. Disclosure H. Alshannaq: Employee; Dexcom, Inc., Other Relationship; Vertex Pharmaceuticals Incorporated. G. J. Norman: Employee; Dexcom, Inc. M. Willis: None. A. Nilsson: None. Funding Dexcom, Inc.

573-P: Impact of Impaired Awareness of Hypoglycemia on Glucose Changes During and After Exercise in Type 1 Diabetes—Results from the T1DEXI Study Cohort

Prior exposure to hypoglycemia and exercise may each dampen the sympathoadrenal response to subsequent hypoglycemia, leading to impaired awareness of hypoglycemia (IAH) and increased risk for experiencing clinically significant hypoglycemia. Whether glucose changes during exercise differ in those with IAH vs. intact awareness of hypoglycemia (Aware) has not been assessed in a large sample of ambulatory adults with type 1 diabetes, nor is the risk for hypoglycemia events in the next 24 hours known in such individuals. Using a case-control design, we compared participants with IAH (Clarke score ≥4 or ≥1 severe hypoglycemic event [SHE] within the past year) to Aware participants (Clarke score of ≤2 and no SHE within the past year), matching on sex, insulin modality, baseline HbA1c, and age. The analysis cohort included 95 adults with IAH matched to 95 Aware adults (in both groups, 74% female, mean ± SD age of 43 ± 14 yr, and HbA1c of 6.5 ± 0.7%) with a total of 4,236 exercise sessions and 1,794 post-exercise and 839 sedentary days available for analysis. IAH had a trend toward a greater but not clinically significant decline in glucose during exercise compared to Aware (−21 ± 44 vs. −19 ± 43 mg/dL, adjusted group difference of −4.2 [95% CI: −8.7 to 0.3] mg/dL, p=0.06). IAH had a higher proportion of hypoglycemic events (≥15 minutes &amp;lt;70 mg/dL) vs. Aware on both post-exercise days (51% vs. 43%, p=0.008) and sedentary days (48% vs. 30%, p=0.002). There was no evidence that the increased odds of hypoglycemia for IAH compared with Aware differed between post-exercise and sedentary days (interaction p=0.36). In summary, participants with IAH have an overall higher baseline risk of hypoglycemia than Aware participants. However, for those with IAH exercise itself does not appear to differentially increase the risk for hypoglycemia during the activity, or in the subsequent 24 hours compared to Aware individuals with type 1 diabetes. Disclosure J.L. Jo Kamimoto: None. Z. Li: None. R.L. Gal: None. J.R. Castle: Research Support; Dexcom, Inc. Advisory Panel; Novo Nordisk. Stock/Shareholder; Pacific Diabetes Technologies. Advisory Panel; Zealand Pharma A/S. F.J. Doyle: Stock/Shareholder; Mode AGC. Other Relationship; Insulet Corporation, Roche Diabetes Care, Dexcom, Inc. P.G. Jacobs: Other Relationship; Pacific Diabetes Technologies. Board Member; Pacific Diabetes Technologies. Research Support; Dexcom, Inc. C.K. Martin: Research Support; Pack Health, Evidation Health, Lilly. Board Member; EHE Health, Wondr Health. Other Relationship; ABGIL. Research Support; WW International, Inc. R. Beck: Research Support; Tandem Diabetes Care, Inc., Beta Bionics, Inc., Dexcom, Inc., Bigfoot Biomedical, Inc., Medtronic, Ascensia Diabetes Care, Roche Diabetes Care, Eli Lilly and Company. Consultant; Eli Lilly and Company. Research Support; Novo Nordisk. Consultant; Novo Nordisk, Diasome, Insulet Corporation. P. Calhoun: None. M. Riddell: Stock/Shareholder; Supersapiens. Advisory Panel; Zealand Pharma A/S. Speaker's Bureau; Dexcom, Inc. Consultant; Lilly Diabetes. Speaker's Bureau; Novo Nordisk, Sanofi. Stock/Shareholder; Zucara Therapeutics. Advisory Panel; Zucara Therapeutics, Indigo Diabetes. Consultant; Eli Lilly and Company, Jaeb Center for Health Research. M.R. Rickels: Consultant; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S. Research Support; Dompé. Funding The Leona M. and Harry B. Helmsley Charitable Trust; Verily Life Sciences; Dexcom, Inc.

1022-P: Trends in Glucagon Fill Rates among U.S. Adults with Diabetes and End-Stage Kidney Disease on Dialysis

Patients with diabetes (DM) and end-stage kidney disease (ESKD) on dialysis have a high risk of severe hypoglycemia and more than 70% are treated with insulin therapy. While not all hypoglycemic events can be prevented, glucagon is recommended for patients at high risk for hypoglycemia to revert and prevent hospitalization with severe hypoglycemic events. Prior studies have shown low rates of glucagon utilization, but excluded patients with ESKD who are at highest risk for these events. We used the USRDS, the most comprehensive nationwide database of patients with ESKD in the US, to examine the quarterly rates of glucagon fills among U.S. adults with DM and ESKD receiving dialysis. Among 254,195 adults (≥18 years) with ESKD and type 1 DM (N=27,538) or type 2 DM (N=226,657), with 76.9% using insulin therapy, between 2013-2017. Fewer than 2% of patients with type 2 DM and fewer than 4% of patients with type 1 DM filled a glucagon prescription, with declining fill rates over time among patients with type 2 DM and stable rates among patients with type 1 DM. Clinical Characteristics and trends in glucagon prescriptions are shown in Table 1. Our findings suggest an urgent and critical need for education of clinicians, patients, and caregivers to improve the prescribing and use of glucagon: a life-saving rescue medication. Disclosure R.J.Galindo: Consultant; Novo Nordisk, Eli Lilly and Company, Sanofi, Pfizer Inc., Bayer Inc., WW (Weight Watchers), Research Support; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. S.Inselman: None. B.Moazzami: None. M.K.Ali: Advisory Panel; Bayer Inc., Eli Lilly and Company, Research Support; Merck &amp; Co., Inc. G.Umpierrez: Research Support; Abbott, Dexcom, Inc., Baxter. R.G.Mccoy: Consultant; Emmi.

1086-P: Humanistic Burden of Type 1 Diabetes in U.S. Adults across Different Age Cohorts—A Qualitative Interview Study

Introduction: This study explores the perceived humanistic burden of type 1 diabetes (T1D) across different age cohorts of adults (18-35 yrs., 36-64 yrs., and 65+ yrs.) in the US who are using continuous glucose monitors (CGM). Methods: Adult CGM users (≥18 years of age) with self-reported T1D diagnosis (≥ 5 yrs.) were interviewed to evaluate the impact of T1D on quality of life (QoL). Participants ranked the ‘top 3’ negative impacts of T1D on QoL using a “Wheel of Life” visual framework, which helped participants identify and describe the multi-faceted impacts of T1D on QoL. Interview transcripts were thematically analyzed. Subgroup analyses were conducted by age cohort. Results: Overall, 31 participants (18-35 yrs., n=10; 36-64 yrs., n=12; 65+ yrs., n=9) took part in the study. Participants were mostly female (74%) and married (81%), with a mean age at diagnosis of 28 yrs. and a reported mean HbA1c level of 7.1% (range: 5.0% - 9.9%); 42% reported having ≥ 2 severe hypoglycemic events (SHEs) in the past year. Impacts on physical health, mental health, sleep, relationships, leisure activities, work/studies, and sex life were reported by participants as affecting their daily lives. Physical health impacts were most frequently ranked in “top 3” negative impacts across age cohorts. Negative impacts on physical health, mental health and sleep were ranked as “top 3” for both the 18-35 yrs. and the 36-64 yrs. age cohorts, while negative impacts on physical health, leisure activities, and relationships were top ranked by the 65+ yrs. cohort. Conclusions: Despite use of advanced diabetes technologies, the humanistic burden of T1D persists across adults of different age cohorts. Participants in all age cohorts reported physical health as the leading negative impact to QoL, while other perceived negative impacts varied in rank order across age cohorts. Disclosure P. Callahan: Employee; Vertex Pharmaceuticals Incorporated, Genesis Research. Consultant; Rhythm Pharmaceuticals, Inc., Abbott Diabetes, HealthCore Inc., BMS. A. Boateng-Kuffour: None. K. Chandarana: Employee; Vertex Pharmaceuticals Incorporated. Stock/Shareholder; Vertex Pharmaceuticals Incorporated. J.L. Gaglia: Consultant; Vertex Pharmaceuticals Incorporated. Stock/Shareholder; Vertex Pharmaceuticals Incorporated. Consultant; Abata Therapeutics, Avotres Inc. Research Support; Avotres Inc. Advisory Panel; Dompé. Research Support; Dompé, Imcyse. Consultant; Current Health. M. Phinney: None. E. Guzman Ortega: Research Support; Vertex Pharmaceuticals Incorporated. R.N. Krupnick: Consultant; Vertex Pharmaceuticals Incorporated. M. Reaney: None. W.H. Polonsky: Consultant; Abbott Diabetes, Boehringer Ingelheim and Eli Lilly Alliance, Eli Lilly and Company, Insulet Corporation, Intuity Medical, Inc., MannKind Corporation, Provention Bio, Inc., Sanofi-Aventis U.S., Vertex Pharmaceuticals Incorporated.

936-P: Three-Month Interim Analysis from the Prospective Bigfoot Unity Real World Study (BURST)

Background: The Bigfoot Unity® System is an FDA-cleared smart pen cap system incorporating CGM data (Abbott FreeStyle Libre 2), real-time alerts, and clinician-directed insulin dose recommendations. The objective was to analyze real world, 3-month data for System users. Methods: We conducted a per-protocol 3-month interim analysis (N=54, 15 clinics) from the prospective, BURST study (NCT05088265). Participants reported baseline demographics and completed adverse event surveys every 2 weeks. For A1C data, an at-home kit or electronic medical record was used for baseline and 3-month values; CGM metrics were collected post System initiation. Results: Most (85%) had T2D and median age was 57 years; 58% were Caucasian and 58% were female. Mean A1C decreased from 9.2±1.8% at baseline to 7.9±1.3% at 3 months (mean difference −1.2%, 95%CI −1.6 to −0.8, p&amp;lt;0.001). Four severe hypoglycemia events in 3 participants and 1 DKA occurred and were not related to the System. Percent time below range and other 3-month glycemic outcomes and System use data are shown (Table). Discussion: In this cohort, consisting primarily of older adults with T2D using MDI and suboptimal glycemic control, durable glycemic improvement occurred using Bigfoot Unity at 3 months. The observed reduction in A1C in this older cohort does not compromise them in meeting established hypoglycemia targets of &amp;lt;4 and &amp;lt;1% for percent time below 70 and 54 mg/dL, respectively. Disclosure J.K.Malone: Employee; Bigfoot Biomedical, Inc. R.Beck: Consultant; Eli Lilly and Company, Novo Nordisk, Diasome, Insulet Corporation, Research Support; Tandem Diabetes Care, Inc., Beta Bionics, Inc., Dexcom, Inc., Bigfoot Biomedical, Inc., Medtronic, Ascensia Diabetes Care, Roche Diabetes Care, Eli Lilly and Company, Novo Nordisk. J.Tillman: Employee; Bigfoot Biomedical, Inc. P.Calhoun: None. T.J.Mouse: None. R.Bailey: None. B.P.Olson: Employee; Bigfoot Biomedical, Inc. S.Vaughan: Employee; Bigfoot Biomedical, Inc. F.Sheikh: Employee; Bigfoot Biomedical, Inc. Funding Bigfoot Biomedical, Inc.

763-P: Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of a Dual GLP-1/GIP Receptor Agonist (HRS9531) in Healthy Subjects—A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose (SAD and MAD) Study

Background: Accumulating evidences suggest that dual GLP-1/GIP receptor agonist can achieve prominent glycemic control and body weight loss. Here we report the results of a phase 1 SAD and MAD study of HRS9531 in healthy subjects (NCT05152277). Methods: In the SAD, healthy subjects were randomized (4:1) to receive subcutaneous injection of HRS9531 (0.1, 0.3, 0.9, 2.7, 5.4, and 8.1 mg) or placebo. In the MAD, healthy subjects were randomized (4:1) to receive HRS9531 (0.9, 2.7, and 5.4 mg [2.7/2.7/4.0/5.4 mg titration]) or placebo once a week for 4 wks. The primary endpoints for both parts were safety and tolerability. Results: Sixty and 30 subjects were recruited into SAD and MAD respectively. The most common adverse events were abdominal distension and nausea in SAD, and urine ketone body present and nausea in MAD; all considered mild to moderate in severity (mostly mild). No severe hypoglycemia or serious events occurred. Drug exposure were proportional to dose from 0.9-8.1 mg. The median Tmax and mean t1/2 were 48-72 h and 156-182 h in SAD, and 48-72 h and 169-192 h after the fourth dosing in MAD, respectively. Fasting plasma glucose (FPG) levels decreased dose-dependently after single and multiple dosing. The 0 to 2 h glucose AUC during oral glucose tolerance test (OGTT) on D23 decreased dose-dependently relative to placebo in MAD. In SAD, body weight loss was dose-dependent and the maximal mean loss on D8 was 3.8 kg (4.9%) in 8.1 mg group. In MAD, the mean weight loss on D29 (after 4 wks treatment) ranged 4.3-7.7 kg (6.7%-9.3%) across 0.9-5.4 mg groups, and maximal loss (8.0 kg, 10.0%) occurred on D36 in 5.4 mg group. Conclusions: HRS9531 was well tolerated, had favorable PK, and led to evident glucose decrease and body weight loss. These data support further clinical development of HRS9531 for metabolism-related disorders such as T2DM and obesity. Disclosure K.He: None. F.Wei: None. H.Chen: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y.Zhang: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Z.Sheng: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Q.Wen: None. Funding Jiangsu Hengrui Pharmaceuticals Co., Ltd.

139-LB: Use of Digital Diabetes Solution Is Associated with Improved Glycemic Control without Increased Risk of Severe Hypoglycemia in Adults with Type 2 Diabetes Mellitus in the United States—Retrospective Cohort Study

Background: Dario Diabetes Solution (DDS) is a digital health application (app) that combines blood glucose (BG) monitoring system with a smartphone app, allowing tracking of BG levels in real time. This study assessed effects of DDS on HbA1c levels in adults with type 2 diabetes mellitus (T2DM) with baseline (BL) HbA1c ≥8% and on severe hypoglycemia (SH). Methods: This retrospective cohort analysis included adults with T2DM who used DDS (users) and nonusers from 1JAN2017 to 31OCT2021. BL period was 1 year before index date (users, first DDS registration; nonusers, first claim date in the quarter); follow up was 6 months. DDS users and nonusers were sequentially matched 1:3 using exact and propensity score matching. Secondary endpoints included SH (event requiring medical intervention) rates for all patients (pts) and for pts with BL HbA1c ≥8% who achieved predefined target HbA1c &amp;lt;8%. SH incidence in users vs nonusers was examined. Results: Overall cohort included 568 DDS users and 1699 nonusers: mean age, 57.5±11.3 years; mean BL HbA1c, 9.14±1.83%; oral antidiabetic drugs, 51%; insulin, 6%. BL SH was rare (users, 7/568; nonusers, 12/1699). There were 387 users and 1089 nonusers with BL HbA1c ≥8% (mean BL HbA1c, 10.0±1.7%). In this subgroup, HbA1c &amp;lt;8% was achieved by 9% more DDS users (174/387 [45%]) vs nonusers (393/1089 [36%]) at 6 months; P=0.002. At 6 months, overall SH rate was 38.8 (users) vs 10.6 (nonusers) events/1000 pts per year (incidence rate ratio, 0.9; P=0.9). No observed increase in SH risk was associated with DDS in this population. SH was rare in pts who achieved HbA1c &amp;lt;8% (users, 1/174; nonusers, 3/393). Conclusions: In this retrospective study, a larger proportion of adults with uncontrolled T2DM (BL HbA1c ≥8%) achieved HbA1c &amp;lt;8% after using DDS vs nonusers, with no increased risk of SH. Disclosure N. Thingalaya: None. F. Lee: Employee; Sanofi, Stock/Shareholder; Sanofi. D. Kerr: Consultant; Sanofi-Aventis U. S. P. Potukuchi: None. L. Wilson: Employee; Sanofi. K. C. Lee: Employee; Sanofi. E. K. Han-burgess: Employee; Sanofi. A. Edwards: Employee; Symphony Health, an ICON plc company, Other Relationship; Sanofi. X. Yu: None. A. Kennedy: None. Funding Sanofi

105-LB: Safety and Performance of an Advanced Hybrid Closed-Loop (AHCL) Algorithm with Ultra-rapid Lispro (URLi) and Lispro

Tuning a multi-model predictive control AHCL algorithm to the PK/PD properties of URLi may result in improved performance vs Lispro with no increased safety concerns. This was a randomized, double-blind, inpatient, 2-period crossover study in 22 adults with T1D on insulin pumps. Each URLi and Lispro treatment period had a 4-day inpatient visit with insulin doses calculated using the tuned AHCL algorithm. To challenge the algorithm, tests included unannounced exercise, 1 hr delayed bolus, underbolus, and overbolus. Participants (59% male) had mean ±SD age 43.4±13.77 years, T1D duration 25.9±9.61 yrs, and HbA1c 7.6±0.47%. Mean time in range (TIR; 70-180 mg/dL) during the overall inpatient period: URLi 79.4%; Lispro 78.7 % (p=0.80) with a trend towards decreased time &amp;lt;70 mg/dl (1.5 vs 2.4, p=0.08) for URLi. URLi had a significant difference in Level 1 hypoglycemia (30 vs 55 events, p = 0.01) but not Level 2 (4 vs 9 events, p=0.3). TIRs were similar including during meal/challenge periods (Table) with a trend towards greater TIR during the postprandial period and reduced time &amp;lt;70 mg/dl during exercise for URLi. There was greater TIR during overbolus with Lispro. No severe hypoglycemia events occurred. Results suggest reduced hypoglycemia with URLi vs Lispro with comparable glycemic control. The AHCL algorithm showed promising glycemic performance in a supervised setting when used with URLi or Lispro. Disclosure R. Pollom: None. E. Dassau: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M. Katz: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. L. Nosek: None. H. Coester: None. E. Zijlstra: Other Relationship; Eli Lilly and Company, Speaker's Bureau; Gan &amp; Lee Pharmaceuticals, Novo Nordisk A/S. A. Ghosh: None. A. Haidar: Consultant; Eli Lilly and Company, Other Relationship; Bigfoot Biomedical, Inc., Research Support; Adocia, Dexcom, Inc., Tandem Diabetes Care, Inc. R. Jones: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J. Leohr: None. S. E. Gleissner: None.

381-P: Studying the Impact of Nasal Glucagon on Real-Life Experiences of Severe Hypoglycemia Treatment (SIMPLEST)

Background: Severe hypoglycemia (SH) is feared by people with diabetes (PwD) and those who care for them due to its impact on everyday life. Studies have shown that ready-to-use nasal glucagon (NG) is preferred over reconstitutable injectable glucagon; however, real-life experiences that PwD and health care providers (HCPs) have with NG are unknown. Objective and Methods: A cross-sectional, web-based study was conducted in the US and Germany among: i) insulin-treated adults who owned NG for at least 2 months to assess impact of NG on everyday life, and ii) HCPs who prescribed NG within 6 months of study initiation to assess HCPs’ experiences with NG in meeting their patients’ needs. Data were analysed descriptively, and US results are presented. Results: Of 292 PwD (mean age 42, 47% T1D, 86% high fear of hypoglycemia total screener score, 37% impaired hypoglycemia awareness), 68% had been treated with NG. Over 90% agreed that NG had positively impacted quality of life (QoL) items (Figure). Of 71 HCPs (endocrinologists 87%), 90% were satisfied with NG meeting patients’ needs. Over 80% of HCPs were satisfied with training time on NG and confident with patient and caregiver’s ability to apply the training for a SH event. Conclusion: The positive impact of NG on QoL, less fear of hypoglycemia, and high confidence in caregiver’s ability to use NG may help improve PwD’s everyday life related to hypoglycemia management. Disclosure B.Mitchell: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Ponce-ibarra: Employee; Lilly Deutschland GmbH, Stock/Shareholder; Eli Lilly and Company. E.Moennig: Employee; Lilly Deutschland GmbH, Stock/Shareholder; Eli Lilly and Company. S.Odak: Other Relationship; Eli Lilly and Company. D.J.Mcsorley: Other Relationship; Eli Lilly and Company, Sage Pharmaceuticals, Novavax, Bristol-Myers Squibb Company, Seattle Genetics, Inc., Boston Scientific Corporation, Blood Centers of America, Inc. E.Spaepen: Consultant; Eli Lilly and Company. L.Jackson: Other Relationship; Eli Lilly and Company. L.Zografos: Other Relationship; Eli Lilly and Company. Y.Yan: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

Evaluating the correlations of cost and utility parameters from summary statistics for probabilistic analysis in economic evaluations

ABSTRACT Objectives The correlations between economic modeling input parameters directly impact the variance and may impact the expected values of model outputs. However, correlation coefficients are not often reported in the literature. We aim to understand the correlations between model inputs for probabilistic analysis from summary statistics. Methods We provide proof that for correlated random variables X and Y (e.g. inpatient visits and outpatient visits), the Pearson correlation coefficients of sample means and samples are equal to each other (). Therefore, when studies report summary statistics of correlated parameters, we can quantify the correlation coefficient between parameters. Results We use examples to illustrate how to estimate the correlation coefficient between the incidence rates of non-severe and severe hypoglycemia events, and the common coefficient of five cost components for patients with diabetic foot ulcers. We further introduce three types of correlations for utilities and provide two examples to estimate the correlations for utilities based on published data. We also evaluate how correlations between cost parameters and utility parameters impact the cost-effectiveness results using a Markov model for major depression. Conclusion Incorporation of the correlations can improve the precision of cost-effectiveness results and increase confidence in evidence-based decision-making. Further empirical evidence is warranted.

Emerging Adult and Caregiver Psychosocial Experiences with Severe Hypoglycemic Events and the Perceived Impact of Nasal Glucagon: A Cross-Sectional Study.

Severe hypoglycemic events are distressing. Although past studies have shown that young adulthood is a potentially distressing time, few studies have explored distress about severe hypoglycemia in this age group. The real-world psychosocial experiences of potential severe hypoglycemic events and the perceived impact of glucagon treatments like nasal glucagon are currently unknown. We explored perceptions of severe hypoglycemic events and impact of nasal glucagon on psychosocial experiences with these events in emerging adults with type1 diabetes and caregivers of emerging adults and children/teens. Further, we compared perceptions of preparedness and protection in handling severe hypoglycemic events with nasal glucagon versus the emergency glucagon kit that requires reconstitution (e-kit). This observational, cross-sectional study enrolled emerging adults (aged 18-26; N = 364) with type1 diabetes, caregivers of emerging adults (aged 18-26; N = 138) with type1 diabetes, and caregivers of children/teens (aged 4-17; N = 315) with type1 diabetes. Participants completed an online survey about their experiences with severe hypoglycemia, perceptions of nasal glucagon impact on psychosocial experiences, and perceptions of feeling prepared and protected with nasal glucagon and the e-kit. Many emerging adults (63.7%) agreed that the experience of severe hypoglycemic events was distressing; 33.3% and 46.7% of caregivers of emerging adults and children/teens, respectively, reported distress. Participants reported positive perceptions of nasal glucagon impact, particularly improved confidence in other people's ability to help during severe hypoglycemic events: emerging adults, 81.4%; caregivers of emerging adults, 77.6%; caregivers of children/teens, 75.5%. Participants demonstrated higher perceptions of preparedness and protection for nasal glucagon than for the e-kit (p < 0.001). Participants reported improved confidence in other people's ability to help during severe hypoglycemic events since having nasal glucagon available. This suggests that nasal glucagon may help broaden the support network for young people with type1 diabetes and their caregivers.

Multimorbidity, Polypharmacy, Severe Hypoglycemia, and Glycemic Control in Patients Using Glucose-Lowering Drugs for Type2 Diabetes: A Retrospective Cohort Study Using Health Insurance Claims in Japan.

This study aimed to understand the actual status of multimorbidity and polypharmacy among patients with type2 diabetes using glucose-lowering drugs, and to assess the effects of patient characteristics on severe hypoglycemia and glycemic control. 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 type2 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. 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 75years 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. Patients with type2 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. The University Hospital Medical Information Network Clinical Trials Registry (UMIN000046736).

Increased Derived Time in Range Is Associated with Reduced Risk of Major Adverse Cardiovascular Events, Severe Hypoglycemia, and Microvascular Events in Type 2 Diabetes: A Post Hoc Analysis of DEVOTE.

Time spent in glycemic target range (time in range [TIR]; plasma glucose 70-180 mg/dL [3.9-10.0 mmol/L]) as a surrogate endpoint for long-term diabetes-related outcomes requires validation. This post hoc analysis investigated the association between TIR, derived from 8-point glucose profiles (derived TIR [dTIR]) at 12 months, and time to cardiovascular or severe hypoglycemic episodes in people with type 2 diabetes in the DEVOTE trial. At 12 months, dTIR was significantly negatively associated with time to first major adverse cardiovascular event (P = 0.0087), severe hypoglycemic episode (P < 0.0001), or microvascular event (P = 0.024). A nonsignificant trend was seen toward association between 12-month hemoglobin A1c (HbA1c) and these outcomes, but this was no longer seen after addition of dTIR to the model. The results support targeting TIR >70% and suggest dTIR could be used in addition to, or in some instances in place of, HbA1c as a clinical biomarker. Trial registration details: ClinicalTrials.gov, NCT01959529.

Abstract #1413022: Diabetes Related Hypoglycemia, Contributing Factors and Glucagon Prescriptions in Two Community Hospitals

Hypoglycemia has long been recognized as a dangerous adverse effect of the treatment of diabetes mellitus with insulin or insulin secretagogues. Our study was aimed to identify the number of diabetic patients presenting to the emergency department (ED) with hypoglycemia, contributing risk factors for hypoglycemia (including antidiabetic medication regimens), the number of episodes of hypoglycemia requiring medical attention, and how many patients were prescribed glucagon at discharge. Our study is a retrospective analysis across two hospitals from October 2019 to March 2022, including the population of adult persons with diabetes mellitus, above 18 years of age, presenting to the emergency department with hypoglycemia. Patients without a diagnosis of diabetes mellitus, as well as those presenting with hypoglycemic episodes due to other etiology or hypoglycemia episodes during the hospital stay, were excluded. We extracted data from a sample size of 194 patients after excluding patients based on the exclusion criteria. Of the women were 2 African Americans, 25 Caucasians, 17 Hispanics, and 39 from other ethnicities. Of the men were 8 African Americans, 32 Caucasians, 27 Hispanics, and 44 from other ethnicities. The mean age of males was 66.2 years, and females was 72.9 years. 131 patients had no prior visits for hypoglycemia. Of the 194 patients, 54 were discharged from the ED, and 140 were admitted to the hospital. The most common risk factors associated with hypoglycemia requiring medical attention were: age >65, having more than one comorbidity, decreased oral intake, and poor socioeconomic status. Regarding recurrent presentations with hypoglycemia, there was a significant association with insulin use (p-value=0.0007), with a higher-than-expected number of insulin users having a previous visit for hypoglycemia. Only 16.7% of non-insulin-using patients had prior visits, compared to 40.6% of insulin users. Pairwise Chi-square testing did not reveal a significant association between any other medication class and prior visits for hypoglycemia, nor was there an association between risk factors and prior visits. No patients were prescribed glucagon at the time of discharge. To obtain optimal glycemic control, early identification of hypoglycemia risk factors, self-monitoring of blood glucose, and proper selection of anti-diabetic regimens are important to prevent long-term complications. Unfortunately, the three elements that would prevent subsequent severe hypoglycemic events (i.e., education, adjustment of medication, and glucagon prescription) are underutilized. Hypoglycemia is more common in the elderly population which remains an unmodifiable risk factor. Identifying patients with persistent poor oral intake is extremely important as they may be prone to hypoglycemic episodes on their current antidiabetic regimen and will need medication adjustments accordingly. Our future research focuses on whether giving glucagon prescriptions to patients with diabetes mellitus at discharge prevent recurrent ED visits for hypoglycemia.

Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice.

Transplantation of allogeneic pancreatic donor islets has successfully been performed in selected patients with difficult-to-control insulin-dependent diabetes and impaired awareness of hypoglycemia (IAH). However, the required systemic immunosuppression associated with this procedure prevents this cell replacement therapy from more widespread adoption in larger patient populations. We report the editing of primary human islet cells to the hypoimmune HLA class I- and class II-negative and CD47-overexpressing phenotype and their reaggregation into human HIP pseudoislets (p-islets). Human HIP p-islets were shown to survive, engraft, and ameliorate diabetes in immunocompetent, allogeneic, diabetic humanized mice. HIP p-islet cells were further shown to avoid autoimmune killing in autologous, diabetic humanized autoimmune mice. The survival and endocrine function of HIP p-islet cells were not impaired by contamination of unedited or partially edited cells within the p-islets. HIP p-islet cells were eliminated quickly and reliably in this model using a CD47-targeting antibody, thus providing a safety strategy in case HIP cells exert toxicity in a future clinical setting. Transplantation of human HIP p-islets for which no immunosuppression is required has the potential to lead to wider adoption of this therapy and help more diabetes patients with IAH and history of severe hypoglycemic events to achieve insulin independence.

Increased Time in Range with Ultra Rapid Lispro Treatment in Participants with Type 2 Diabetes: PRONTO-Time in Range.

To evaluate time in range metrics and HbA1c in people with type 2 diabetes (T2D) treated with ultra rapid lispro (URLi) using continuous glucose monitoring (CGM) for the first time in this population. This was a Phase 3b, 12-week, single-treatment study in adults with T2D on basal-bolus multiple daily injection (MDI) therapy using basal insulin glargine U-100 along with a rapid-acting insulin analog. Following a 4-week baseline period, 176 participants were newly treated with prandial URLi. Participants used unblinded CGM (Freestyle Libre). Primary endpoint was time in range (TIR) (70-180mg/dl) during the daytime period at Week 12 compared to baseline with gated secondary endpoints of HbA1c change from baseline and 24-h TIR (70-180mg/dl). Improved glycemic control was observed at Week 12 versus baseline including mean daytime TIR (change from baseline [Δ] 3.8%; P = 0.007), HbA1c (Δ - 0.44%; P < 0.001), and 24-h TIR (Δ 3.3%; P = 0.016) with no significant difference in time below range (TBR). After 12weeks, there was a statistically significant decrease in postprandial glucose incremental area under curve, overall, across all meals, within 1h (P = 0.005) or 2h (P < 0.001) after the start of a meal. Basal, bolus, and total insulin dose were intensified with increased bolus/total dose ratio at Week 12 (50.7%) versus baseline (44.5%; P < 0.001). There were no severe hypoglycemia events during the treatment period. In people with T2D, URLi in an MDI regimen was efficacious with improved glycemic control including TIR, HbA1c, and postprandial glucose without increased hypoglycemia/TBR. CLINICALTRIAL REGISTRATION NUMBER: NCT04605991.

Early and sustained increase in time in range 1 year after initiation of hybrid close loop therapy via telemedicine in type 1 diabetes patients

Background and AimsEvidence supports the efficacy and safety of the Hybrid Close loop (HCL) system in patients with type 1 diabetes (T1D). However, limited data are available on the long-term outcomes of patients on HCL with telemedicine follow-up.MethodsA prospective observational cohort study including T1D patients, who were upgrading to HCL system. Virtual training and follow-up were done through telemedicine. CGM data were analyzed to compare the baseline time in range (TIR), time below range (TBR), glycemic variability and auto mode (AM), with measurements performed at 3, 6 and 12 months.Results134 patients were included with baseline A1c 7.6% ± 1.1. 40.5% had a severe hypoglycemia event in the last year. Baseline TIR, measured two weeks after starting AM was 78.6 ± 9.94%. No changes were evident at three (Mean difference − 0.15;CI-2.47,2.17;p = 0.96), six (MD-1.09;CI-3.42,1.24;p = 0.12) and 12 months (MD-1.30;CI-3.64,1.04;p = 0.08). No significant changes were found in TBR or glycemic variability throughout the follow-up. Use of AM was 85.6 ± 17.5% and percentage of use of sensor was 88.75 ± 9.5% at 12 months. No severe hypoglycemic (SH) events were reported.ConclusionsHCL systems allow to improve TIR, TBR and glycemic variability safely, early and sustained up to 1 year of follow-up in patients with T1D and high risk of hypoglycemia followed through telemedicine.

Matching for HLA-DR excluding diabetogenic HLA-DR3 and HLA-DR4 predicts insulin independence after pancreatic islet transplantation.

In pancreatic islet transplantation, the exact contribution of human leukocyte antigen (HLA) matching to graft survival remains unclear. Islets may be exposed to allogenic rejection but also the recurrence of type 1 diabetes (T1D). We evaluated the HLA-DR matching, including the impact of diabetogenic HLA-DR3 or HLA-DR4 matches. We retrospectively examined the HLA profile in 965 transplant recipients and 2327 islet donors. The study population was obtained from patients enrolled in the Collaborative Islet Transplant Registry. We then identified 87 recipients who received a single-islet infusion. Islet-kidney recipients, 2nd islet infusion, and patients with missing data were excluded from the analysis (n=878). HLA-DR3 and HLA-DR4 were present in 29.7% and 32.6% of T1D recipients and 11.6% and 15.8% of the donors, respectively. We identified 52 T1D islet recipients mismatched for HLA-DR (group A), 11 with 1 or 2 HLA-DR-matches but excluding HLA-DR3 and HLA- DR4 (group B), and 24 matched for HLA-DR3 or HLA-DR4 (group C). Insulin-independence was maintained in a significantly higher percentage of group B recipients from year one through five post-transplantation (p<0.01). At five-year post-transplantation, 78% of group B was insulin-independent compared to 24% (group A) and 35% (group C). Insulin-independence correlated with significantly better glycemic control (HbA1c <7%), fasting blood glucose, and reduced severe hypoglycemic events. Matching HLA-A-B-DR (≥3) independently of HLA- DR3 or HLA-DR4 matching did not improve graft survival. This study suggests that matching HLA-DR but excluding the diabetogenic HLA-DR3 and/or 4 is a significant predictor for long-term islet survival.