Severe Hypoglycemic Events Research Articles

101-LB: Eighteen-Month Use of Closed-Loop Control (CLC): A Randomized, Controlled Trial

While the use of CLC systems is increasing, data on durable use for >1 year are limited. We present 18-month data on a recently approved CLC system (Control-IQ, Tandem Diabetes Care) in a randomized controlled trial with follow-up extension phase. The study had 164 participants with T1D (14-71 years old) who for this analysis were divided in 3 groups: Group 1: CLC for 6 months, then continued CLC to study end; Group 2: CLC for 6 months, then PLGS (Basal-IQ) for 3 months, then CLC to study end; and Group 3: SAP for 6 months, then CLC to study end. Data were evaluated in 3-month intervals for the primary outcome of time in range (TIR, 70-180mg/dL) and secondary outcomes of hypoglycemia, hyperglycemia and HbA1c. Participants in Group 1 maintained significant improvements in TIR over 18 months with overall mean of 69.9% and sustained reductions in HbA1c. TIR improvement was seen within one month of initiation of CLC and retained its durability over 18 months of use. Group 2 had deterioration in time in range and HbA1c when placed on PLGS for 3 months and restored TIR and HbA1c once resuming CLC. Group 3 had persistent improvements in TIR and HbA1c after transitioning from SAP to CLC. There were 4 severe hypoglycemic events (all after month 9) and 4 DKA events. CLC use was generally 90% or higher with no trend toward decreased use over time. Sustained use of CLC over 18 months demonstrated rapid and consistent improvements in TIR, HbA1c, and hypoglycemia. Disclosure S.A. Brown: Research Support; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care, Tandem Diabetes Care, Tolerion, Inc. D. Raghinaru: None. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Medtronic. Research Support; Self; Beta Bionics, Inc., Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. Y.C. Kudva: Research Support; Self; Dexcom, Inc., Roche Diabetes Care. Other Relationship; Self; Abbott. L.M. Laffel: Advisory Panel; Self; Roche Diabetes Care. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Insulogic LLC, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Sanofi US. C.J. Levy: Consultant; Self; Dexcom, Inc. Employee; Spouse/Partner; Allergan plc. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation. J.E. Pinsker: Advisory Panel; Self; Medtronic. Consultant; Self; Eli Lilly and Company, Tandem Diabetes Care. Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Tandem Diabetes Care. Speaker’s Bureau; Self; Tandem Diabetes Care. R. Wadwa: Advisory Panel; Self; Eli Lilly and Company, Medtronic. Research Support; Self; Dexcom, Inc., Eli Lilly and Company, MannKind Corporation, Medtronic, Novo Nordisk Inc., Tandem Diabetes Care. J. Lum: None. C. Kollman: Other Relationship; Self; Dexcom, Inc., Tandem Diabetes Care. R. Beck: None. B. Kovatchev: Advisory Panel; Self; Dexcom, Inc. Research Support; Self; Dexcom, Inc., Tandem Diabetes Care. Speaker’s Bureau; Self; Dexcom, Inc., Sanofi, Tandem Diabetes Care. Other Relationship; Self; Dexcom, Inc., Johnson & Johnson, Sanofi. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UC4108483); University of Virginia Strategic Investment Fund (Project 88); Tandem Diabetes Care

378-P: Real-Time Inpatient Hypoglycemia Intervention Reduces the Rate of Recurrent Severe Hypoglycemia

Hypoglycemic events are a common inpatient safety issue; over half are preventable. There are no studies of real-time detection/response to prevent recurrence of hypoglycemia. We evaluated the effectiveness of real-time electronic hypoglycemia surveillance program (REHSP) to reduce the rate of recurrent severe hypoglycemic events (RHE) in hospitalized patients. REHSP is driven by a multidisciplinary team of endocrinologists and nurse practitioners who review an electronic database of all inpatient hypoglycemia events in the last 24hrs. Recommendations to reduce RHE are given to primary teams and appropriate response is monitored. We compared recurrence rates of severe hypoglycemia (BG <50 mg/dL) in inpatients with at least one severe hypoglycemic event (index event) 1 year Pre-REHSP vs. 1 year Post-REHSP implementation. RHE were defined as severe hypoglycemia occurring 20 hours and more after the index event (based on CMS criteria). The primary outcomes were rates of RHE and appropriate response by the primary teams. The Table shows that demographic and clinical characteristics were similar in both groups. In the Post-REHSP group the rates of RHE and length of stay declined significantly and the appropriate response of the teams significantly increased. This study highlights the potential of reducing recurrent hypoglycemia through real-time intervention. Disclosure Y. Gorantla: None. S.T. Yap: None. Y. Guerra: None. L. Fogelfeld: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Gan & Lee Pharmaceuticals, Gilead Sciences, Inc., Merck & Co., Inc., Sanofi.

2194-PUB: Structured Basal-Bolus Insulin Injection in Hospitalized Patients with Type 2 Diabetes: Tertiary Teaching Hospital Experience

Objectives: Although the efficacy of basal-bolus insulin regimen (BBI) in type 2 diabetes (T2D) patients has been demonstrated in clinical studies, few studies have revealed changes in glycemic control following the introduction of BBI in hospital practice. This study was aimed to evaluate the effect of structured BBI in clinical practice for hospitalized patients with T2D. Methods: We retrospectively analyzed non-critically ill T2D patients treated with insulin, who were hospitalized for glycemic control at Seoul National University Hospital (SNUH) from 2004 to 2018. The effects of BBI in T2D patients after 2007, when the current BBI protocol was introduced to SNUH, compared to that of the other types of insulin in T2D patients until 2007. Patients were propensity-score-matched in a 1:1 ratio. Results: Among 294 BBI treated patients (age, 60.4 ± 13.8 years; male, 141 [48.0%]; HbA1c, 10.4 ± 1.9%) and 294 other insulin-treated patients (age, 59.9 ± 12.6 years; male, 148 [50.3%]; HbA1c, 10.3 ± 1.9%), mean admission pre-prandial blood glucose level were 181.0 ± 37.7 mg/dl and 200.0 ± 34.0 mg/dl, respectively (P <0.05). Blood glucose target of <140 mg/dl was achieved in 56.1% of patients in the BBI group and in 33.7% of those in the other insulin group on the sixth day of admission. The mean first target achievement day was 3.6 ± 1.3 days in the BBI group and 4.2 ± 1.5 days in other insulin groups, respectively (P <0.05). Events of hypoglycemia (≤70 mg/dL) and severe hypoglycemia (<55 mg/dL) were not different between the groups. Conclusion: In this study of clinical practice in a tertiary hospital, structured BBI showed significantly improved glycemic control compared to other types of insulin regimens for T2D patients. Disclosure S. Moon: None. H. Jang: None. Y. Yang: None. S. Kwak: None. H. Jung: None. K. Park: None. Y. Cho: None.

1103-P: Balancing the Risk of DKA and Severe Hypoglycemia with Sotagliflozin in Adults with Type 1 Diabetes

Background: DKA and severe hypoglycemia (SH) are the 2 most important acute complications of type 1 diabetes (T1D). SGLT inhibitors are associated with an increased risk of ketosis and DKA. Sotagliflozin (SOTA), a dual SGLT 1 and 2 inhibitor, has been shown to reduce the incidence of documented hypoglycemia and SH as adjunct to insulin therapy in T1D. The objective was to determine if the increased risk of DKA with SOTA was offset by the reduction of SH. Methods: Data were pooled from the inTandem 1 and 2, 52-week, placebo (PBO)-controlled studies in adults with T1D (N=1575). Events of DKA and SH were adjudicated by an IRC. Incidence and exposure-adjusted incidence rates (EAIR) were calculated along with numbers needed to treat or harm (NNT/NNH). Results: A higher incidence of adjudicated DKA was seen with SOTA 200 and 400 mg (2.9 and 3.8%) compared to PBO (0.2%). However, SOTA was associated with a lower rate of hypoglycemia events with blood glucose levels ≤55 mg/dL and a lower incidence of adjudicated SH with SOTA 200 and 400 mg (5.7 and 4.4%) compared with PBO (7.4%). The absolute risk difference in EAIR between SOTA and PBO was 2.9 to 4.0 events per 100 patient-yr for DKA and -1.9 to -3.4 events per 100 patient-yr for SH (Figure). NNH for DKA (28) was similar to the NNT for SH (33) with SOTA 400 mg. Conclusions: With SOTA added to insulin, the increase in DKA was similar in magnitude to the decrease in SH in adults with T1D. Disclosure J. Pettus: Consultant; Self; Diasome Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., MannKind Corporation, Novo Nordisk Inc., Sanofi. B. Cariou: Advisory Panel; Self; Bristol-Myers Squibb, Gilead Sciences, Inc., Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi-Aventis. Board Member; Self; GENFIT. Research Support; Self; Amgen, Regeneron Pharmaceuticals. Speaker’s Bureau; Self; Abbott, AstraZeneca. S. Sawhney: None. P.L. Banks: Employee; Self; Lexicon Pharmaceuticals, Inc. M.J. Davies: Employee; Self; Lexicon Pharmaceuticals, Inc. P. Lapuerta: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc.

1062-P: Real-World Effectiveness of Gliclazide MR vs. Sitagliptin as Second-Line Therapy in People with Type 2 Diabetes Uncontrolled on Metformin

Background: International guidelines recommend metformin as first-line therapy in people with type 2 diabetes (T2D). Many patients will eventually need dual therapy; sulfonylureas (SUs) and dipeptidyl-peptidase 4 inhibitors (DPP-4i) remain the most commonly prescribed second-line therapies. Available evidence, mostly from RCTs, generally indicates greater HbA1c reductions with SUs. No real-world comparative effectiveness studies have compared gliclazide MR, a later generation SU, and sitagliptin, the most commonly used DPP-4i. Aim: To investigate the effectiveness of gliclazide MR vs. sitagliptin as second-line therapies in people with T2D uncontrolled on metformin monotherapy. Methods: New users of gliclazide MR or sitagliptin were identified (1:1 high-dimensional propensity score matching) in the UK Clinical Practice Research Datalink (CPRD) database between 1/1/2010 and 21/10/2019, from a cohort of adults with T2D. A Cox model was used to estimate time to HbA1c <7.0% (primary outcome); secondary outcomes included time to HbA1c ≤6.5%. Results: A total of 2346 patients (59.3% men; mean age 63 years, HbA1c 8.5%, diabetes duration 4.3 years) were included. Patients were 28% more likely to reach HbA1c <7% (HR [95% CI]: 1.28 [1.10-1.49]) and 50% more likely to reach HbA1c ≤6.5% (1.50 [1.19-1.93]) with gliclazide MR vs. sitagliptin. The difference in favour of gliclazide MR was maintained across patients’ characteristics (ethnicity, cardiorenal disease, age, diabetes duration, baseline HbA1c). Durability (time until switch or an add-on of a new drug or a stop) and persistence (duration of index drug) were similar. There was no significant difference in severe and nonsevere hypoglycaemic events. Conclusion: These results demonstrate greater real-world effectiveness of gliclazide MR vs. sitagliptin as second-line therapy after metformin, with a similar persistence, durability and rate of hypoglycaemia. Disclosure F. Zaccardi: Speaker’s Bureau; Self; Napp Pharmaceuticals. V. Cortese: Employee; Self; Servier. E. Jacquot: Employee; Self; Servier. F. Tyrer: None. S. Seidu: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Servier. Board Member; Self; Novartis Pharmaceuticals Corporation, Novo Nordisk Inc. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Sanofi-Aventis. Speaker’s Bureau; Self; Amgen, Lilly Diabetes, Merck Sharp & Dohme Corp. M.J. Davies: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi, Sanofi US. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Napp Pharmaceuticals, Novo Nordisk A/S, Sanofi. Other Relationship; Self; Ingeus UK. K. Khunti: Advisory Panel; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Board Member; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Servier. Speaker’s Bureau; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier.

658-P: Regular Diabetes Ward Round Is Associated with Better Infection Control and Lower Mortality Rate in Inpatients Younger than 80 Years Old

Background: While good glycemic control during hospitalization has been reported to have better outcomes and reduced complications, achieving this is difficult in hospitals where diabetes specialists are not present or understaffed. Diabetes ward round by an independent and specialized team (DMWR) is one of the solutions for regular monitoring of glycemic control in inpatients, few studies existed to assess its effectiveness. Material and Methods: A team composed of two diabetes specialists, one specialized nurse, one dietician, one pharmacist, and one assistant conducted DMWR from May 2017. Hospital inpatients who were at risk of poorly controlled glycemia were given adequate advice to prevent hyperglycemia and hypoglycemia. A total of 384,422 capillary blood glucose measurements were taken from all hospitalized patients from April 2015 to March 2019 and the changes in frequency of hyperglycemic and hypoglycemic episodes were analyzed. Infection control was evaluated by episodes of blood cultures. The mortality rate at discharge and within 90 days of discharge were also calculated. Results: The odds ratio (OR) for the frequency of pre-prandial hyperglycemia before and after DMWR was 0.430 (95% confidence interval (CI): 0.407, 0.454). The OR for that of severe hypoglycemia was 0.371 (95% CI: 0.265, 0.520). The number of blood cultures was significantly reduced by 26% after DMWR. The mortality rate within 90 days of discharge was also significantly decreased in patients aged less than 65 (OR 0.363, 95%CI: 0.216, 0.609) and from 65 to 79 (OR 0.689, 95%CI: 0.541, 0.856), respectively. Conclusion: DMWR resulted in improved glycemic control and reduced staff burden for managing severe hypoglycemia and preventable infection events. Moreover, the mortality rate of patients less than 80 years of age was also reduced over the same period, suggesting that stabilizing blood sugar was beneficial for lowering mortality rate in the younger patient population. Disclosure S. Chou: None. M. Haraguchi: None. M. Imai: None. M. Ishibashi: None. M. Masano: None. Y. Iwata: None. Y. Oda: None. T. Motogami: None. S. Nakamura: None.

Risk of severe hypoglycemic events from amiodarone-sulfonylureas interactions: A population-based nested case-control study.

To evaluate whether concomitant use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia. We conducted two nested case-control studies by analyzing the Taiwan National Health Insurance Research Database from 2008 to 2013 among diabetic patients continuously receiving sulfonylureas. Cases were defined as patients with severe hypoglycemia and those with a composite outcome of severe hypoglycemia, altered consciousness, and fall-related fracture in the first and second study, respectively. In both studies, each case was individually matched up to 10 randomly-selected controls. Conditional logistic regressions were employed to estimate odds ratios (ORs). We identified 1343 cases and 11 597 controls as well as 2848 cases of composite events and 24 808 controls among 46 317 sulfonylurea users. Concurrent use of amiodarone with sulfonylureas was associated with a 1.56-fold (95% CI: 0.98-2.46) increased risk of severe hypoglycemia, despite not statistically significant. Notably, an approximately 2-fold increased risk of severe hypoglycemia was observed with amiodarone therapy lasting for >180 days (adjusted OR: 2.08; 95% CI: 1.01-4.30) or at a daily dose greater than 1 defined daily dose (adjusted OR: 2.21; 95% CI: 1.25-3.91) when concurrently administrating sulfonylureas. A significantly increased risk of hypoglycemia-related composite events was also found with amiodarone concurrently used with sulfonylureas (adjusted OR: 1.59; 95% CI: 1.13-2.24). Concurrent use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia among diabetic patients, with an elevated risk for amiodarone used in a long-term or at a high daily dose.

1091-P: PK/PD of Glucagon and the Novel Glucagon Analog Dasiglucagon in Aqueous or Nonaqueous Formulations following SC Administration in Rats

Endogenous peptide hormones, such as glucagon used for treatment of severe hypoglycemia events in patients with diabetes, are commonly unstable in aqueous solution making development of ready-to-use injection solutions a challenge. Analogs of endogenous peptide hormones can be designed to increase the stability of the molecules. Another approach to enable easy administration of unstable peptides is to formulate them in non-aqueous formulations, such as DMSO (dimethyl sulfoxide). The current study was conducted to compare the PK/PD of glucagon following SC administration in rats when formulated in DMSO or an aqueous formulation (Phosphate buffered solution (PBS)). The PD data were compared to data generated for the stable glucagon analog dasiglucagon in rats. Four to six male Sprague-Dawley rats received 3 nmol/kg of glucagon in DMSO or in a PBS formulation or dasiglucagon at 2 nmol/kg in a PBS formulation. Blood samples for bioanalysis (glucagon groups only) and blood glucose measurement were taken at pre-dose (0) and 15, 30, 45, 60, 75, 90, 105 and 120 min post dose. Glucagon in PBS demonstrated a faster absorption, a higher Cmax (98.3 versus 39.9 pmol/L) and faster Tmax (15 versus 45 minutes) compared to glucagon in DMSO. The increase in blood glucose was similar for glucagon and dasiglucagon in PBS and faster compared to glucagon in DMSO. Disclosure C. Wenander: Employee; Self; Zealand Pharma A/S. A.H. Valeur: Employee; Self; Zealand Pharma A/S. M. Elander: Employee; Self; Zealand Pharma A/S.

Natural Language Processing Improves Detection of Nonsevere Hypoglycemia in Medical Records Versus Coding Alone in Patients With Type 2 Diabetes but Does Not Improve Prediction of Severe Hypoglycemia Events: An Analysis Using the Electronic Medical Record in a Large Health System.

OBJECTIVETo determine if natural language processing (NLP) improves detection of nonsevere hypoglycemia (NSH) in patients with type 2 diabetes and no NSH documentation by diagnosis codes and to measure if NLP detection improves the prediction of future severe hypoglycemia (SH).RESEARCH DESIGN AND METHODSFrom 2005 to 2017, we identified NSH events by diagnosis codes and NLP. We then built an SH prediction model.RESULTSThere were 204,517 patients with type 2 diabetes and no diagnosis codes for NSH. Evidence of NSH was found in 7,035 (3.4%) of patients using NLP. We reviewed 1,200 of the NLP-detected NSH notes and confirmed 93% to have NSH. The SH prediction model (C-statistic 0.806) showed increased risk with NSH (hazard ratio 4.44; P < 0.001). However, the model with NLP did not improve SH prediction compared with diagnosis code–only NSH.CONCLUSIONSDetection of NSH improved with NLP in patients with type 2 diabetes without improving SH prediction.

A Comparison of Familial and Sporadic Type 1 Diabetes Among Young Patients.

To investigate natural course, treatment, and outcomes in familial versus sporadic type 1 diabetes. In a population-based study, we compared patients with onset of type 1 diabetes before the age of 20 years who had a first-degree relative with type 1 diabetes (familial diabetes) with patients with type 1 diabetes who had no first-degree relative with type 1 diabetes (sporadic diabetes) at diagnosis and over the first 10 treatment years, using multivariable regression and proportional hazards models. Patients were identified from the Diabetes Prospective Follow-up Registry (DPV) between 1995 and 2018. Of 57,371 patients with type 1 diabetes, 53,606 (93.4%) had sporadic diabetes and 3,765 (6.6%) had familial diabetes. Familial diabetes, compared with sporadic diabetes, was associated with younger age (median 7.9 vs. 9.7 years, P < 0.001), lower prevalence of ketoacidosis (11.9% vs. 20.4%, P < 0.001), and lower HbA1c levels (9.7% vs. 11.1%, P < 0.001) at onset and higher prevalence of associated autoimmune disease (16.7% vs. 13.6%, P < 0.001). Over 10 years, patients with familial diabetes, in comparison with sporadic diabetes, more often used insulin pumps (P < 0.001) and had a lower rate of severe hypoglycemia (12.97 vs. 14.44 per 100 patient-years, P < 0.001) but similar HbA1c levels (P ≥ 0.08) and ketoacidosis rates (1.85 vs. 2.06 per 100 patient-years, P = 0.11). In familial and sporadic diabetes, absence of ketoacidosis at onset predicted fewer events of severe hypoglycemia (hazard ratio [HR] 0.67, P < 0.001, and 0.91, P < 0.001, respectively) and of ketoacidosis (HR 0.64, P = 0.007, and 0.66, P < 0.001, respectively) after 10 years. Familial type 1 diabetes, compared with sporadic type 1 diabetes, is characterized by earlier disease manifestation and higher autoimmune comorbidity as well as less metabolic decompensation at onset, likely related to higher disease awareness in affected families, while the course of disease is similar. These findings may have implications for the generalizability of results of diabetes prevention trials from patients with familial type 1 diabetes to patients with sporadic type 1 diabetes.

SUN-LB126 Real-World Safety and Effectiveness of Insulin Glargine 300 U/ML (Gla-300) in People With Type 2 Diabetes Who Fast During Ramadan

ORION was a prospective, observational study evaluating the safety and effectiveness of the second-generation basal insulin analog Gla-300 in people with type 2 diabetes (T2DM) who fast during Ramadan. Adults with T2DM who intended to fast for ≥15 days during Ramadan, had taken Gla-300 for ≥8 weeks prior to inclusion, and intended to continue its use during Ramadan were enrolled in 11 countries. During Ramadan, Gla-300 treatment was adjusted as per routine practice by the treating physician. Overall, the majority of people (402 [85%]) fasted for the entire Ramadan period and 10.8% fasted for ≥25 days but with at least one missed day. Mean (SD) age was 54.4 (11.0) years, 51.7% were male, BMI was 29.7 (5.3) kg/m2, and duration of diabetes was 10.7 (7.0) years. Risks of diabetes-related complications associated with fasting were assessed by physicians according to IDF-DAR fasting risk category; risk was low/moderate in 82.8%, high in 14.3%, and very high in 2.9% of people. The proportion of people with ≥1 severe and/or documented symptomatic (SMPG ≤70 mg/dL) hypoglycemia event was low (2.2% [event rate: 0.021 per participant-month (PPM)] in pre-Ramadan, 2.6% [0.039 PPM] in Ramadan and 0.2% in post-Ramadan [0.003 PPM]). Overall, 0.8% (0.005 PPM) of participants experienced severe and/or documented symptomatic hypoglycemia at SMPG <54 mg/dL, and only during pre-Ramadan. No participants had severe hypoglycemia during Ramadan or post-Ramadan; 1 participant had severe hypoglycemia pre-Ramadan. Most of those who experienced symptomatic hypoglycemia during Ramadan did so during fasting hours (11/13 people). Reductions were shown pre- to post-Ramadan for mean (SD) HbA1c (8.10 % [1.29] pre-Ramadan to 7.64 % [1.05] post-Ramadan; change of −0.44 % [0.97]), FPG (144.3 [45.8] mg/dL pre-Ramadan to 128.5 [37.8] mg/dL post-Ramadan; change of −13.5 [44.1] mg/dL), and fasting SMPG (130.7 [32.9] mg/dL pre-Ramadan to 126.8 [28.5] mg/dL post-Ramadan; change of −3.3 [26.6] mg/dL). Mean Gla-300 dose was reduced slightly between pre-Ramadan and Ramadan (25.6 [11.9] U/0.32 [0.14] U/kg pre-Ramadan to 24.4 [11.5] U/0.30 [0.13] U/kg in Ramadan) and returned to 26.0 (12.2) U/0.32 (0.14) U/kg in the post-Ramadan period. AE incidence was low (5.5%); 3 (0.6%) participants had an AE of hyperglycemia, 2 (0.4%) during Ramadan. In this study, performed in a real-world setting, incidence of hypoglycemia was low in people with T2DM treated with Gla-300 who fasted for Ramadan, with no incidence of severe hypoglycemia during the Ramadan period; HbA1c, FPG and fasting SMPG reductions were also observed. Supported By: Sanofi

A ready-to-use liquid glucagon for treatment of severe hypoglycemia demonstrates reduced healthcare payer costs in a budget impact model

Research aim: To model the annual value of a novel ready-to-use, room-temperature stable liquid glucagon rescue pen and prefilled syringe (GRP, G-PFS; Xeris Pharmaceuticals, Inc.) for treatment of severe hypoglycemia events (SHE) versus current lyophilized powder glucagon emergency kits (GEK). GRP is a prefilled auto-injector designed to promptly administer concentrated liquid glucagon in a simple two-step process. G-PFS is a stable liquid formulation of glucagon in a prefilled syringe. In simulated emergencies, GRP and G-PFS demonstrated high functional efficacy, where 99% of users successfully administered a full-dose of drug. Studies with currently available injectable GEK suggest very low success rates (6–31%). The high functional efficacy of GRP and G-PFS significantly reduces user errors and may reduce utilization across emergency medical services (EMS), emergency departments (ED), and inpatient and outpatient costs for SHE.Methods: To estimate the economic impact of GRP and G-PFS, we developed a one-year budget impact model from a US commercial health plan perspective. Cost offsets from successful glucagon administration incorporated EMS, ED, inpatient, and outpatient utilization. Diabetes prevalence and event probabilities were estimated from publicly-available sources and clinical expert opinion. Costs (US$) were obtained from the 2018 Medicare Fee Schedules and adjusted to represent commercial payer costs.Results: GRP and G-PFS led to fewer EMS, ED, inpatient, and outpatient costs compared to GEK and no kit, resulting in total per-patient SHE costs of $2,564, $3,606, and $3,849, respectively. Costs for 1 million covered lives were 8.2 million following the introduction of GRP and G-PFS compared to almost 9 million before GRP and G-PFS.Limitations: The model is limited by reliance on assumptions based on expert opinion for key variables, primarily the probability of: (1) ambulance calls, (2) ambulance transport to the ED, and (3) non-ambulance transport to the ED.Conclusions: A budget impact model suggests GRP and G-PFS can lead to significant annual cost savings for US commercial payers.

Real-world safety and effectiveness of insulin glargine 300 U/mL in participants with type 2 diabetes who fast during Ramadan: The observational ORION study

AimsORION evaluated the safety and effectiveness of Gla-300 in insulin-treated people with T2DM before, during and after Ramadan, in a real-world setting. MethodsThis prospective, observational study across 11 countries included participants with T2DM treated with Gla-300 in pre-Ramadan, Ramadan and post-Ramadan periods. The primary endpoint was the percentage of participants experiencing ≥1 event of severe and/or symptomatic documented hypoglycaemia with self-monitored plasma glucose (SMPG) ≤70 mg/dL during Ramadan. Secondary endpoints included change in HbA1c and insulin dose and adverse events (AEs). ResultsThe mean ± SD number of fasting days was 30.1 ± 3.2. The percentage of participants experiencing ≥1 event of severe and/or symptomatic documented hypoglycaemia (SMPG ≤70 [<54] mg/dL) was low in the pre-Ramadan (2.2% [0.8%]), Ramadan (2.6% [0%]) and post-Ramadan (0.2% [0%]) periods. No participants reported severe hypoglycaemia during Ramadan or post-Ramadan; one participant reported severe hypoglycaemia in pre-Ramadan. HbA1c fell pre- to post-Ramadan, and Gla-300 daily dose (mean ± SD) was reduced pre-Ramadan to Ramadan (from 25.6 ± 11.9 U/0.32 ± 0.14 U/kg to 24.4 ± 11.5 U/0.30 ± 0.13 U/kg). Incidence of AEs was 5.5%. ConclusionsIn ORION, people with T2DM treated with Gla-300 who fasted during Ramadan had a low risk of severe/symptomatic hypoglycaemia and improved glycaemic control.

Safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes (PIONEER 10): an open-label, randomised, active-controlled, phase 3a trial

New glucose-lowering medications need to be investigated in east Asian populations, as the clinical characteristics of type 2 diabetes differ between western and east Asian patients. The PIONEER 10 study aimed to evaluate the safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes. PIONEER 10 was an open-label, randomised, active-controlled, phase 3a trial done at 36 sites (clinics and university hospitals) in Japan. Patients aged 20 years and older with uncontrolled type 2 diabetes were randomly assigned (2:2:2:1) to receive once-daily oral semaglutide 3 mg, 7 mg, or 14 mg, or once-weekly subcutaneous dulaglutide 0·75 mg for 52 weeks, as an add-on to their background medication. The primary endpoint was the number of treatment-emergent adverse events over 57 weeks. Supportive secondary endpoints (not controlled for multiplicity) included mean change from baseline in HbA1c and bodyweight at 52 weeks. This trial is registered with ClinicalTrials.gov, NCT03015220. Between Jan 10, and May 30, 2017, 492 patients were screened and 458 were randomly assigned to oral semaglutide 3 mg (n=131), 7 mg (n=132), or 14 mg (n=130), or dulaglutide 0·75 mg (n=65). 448 (98%) patients completed the trial. Adverse events occurred in 101 (77%) of 131 patients with oral semaglutide 3 mg, 106 (80%) of 132 with oral semaglutide 7 mg, 111 (85%) of 130 with oral semaglutide 14 mg, and 53 (82%) of 65 with dulaglutide. The most common adverse events were infections and gastrointestinal events. Gastrointestinal adverse events (mostly mild and transient constipation and nausea) occurred in a dose-dependent manner with oral semaglutide. Adverse events led to premature treatment discontinuation in four (3%) of 131 patients receiving oral semaglutide 3 mg, eight (6%) of 132 receiving oral semaglutide 7 mg, eight (6%) of 130 receiving oral semaglutide 14 mg, and two (3%) of 65 receiving dulaglutide. No deaths or severe hypoglycaemic events were reported. Based on the treatment policy estimand (ie, regardless of study drug discontinuation or rescue medication use), estimated mean reductions in HbA1c from baseline (8·3%) to week 52 were -0·9 percentage points (SE 0·1) with oral semaglutide 3 mg, -1·4 percentage points (0·1) with oral semaglutide 7 mg, -1·7 percentage points (0·1) with oral semaglutide 14 mg, and -1·4 percentage points (0·1) with dulaglutide (estimated treatment difference -0·3% [95% CI -0·6 to -0·1] for oral semaglutide 14 mg vs dulaglutide; p=0·0170). Estimated mean changes in bodyweight from baseline (72·1 kg) to week 52 were 0·0 kg (SE 0·3) with oral semaglutide 3 mg, -0·9 kg (0·3) with oral semaglutide 7 mg, -1·6 kg (0·3) with oral semaglutide 14 mg, and 1·0 kg (0·4) with dulaglutide (estimated treatment difference -2·6 kg [95% CI -3·5 to -1·6] for oral semaglutide 14 mg vs dulaglutide; p<0·0001). Oral semaglutide was well tolerated in Japanese patients with type 2 diabetes. Once-daily oral semaglutide significantly reduced HbA1c (14 mg dose) and bodyweight (7 mg and 14 mg doses) versus weekly subcutaneous dulaglutide 0·75 mg by week 52. Novo Nordisk.

Successful Treatment with Bedtime Basal Insulin Added to Metformin without Weight Gain or Hypoglycaemia over Three Years.

The aim of this observational study was to follow-up patients with bedtime basal insulin (NPH insulin) added to metformin. In 285 patients with type 2 diabetes, a therapy with bedtime basal insulin added to metformin was started due to failure to achieve a glycaemic goal. Up until July 2019, 272 patients (95.4%) were followed-up (59.5 y, 92.6 kg, diabetes duration 6.6 y, HbA1c 8.4%/68.6 mmol/mol). HbA1c decreased by −1.2% and bodyweight by −1.7 kg after a duration of 31.7 ± 29.1 (range 2–133) months. Severe hypoglycaemia did not occur. In 144/272 patients (52.9%), the therapeutic goal for HbA1c was achieved over 32.7 months. In 69/272 patients (25.4%), the HbA1c target was achieved over 25.0 months (afterwards, therapy with basal insulin was discontinued because HbA1c was under target). In 36/272 patients (13.2%), the HbA1c goal was achieved until the submission of this manuscript (mean duration of treatment 57.4 ± 28.2 (range 13–121) months). Over 90% of patients with type 2 diabetes and failure of metformin reached their HbA1c goal with additional basal insulin at bedtime over several years in association with a reduction of bodyweight and without any event of severe hypoglycaemia.

Changes in incidence of severe hypoglycaemia in people with type 2 diabetes from 2006 to 2016: analysis based on health insurance data in Germany considering the anti-hyperglycaemic medication.

To investigate the incidence of severe hypoglycaemia over the past 10 years, taking into account changes in anti-hyperglycaemic therapy. This retrospective population-based study used German health insurance data. All adults diagnosed with documented type 2 diabetes (extrapolated to the German population: 6.6 million in 2006; 7.9 million in 2011; 8.86 million in 2016) were screened for severe hypoglycaemia. Anti-hyperglycaemic agents were identified by Anatomical Therapeutic Chemical (ATC) code. The event rate for severe hypoglycaemia was 460 per 100000 people in 2006, 490 per 100000 in 2011 and 360 per 100000 in 2016. The proportion of people with severe hypoglycaemia receiving sulfonylureas, as well as receiving combination therapy of metformin and sulfonylureas decreased from 2006 to 2016 (23.6% vs. 6.2%) Among those with severe hypoglycaemia in 2006, there were no prescriptions for dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists or sodium-glucose co-transporter 2 (SGLT2) agonists. The proportions of people with severe hypoglycaemia receiving DPP-4 inhibitors, GLP-1 receptor agonists or SGLT2 agonists in 2011 and 2016 were low. The proportion of people receiving human insulin also decreased (from 11.3% in 2006 to 10.3% in 2011 and 4.3% in 2016); the proportion of people receiving insulin analogues increased from 5.4% in 2006 to 11.5% in 2016. Therapy with mixed insulins was used by 19.7% of people with severe hypoglycaemia in 2006, by 14.0% in 2011 and by 7.3% in 2016. People undergoing therapy with insulin analogues have the highest risk of severe hypoglycaemia adjusted by age, gender, nephropathy diagnosis and year of survey [odds ratio (OR) 14.4, 95% confidence interval (95% CI) 13.5-15.5]. The incidence of severe hypoglycaemic events in Germany increased between 2006 and 2011, and decreased in 2016.

Effects of Intensive Glycemic Control on Clinical Outcomes Among Patients With Type 2 Diabetes With Different Levels of Cardiovascular Risk and Hemoglobin A1c in the ADVANCE Trial

To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A1c (HbA1c) at baseline. We studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models. During 5 years' follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83-0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbA1c level (P for interaction = 0.29 and 0.94, respectively). Similarly, the beneficial effects of intensive glycemic control on all-cause mortality were not significantly different across baseline ASCVD risk (P = 0.15) or HbA1c levels (P = 0.87). The risks of severe hypoglycemic events were higher in the intensive glycemic control group compared with the standard glycemic control group (HR 1.85 [1.41-2.42]), with no significant heterogeneity across subgroups defined by ASCVD risk or HbA1c at baseline (P = 0.09 and 0.18, respectively). The major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA1c.

Insulin/carbohydrates ratio during the first 6-month therapy with insulin degludec in a paediatric population with type 1 diabetes previously treated with insulin glargine. An observational longitudinal study.

BackgroundNo data exist about the changes induced by the transition from first‐generation long‐acting insulins to second‐generation long‐acting analogues in the paediatric population.ObjectiveTo assess changes in insulin/carbohydrate ratio (I:CHO) after the first 6 months of degludec therapy in a paediatric population with type 1 diabetes previously treated with glargine U100.SubjectsAll patients treated with degludec under routine clinical practice conditions were retrospectively analysed.MethodsNonprofit observational retrospective study. Changes during the follow‐up in mean CHO/I ratio were assessed using longitudinal linear models for repeated measures. Rate of hypoglycaemia, ketoacidosis and adverse events was evaluated.ResultsOverall, 51 children (mean age 13.8 ± 4.6 years; mean diabetes duration 5.8 ± 3.9 years) started therapy with degludec in the period between April 2017 and April 2018. I:CHO ratio before starting degludec therapy significantly differed among the three meals, being the lowest at breakfast and the highest at dinner. After introducing degludec, I:CHO ratio at lunch (−1.29 95% CI −2.02;−0.57) and at dinner (−3.08 95% CI −4.35;−1.8) significantly decreased, while it slightly increased at breakfast (+1.37 95% CI 0.47;2.28). No episodes of severe hypoglycaemia, ketoacidosis and adverse event were recorded during 6 months.ConclusionsOur data show that the use of degludec is associated with a significant change in the I:CHO ratio at the different meals compared to the previous glargine therapy. This could derive from the flat and prolonged pharmacokinetic profile of degludec. This has important clinical implications for daily insulin dose adjustments.

SGLT2 Inhibitors, GLP-1 Receptor Agonists, or Bariatric Surgery and Risks of All-Cause Mortality, Cardiovascular Diseases, End-Stage Renal Diseases, and Severe Hypoglycemia in Obese Patients with Type 2 Diabetes Mellitus

Background: The risks of all-cause mortality, cardiovascular diseases (CVD), end-stage renal diseases (ESRD), and severe hypoglycaemia (SH) among obese patients with T2DM initiating novel glucose-lowering medications (SGLT2i and GLP-1RA) and those undergoing bariatric surgery were unknown. Methods: This was a population-wide retrospective cohort study. Data were collected from the Hong Kong Hospital Authority database from 2006 to 2017. Generalized matching weights of propensity score was applied to balance out baseline covariates of obese patients with T2DM who underwent bariatric surgery, or initiated SGLT2i or GLP-1RA. Hazard ratios (HRs) for CVD, ESRD, and mortality from any causes were assessed among three groups using Cox proportional hazard models. Findings: Over a median follow-up period of 14 months with 2916·25 person-years, incidence of CVD was the highest in SGLT2i group (7·156/100 person-years). Incidences of ESRD and all-cause mortality were the highest in bariatric surgery group (0·453 and 2·316/100 person-years). SGLT2i users had not significantly lower risk of all-cause mortality (HR=0·343, 95%CI=0·089-1·326, p=0·121), CVD (HR=1·125, 95%CI=0·576-2·198, p=0·729), ESRD (HR=0·480, 95%CI=0·109-2·107, p=0·331) and SH (HR=2·654, 95%CI=0·713-9·871, p=0·145) than bariatric surgery candidates. When comparing with bariatric surgery, GLP-1RA was not associated with significant reduction in risks of all-cause mortality (HR=0·350, 95%CI=0·117-1·045, p=0·060), CVD (HR=0·722, 95%CI=0·327-1·596, p=0·421), ESRD (0·251, 95%CI=0·034-1·836, p=0·173) and SH (1·923, 95%CI=0·418-8·853, p=0·401) events. Patients undergoing bariatric surgery had significantly greater improvement in BMI (-6·879kg/m2 , -0·787kg/m2 , -1·160kg/m2 , p<0·001), HbA1c (-1·723%, -0·875%, -0·607%, p<0·001), fasting glucose (-2·699, -1·345, -0·386, p<0·001) and triglyceride (-0·746, -0·204, -0·007, p<0·001) after 12-month, and higher 12-month cumulative direct healthcare costs (US34,736, US11,266, US10,929, p<0·001) than SGLT2i and GLP-1RA users. Interpretation: Among obese patients with T2DM, risks of all-cause mortality, CVD, ESRD and SH did not differ across three groups over the study period. Beneficial weight loss, metabolic outcomes, and higher direct healthcare costs at 12-month after bariatric surgery were observed. Funding Statement: This study was funded by the Health and Medical Research Fund Research Fellowship Scheme, Food and Health Bureau, Hong Kong SAR (Ref No. #02160087). Declaration of Interests: Dr Wong reports receipt of research funding from the EuroQoL Group Research Foundation, the Hong Kong Research Grants Council, and the Hong Kong Health and Medical Research Fund. Dr Man reports receipt of CW Maplethorpe Fellowship. Dr Chan reports receipt of research funding from Bristol-Myers Squibb, Pfizer, Janssen, Takeda Pharmaceuticals, the Hong Kong Beat Drugs Fund Association, the Hong Kong Research Grants Council, and the Hong Kong Health and Medical Research Fund. Prof Wong reports receipt of research funding from BristolMyers Squibb, Pfizer, Janssen, the Hong Kong Research Grants Council, and the Hong Kong Health and Medical Research Fund. Prof Lam reports receipt of research funding from the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, and the Kerry Group and Kouk Foundation Endowed Primary Care Research Fund of the University of Hong Kong. No other disclosures were reported. Ethics Approval Statement: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethics approval of this study was granted by the Institutional Review Board of the University of Hong Kong /Hospital Authority Hong Kong West Cluster (HKU/HA HKW IRB) (Ref No. UW 16-1018).

Confirming the Bidirectional Nature of the Association Between Severe Hypoglycemic and Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL.

We sought to confirm a bidirectional association between severe hypoglycemic events (SHEs) and cardiovascular (CV) event risk and to characterize individuals at dual risk. In a post hoc analysis of 14,752 Exenatide Study of Cardiovascular Event Lowering (EXSCEL) participants, we examined time-dependent associations between SHEs and subsequent major adverse cardiac events (CV death, nonfatal myocardial infarction [MI] or stroke), fatal/nonfatal MI, fatal/nonfatal stroke, hospitalization for acute coronary syndrome (hACS), hospitalization for heart failure (hHF), and all-cause mortality (ACM), as well as time-dependent associations between nonfatal CV events and subsequent SHEs. SHEs were uncommon and not associated with once-weekly exenatide therapy (hazard ratio 1.13 [95% CI 0.94-1.36], P = 0.179). In fully adjusted models, SHEs were associated with an increased risk of subsequent ACM (1.83 [1.38-2.42], P < 0.001), CV death (1.60 [1.11-2.30], P = 0.012), and hHF (2.09 [1.37-3.17], P = 0.001), while nonfatal MI (2.02 [1.35-3.01], P = 0.001), nonfatal stroke (2.30 [1.25-4.23], P = 0.007), hACS (2.00 [1.39-2.90], P < 0.001), and hHF (3.24 [1.98-5.30], P < 0.001) were all associated with a subsequent increased risk of SHEs. The elevated bidirectional time-dependent hazards linking SHEs and a composite of all CV events were approximately constant over time, with those individuals at dual risk showing higher comorbidity scores compared with those without. These findings, showing greater risk of SHEs after CV events as well as greater risk of CV events after SHEs, validate a bidirectional relationship between CV events and SHEs in patients with high comorbidity scores.